Specification
The present application claims the benefit from and incorporates by reference the entire
content of U.S Provisional Application Serial No. 61/186,291, filed June 11, 2009, U.S. Provisional
Application Serial No. 61/242,836, filed September 16,2009, and U.S. Provisional Application Serial
No. 61/243,596, filed September 18, 2009.
FIELD
The present invention relates to compounds effective in inhibiting replication of Hepatitis C
virus ("HCV"). The present invention also relates to compositions comprising these compounds and
methods of using these compounds to treat HCV infection.
BACKGROUND
HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The
enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific
proteins in a single, uninterrupted, open reading frame. The open reading frame comprises
approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids.
The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein
p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
HCV infection is associated with progressive liver pathology, including cirrhosis and
hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in
combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users
suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a
need for new drugs to treat HCV infection.
SUMMARY
The present invention features compounds of Formulae I, IA, IB, Ic and ID, and
pharmaceutically acceptable salts thereof. These compounds and salts can inhibit the replication of
HCV and therefore are useful for treating HCV infection.
The present invention also features compositions comprising the compounds or salts of the
present invention. The compositions can also include additional therapeutic agents, such as HCV
helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors,
CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors.
The present invention further features methods of using the compounds or salts of the present
invention to inhibit HCV replication. The methods comprise contacting cells infected with HCV virus
with a compound or salt of the present invention, thereby inhibiting the replication of HCV virus in
the cells.
In addition, the present invention features methods of using the compounds or salts of the
present invention, or compositions comprising the same, to treat HCV infection. The methods
comprise administering a compound or salt of the present invention, or a pharmaceutical composition
comprising the same, to a patient in need thereof, thereby reducing the blood or tissue level of HCV
virus in the patient.
The present invention also features use of the compounds or salts of the present invention for
the manufacture of medicaments for the treatment of HCV infection.
Furthermore, the present invention features processes of making the compounds or salts of the
invention.
Other features, objects, and advantages of the present invention are apparent in the detailed
description that follows. It should be understood, however, that the detailed description, while
indicating preferred embodiments of the invention, are given by way of illustration only, not
limitation. Various changes and modifications within the scope of the invention will become apparent
to those skilled in the art from the detailed description.
DETAILED DESCRIPTION
The present invention features compounds having Formula I and pharmaceutically acceptable
salts thereof,
wherein:
X is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA;
L1 and L2 are each independently selected from bond; or C1-C6alkylene, C2-C6alkenylene or
C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more RL;
L3 is bond or -Ls-K-Ls'-, wherein K is selected from bond, -O-, -S-, -N(RB)-, -C(O)-, -
S(O)2- -S(O)-, -OS(O)- -OS(O)2- -S(O)2O -S(O)O-, -C(O)O-, -OC(O)-, -
OC(O)O-, -C(O)N(RB)- -N(RB)C(O)-, -N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-,
-N(RB)S(O)2- -S(O)N(RB)-, -S(O)2N(RB)- -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -
N(RB)SO2N(RB')-, or -N(RB)S(O)N(RB')-;
A and B are each independently C3-C12carbocycle or 3- to 12-membered heterocycle, and are
each independently optionally substituted with one or more RA;
D is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA; or D is hydrogen or RA;
Y is selected from -T'-C(R1R2)N(R5)-T-RD, -T'-C(R3R4)C(R6R7)-T-RD, -LKT-RD, or -
LK-E;
R1 and R2 are each independendy RC, and R5 is RB; or R1 is Rc, and R2 and R5, taken together
with the atoms to which they are attached, form a 3- to 12-membered heterocycle which
is optionally substituted with one or more RA;
R3, R4, R6, and R7 are each independendy Rc; or R3 and R6 are each independently Rc, and R4
and R7, taken together with the atoms to which they are attached, form a 3- to 12-
membered carbocycle or heterocycle which is optionally substituted with one or more RA;
Z is selected from -T'-C(R8R9)N(R12)-T-RD, -T'-CCRioRiOCCRisRi^-T-Rn, -LK-T-RD, or
-LK-E;
R8 and R9 are each independendy Rc, and R12 is RB; or R8 is Rc, and R9 and R12, taken
together with the atoms to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more RA;
Rio, Rn, R13, and R14 are each independently Rc; or R10 and Ri3 are each independendy Rc,
and R11 and R14, taken together with the atoms to which they are attached, form a 3- to
12-membered carbocycle or heterocycle which is optionally substituted with one or more
RA;
T and T" are each independendy selected at each occurrence from bond, -Ls-, -Ls-M-Ls'-,
or -Ls-M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each
occurrence from bond, -O-, -S-, -N(RB)-, -C(O)-, -S(O)2- -S(O)-, -OS(O)- -
OS(O)2-, -S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -
N(RB)C(O)- -N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-, -N(RB)S(O)2- -
S(O)N(RBK -S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -
N(RB)SO2N(RB')-, -N(RB)S(O)N(RB')-, C3-C12carbocycle or 3- to 12-membered
heterocycle, and wherein said C3-C12carbocycle and 3- to 12-membered heterocycle are
each independendy optionally substituted at each occurrence with one or more RA;
LK is independendy selected at each occurrence from bond, -Ls-N(RB)C(O)-Ls'- or -Ls-
C(O)N(RB)-Ls'-; or C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which
is independently optionally substituted at each occurrence with one or more RL; or C3-
C12carbocycle or 3- to 12-membered heterocycle, each of which is independendy
optionally substituted at each occurrence with one or more RA;
E is independently selected at each occurrence from C3-C12carbocycle or 3- to 12-membered
heterocycle, and is independently optionally substituted at each occurrence with one or
more RA;
RD is each independently selected at each occurrence from hydrogen or RA;
RA is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -LS-RE, wherein two adjacent RA, taken together with the
atoms to which they are attached and any atoms between the atoms to which they are
attached, can optionally form carbocycle or heterocycle;
RB and RB' are each independendy selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-
membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle;
wherein each 3- to 6-membered carbocycle or heterocycle in RB or RB' is independently
optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-
C6aloalkenyl or C2-C6haloalkynyl;
RC is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or d-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independendy optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is
independendy optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6
haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RsRs'), -S(O)Rs, -SO2Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs -
N(Rs)C(O)N(Rs'Rs"), -N(Rs)SO2Rs' -SO2N(RsRs'), -N(Rs)SO2N(Rs'Rs"), -
N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O)2-Rs, -S(O)2ORs, -S(O)ORs, -OC(O)ORs, -
N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(O)-Rs' -S(O)N(RsRs') or -
C(O)N(Rs)C(O)-Rs'; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independendy optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RSRS'), -
S(O)Rs, -SO2Rs, -C(O)N(RsRs') or -N(Rs)C(O)Rs'; or C3-C6carbocycle 3- to 6-
membered heterocycle, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
wherein two adjacent RL, taken together with the atoms to which they are attached and
any atoms between the atoms to which they are attached, can optionally form carbocycle
or heterocycle;
Ls, Ls' and Ls" are each independently selected at each occurrence from bond; or C1-
C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently
optionally substituted at each occurrence with one or more RL; and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; C1-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs , Rs' or Rs'
is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, d-
C6haloalkyl, C1-C6haloalkenyl or C2-C6haloalkynyl.
A and B preferably are independently selected from C5-C6carbocycle (e.g., phenyl), 5- to 6-
membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such as
independently selected at each occurrence from O, S, NH or CH2,72 is independently selected at each
occurrence from N or CH, Z3 is independently selected at each occurrence from N or CH, Z4 is
is and B is wherein each A and B is independendy optionally
substituted with one or more RA.
D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-
membered bicycles, and is optionally substituted with one or more RA. D can also be preferably
selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or
more substituents selected from RL. More preferably, D is C5-C6carbocycle (e.g., phenyl), 5- to 6-
membered heterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to 12-membered bicycles (e.g.,
indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl),
and is substituted with one or more RM, where RM is halogen, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano, or -LS-RE- Also preferably, D is phenyl, and is optionally substituted with one or more
RA. More preferably, D is phenyl, and is substituted with one or more RM, wherein RM is as defined
above. Highly preferably, D is wherein RM is as defined above, and each
RN is independendy selected from RD and preferably is hydrogen. One or more RN can also preferably
be halo such as F.
D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or
more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
more RM. Highly preferably, D is wherein RM
is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One
or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7-
tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or
more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,
indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D
and is optionally substituted with
one or more RM.
Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl. More
preferably, RM is halogen, hydroxy, mercapto, amino, carboxy; or C2-C6alkyl, C2-C6alkenyl or C2-
C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is
C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy.
Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, or cyano; or RM is -LS-RE, wherein Ls is a bond or C1-C6alkylene, and R6 is -
N(RSRS'), -O-Rs, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), -N(Rs)C(O)Rs', -N(Rs)C(O)ORs-
N(Rs)SO2Rs', -SO2Rs, -SRs, or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each
independently selected at each occurrence from (1) hydrogen or (2) C1-C6alkyl optionally substituted
at each occurrence with one or more halogen, hydroxy, -O-C1-C6alkyl or 3- to 6-membered
heterocycle; or RM is C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(O)ORs, or -
N(RSRS'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C1-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each
of which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RM is CF3, -
C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RM is -Ls- R6 where Ls is a bond and R6 is -N(RSRS), -O-Rs, -N(Rs)C(O)ORs', -N(Rs)SO2Rs', -SO2Rs, or -
SRS. For example where Ls is a bond, R6 is -N(C1-C6alkyl)2 (e.g., -NMe2); -N(C1-C6alkylene-O-Cr
C6alkyl)2 (e.g. -N(CH2CH2OMe)2); -N(C1-C6alkyl)(C1-C6alkylene-O-C1-C6alkyl) (e.g. -
N(CH3)(CH2CH2OMe));—O-C1-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-
hexyl); -O-C1-C6haloalkyl (e.g., - OCF3, -OCH2CF3); -O-C1-C6alkylene-piperidine (e.g., -O-
CH2CH2-l-piperidyl); -N(C1-C6alky)C(O)OC1-C6alkyl (e.g., -N(CH3)C(O)O-CH2CH(CH3)2), -
N(C1-C6alky)SO2C1-C6alkyl (e.g., -N(CH3)SO2CH3); -SO2C1-C6alkyl (e.g., -SO2Me); -SO2C1
C6haloalkyl (e.g., -SO2CF3); or -S-C1-C6haloalkyl (e.g., SCF3). Also preferably RM is -Ls-RE where
Ls is C1-C6alkylene (e.g., -CH2- -C(CH3)2- -C(CH3)2-CH2-) and R6 is -O-Rs, -C(O)ORs, -
N(Rs)C(O)ORs', or -P(O)(ORs)2. For example RM is -C1-C6alkylene-O-Rs (e.g., -C(CH3)2-CH2-
OMe); -CrC6alkylene-C(O)ORs (e.g., -C(CH3)2-C(O)OMe); -C1-C6alkylene-N(Rs)C(O)ORs' (e.g.,
-C(CH3)2-CH2-NHC(O)OCH3); or -C1-C6alkylene-P(O)(ORs)2, (e.g., -CH2-P(O)(OEt)2). Also more
preferably RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6haloalkenyl, C1-C6haloalkynyl, -
C(O)ORs, or -N(RsRs'). For example RM is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-
methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1-
dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1-
yl, piperidin-1-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,
tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RM
is C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).
X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
bicycles, and is optionally substituted with one or more RA. X can also be C5-C6carbocycle or 5- to 6-
membered heterocycle which is optionally substituted with one or more RA, wherein two adjacent RA
on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-
membered carbocycle or heterocycle. Also preferably, X is wherein X3 is C(H)
or preferably N and is directly appended to -L3-D; X4 is C2-C4a]kylene, C2-C4alkenylene or C2-
C4alkynylene, each of which optionally contains one or two heteroatoms selected from O, S or N; and
X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the
ring atoms to which they are attached, can optionally form a 5- to 6-membered carbocycle or
heterocycle. In addition, X can be wherein X3 is C and is
directly linked to -L3-D, X4 is C2-C4alkylene, C2-C4alkenylene or C2-C4alkynylene each of which
optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted
with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are
attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
independently selected at each occurrence from CH2, O, S or NH, X2 is independently selected at each
occurrence from CH or N, X3 is N and is directly linked to -L3-D, and X3' is C and is directly linked
to -L3-D; and X is optionally substituted with one or more RA, and two adjacent RA on X, taken
together with the ring atoms to which they are attached, optionally form a 5- to 6-membered
each occurrence from CH2, O, S or NH, X2 is independently selected at each occurrence from CH or
N, X3 is N and is directly linked to -L3-D, and X3' is C and is directly linked to -L3-D; and wherein
X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the
ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
Highly preferably, X is wherein X3 is C(H)
or N and is directly linked to -L3-D, X3' is C and is directly linked to -L3-D, and wherein X is
optionally substituted with one or more RA, and two adjacent RA on X, taken together with the ring
atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
More preferably, X3 is N.
Non-limiting examples of X include:
wherein "—" indicates the covalent attachment to -L3-D. Each X can be optionally substituted with
one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are
attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
Non-limiting examples of preferred X include the following pyrrolidine rings, each of which
is optionally substituted with one or more RA:
As shown, the relative stereochemistry at the 2- and 5-positions of the above pyrrolidine ring may be
either cis or trans. The stereochemistries of optional substituents RA at the 3- or 4-positions of the
pyrrolidine may vary relative to any substituent at any other position on the pyrrolidine ring.
Depending on the particular substituents attached to the pyrrolidine, the stereochemistry at any carbon
may be either (R) or (S).
Non-limiting examples of preferred X also include the following pyrrole, triazole or
thiomorpholine rings, each of which is optionally substituted with one or more RA:
As shown, the relative stereochemistry at the 3- and 5-positions of the thiomorpholine ring may be
either cis or trans. Depending on the particular substituents attached to the thiomorpholine, the
stereochemistry at any carbon may be either (R) or (S).
L1 and L2 are preferably independently bond or C1-C6alkylene, L3 is preferably selected from
bond, C1-C6alkylene or -C(O)-, and L1 L2, and L3 are each independently optionally substituted with
one or more RL. More preferably, L1, L2 and L3 are each independently bond or C1-C6alkylene (e.g., -
CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly
preferably, L1, L1 and L3 are bond.
Y is preferably selected from -Ls-C(R1R2)N(R5)-T-RD, -LS-C(R3R4)C(R6R7)-T-RD, -G-
C(R1R2)N(R5)-T-RD, -G-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(R5)-T-RD,
N(RB)C(O)C(R3R4)C(R6R7)-T-RD, -C(O)N(RB)C(R1R2)N(R5)-T-RD, -C(O)N(RB)C(R3R4)C(R6R7)-
T-RD, -N(RB)C(O)-LS-E, or -C(O)N(RB)-Ls-E. G is C5-C6carbocycle or 5- to 6-membered
heterocycle, such as and is optionally
substituted with one or more RA (e.g., one or more chloro or bromo). E preferably is a 7- to 12-
membered bicycle (such as wherein U is independently selected at each occurrence from
-(CH2)- or -(NH)-; V and Z20 are each independently selected from Ci-C4alkylene, C2-C4alkenylene or
C2-C4alkynylene, in which at least one carbon atom can be independently optionally replaced with O,
S or N), and is optionally substituted with one or more RA. More preferably, R1 is Rc, and R2 and R5,
taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6-
which is optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g.,
fluoro), C1-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)); and R3 and R6 are each independently
Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., which is
optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C1-
C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)).
Y can also be selected from -M-C(R1R2)N(R5)-C(O)-LY'-M'-RD, -M-C(R1R2)N(R5)-LY'-
M'-RD, -Ls-C(R1R2)N(R5)-C(O)-LY'-M'-RD, -LS-C(R1R2)N(-LY'-M'-RD, -M-
C(R3R4)C(R6R7)-C(O)-LY'-M'-RD,-M-C(R3R4)C(R6R7)-LY'-M'-RD,-LS-C(R3R4)C(R6R7)-C(O)-
LY'-M'-RD, or -Ls-C(R3R4)C(R6R7)-LY'-M'-RD, wherein M preferably is bond, -C(O)N(RB)- or -
N(RB)C(O)- M' preferably is bond, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(O)O-,
N(RB)C(O)N(RB')-, -N(RB)S(O)- or -N(RB)S(O)2-, and LY' preferably is CrC6alkylene which is
optionally substituted with one or more RL. LY', for example, is a C1-C6alkylene such as, but not
limited to, and the optional RL is a
substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon
within the group LY' can be either (R) or (S). More preferably, R1 is Rc, and R2 and R5, taken
together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-
membered bicycle (e.g., which is optionally substituted with one or
more RA (e.g., one or more hydroxy); and R3 and R6 are each independently Rc, and R4 and R7, taken
together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle
or 6- to 12-membered bicycle (e.g.,which is optionally substituted with
one or more RA.
Also preferably, Y is selected from-N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)O-RD, -
N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-
N(RB)S(O)2-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R1R2)N(R5)-
C(O)-LY'-O-RD, -N(RB)CO-C(R1R2)N(R5)-C(O)Y'-RD, -N(RB)CO-C(R1R2)N(R5)-RD, -LS-
C(R1R2)N(R5)-C(O)-LY'-N(RB)C(O)O-RD, -Ls-C(R!R2)N(R5)-C(O)-LY'-N(RB)C(O)-RD, -LS-
C(R1R2)N(R5)-C(O)-LY'-N(RB)S(O)2-RD, -Ls-C(R1R2)N(R5)-C(O)-LY'-N(RBRB')-RD, -Ls-
C(R1R2)N(R5)-C(O)-LY'-O-RD, -Ls-C(R1R2)N(R5)-C(O)-LY'-RD, -LS-C(R1R2)N(R5)-RD, -
N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-
N(RB)C(O)-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)S(O)2-RD, -N(RB)CO-
C(R3R4)C(R6R7)-C(O)-LY'-N(RBRB')-RD, -N(RB)C0-C(R3R4)C(R6R7)-C(O)-LY'-O-RD,
N(RB)CO-C(R3R4)C(R6R7)-C(O)-LY'-RD, -N(RB)CO-C(R3R4)C(R6R7)-RD, -LS-C(R3R4)C(R6R7)-
C(O)-LY'-N(RB)C(O)O-RD, -Ls-C(R3R4)C(R6R7)-C(O)-LY'-N(RB)C(O)-RD, -LS-
C(R3R4)C(R6R7)-€(O)-LY'-N(RB)S(O)2-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-N(RBRB')-RD, -LS-
C(R3R4)C(R6R7)-C(O)-LY'-O-RD, -LS-C(R3R4)C(R6R7)-C(O)-LY'-RD, or -Ls-C(R3R4)C(R6R7)-
RD, wherein LY' preferably is C1-C6alkylene which is optionally substituted with one or more RL. R1
may be Rc, and R2 and R5, taken together with the atoms to which they are attached, may form a 5- to
6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is
optionally substituted with one or more RA; and R3 and R6 may be each independendy Rc, and R4 and
R7, taken together with the atoms to which they are attached, may form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,which is
optionally substituted with one or more RA.
Highly preferably, Y is selected from -N(RB")CO-C(R1R2)N(R5)-C(O)-LY-N(RB")C(O)-
Ls-RE or -C(R1R2)N(R5)-C(O)-LY-N(RB")C(O)-LS-RE, or Y is -G-C(R1R2)N(R5)-C(O)-LY-
N(RB")C(O)-LS-RE, wherein LY is C1-C6alkylene optionally substituted with one or more RL, and
RB" is each independendy RB. RB" and R1 are each preferably hydrogen or C1-C6alkyl, and R2 and
R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered
heterocycle or 6- to 12-membered bicycle (e.g., which is optionally
substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C1-C6alkyl
(e.g., methyl), or C2-C6alkenyl (e.g., allyl)). Preferably, LY is C1-C6alkylene substituted with one or
more RL such as a C3-C6carbocycle 3- to 6-membered heterocycle which is optionally substituted with
one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyi, C2-C6alkenyl, C2-C6alkynyl, d-
Cehaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl. Highly preferably, LY is a C1-C6alkylene such as,
but not limited to, (stereochemistry at a
carbon within the group LY can be either (R) or (S)), LY is optionally substituted with one or more RL
(e.g., one or more phenyl or methoxy), G preferably is RB'' is hydrogen; -C(R1R2)N(R5)-
; Ls is a bond; and R6 is methoxy.
C6carbocycle or 5- to 6-membered heterocycle, such as
and is optionally substituted with one or more RA (e.g., one or more chloro or bromo).
E preferably is a 8- to 12-membered bicycle (such as wherein U is independently
selected at each occurrence from -(CH2)- or -(NH)-; and V and Z20 are each independently selected
from Ci-C4alkylene, C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom is
independently optionally replaced with O, S or N), and is optionally substituted with one or more RA.
More preferably, R8 is Re, and R9 and R12, taken together with the atoms to which they are attached,
(such as, but not limited to hydroxy, halo (e.g., fluoro), C1-C6alkyl (e.g., methyl), or C2-C6alkenyl
(e.g., allyl)); and Ri0 and R13 are each independently Rc, and Rn and R14, taken together with the
atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-
membered bicycle (e.g., which is optionally substituted with one or
more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C1-C6alkyl (e.g., methyl), or C2-
C6alkenyl (e.g., allyl)).
Z can also be selected from-M-C(R8R9)N(R12)-C(O)-LY'-M'-RD, -M-C(R8R9)N(R12)-LY'-
M'-RD, -Ls-C(R8R9)N(R12)-C(O)-LY'-M'-RD, -LS-C(R8R9)N(R12)-LY'-M'-RD, -M-
C(R10R11)C(R13R14)-C(O)-LY'-M'-RD, -M-C(R10R11)C(R13R14)-LY'-M'-RD, -LS-
C(R10R11)C(R13R14)-C(O)-LY'-M'-RD, or -Ls-C(R10R11)C(R13R14)-LY'-M'-RD, wherein M
preferably is bond, -C(O)N(RB)- or -N(RB)C(O)-, M' preferably is bond, -C(O)N(RB)-, -
N(RB)C(O)- -N(RB)C(O)O-, N(RB)C(O)N(RB')- -N(RB)S(O)- or -N(RB)S(O)2- and LY'
preferably is C1-C6alkylene which is optionally substituted with one or more RL. LY for example, is
a C1-C6alkylene such as, but not limited to,
and the optional RL is a substituent such as, but not limited to phenyl, -SMe, or methoxy.
Any stereochemistry at a carbon within the group LY' can be either (R) or (S). More preferably, R8 is
Rc, and R9 and R12, taken together with the atoms to which they are attached, form a 5- to 6-
membered heterocycle or 6- to 12-membered bicycle (e.g., which is
optionally substituted with one or more RA (e.g., one or more hydroxy); and R10 and R13 are each
independently Rc, and R11 and R14, taken together with the atoms to which they are attached, form a
5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,
which is optionally substituted with one or more RA.
Also preferably, Z is selected from -N(RB)CO-C(R8R9)N(RI2)-C(O)-LY'-N(RB)C(O)O-RD,
-N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY-
N(RB)S(O)2-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R8R9)N(R12)-
C(O)-LY'-O-RD, -N(RB)CO-C(R8R9)N(R12)-C(O)-LY'-RD, -N(RB)CO-C(R8R9)N(R12)-RD, -Ls-
C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)O-RD, -Ls-C(R8R9)N(R12)-C(O)-LY'-N(RB)C(O)-RD, -Ls-
C(R8R9)N(R12)-C(O)-LY'-N(RB)S(O)2-RD, -LS-C(R8R9)N(R12)-C(O)-LY'-N(RBRB')-RD, -LS-
C(R8R9)N(R12)-C(O)-LY'-O-RD, -Ls-C(R8R9)N(R12)-C(O)-LY'-RD, -LS-C(R8R9)N(R12)-RD, -
N(RB)CO-C(R10R11)C(R13Ri4)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R10Rii)C(R13Ri4)-C(O)-
LY'-N(RB)C(O)-RD, -N(RB)CO-C(R10R11)C(Ri3R14H:(O)-LY'-N(RB)S(O)2-RD, -N(RB)CO-
C(R10RII)C(R13R14)-C(O)-LY'-N(RBRB')-RD, -N(RB)CO-C(R10R11)C(Ri3R14)-C(O)-LY'-O-RD, -
N(RB)CO-C(R10R11)C(R13R14)-C(O)-LY'-RD, -N(RB)CO-C(R10R11)C(R13R14)-RD, -Ls-
C(R10R11)C(R13R14)-C(O)-LY'-N(RB)C(O)O-RD, -Ls-C(R10R1)C(R13R14)-C(O)-LY'-N(RB)C(O)-
RD, -Ls-C(R10R11)C(R13R14)-C(O)-LY'-N(RB)S(O)2-RD, -Ls-C(R10R11)C(R13R14)-C(O)-LY'-
N(RBRB')-RD, -LS-C(R10R11)C(R13R14)-C(O)-LY-O-RD, -Ls-C(R10R11)C(R13R14)-C(O)-LY'-RD, or
-LS-C(R10R11)C(R13R14)-RD, wherein LY' preferably is C1-C6alkylene which is optionally substituted
with one or more RL. Rg may be Rc, and R9 and R12, taken together with the atoms to which they are
Highly preferably, Z is selected from -N(RB")CO-C(R8R9)N(R12)-C(O)-L^-N(RB")C(O)-
LS-RE or -C(R8R9)N(R12)-C(O)-LY-N(RB")C(O)-LS-RE, or Z is -G-C(R8R9)N(R12)-C(O)-LY-
N(RB")C(O)-LS-RE, wherein LY is C1-C6alkylene optionally substituted with one or more RL, and
RB" is each independently RB. RB" and R8 are each preferably hydrogen or C1-C6alkyl, and R9 and
R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered
heterocycle or 6- to 12-membered bicycle (e.g., which is optionally
substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C1-C6alkyl
(e.g., methyl), or C2-C6alkenyl (e.g., allyl)). Preferably, LY is C1-C6alkylene substituted with one or
more RL such as a C3-C6carbocycle 3- to 6-membered heterocycle which is optionally substituted with
one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-
Cehaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl. Highly preferably, LY is a C1-C6alkylene such as,
but not limited to, (stereochemistry at a
carbon within the group LY can be either (R) or (S)); LY is optionally substituted with one or more RL
T can be, without limitation, independently selected at each occurrence from -C(O)-Ls'-, -
C(O)O-Ls'-, -C(O)-Ls'-N(RB)C(O)-Ls"-, -C(O)-Ls'-N(RB)C(O)O-Ls"-, -N(RB)C(O)-Ls'-
N(RB)C(O)-Ls"-, -N(RB)C(O)-LS'—N(RB)C(O)O-LS"-, or _N(RB)C(O)-Ls'—N(RB)-Ls"-.
Preferably, T is independently selected at each occurrence from -C(O)-Ls'—M'-LS"- or -
N(RB)C(O)-Ls'-M'-Ls"-. More preferably, T is independently selected at each occurrence from -
C(O)-Ls'-N(RB)C(O)-Ls"- or -C(O)-Ls'-N(RB)C(O)O-Ls''-.
T can also be, for example, -Ls-M-Ls'-M'-Ls"- where Ls is a bond; M is C(O); Ls' is d-
C6alkylene (e.g., where Ls' is optionally substituted with RT; the optional RT is a
substituent selected from -C1-C6alkyl, -C2-C6alkenyl, -Cj-C6alkyl-OH, -C1-C6alkyl-O-Cj-C6alkyl,
3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C3-C6carbocyclyl (e.g., phenyl,
cyclohexyl); M' is -NHC(O)-, -N(Et)C(O)- or -N(Me)C(O)-; and LS" is a bond. RD preferably is
hydrogen, -Ci-Cgalkyl (e.g., methyl), -O-C1-C6alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or
-N^rCealkyl), (e.g., -NMe2).
T can also be, without limitation, -Ls-M-Ls'- where Ls is a bond; M is C(O); Ls' is Cr
C6alkylene (e.g., where Ls' is optionally substituted with RT; the optional RT is a
substituent selected from -CrC6alkyl, -C1-C6alkyl-OH, -C1-C6alkyl-O-C1-C6alkyl, or a C3-
Cecarbocyclyl (e.g., phenyl, cyclohexyl). RD, for example is -OH; -OC(O)Me; -NH(C1-C6alkyl)
(e.g., -NHMe, -NHEt); -N(CrC6alkyl)2 (e.g., -NMe2, -NEt2); a 3- to 10-membered heterocyclyl
(e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl) optionally
substituted with one or more halogen, oxo; C3-Ciocarbocycle (e.g., cyclopentyl) optionally substituted
with -OH; -Ci-Cgalkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -OH; or NHRT where RT
is a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrimidinyl). T-RD includes, but is not limited to:
stereochemistry at a carbon within the group T-RD can be either (R) or (S).
For each compound of Formula I, LK can also be independently selected at each occurrence
from a bond; -Ls'-N(RB)C(O)-Ls-; -LS'-C(O)N(RB)-LS-; or C1-C6alkylene, C2-C6alkenylene, C2-
C6alkynylene, C3-Ci0carbocycle or 3- to 10-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen, RT, -
0-Rs, -S-Rs, -N(RsRs'), -OC(O)Rs, -C(O)ORs, nitro, oxo, phosphonoxy, phosphono, thioxo,
formyl or cyano, wherein Ls and Ls' are as defined above.
For Formula I as well as Formulae IA, IB, Ic and ID described below, including each and every
embodiment described thereunder, RA preferably is halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl,
each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6aikenyl, C2-C6alkynyl, Ci-Gshaloalkyl, C2-C6haloalkenyl or
C2-C6haloalkynyl; or -LA-O-Rs, -LA-S-Rs, -LA-C(O)Rs, -LA-OC(O)Rs, -LA-C(O)ORs, -LA-
N(RSRS'), -LA-S(O)Rs, -LA-SO2Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs\ -LA-
N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO2Rs', -LA-SO2N(RsRs'), -LA-N(RS)SO2N(RS'RS"), -LA-
N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA-OS(O)2-RS, -LA-S(O)2ORs, -LA-S(O)ORs, -LA-
OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA-OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or
-LA-C(O)N(Rs)C(O)-Rs', wherein LA is bond, C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyi, C2-C6haloalkenyl or C2-C6haloalkynyl.
Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or
C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
A and B can be the same or different. Likewise, Lx and L2, or Y and Z, or Y-A- and Z-B-,
or -A-Li- and -B-L2-, can be the same or different. In some instances, Y-A-Li- is identical to Z-
B-L2-. hi some other instances, Y-A-Li- is different from Z-B-L2-.
In one embodiment, A and B are each independently 5- or 6-membered carbocycle or
heterocycle (e.g., phenyl such as and are each independendy optionally substituted
with one or more RA. X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle
wherein X3 is N and is directly linked to -L3-D) and is
optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is
C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with
one or more RA. Preferably, D is wherein RM and RN are as defined
above. L1 and L2 are each independendy bond or C1-C6alkylene, and L3 is bond, CrC6alkylene or -
C(O)-, and L1, L2, and L3 are each independently optionally substituted with one or more RL.
Preferably, Ll5 L2, and U are bond. Y is -N(RB)C(O)C(R1R2)N(R5)-T-RD, or -
N(RB)C(O)C(R3R4)C(R5R7)-T-RD, and Z is -N(RB)C(O)C(R8R9)N(R12)-T-RD, or -
N(RB)C(O)C(RioRii)C(R13R14)-T-RD. R1 is Rc, and R2 and R5, taken together with die atoms to
which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is
optionally substituted with one or more RA; R3 and R6 are each independently Rc, and R4 and R7,
taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
heterocyclic ring (e.g., which is optionally substituted wirn one or more RA. R8 is Rc,
and R9 and Ri2, taken together with the atoms to which they are attached, form a 5- to 6-membered
heterocyclic ring (e.g., which is optionally substituted with one or more RA; and R10 and
R13 are each independently Rc, and Ru and Ri4, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is
optionally substituted with one or more RA. T is preferably independently selected at each occurrence
from -C(O)-LY'-N(RB)C(O)-Ls"- or -C(O)-LY'-N(RB)C(O)O-Ls"-. LY' is each independently
Ls' and, preferably, is each independently C1-C6alkylene (e.g., -CH2-) and optionally substituted with
one or more substituents selected from RL. T can also be, without limitation, selected from -C(O)-
LY'-LS"-, -C(O)-LY'-O-LS'S -C(O)-LY'-N(RB)-LS"-, or -C(O)-LY'-N(RB)S(O)2-LS"-. In
some cases, at least one of Y and Z is, or both Y and Z are independently,
wherein non-limiting examples of RD include (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-
Cealkynyl, C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-
Cecarbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered
heterocycle each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-
Cfshaloalkenyl or C2-C6haloalkynyl; and non-limiting examples of LY' include C1-C6alkylene
optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci-
Cealkyl, -O-C2-C6alkenyl, -O-C2-C6alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3-
to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or
C2-C6haloalkynyl.
In another embodiment, A is
substituted with one or more R^s B is
substituted with one or more RA. Zi is independently selected at each occurrence from O, S, NH or
CH2; and Z2 is independently selected at each occurrence from N or CH. X is 5- or 6-membered
carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,
wherein X3 is N and is directly linked to -L3-D) and is optionally substituted with one or more RA.
Specific examples of X are described hereinabove. D is C5-C6carbocycle or 5- to 6-membered
heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is
wherein RM and RN are as defined above. L1 and L2 are each
independently bond or Ci-Cgalkylene, and L3 is bond, C1-C6alkylene or -C(O)-, and L1, L2, and L3 are
each independently optionally substituted with one or more RL. Preferably, Lb L2, and L3 are bond.
Y is -LS-C(R1R2)N(R5)-T-RD or -LS-CXRSR^CXR^-T-RD, and Z is -LS-C(R8R9)N(R12)-T-RD or
-Ls-C(R10R11)C(R13R14)-T-RD. R1 is Rc, and R2 and R5, taken together with the atoms to which they
are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is optionally
substituted with one or more RA; R3 and R6 are each independently Rc, and R4 and R7, taken together
with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
which is optionally substituted with one or more RA. R8 is Rc, and R9 and Ri2,
taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring
which is optionally substituted with one or more RA; and Ri0 and R13 are each
independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a
5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is optionally substituted
with one or more RA. T is preferably independently selected at each occurrence from -C(O)-LY'-
N(RB)C(O)-Ls"- or -C(O)-LY'-N(RB)C(O)O-Ls"-. LY' is each independently LS' and, preferably,
is independently C1-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents
selected from RL. T can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-Ly'-O-
Ls"-, -C(O)-LY'-N(RB)-Ls"- or -C(O)-LY'-N(RB)S(O)2-Ls"-. In some cases, at least one of Y
and Z is, or both Y and Z are independently, wherein non-limiting
examples of RD include (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6alkynyl, C1-C6alkyl, C2-
Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle;
or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl; and non-limiting
examples of LY' include C1-C6alkylene optionally substituted with halogen, hydroxy, mercapto,
amino, carboxy, phosphonoxy, -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6alkynyl, or 3- to 6-
membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being
optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-
Cealkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
In still yet another embodiment, A and B are each independently 5- or 6-membered
carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as and
are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle
or heterocycle or 6- to 12-membered bicycle (e.g., wherein X3 is N
and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples
of X are described hereinabove. D can be, for example, C5-C6carbocycle or 5- to 6-membered
heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is
wherein RM and RN are as defined above. Lj and L^ are each
independently bond or Ci-Cgalkylene, and L3 is bond, CrCgalkylene or -C(O)-, and Lb 1^, and L3 are
each independently optionally substituted with one or more RL. Preferably, L1, L^, and L3 are bond.
Y is -G-C(R1R2)N(R5)-T-RD or -G-C(R3R4)C(R6R7)-T-RD, and Z is -G-C(R8R9)N(Ri2)-T-RD or -
G-C(RIORII)C(R13R14)-T-RD. G is independently C5-C6carbocycle or 5- to 6-membered heterocycle,
such as and is independently optionally substituted with one or more RA.
Ri is Rc, and R2 and R5, taken together with the atoms to which they are attached, form a 5- to 6-
membered heterocyclic ring (e.g., which is optionally substituted with one or more RA;
R3 and Rs are each independently Rc, and R4 and R7, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is
optionally substituted with one or more RA. R8 is Rc, and R9 and R12, taken together with the atoms to
which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is
optionally substituted with one or more RA; and R10 and R13 are each independently Rc, and RH and
RM, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
heterocyclic ring (e.g., which is optionally substituted with one or more RA. T is
preferably independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-LS' '- or -C(O)-
LY'-N(RB)C(O)O-Ls"-. LY' is each independendy LS' and, preferably, is each independently Cr
Cealkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL. T
can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-LY'-O-Ls"-, -C(O)-LY'-
N(RB)-LS"-, or -C(O)-LY'-N(RB)S(O)2-LS"--. hi some cases, at least one of Y and Z is, or both Y
and Z are independently, wherein
non-limiting examples of RD include (1) -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6alkynyl, Cr
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered
heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl; and non-
limiting examples of LY' include C1-C6alkylene optionally substituted with halogen, hydroxy,
mercapto, amino, carboxy, phosphonoxy, -O-C1-C6alkyl, -O-C2-C6alkenyl, -O-C2-C6alkynyl, or 3-
to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being
optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-
Cealkenyl, C2-C6alkynyl, Ci-Gshaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
In yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or
heterocycle (e.g., A and B are each independently phenyl, such as and are each
independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle or
heterocycle or 6- to 12-membered bicycle (e.g., wherein X3 is N and
is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of
X are described hereinabove. D can be, for example, C5-C6carbocycle or 5- to 6-membered
heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is
wherein RM and RN are as defined above. Lt and L2 are each
independently bond or C1-C6alkylene, and L3 is bond, C1-C6alkylene or -C(O)-, and L1, L2, and L3 are
each independendy optionally substituted with one or more RL. Preferably, L1, L2, and L3 are bond.
Y is -N(RB)C(O)C(R1R2)N(R5)-T-RD or -N(RB)C(O)C(R3R4)C(R6R7)-T-RD, and Z is -G-
C(R8R9)N(R12)-T-RD or -G-C(R10RH)C(R13R14)-T-RD; or Y is -G-C(R1R2)N(R5)-T-RD or -G-
C(R3R4)C(R6R7)-T-RD, and Z is -N(RB)C(O)C(R8R9)N(R12)-T-RD or
N(RB)C(O)C(RIORII)C(R13R14)-T-RD. Rx is Rc, and R2 and R5, taken together with the atoms to
which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is
optionally substituted with one or more RA; R3 and R6 are each independently Rc, and R4 and R7,
taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
heterocyclic ring (e.g., which is optionally substituted with one or more RA. R8 is Rc,
and R9 and Ri2, taken together with the atoms to which they are attached, form a 5- to 6-membered
heterocyclic ring (e.g., which is optionally substituted with one or more RA; and R10 and
R13 are each independently Rc, and Rn and Rw, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is
optionally substituted with one or more RA. G is independently C5-C6carbocycle or 5- to 6-membered
heterocycle, such as and is independently optionally substituted with one or
more RA. T is preferably independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-
Ls"- or -C(O)-LY'-N(RB)C(O)O-Ls"-. LY' is each independently LS' and, preferably, is each
independently C1-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents
selected from RL. T can also be, without limitation, selected from -C(O)-LY'-Ls"-, -C(O)-LY'-O-
Ls"-, -C(O)-LY'-N(RB)-Ls"-, or -C(O)-LY'-N(RB)S(O)2-LS"-. In some cases, Y is
independently optionally substituted with one or more RA. Zj is independently selected at each
occurrence from O, S, NH or CH2; and Z2 is independently selected at each occurrence from N or CH.
X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.
wherein X3 is N and is directly linked to -L3-D) and is optionally substituted with
one or more RA. Specific examples of X are described hereinabove. D is C5-C6carbocycle or 5- to 6-
membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D
wherein RM and RN are as defined above. L1 and L2 are each
independently bond or C1-C6alkylene, and L3 is bond, C1-C6alkylene or -C(O)-, and L1, L2, and L3 are
each independently optionally substituted with one or more RL. Preferably, Lb Lj, and L3 are bond.
When A. is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as
N(RB)C(O)C(R1R2)N(R5)-T-RD, -N(RB)C(O)C(R3R4)C(R6R7)-T-RD, -G-C(R1R2)N(R5)-T-RD or -
G-C(R3R4)C(R6R7)-T-RD, and Z is -LS-C(R8R9)N(R12)-T-RD or -Ls-C(R10Rii)C(R13R14)-T-RD.
When B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as
C(R!R2)N(R5>-T-RD or -LS-C(R3R4)C(R6R7)-T-RD, and Z is -N(RB)C(O)C(R8R9)N(R12)-T-RD, -
N(RB)C(O)C(R10RII)C(R13R14)-T-RD, -G-C(R8R9)N(R12)-T-RD or -G-C(R10R11)C(R13R14)-T-RD. R1 is Rc, and R2 and R5, taken together with the atoms to which they are attached, form a 5- to 6-
membered heterocyclic ring (e.g., which is optionally substituted with one or more RA;
R3 and Rg are each independently Rc, and R4 and R7, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is
optionally substituted with one or more RA. R8 is Rc, and R9 and R12, taken together with the atoms to
which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is
optionally substituted with one or more RA; and Ri0 and R13 are each independently Rc, and Rn and
R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
heterocyclic ring (e.g., which is optionally substituted with one or more RA. G is
independently C5-C6carbocycle or 5- to 6-membered heterocycle, such as
and is independently optionally substituted with one or more RA- T is preferably independently
selected at each occurrence from -C(O)-LY'-N(RB)C(O)-Ls"- or -C(O)-LY'-N(RB)C(O)O-Ls"-.
LY' is each independently Ls' and, preferably, is each independently C1-C6alkylene (e.g., -CH2-) and
optionally substituted with one or more substituents selected from RL. T can also be, without
limitation, selected from -C(O)-LY'-Ls"-, -C(O)-LY'-O-Ls"-, -C(O)-LY'-N(RB)-Ls"-, or -
C(O)-LY'-N(RB)S(O)2-LS"-. In some cases when A is 5- or 6-membered carbocycle or heterocycle
wherein:
RMB is each independently selected from RB;
Re' is each independently selected from Rc;
RD' is each independently selected from RD;
R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
R9 and Ri2, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
A, B, D, X, L1, L2, L3, T, RA, RB, RC> and RD are as described above in Formula I.
In this aspect, A and B preferably are independently selected from Cs-Cgcarbocycle or 5- to 6-
membered heterocycle, and are each independently optionally substituted with one or more RA. More
preferably, at least one of A and B is phenyl (e.g., and is optionally substituted with
one or more RA. Highly preferably, both A and B are each independently phenyl (e.g.,
and are each independently optionally substituted with one or more RA.
D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 8- to 12-
membered bicycles, and is optionally substituted with one or more RA. D can also be preferably
selected from d-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or
more RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-
membered bicycles, and is substituted with one or more RM, where RM is halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -LS-RE- Also preferably, D is phenyl, and is optionally
substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more
RM, wherein RM is as defined above. Highly preferably, D is wherein RM is
as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or
more RN can also preferably be halo such as F.
D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or
more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
more RM. Highly preferably, D is wherein RM
is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One
or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7-
tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or
more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,
indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM- Highly preferably, D
and is optionally substituted with
one or more RM.
Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr
Csalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C^-Cishaloalkenyl or C2-C6haloalkynyl. More
preferably, RM is halogen, hydroxy, mercapto, amino, carboxy; or CrC6alkyl, C2-C6alkenyl or C2-
Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is
C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy.
Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, or cyano; or RM is -LS-RE, wherein Ls is a bond or d-C6alkylene, and RB is -
N(RsRs'), -O-Rs, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), -N(Rs)C(O)Rs', -N(Rs)C(O)ORs', -
N(Rs)SO2Rs', -SO2Rs, -SRs, or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each
independently selected at each occurrence from (1) hydrogen or (2) C1-C6alkyl optionally substituted
at each occurrence with one or more halogen, hydroxy, -O-Ci-Cgalkyl or 3- to 6-membered
heterocycle; or RM is C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, CVCehaloalkenyl, QrCehaloalkynyl, -C(O)ORs, or -
N(RsRs')- More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C1-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each
of which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RM is CF3, -
C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RM is -Ls- R6 where Ls is a bond and R6 is -N(RsRsO, -O-Rs, -N(Rs)C(O)ORs', -N(Rs)SO2Rs', -SO2Rs, or -
SRS. For example where Ls is a bond, R6 is -N(C1-C6alkyl)2 (e.g., -NMe2); -N(C1-C6alkylene-O-Ci-
C6alkyl)2 (e.g. -N(CH2CH2OMe)2); -N^x-CsalkylXC1-C6alkylene-O-C1-C6alkyl) (e.g. -
N(CH3)(CH2CH2OMe));—O-C1-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-
hexyl); -O-C1-C6haloalkyl (e.g., - OCF3, -OCH2CF3); -O-Ci-Cgalkylene-piperidine (e.g., -O-
CH2CH2-l-piperidyl); -N(C1-C6alkyl)C(O)OC1-C6alkyl (e.g., -N(CH3)C(O)O-CH2CH(CH3)2), -
N^j-C6alkyDSOzC2-C6alkyl (e.g., -N(CH3)SO2CH3); -SO2d-C6alkyl (e.g., -SO2Me); -SO2Cr
Cshaloalkyl (e.g., -SO2CF3); or -S-C1-C6haloalkyl (e.g., SCF3). Also preferably RM is -LS-RE where
Ls is C1-C6alkylene (e.g., -CH2- -C(CH3)2- -C(CH3)2-CH2-) and R6 is -O-Rs, -C(O)ORs, -
N(Rs)C(O)ORs', or -P(O)(ORs)2. For example RM is -C1-C6alkylene-O-Rs (e.g., -C(CH3)2-CH2-
OMe); -C1-C5alkylene-C(O)ORs (e.g., -C(CH3)2-C(O)OMe); -C1-C6alkylene-N(Rs)C(O)ORs' (e.g.,
-C(CH3)2-CH2-NHC(O)OCH3); or -C1-C6alkylene-P(O)(ORs)2 (e.g., -CH2-P(O)(OEt)2). Also more
preferably RM is C3-C<5carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl, Cz-Cehaloalkynyl, -
C(O)ORs, or -N(RsRs'). For example RM is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-
methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1-
dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1-
yl, piperidin-1-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,
tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RM
is Ci-Cgalkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).
X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
bicycles (e.g. wherein X3 is N and is directly linked to -L3-D), and
is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove.
L1 and L2 are preferably independently bond or C1-C6alkylene, L3 is preferably selected from
bond, C1-C6alkylene or -C(O)-, and L1, L2, and l^ are each independently optionally substituted with
one or more RL. More preferably, L1, L2 and L3 are each independently bond or C1-C6alkylene (e.g., -
CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly
preferably, L1, L2 and L3 are bond.
R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-
membered heterocycle or 6- to 12-membered bicycle (e.g.,which is
optionally substituted with one or more RA.
R9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to
6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is
optionally substituted with one or more RA.
-T-RD' can be, without limitation, independently selected at each occurrence from -C(O)-
LY'- -C(O)O-LY'-RD', -C(O)-LY'-N(RB)C(O)-Ls"-RD\ -C(OHV-N(RB)C(O)O-Ls''-RD\ -
N(RB)C(O)-LY'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LY'—N(RB)C(O)O-LS"-RD\ or -N(RB)C(O)-
LY'—N(RB)-LS"-RD', wherein LY' is each independently Ls' and, preferably, is each independently
Ci-C5alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL.
Preferably, -T-RD' is independently selected at each occurrence from -C(O)-LY'-M'-Ls' '-RD' or -
N(RB)C(O)-LY'-M'-LS"-RD'- More preferably, -T-RD' is independently selected at each occurrence
from -C(O)-LY'-N(RB)C(O)-LS"-RD' or -C(O)-LY'-N(RB)C(O)O-LS"-RD\ Highly preferably, -
T-RD' is independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-RD' or -C(O)-LY'-
N(RB)C(O)O-RD\ wherein LY' preferably is each independently C1-C6alkylene (e.g., -CHr) and
optionally substituted with one or more substituents selected from RL.
RNB and Rc' are preferably hydrogen, and RD' preferably is independendy selected at each
occurrence from RE. More preferably, RD' is independently selected at each occurrence from d-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered
heterocycle; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
C6alkyl, C2-C6alkenyl, C2-C5alkynyl, d-Cshaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; or -LA-
0-Rs, -LA-S-Rs, -LA-C(O)Rs, -LA-OC(O)Rs, -LA-C(O)ORs, -LA-N(RsRs'), -LA-S(O)Rs, -LA-
SO2Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs', -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO2Rs', -
LA-SO2N(RsRs'), -LA-N(Rs)SO2N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA-
OS(O)2-Rs, -LA-S(O)2ORs, -LA-S(O)ORs, -LA-OC(O)ORs, -LA-N(Rs)C(O)ORs\ -LA-
OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or -LA-C(O)N(Rs)C(O)-Rs\ wherein LA
is bond, C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independendy optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or Cs-Cgcarbocycle or 3- to 6-membered heterocycle, each of which is independendy
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Q-Cehaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or
C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
A and B can be the same or different. Likewise, Lt and L2 can be the same or different.
In one embodiment of this aspect, A, B, and D are each independently phenyl, and are each
independently optionally substituted with one or more RA. Preferably, D is
wherein RM and RN are as defined above. Lj and L2 are each independently bond or d-
C6alkylene, and L3 is bond, C1-C6alkylene or -C(O)-, and L1, L^, and L3 are each independently
optionally substituted with one or more RL. Preferably, L1, L^, and L3 are bond. -T-RD' is
independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-LS"-RD' or -C(O)-LY'-
N(RB)C(O)O-LS"-RD', wherein LY' is C1-C6alkylene (e.g., -CH2-) and optionally substituted with
one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without
limitation, selected from -C(O)-LY'-Ls"-RD', -C(O)-LY'-O-LS"-RD', -C(O)-LY'-N(RB)-LS"-
RD', or -C(O)-LY'-N(RB)S(O)2-Ls"-RD'.
In still another aspect, the present invention features compounds of Formula IB and
pharmaceutically acceptable salts thereof:
wherein:
Re' is each independendy selected from Rc;
RD' is each independendy selected from RD;
R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
C5-C6carbocycle or 5- to 6-membered heterocycle, and A and B are independently optionally
substituted with one or more RA.
D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-
membered bicycles, and is optionally substituted with one or more RA. D can also be preferably
selected from Ci-Cgalkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or
more substituents selected from RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more RM, where RM is
halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE- Also preferably, D is
phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is
substituted with one or more RM, wherein RM is as defined above. Highly preferably, D is
wherein RM is as defined above, and each RN is independently selected from
RD and preferably is hydrogen. One or more RN can also preferably be halo such as F.
D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or
more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
more RM- Highly preferably, D is wherein RM
is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One
or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7-
tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or
more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,
indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D
one or more RM-
Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-Cecarbocycle or 3- to 6-membered heterocycle, each of which is independendy
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cghaloalkyl, C2-C5haloalkenyl or CrCghaloalkynyl. More
preferably, RM is halogen, hydroxy, mercapto, amino, carboxy; or C1-C6alkyl, C2-C6alkenyl or C2-
C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is
C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy.
Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, or cyano; or RM is -LS-RE, wherein Ls is a bond or Ci-Cgalkylene, and R6 is -
N(RsRs'), -O-Rs, -C(O)Rs, -C(O)ORS, -C(O)N(RSRS'), -N(RS)C(O)RS\ -N(RS)C(O)ORS\ -
N(Rs)SO2Rs\ -SO2Rs, -SRS, or -P(O)(ORs)2, wherein Rs and RS' can be, for example, each
independendy selected at each occurrence from (1) hydrogen or (2) C1-C6alkyl optionally substituted
at each occurrence with one or more halogen, hydroxy, -O-C1-C6alkyl or 3- to 6-membered
heterocycle; or RM is C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independendy optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C5alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-Cehaloalkenyl, C2-Cehaloalkynyl, -C(O)ORs, or -
N(RsRs')- More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C1-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each
of which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RM is CF3, -
C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RM is -Ls-
RE where Ls is a bond and R6 is -N(RSRS), -O-Rs, -N(Rs)C(O)ORs\ -N(Rs)SO2Rs', -SO2Rs, or -
SRS. For example where Ls is a bond, R6 is -N(C1-C6alkyl)2 (e.g., -NMe2); -NCC1-C6alkylene-O-Cr
C6alkyl)2 (e.g. -N(CH2CH2OMe)2); -Ntd-C6alkyD^i-C6alkylene-O-C1-Cfialkyl) (e.g. -
N(CH3)(CH2CH2OMe));—O-C1-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-
hexyl); -O-C1-C6haloalkyl (e.g., - OCF3, -OCH2CF3); -O-C1-C6alkylene-piperidine (e.g., -O-
CH2CH2-l-piperidyl); -N(C1-C6alkyl)C(O)OC1-C6a]kyl (e.g., -N(CH3)C(O)O-CH2CH(CH3)2), -
N^x-C6alky^SOzC1-C6alkyl (e.g., -N(CH3)SO2CH3); -SO2CrC6alkyl (e.g., -SO2Me); -SO2Cr
Cehaloalkyl (e.g., ^SO2CF3); or -S-C1-C6haloalkyl (e.g., SCF3). Also preferably RM is -Ls-RE where
Ls is CrC6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and R6 is -O-Rs, -C(O)ORs, -
N(Rs)C(O)ORs\ or -P(O)(ORs)2. For example RM is -C1-C6alkylene-O-Rs (e.g., -C(CH3)2-CH2-
OMe); -C1-C6alkylene-C(O)ORs (e.g., -C(CH3)2-C(O)OMe); -CrC6alkylene-N(Rs)C(O)ORs' (e.g.,
-C(CH3)2-CH2-NHC(O)OCH3); or -C1-C6alkylene-P(O)(ORs)2 (e.g., -CH2-P(O)(OEt)2). Also more
preferably RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Cj-Cehaloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -
C(O)ORs, or -N(RSRS'). For example RM is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-
methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1-
dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1-
yl, piperidin-1-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,
tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RM
is C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).
X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
bicycles (e.g. wherein X3 is N and is directly linked to -L3-D), and
is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove.
Lj and 1^ are preferably independently bond or C1-C6alkylene, L3 is preferably selected from
bond, C1-C6alkylene or -C(O)-, and L1, L2, and L3 are each independendy optionally substituted with
one or more RL. More preferably, Lb 1^ and 1^ are each independently bond or C1-C6alkylene (e.g., -
CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly
preferably, L1, L^ and L3 are bond.
R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-
membered heterocycle or 6- to 12-membered bicycle (e.g., which is
optionally substituted with one or more RA. R9 and Rn, taken together with the atoms to which they
are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
which is optionally substituted with one or more RA.
-T-RD' can be, without limitation, independently selected at each occurrence from -C(O)-
LY'-RD', -C(O)O-LY'-RD\ -C(O)-LY'-N(RB)C(O)-LS"-RD', -C(O)-LY'-N(RB)C(O)O-LS"-RD\ -
N(RB)C(O)-LY'-N(RB)C(O)-Ls"-RD\ -N(RB)C(O)-LY'—N(RB)C(O)O-LS"-RD\ or -N(RB)C(O)-
LY'—N(RB)-LS"-RD', wherein LY' is each independently Ls' and, preferably, is each independently
C1-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL.
Preferably, -T-RD' is independently selected at each occurrence from ~C(O)-LY'-M'-Ls"-RD' or -
N(RB)C(O)-LY'-M'-LS"-RD'- More preferably, -T-RD' is independently selected at each occurrence
from -C(O)-LY'-N(RB)C(O)-Ls"-RD' or -C(O)-LY'-N(RB)C(O)O-Ls"-RD'. Highly preferably, -
T-RD' is independendy selected at each occurrence from -C(O)-LY'-N(RB)C(O)-RD' or -C(O)-LY'-
N(RB)C(O)O-RD\ wherein LY' preferably is each independentiy C1-C6alkylene (e.g., -CH2-) and
optionally substituted with one or more substituents selected from RL.
Re' is preferably hydrogen, and RD' preferably is independently selected at each occurrence
from RE. More preferably, RD' is independendy selected at each occurrence from C1-C6alkyl, C2-
Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle;
or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C(>haloalkenyl or C2-C6haloalkynyl; or -LA-
O-Rs, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RsRs'), -LA-S(O)RS, -LA-
SO2Rs, -LA-C(O)N(RsRs'), -LA-N(RS)C(O)RS', -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO2Rs', -
LA-SO2N(RsRs'), -LA-N(RS)SO2N(RS!RS"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-RS, -LA-
OS(O)2-Rs, -LA-S(O)2ORs, -LA-S(O)ORS, -LA-OC(O)ORS, -LA-N(RS)C(O)ORS', -LA-
OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RSRS') or -LA-C(O)N(RS)C(O)-Rs\ wherein LA
is bond, C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, CrCghaloalkenyl or C2-C6haloalkynyl.
Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or CrC6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or
C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
A and B can be the same or different. Likewise, L1 and L2 can be the same or different.
optionally substituted with one or more RA; and D is C5-C6carbocycle or 5- to 6-membered
heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is
wherein RM and RN are as defined above. Zi is independently selected at
each occurrence from O, S, NH or CH2; and 2^ is independently selected at each occurrence from N
or CH. L1 and L2 are each independently bond or C1-C6alkylene, and L3 is bond, Ci-Cgalkylene or -
C(O)-, and Lu L2, and L3 are each independently optionally substituted with one or more RL.
Preferably, L1, L2, and L3 are bond. -T-RD' is independently selected at each occurrence from -C(O)-
LY'-N(RB)C(O)-Ls"-RD' or -C(O)-LY'-N(RB)C(O)O-Ls"-RD', wherein LY' is d-C6alkylene (e.g.,
-CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably
is bond. -T-RD' can also be, without limitation, selected from -C(O)-LY'-Ls"-RD', -C(O)-LY'-O-
Ls"-RD\ -C(O)-LY'-N(RB)-LS"-RD', or-C(O)-LY'-N(RB)S(O)2-Ls"-RD'.
In yet another aspect, the present invention further features compounds of Formula Ic and
pharmaceutically acceptable salts thereof.
wherein:
RNB is RB!
RC' is each independently selected from Rc;
RD' is each independently selected from RD;
R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
R9 and Ri2, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
A, B, D, X, L1, L2, L3, T, RA, RB, RC, and RD are as described above in Formula L
In this aspect, A preferably is C5-C6carbocycle or 5- to 6-membered heterocycle, and is
optionally substituted with one or more RA; and B preferably is 8- to 12-membered bicycle (such as
and is optionally substituted with one or more
RA. Zx is 0, S, NH or CH2; Zj is N or CH; Z3 is N or CH; Z4 is O, S, NH or CH2; and Wl5 W2, W3,
W4, W5 and W6 are each independently selected from CH or N.
or more RA, where Zu Z2, Z3, Z4, Wi, W2, W3, W4, W5, W6 are as defined above. Preferably, Z3 is N
from C5-C6carbocycle or 5- to 6-membered heterocycle. A and B are independently optionally
substituted with one or more RA.
D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-
membered bicycles, and is optionally substituted with one or more RA. D can also be preferably
selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or
more substituents selected from RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more RM, where RM is
halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is
phenyl, and is optionally substituted with one or more RA- More preferably, D is phenyl, and is
substituted with one or more RM, wherein RM is as defined above. Highly preferably, D is
wherein RM is as defined above, and each RN is independently selected from
RD and preferably is hydrogen. One or more RN can also preferably be halo such as F.
D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or
more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
more RM. Highly preferably, D is wherein RM
is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One
or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7-
tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or
more RA- More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,
indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D
one or more RM-
Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C<>haloalkyl, C2-C5haloalkenyl or C2-C6haloalkynyl. More
preferably, RM is halogen, hydroxy, mercapto, amino, carboxy; or C1-C6alkyl, C2-C6alkenyl or C2-
C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is
C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy.
Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, or cyano; or RM is -LS-RE, wherein Ls is a bond or C1-C6alkylene, and R6 is -
N(RSRS'), -O-Rs, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), -N(Rs)C(O)Rs', -N(Rs)C(O)ORs\ -
N(Rs)SO2Rs\ -SO2Rs, -SRs, or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each
independently selected at each occurrence from (1) hydrogen or (2) C1-C6alkyl optionally substituted
at each occurrence with one or more halogen, hydroxy, -O-C1-C6alkyl or 3- to 6-membered
heterocycle; or RM is C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independendy
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-Cehaloalkenyl, C2-Cehaloalkynyl, -C(O)ORs, or -
N(RsRs')- More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C1-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each
of which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, cyano, or carhoxy. For example RM is CF3, -
C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RM is -Ls- R6 where Ls is a bond and R6 is -N(RSRS), -O-Rs, -N(Rs)C(O)ORs', -N(Rs)SO2Rs', -SO2Rs, or -
SRS. For example where Ls is a bond, R6 is -N(C1-C6alkyl)2 (e.g., -NMe2); -N(C1-C6alkylene-O-Cr
C6alkyl)2 (e.g. -N(CH2CH2OMe)2); -N^i-CfialkylXd-C6alkylene-O-C1-C6alkyl) (e.g. -
N(CH3)(CH2CH2OMe));—O-C1-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-
hexyl); -O-C1-Cehaloalkyl (e.g., - OCF3, -OCH2CF3); -O-d^alkylene-piperidine (e.g., -O-
CH2CH2-l-piperidyl); -N(d-C6alkyl)C(O)Od-dalkyl (e.g., -N(CH3)C(O)O-CH2CH(CH3)2), -
^d-CfialkyDSOzd-C6alkyl (e.g., -N(CH3)SO2CH3); -SO2d-C6alkyl (e.g., -SO2Me); -SO2Cr
C^aloalkyl (e.g., -SO2CF3); or -S-C1-C^aloalkyl (e.g., SCF3). Also preferably RM is -Ls-RE where
Ls is d-C6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and R6 is -O-Rs, -C(O)ORs, -
N(Rs)C(O)ORs', or -P(O)(ORs)2. For example RM is -C1-C6alkylene-O-Rs (e.g., -C(CH3)2-CH2-
OMe); -C1-C6alkylene-C(O)ORs (e.g., -C(CH3)2-C(O)OMe); -C1-C6alkylene-N(Rs)C(O)ORs' (e.g.,
-C(CH3)2-CH2-NHC(O)OCH3); or -C1-C6alkylene-P(O)(ORs)2 (e.g., -CH2-P(O)(OEt)2). Also more
preferably RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
dalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, d-Cshaloalkenyl, C2-C6haloalkynyl, -
C(O)ORs, or -N(RsRs')- For example RM is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-
methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1-
dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1-
yl, piperidin-1-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,
tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RM
is C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).
X preferably is d-dcarbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
bicycles (e.g., wherein X3 is N and is directly linked to -L3-D), and
is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove.
L1 and L2 are preferably independently bond or d-dalkylene, L3 is preferably selected from
bond, d-dalkylene or -C(O)-, and L1; 1^, and 1^ are each independently optionally substituted with
one or more RL. More preferably, L1; L2 and L^ are each independently bond or d-C6alkylene (e-g-, -
CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly
preferably, Lh L2 and L3 are bond. L1 and L2 can be the same or different.
R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-
membered heterocycle or 6- to 12-membered bicycle (e.g., which is
optionally substituted with one or more RA. R9 and R12, taken together with the atoms to which they
are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
which is optionally substituted with one or more RA.
-T-RD' can be, without limitation, independently selected at each occurrence from -C(O)-
IV-RD\ ~C(O)O-LY'-RD', -C(O)-Ly'-N(RB)C(O)-Ls"-RD', -C(O^LY'-N(RB)C(O)O-Ls"-RD', -
N(RB)C(O)-LY'-N(RB)C(O)-LS"-RD', -N(RB)C(O)-LY'—N(RB)C(O)O-LS"-RD\ or -N(RB)C(O)-
LY'—N(RB)-LS"-RD\ wherein LY' is each independently Ls' and, preferably, is each independently
C1-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL.
Preferably, -T-RD' is independently selected at each occurrence from -C(O)-LY'-M'-Ls"-RD' or -
N(RB)C(O)-LY'-M'-LS"-RD'- More preferably, -T-RD' is independently selected at each occurrence
from -C(O)-LY'-N(RB)C(O)-Ls"-RD' or -C(O)-LY'-N(RB)C(O)O-LS"-RD'. Highly preferably, -
T-RD' is independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-RD' or -C(O)-LY'-
N(RB)C(O)O-RD', wherein LY' preferably is each independently C1-C6alkylene (e.g., -CH2-) and
optionally substituted with one or more substituents selected from RL.
RNB and Rc' are preferably hydrogen, and RD' preferably is independendy selected at each
occurrence from RE. More preferably, RD' is independently selected at each occurrence from Cr
Csalkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered
heterocycle; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cfjhaloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
Qalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyi, C2-C6haloalkenyl or C2-C5haloaIkynyl; or -LA-
O-Rs, -LA-S-RS, -LA-C(O)RS, -LA-OC(O)RS, -LA-C(O)ORS, -LA-N(RSRS'), -LA-S(O)RS, -LA-
SO2Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs\ -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO2Rs', -
LA-SO2N(RsRs'), -LA-N(Rs)SO2N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs> -LA-
OS(O)2-Rs, -LA-S(O)2ORs, -LA-S(O)ORs, -LA-OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA-
OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or -LA-C(O)N(Rs)C(O)-Rs\ wherein LA
is bond, C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or
CrC6alkylene, C2-C6alkenylene or C2-C6alkynylene.
In one embodiment of this aspect, A is phenyl, and is optionally substituted with one or more
RA; and B is and is optionally substituted with one or
more RA, wherein Zi is 0, S, NH or CH2; and Z2 is N or CH. D is C5-C6carbocycle or 5- to 6-
membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D
is wherein RM and RN are as defined above. L1 and 1^ are each
independently bond or C1-C6alkylene, and L3 is bond, C1-C6alkylene or -C(O)-, and L1, 1^, and L3 are
each independently optionally substituted with one or more RL. Preferably, Ll5 L2, and L3 are bond. -
T-RD' is independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-LS"-RD' or -C(O)-
LY'-N(RB)C(O)O-LS"-RD', wherein LY' is C1-C6alkylene (e.g., -CH2-) and optionally substituted
with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be,
without limitation, selected from -C(O)-LY'-Ls"-RD\ -C(O)-LY'-O-LS"-RD\ -C(O)-LY'-N(RB)-
LS"-RD', or -C(O)-LY'-N(RB)S(O)2-LS"-RD'.
In yet another aspect, the present invention features compounds of Formula ID and
pharmaceutically acceptable salts thereof.
wherein:
d and G2 are each independendy selected from C5-C6carbocycle or 5- to 6-membered
heterocycle, and are each independendy optionally substituted with one or more RA;
Re' is each independently selected from Re;
RD' is each independendy selected from RD;
R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
R9 and Ri2, taken together with die atoms to which diey are attached, form a 3- to 12-
membered heterocycle which is optionally substituted with one or more RA;
A, B, D, X, L1, L2, L3, T, RA, R& and RD are as described above in Formula I.
In this aspect, A and B preferably are independendy selected from C5-C6carbocycle or 5- to 6-
membered heterocycle, and are each independently optionally substituted with one or more RA. More
preferably, at least one of A and B is phenyl (e.g., and is optionally substituted wifli
one or more RA. Highly preferably, both A and B are each independently phenyl (e.g.,
and are each independendy optionally substituted with one or more RA.
D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 8- to 12-
membered bicycles, and is optionally substituted with one or more RA. D can also be preferably
selected from C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or
more RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-
membered bicycles, and is substituted with one or more RM, where RM is halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -LS-RE- Also preferably, D is phenyl, and is optionally
substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more
RM, wherein RM is as defined above. Highly preferably, D is
wherein RM is as defined above, and each RN is independently selected from RD and
preferably is hydrogen. One or more RN can also preferably be halo such as F.
D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or
more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
more RM- Highly preferably, D is wherein RM
is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One
or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7-
tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or
more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl,
indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM- Highly preferably, D
and is optionally substituted with
one or more RM.
Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or d-C&Ikyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl. More
preferably, RM is halogen, hydroxy, mercapto, amino, carboxy; or CrC6alkyl, C2-C6alkenyl or C2-
C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is
C1-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy.
Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, or cyano; or RM is -LS-RE, wherein Ls is a bond or C1-C6alkylene, and RB is -
N(RsRs'), -O-Rs, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), -N(Rs)C(O)Rs', -N(Rs)C(O)ORs', -
N(Rs)SO2Rs\ -SO2Rs, -SRs, or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each
independently selected at each occurrence from (1) hydrogen or (2) C1-C6alkyl optionally substituted
at each occurrence with one or more halogen, hydroxy, -O-C1-C6alkyl or 3- to 6-membered
heterocycle; or RM is C!-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
RM is C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, CVCehaloalkenyl, C2-C6haloalkynyl, -C(O)ORs, or -
N(RsRs')- More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C!-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each
of which is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RM is CF3, -
C(CF3)r-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RM is -Ls- R6 where Ls is a bond and R6 is -N(RSRS), -O-Rs, -N(Rs)C(O)ORs', -N(Rs)SO2Rs', -SO2Rs, or -
SRS. For example where Ls is a bond, R6 is -N(CrC6alkyl)2 (e.g., -NMe2); -N(C1-C6alkylene-O-Ci-
C6alkyl)2 (e.g. -N(CH2CH2OMe)2); -N(C1-C6alkyl)(C1-C6alkylene-O-C1-C6alkyl) (e.g. -
N(CH3)(CH2CH2OMe));—0-C1-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-
hexyl); -O-C1-C6haloalkyl (e.g., - OCF3, -OCH2CF3); -O-C1-C6alkylene-piperidine (e.g., -O-
CH2CH2-l-piperidyl); -N(CrC6alkyl)C(O)OC1-C6alkyl (e.g., -N(CH3)C(O)O-CH2CH(CH3)2), -
N(C1-C6alkyl)SO2C1-C6alkyl (e.g., -N(CH3)SO2CH3); -SO2CrC6alkyl (e.g., -SO2Me); -SO2Cr
Cehaloalkyl (e.g., -^SO2CF3); or -S-C1-C6haloalkyl (e.g., SCF3). Also preferably RM is -LS-RE where
Ls is d-C6alkylene (e.g., -CH2- -C(CH3)2- -C(CH3)2-CH2-) and R6 is -O-Rs, -C(O)ORs, -
N(Rs)C(O)ORs', or -P(O)(ORs)2. For example RM is -C1-C6alkylene-O-Rs (e.g., -C(CH3)2-CH2-
OMe); -CrC6alkylene-C(O)ORs (e.g., -C(CH3)2-C(O)OMe); -CrC6a]kylene-N(Rs)C(O)ORs' (e.g.,
-C(CH3)2-CH2-NHC(O)OCH3); or -CrC6alkylene-P(O)(ORs)2 (e.g., -CH2-P(O)(OEt)2). Also more
preferably RM is C3-C(scarbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -
C(O)ORs, or -N(RSRS'). For example RM is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-
methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1-
dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1-
yl, piperidin-1-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,
tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RM
is Q-C6alkyl which is optionally substituted with one or more substituents selected from halogen,
hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).
X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
bicycles (e.g., wherein X3 is N and is directly linked to -L3-D), and
is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove.
L1 and Lt are preferably independently bond or C1-C6alkylene, L3 is preferably selected from
bond, C1-C6alkylene or -C(O)-, and L1; L2, and Ls are each independently optionally substituted with
one or more RL. More preferably, Lh L2 and YA, are each independently bond or C1-C6alkylene (e.g., -
CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly
preferably, L1, 1^ and L3 are bond.
R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-
membered heterocycle or 6- to 12-membered bicycle (e.g.,which is
optionally substituted with one or more RA.
R9 and Ri2, taken together with the atoms to which they are attached, preferably form a 5- to
6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is
optionally substituted with one or more RA.
d and G2 preferably are each independently selected from
and are each independently optionally substituted with one or more
RA (e.g., one or more chloro or bromo). More preferably, Gi is (including any tautomer
thereof), and G2 is (including any tautomer thereof), and each Gi and G2 is independently
optionally substituted with one or more RA (e.g., one or more chloro or bromo).
-T-RD' can be, without limitation, independently selected at each occurrence from -C(O)-
W- -C(O)O-LY'-RD\ -C(O)-Ly'-N(RB)C(O)-Ls"-RD', -C(O)-LY'-N(RB)C(O)O-LS"-RD', -
N(RB)C(O)-LY'-N(RB)C(O)-Ls"-RD', -N(RB)C(O)-LY'-N(RB)C(O)O-Ls"-RD', or -N(RB)C(O)-
LY'—N(RB)-LS"-RD', wherein Ly' is each independently Ls' and, preferably, is each independently
C1-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL-
Preferably, -T-RD' is independently selected at each occurrence from -C(O)-LY'-M'-LS"-RD' or -
N(RB)C(O)-LY'-M'-LS"-RD'- More preferably, -T-RD' is independently selected at each occurrence
from -C(O)-LY'-N(RB)C(O)-LS"-RD' or -C(O)-LY'-N(RB)C(O)O-LS''-RD'- Highly preferably, -
T-RD' is independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-RD' or -C(O)-LY'-
N(RB)C(O)O-RD', wherein LY' preferably is each independendy C1-C6alkylene (e.g., -CH2-) and
optionally substituted with one or more substituents selected from RL.
Re' is preferably hydrogen, and RD' preferably is independently selected at each occurrence
from RE. More preferably, RD' is independendy selected at each occurrence from C1-C6alkyl, C2-
C6alkenyl or C2-C6alkynyl, each of which is independendy optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle;
or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, CVCehaloalkenyl or Cz-Cehaloalkynyl.
RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano; or C2-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independendy optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independendy
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyi, C2-C6haloalkenyl or C2-C,5haloalkynyl; or -LA-
O-Rs, -LA-S-RS, -LA-C(O)Rs, -LA-OC(O)Rs, -LA-C(O)ORs, -LA-N(RsRs'), -LA-S(O)Rs, -LA-
SO2Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs', -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO2Rs', -
LA-SO2N(RsRs'), -LA-N(Rs)SO2N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA-
OS(O)^Rs, -LA-S(O)2ORs, -LA-S(O)ORs, -LA-OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA-
OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or -LA-C(O)N(Rs)C(O)-Rs\ wherein LA
is bond, d-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or d-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, d-
Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano; or C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which
is independently optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or
C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.
A and B can be the same or different. Likewise, L1 and L2 can be the same or different.
In one embodiment of this aspect, A, B, and D are each independently phenyl, and are each
independently optionally substituted with one or more RA; and d is
and each d and G2 is independently optionally substituted with one or more RA (e.g., one or more
chloro or bromo). Preferably, D is wherein RM and RN are as defined
above. Lj and L2 are each independently bond or C1-C6alkylene, and L3 is bond, C1-C6alkylene or -
C(O)-, and L1, 1^, and L3 are each independently optionally substituted with one or more RL.
Preferably, L1; L2, and L3 are bond. -T-RD' is independently selected at each occurrence from -C(O)-
LY'-N(RB)C(O)-Ls"-RD' or-C(O)-LY'-N(RB)C(O)O-LS"-RD', wherein LY' is C1-C6alkylene (e.g.,
-CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably
is bond. -T-RD' can also be, without limitation, selected from -C(O)-LY'-Ls"-RD', -C(O)-LY'-O-
LS"-RD', -C(O)-LY'-N(RB)-Ls"-RD\ or -C(O)-LY'-N(RB)S(O)2-Ls"-RD'.
The present invention also features the compounds of Formulae I, IA, IB, Ic and ID as
described herein (including each embodiment described herein) or salts thereof, except that D is C3-
C12carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted
with one or more RA, where J is C3-C12carbocycle or 3- to 12-membered heterocycle and is optionally
substituted with one or more RA, or J is -SF5. Preferably, D is C5-C6carbocycle, 5- to 6-membered
heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and J is
C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA.
More preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is optionally substituted
with one or more RA, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally
substituted with one or more RA. Highly preferably, D is phenyl substituted with J and optionally
substituted with one or more RA, where J is C3-C6carbocycle or 3- to 6-membered heterocycle and is
optionally substituted with one or more RA. Preferred RAs are as described above. In one
embodiment, D is wherein each RN is independently selected from RD and preferably
is hydrogen, and J is as defined above and preferably is C3-C6carbocycle or 3- to 6-membered
heterocycle optionally substituted with one or more RA. hi another embodiment, D is and J is
C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA.
Moreover, the present invention features the compounds of Formulae I, IA, IB, Ic and ID as
described herein (including each embodiment described herein, as well as where D is C3-
Cncarbocycle or 3- to 12-membered heterocycle substituted with J and optionally substituted with
one or more RA as described hereinabove) or salts thereof, except that X is optionally substituted with
one or more RA'. Specific examples of X are as described above, such as
wherein X3 is N and is directly linked to -L3-D. Each RA' is independently RA; or Ci-
Ci0alkyl, C2-Ci0alkenyl or C2-Cioalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms
selected from O, S or N and is optionally substituted with one or more RL. RA is as defined above. In
one embodiment, each RA' is independently RA; or Ci-Ci0alkyl, C2-Cioalkenyl or C2-Cioalkynyl, each
of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is optionally substituted
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl or cyano. In another embodiments, each RA' is
independently selected from RA; or Ci-Ci0alkyl, C2-Ci0alkenyl or C2-C10alkynyl, each of which
contains 0, 1, 2, 3, 4 or 5 O and is optionally substituted with one or more RL. In a further
embodiment, each RA' is independendy selected from Ci-Ci0alkyl, C2-Ci0alkenyl or C2-C10alkynyl,
each of which contains 0, 1, 2 or 3 O and is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl or cyano.
In another aspect of the invention, each RA' is independently RA or -(RX-RY)N-(RX-RY'))
wherein N is 0, 1, 2, 3, 4; each Rx is independently O, S or N(RB); each RY is independently Cr
Cealkylene, C2-C6alkenylene or C2-C6alkynylene each of which is optionally substituted with one or
more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl or cyano; and RY' is independently C1-C6alkyl, C2-
C6alkenyl or C2-C6alkynyl each of which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl or cyano. RA and RB are as defined above. In one embodiment, each Rx is O. For
example, each RA' is selected from -(0-C1-C6a]kylene)N-(0-C1-C6alkyl), wherein N preferably is 0,
1, 2 or 3.
In addition, the present invention features the compounds of Formulae I, IA, IB, Ic and ID as
described herein (including each embodiment described herein, as well as where D is C3-
C12carbocycle or 3- to 12-membered heterocycle substituted with J and optionally substituted with
one or more RA as described hereinabove, or where X is optionally substituted with one or more RA'
as described herein above), wherein:
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RSRS'), -S(O)Rs, -SO2Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs\ -
N(Rs)C(O)N(Rs'Rs"), -N(Rs)SO2Rs\ -SO2N(RsRs'), -N(Rs)SO2N(Rs'Rs"), -
N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O)2-Rs, -S(O)2ORs, -S(O)ORs, -OC(O)ORs, -
N(Rs)C(O)ORs\ -OC(O)N(RSRS'), -N(Rs)S(O)-Rs', -S(O)N(RsRs'), -P(O)(ORs)2, or-
C(O)N(Rs)C(O)-Rs'; or CrC6alkyl, C2-C6alkenyl or C2-C5alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered
heterocycle, each of which is independendy optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C1-C6haloalkyl, Cz-Cshaloalkenyl, Cj-C^aloalkynyl, C(O)ORs, or -
N(RSRS'); and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; Cr
Cealkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano, -O-C1-C6alkyl, -O-C1-C6alkylene-O-C1-C6alkyl, or 3- to 6-membered
carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each
3- to 6-membered carbocycle or heterocycle in Rs , Rs' or Rs' is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C as appreciated by those skilled in the art.
As another non-limiting example, the compounds of the present invention can be prepared
starting from compounds of Formula II and Formula III as shown in Scheme n. The 1,4-diketones
such as Formula IV may be prepared using known methods (see Nevar, et al., Synthesis: 1259-1262
(2000), such as the reaction of oc-bromoketones such as Formula II with methyl ketones such as
Formula IE in the presence of a suitable Lewis acid such as ZnCl2 or Ti(0iPr)4. The 1,4-diketones IV
may be reduced to the 1,4-diols such as V by the action of NaBH4, LiAlH4, or DIBAL. Alternatively,
enantioselective reduction of 1,4-diketones such as Formula IV can be accomplished by analogy with
reported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418 (1995), L1, et al.,
Tetrahedron 63:8046-8053 (2007), Aldous, et al., Tetrahedron: Asymmetry 11:2455-2462 (2000),
Masui, et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal. 347:1193-1197 (2005), Sato, et
al., Synthesis: 1434-1438 (2004)), such as reduction with (-) or (+)-diisopinocamheylchloroborane
(DIP-chloride), with borane and an oxazaborolidine catalyst, or with asymmetric hydrogenation in the
presence of a suitable Ruthenium (IT) catalyst, such as [RuC12{(R)-BINAP}{(R,R)-DPEN}]
(BIN AP=2,2' -bis(diarylphosphino) -1,1' -binaphthyl; DPEN= 1,2-diphenylethylenediamine). The
resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be reacted with
methanesulfonyl chloride to provide the dimesylate Formula VI. Alternatively Formula V may be
converted to a ditriflate or ditosylate by the action of p-toluenesulfonyl chloride or triflic anhydride,
or to a dihalide such as a dibromide or dichloride by the action of PPh3 in the presence of CC14 or
CBR4, or by the action of SOCl2, POCl3, or PBR3. The dimesylate, ditriflate, ditosylate, or dihalide may
be reacted with an amine, such as 4-fluoroaniline (as shown for illustration in Scheme H), with or
without a co-solvent such as DMF at room temperature to 100 °C, to give the pyrrolidines such as
Formula VII. fn addition to 4-fluoroaniline, alternative amines may be reacted with the dimesylate
Formula VI, including but not limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 3-
fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl
amines, substituted benzylamines, or allylamine. The dinitro Formula VII may be reduced to the
diamino Formula V1H using Fe in the presence of NH4CI, HC1, or acetic acid, or by treatment with a
hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal
salt, such as BiCl3, SbCl3, NiCl2, Cu2Cl2, or CoCl2) in a solvent such as ethanol or THF.
Alternatively, Formula VII can be reduced to the product Formula VEI by hydrogenation in the
presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. The diamine
Formula Vm may be reacted with a suitably protected proline acid (Boc is shown, although Cbz,
Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as
EDAC/HOBT, PyBOP, HATU, or DEBPT, in a solvent such as THF, DMF, dichloromethane, or
DMSO, with or without the addition of an amine base such as Hunig's base, pyridine, 2,6-lutidine, or
triethylamine, to give Formula DC. Removal of the Boc protecting groups to give X may be
accomplished by treatment with an acid, such as TFA, HC1, or formic acid. Compounds of the present
invention may be prepared by coupling of Formula X with an acid of choice using the standard
peptide coupling reagents and conditions described above. Alternately, diamine VIII may be reacted
with an N-substituted proline in the presence of a peptide coupling reagent such as EDAC/HOBT,
PyBOP, HATU, T3P, or DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with
or without the addition of an amine base such as Hunig' s base, pyridine, 2,6-lutidine, or triethylamine,
to directly give compounds of the present invention (Formula XI). in each Formula within
Scheme II can be replaced with where D is defined above, and such compounds can be
readily prepared according to the process described in Scheme II (including making compound XI
directly from compound VIH).
i
As yet another non-limiting example, the compounds of the present invention can be prepared
starting from compounds of Formula II and Formula HI as shown in Scheme HI, where A, B, D, Y,
) and Z are as described above, using conditions similar to those described above for the preparation of
IV in Scheme II. Similarly, the resulting 1,4-diketone IV may be reduced to the 1,4-diols V using the
methods described above for Scheme II. The resultant racemic, enantiomerically enriched, or meso
1,4-diols V may be converted to the dimesylate VI or alternatively to a ditriflate, ditosylate, or
dihalide by the methods described above. The dimesylate VI, ditriflate, ditosylate, or dihalide may be
reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-
fluoroaniline, 3-fluoroaniline, 4-trifluoromethylanilme, 4-chloroaniline, heteroaryl amines, alkyl
amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described
above the give the compounds of the invention. Alternatively, compounds such as VM, where R is a
group such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, may be treated with reagents useful
for the removal of the R group (rhodium catalyst such as Rh(Ph3P)3Cl for R = allyl, treatment with an
acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd
catalyst for R = substituted benzyl) to generate compounds such as IX. Amine IX may be reacted
with an aryl halide or triflate such as X (iodide shown for illustration) employing the Buchwald-
Hartwig reaction in the presence of a palladium catalyst (such as Pd(OAc)2 or Pd2(dba)3) and a
phosphine ligand (such as triphenylphosphine or XantPhos) and a base (such as sodium
bis(trimethylsilyl)amide, potassium tert-butoxide, or K3PO4) to give the compounds of the present
invention. Alternatively, the compounds of the present invention may be obtained by reaction of DC
with an aldehyde or ketone through reductive amination in the presence of a hydride reducing agent,
such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid,
such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane. Alternatively the
reductive amination may be conducted through the use of hydrogenation in the presence of a suitable
catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, amine IX may react
with electrophilic reagents, such as alkyl halides, or with aryl electrophiles (suitably electron deficient
aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give
the compounds of the present invention.
As a further non-limiting example, the compounds of the present invention can be prepared
starting from compounds of Formula n and Formula EH as shown in Scheme IV, where X5 in Formula
II and Formula III represents a halogen (e.g., CI, Br, or F) or a nitro group. The 1,4-diketones such as
IV may be prepared using known methods described above for the preparation of IV for Scheme II.
The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of NaBELt, LiAlHt, or
DB3AL. Alternatively, enantioselective reduction of 1,4-diketone such as IV can be accomplished by
the methods described above for the preparation of V for Scheme II. The resultant racemic,
enantiomerically enriched, or meso 1,4-diols V may be reacted with methansulfonyl chloride to
provide the dimesylate VI. Alternatively V may be converted to a ditriflate or ditosylate by the
methods described above for Scheme IL The dimesylate, ditriflate, ditosylate, or dihalide may be
reacted with an amine including but not limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-
fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl
amines, cycloalkyl amines, substituted benzylamines, or allylamine to give VII. When X5 in Formula
VII is nitro, the nitro groups may be reduced to the tetraamino product IX using Fe in the presence of
NH4CI, HC1, or acetic acid, or with a hydride reducing agent, such as sodium borohydride (with or
without the addition of a transition metal salt, such as BiCl3, SbCl3, NiCl2, Cu2Cl2, or CoCl2) in a
solvent such as ethanol or THF. Alternatively, VII (X5 = nitro) can be reduced to the product IX by
hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney
nickel. Alternatively, compounds VH where X5 = halogen may be reacted with ammonia (R = H) or
an amine bearing a suitable protecting group (R = substituted benzyl such as 4-methoxybenzyl or 2,4
dimethoxybenzyl or R = allyl). The resulting products VHI may be treated with a reagent useful for
the removal of the R protecting group (rhodium catalyst such as Rh(Ph3P)3Cl for R = allyl, treatment
with an acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis
with a Pd catalyst for R = substituted benzyl) to give the product IX. Formula IX may be reacted with
a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in
the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, or DEBPT, in a
solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine
base, such as Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to give X as a mixture of the
amide products. Conversion to the benzimidazole compound XI may be accomplished by heating X in
acetic acid (50-100 °C). Alternatively, XI may be prepared by reaction of IX with an aldehyde,
followed by treatment with an oxidant, such as Cu(OAc)2 or Mn02 (see Penning, et al., Bioorg. Med.
Chem. 16:6965-6975 (2008). After removal of the Boc protecting groups from XI (accomplished by
treatment with an acid, such as TFA, HC1, or formic acid), the compounds of the present invention
may be prepared by coupling of the resulting diamine XII with an acid of choice using the standard
peptide coupling reagents and conditions described above for Scheme H. in each Formula
within Scheme rv can be replaced with where D is defined above, and such compounds can
be readily prepared according to the process described in Scheme IV.
Alternatively IX in Scheme IV may be prepared from a compound of Formula II as shown in
Scheme V. Compound VHI from Scheme II may be treated with an acylating agent such as acetyl
chloride or acetic anhydride to give compound EI (Scheme V). Nitration of compound EC to provide HI
may be accomplished using known methods, such as treatment with nitric acid or potassium nitrate in
the presence of an acid such as sulfuric acid or treatment with N02BF4. Removal of the acetamide
protecting group may be accomplished by treatment with Boc anhydride in the presence of DMAP to
give IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or LiOH) to
remove the acetyl group and a strong acid such as TFA or HC1 to remove the Boc protecting group.
The nitro groups in V may be reduced to amino groups using the methods described above for
Scheme IV. in each Formula within Scheme V can be replaced with where D is
defined above, and such compounds can be readily prepared according to the process described in
Scheme V.
As still another non-limiting example, the compounds of the present invention can be
prepared starting from compounds of Formula II as shown in Scheme VI, where A, B, D, Y, and Z are
as described above. A 1,4-diketone compound of Formula II (prepared as described in Scheme HI)
may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-
difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl
amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under acid
catalyzed conditions, such as acetic acid, TFA, formic acid or HC1, to give the compounds of the
invention.
As a further non-limiting example, the compounds of the present invention can be prepared
from a compound of Formula II as shown in Scheme VIL A compound of Formula n, where Rx is a
halogen, such as bromo, chloro, or iodo, or a triflate or a nonaflate may be converted to a boronic acid
or ester such as Formula III, where R is hydrogen, methyl, ethyl, or a cyclic pinacolate ester. For
example a compound of Formula II can be transformed to a compound of in by treatment with
pinacol-borane in the presence of a catalyst such as, for example, tris(dibenzylidineacetone)palladium
(O), and a ligand such as, for example, tri-t-butylphosphine, in solvents such as, for example,
tetrahydrofuran, dioxane, or toluene at temperatures ranging from ambient to about 130°C.
Alternatively, compound II can be reacted with bis(pinacolato)diboron in the presence of a catalyst
such as, for example, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA), dichloro[l,l'-
bis(diphenylphosphino)ferrocene] palladium (H) dichloromethane adduct, or palladium acetate in the
presence of a ligand such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
(XPhos), and a base such as, for example, potassium acetate in solvents such as, for example, toluene,
dioxane, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide at temperatures from about 60 to
about 130°C to give compound HL Alternatively, a compound of Formula II may be reacted with an
organolithium reagent, such an n-BuLi, sec-BuLi, or t-BuLi, followed by reaction with trimethyl
borate or triethyl borate, to give a compound of Formula EI.
A compound of Formula HI in Scheme VII can be coupled with a compound of Formula IV,
where RY is a halogen, such as bromo, chloro or iodo, under Suzuki reaction conditions to provide a
compound of Formula V. Such conditions include, for example, use of a palladium catalyst such as,
for example, tris(dibenzylidineacetone)palladium (O), palladium acetate,
bis(triphenylphosphine)palladium (H) chloride, tetrakis(triphenylphosphine)palladium, or
dichloro[l,r-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct; base such as,
for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate,
cesium carbonate, or cesium fluoride; and solvent such as, for example, toluene, ethanol, water, or
tetrahydrofuran, or mixtures thereof heated in the temperature range from about 40 to about 130°C.
Removal of the Boc protecting groups from V may be accomplished by treatment with an
acid, such as TFA, HC1, or formic acid. Compounds of the present invention such as VI may be
prepared by coupling the resulting amino compounds with an acid of choice using the standard
peptide coupling reagents, such as EDAC/HOBT, PyBOP, HATU, or DEBPT, in a solvent such as
THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as
Hunig's base, pyridine, 2,6-lutidine, or triethylamine. Each Rz is independently -LY'-M'-RD (e.g., -
LY-N(RB")C(O)-LS-RE), and D, L3, R1; R2, R5 , LY, RB", Ls, R6 , LY', M' and RD are as defined
above.
As another non-limiting example, the compounds of the present invention can be prepared
according to Scheme Vffl starting from the compound of Formula n, initially cleaving the diol in
oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde
intermediate is then treated with an aryl boronate or aryl boronic acid (compound IV where A and Y
are as described previously, or compound VII) and aniline EI (where W is RM or J, and RM and J are
as defined above) resulting in the formation of Formula V or Formula VIII respectively. Formula V
can be derivatized by deprotonating the hydroxyl groups with a strong base such as sodium hydride,
butyl lithium, or potassium hydride, followed by alkylation with Rs-halogen. Alternatively Formula
VEI can be deprotonated with a strong base (e.g., sodium hydride) and alkylated with Rs-halogen as
well, followed by acid hydrolysis of the phenol protecting groups. The sulfonylation of the phenols
with nonafluorobutylsulfonyl fluoride in the presence of a neutralizing agent such as potassium
carbonate in a polar aprotic solvent such as DMF, followed by heating provides a compound of
Formula DC. Boronate of Formula X is produced by heating Formula DC with bis(pinacolato)diboron
in the presence of X-phos and a palladium catalyst, such as Pd2(dba)3 and a base such as potassium
acetate in an organic solvent such as dioxane. Formula X is further derivatized to final product by
heating a suitably substituted heteroarylhalide in the presence of a palladium catalyst such as
PdC12(dppf) in the presence of a base such as sodium carbonate in a mixture of toluene and ethanol.
Rs is as defined above. in each Formula within Scheme VIII can be replaced with
where D is defined above, and such compounds can be readily prepared according to the process
described in Scheme VITL
As yet another non-limiting example, the compounds of the present invention can be
prepared according to Scheme IX starting from the compounds of Formula II and Formula HI.
Formula HI carboxylic acid is activated towards coupling using reagents such as
isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as
diisopropylethylamine. Upon activation, dianiline of Formula II is added to the reaction, with the
isolation of an intermediate amide, which is heated in acetic acid, preferably at 60 °C, to yield the
compound of Formula IV. The benzimidazole of Formula IV is treated with SEM-C1 in the presence
of a base in an aprotic solvent such as THF, yielding two protected benzimidazole regioisomers V.
The boronate esters VI are produced by heating Formula V with bis(pinacolato)diboron in the
presence of a palladium catalyst, such as PdC12(dppf), X-Phos, and a base such as potassium acetate
in an organic solvent such as dioxane. Heating yields both benzimidazole regioisomers VI. Diol VII
is cleaved in oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This
dialdehyde intermediate is then treated with an aryl boronate VI and aniline VIII (where W is RM or J,
and RM and J are as defined above) resulting in the formation of the 3 benzimidazole regioisomers of
Formula IX. Formula X is produced by deprotonating the hydroxyl groups with a strong base such as
sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with Rs-halogen,
followed by acid hydrolysis of the pyrollidine and benzimidazole protecting groups, preferably by
treatment with mineral acid, such as hydrochloric acid in an alcoholic solvent such as methanol. The
carboxylic acid Rz-COOH is activated towards coupling using reagents such as
isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as
diisopropylethylamine. Upon activation, Formula X is added to the reaction, with the isolation of
Formula XI. in each Formula within Scheme IX can be replaced with where D is
defined above, and such compounds can be readily prepared according to the process described in
Scheme DC.
Compounds of the invention of general formula (8), where R2o is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme X. The bromoalkylketone
(1) can be reacted with an arylalkylketone (2) using the Lewis acid mediated conditions, described
above in Scheme n, to give the diaryldiketone (3). The diketone (3) can be converted to the
bisboronate (4) by reaction with bis(pinacolato)diborane in the presence of a base such as potassium
acetate, a catalyst such as PdCl2(dppf)-CH2Cl2, in a solvent such as DMSO, dimethoxyethane or
dioxane with heating to between 60-100 °C. Bisboronate (4) can be converted to the intermediate (5)
by Suzuki reaction using, in analogous fashion, the Suzuki conditions described in Scheme VII. The
intermediate (5) can be converted to (6) by reaction with an amine D-NH2 under the analogous
conditions described in Scheme VL For example, reaction of (5) with D-NH2 in the presence of an
acid such as, but not limited to, TFA, in a solvent such as, but not limited to, toluene and with heating
up to 110 °C can provide intermediates of general structure (6). Compounds (6) can be converted to
compounds of general formulas (7) and then (8) using, in analogous fashion, the methods described in
Scheme VH.
The intermediates (6) can also be prepared using the route depicted in Scheme XL The
intermediate (3) can be reacted with an amine D-NH2 using, in analogous fashion, the conditions
described in Schemes VI and X to provide intermediates (9), which can be converted to (10) using,
analogously, conditions as described above in Scheme X; and (10),in turn, can be converted to
compounds (6) using the Suzuki reaction conditions described in Scheme VII.
Compounds of the invention of general formula (15), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XII. Compounds (11) can
prepared according to the procedures to convert (3) to (9), using general conditions as described in
Scheme VI, such as by reacting an appropriate nitrophenyldiketone with an amine D-NH2 with
heating in acetic acid to temperature of about 70 °C. The compounds (11) can be converted to (12)
using the reduction conditions described in Scheme II. Compounds (12) can be converted
sequentially to compounds of general formulae (13), (14) and (15) by using, in analogous fashion, the
methods described above in Scheme EI.
I
Compounds of general formula (19), where D is as described above, can be prepared
according to the methods of Scheme XIII. Compounds of general formula (16) can be converted to
compounds of general formula (17) using a Buchwald reaction with tert-butyl-2-
carbamoylpyrrolidine-1-carboxylate. This Buchwald reaction can be conducted in the presence of a
base (e.g., cesium carbonate), a palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(O)), a
phosphine ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) in solvent such as dioxane
with heating to about 80-120 °C. The intermediate (17) can be reduced to (18) and cyclized to (19)
using, in analogous fashion, die conditions described generally in Scheme IV. Compounds (19) can
be further reacted as illustrated in Scheme IV to provide compounds of the invention.
Compounds of the invention of general formula (23), where D is as described above, can be
prepared according to the methods of Scheme XIV. Compounds (16) can be reacted with compound
(20) using a Buchwald reaction as described generally in Scheme XIH to provide compounds (21).
Compounds (21) can be reduced to compounds (22) and cyclized to (23) using, in analogous fashion,
the conditions described generally in the foregoing Schemes.
Compounds of the invention of general formula (29), where R2o is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XV. Compounds of formula
(24) can be converted to compounds of formula (25) (Sonogashira reaction) by reaction with
trimethylsilylacetylene, a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II)chloride), a
copper catalyst (e.g., copper(I)iodide), and a base (e.g., triethylamine) wherein an amine base can also
be used as solvent. The compounds (25) can be desilylated to compounds (26) by reaction with a
fluoride source (e.g., tetrabutylammonium fluoride) in a solvent such as THF. Compounds (26) can
be converted to compounds (27) by formation of the dianion of (26) with n-butyllithium and
subsequent reaction with a Weinreb amide (e.g., N-(tert-butoxycarbonyl)-L-proline-N'-methoxy-
N'methylamide). This reaction can be conducted in an appropriate solvent such as THF or
dimethoxyethane. Compounds (27) can be converted to compounds (28) by reaction with hydrazine
in a solvent such as ethanol. The compounds (28) can be converted to compounds (29) using the
methods described generally in the foregoing Schemes.
Compounds of the invention of general formula (34), where R20 is -Ls'-M'-Ls"-RD and D is
as described above, can be prepared according to the methods of Scheme XVI. Compounds (24) can
be converted to compounds (30) by reaction of (24) with CO(g) under pressure (ca. 60 psi) in the
presence of a palladium catalyst (e.g., PdCl2(dppf)) in methanol as solvent and with heating to around
100 °C. Compounds (30) can be converted to compounds (31) by reaction with hydrazine in a solvent
such as methanol with heating to about 60-80 °C. Compounds (31) can be converted to compounds
(32) by reaction withN-Boc-2-cyano-pyrrolidine in the presence of a base (e.g, potassium carbonate)
in a solvent such as butanol and with heating to around 150 °C with irradiation in a microwave
reactor. Compounds (32) can be deprotected to compounds (33) and acylated to (34) using, in
analogous fashion, the conditions described generally in the foregoing Schemes.
Compounds of the invention of general formula (38), where R2o is —LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XVII. Compounds of
formula (24) can be converted to compounds (35) by reaction with CuCN in a solvent such as DMF
and with heating to about 160 °C with microwave irradiation. Compounds (35) can be converted to
compounds (36) by reaction with HCl(g) in anhydrous methanol at 0 °C with wanning to room
temperature. Compounds (36) can be converted to compounds (37) by reaction with NH3(g) in
anhydrous methanol at 0 °C with warming to room temperature. Compounds (37) can be converted to
compounds (38) by reaction with (41) in THF in the presence of a base (e.g., potassium carbonate).
Compounds of formula (41), where R2o is -Ls'-M'-Ls' '-RD, can be prepared using the
methods of Scheme XVHI. Compounds (39) can be converted to compounds (40) by sequential
reaction of (39) with isobutylchloroformate in THF at 0 °C followed by diazomethane. Compounds
(40) can be converted to compounds (41) by reaction with HBr in acetic acid.
Compounds of the invention of general formula (48), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XIX. Compound (42) can
be reacted with compound (43) using, in analogous fashion, the Lewis acid mediated conditions
described above in Scheme II to provide compound (44). Compound (44) can be converted
sequentially to the diol (45), the mesylate (46) and the cyclic intermediate (47) using, in analogous
fashion, the conditions of Scheme n. Compounds (47) can be converted to compounds (48) by
reaction with (20) under Buchwald conditions such as those referred to Scheme XIV and described in
Scheme XEL
Compounds of the invention of general formula (55), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XX. Diethyl meso-2,5-
dibromoadipate (49) can be reacted with an amine D-NH2 in a solvent such as THF, dioxane, or
dimethoxyethane with heating from 50-100 °C to give compounds (50). Compounds (50) can be
converted to (51) by alkaline hydrolysis with a base (e.g., NaOH, KOH) in an alcohol (e.g., methanol,
ethanol) and water mixture for solvent. Compounds (51) can be converted to (52) by reaction first
with oxalylchloride, and treatment of the intermediate acid chloride with diazomethane at 0 °C.
Compounds (52) can be converted to (53) by reaction with aqueous HBr. Compounds (53) can be
converted to compounds (54) by reaction with thiourea in ethanol or like solvent. Compounds (54)
can be converted to compounds (55) using, in analogous fashion, the conditions described above in
Scheme TL
Compounds of the invention of general formula (60), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XXI. Compound (56) can
be reacted with compound (57) in pyridine with heating to about 135 °C to form compound (58).
Compound (58) can be converted to compounds (59) by reaction of an amine D-NH2 with POCl3
followed by addition of (58) and heating at about 200 °C in 1,2-dichlorobenzene. Compounds (59)
can be converted to compounds (60) using, in analogous fashion, the conditions described above in
Scheme VII.
Compounds of the invention of general formula (66), where R20 is -LS'-M'-LS"-RD and D
are as described above, can be prepared according to the methods of Scheme XXII. Compounds of
general formula (61) can be reacted with borontribromide in dichloromethane at 0 °C to give
compounds (62), which can be subjected to hydrogenation conditions using platinum(II) oxide to give
compounds (63). Coupling between compounds (63) and proline derivatives (64) can be carried out
using standard coupling conditions described above to give compounds (65), which can be converted
to (66) by the action of diethylazodicarboxylate and triphenylphosphine in THF.
Compounds of the invention of general formula (74), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XXTTI. Compound (67) can
be converted to (68) by reduction of the nitro group using tin(]I) chloride in ethanol. Compound (69)
can be made from (68) by peptide coupling with Boc-proline, followed by heating of the resulting
amide in acetic acid at 80 °C. Compound (69) can be reacted with SEM-C1 and
diisopropylethylamine in dichloromethane to give (70), which can be coupled with (71) using a
palladium catalyst such as PXPd using a base such as cesium fluoride in a solvent such as N,N-
dimethylformamide at 100 °C to give (72). Compound (72) can be converted to (73) by reaction with
Selectfluor® in a mixture of THF and water, followed by hydrogenation using 3% Pt on carbon in
ethylacetate and then reduction using sodium borohydride in methanol. Compound (73) can be
reacted with methanesulfonyl chloride and triethylamine in dichloromethane at -10 °C, followed by
addition of an amine (H2N-D) to give an intermediate that can be converted to (74) by deprotection
using 4N HC1 in 1,4-dioxane and then coupling with R20CO2H using peptide coupling procedures
described above.
Compounds of the invention of general formula (81), where R20 is -LS'-M'-LS"-RD and D is
as described above, can be prepared according to the methods of Scheme XXIV. Compound (75) can
be converted to (76) using SnCl2 in ethanol. Coupling of (76) with (64) using peptide coupling
procedures described above to give an amide that can be heated in acetic acid at 100 °C to give (77).
Compound (77) can be reacted with SEM-C1 and diisopropylethylamine in dichloromethane to give
(78), which can be reacted with (71) as described above to give (79). Compound (79) can be
converted to (80) using Selectfluor® in a mixture of THF and water, followed by hydrogenation with
Pt on carbon in ethylacetate and reduction with sodium borohydride in methanol. Compound (80) can
be converted to compounds (81) by mesylation with methanesulfonyl chloride and triethylamine at
temperatures less than 0 °C, followed by reaction with primary amine H2N-D and deprotection using
4N HC1 in 1,4-dioxane.
5
Certain amines, D-NH2, in the foregoing Schemes are represented by formula (84), and may
be prepared according to the general method shown in Scheme XXV, wherein RN is as defined above
(e.g.,halogen, alkyl,haloalkyl) and RMis -N(RsRs) (e.g., -NEt2), heterocyclyl (e.g., pyrrolidin-1-yl,
piperidm-1-yl, etc.), or -ORs (e.g., -O-t-butyl, -O-isopropyl, etc.). Fluoronitrobenzenes (82) can be
reacted with an appropriate amine in the presence of dibasic potassium phosphate in a solvent such as
DMSO optionally with heating to give intermediates (83), wherein RM is -N(RsRs) (e.g., -NEt2) or
heterocyclyl (e.g., pyrrolidin-1-yl, piperidin-1-yl, etc.). Fluoronitrobenzenes (82) can also be reacted
with alkaL1 metal alkoxides (e.g., potassium tert-butoxide) to give intermediates (83), wherein RM is -
ORs (e.g., -O-t-butyl, -O-isopropyl, etc.). Intermediates (83) may be converted to (84) using well-
known nitro reduction conditions. For example, (83) can be converted to (84) by catalytic
hydrogenation using palladium on carbon. Alternatively, (83) can be converted to (84) by reaction
with iron/ammonium chloride in THF/methanol/water as solvent. Other conditions for effecting nitro
reduction include those described in the foregoing schemes and those generally known to one skilled
in the art.
In the foregoing Schemes, compounds are shown wherein an aromatic ring (e.g., phenyl) is
substituted with groups in a particular regiochemistry (e.g., para). A starting material or intermediate
with para-substitution provides a final product with para-substitution in the foregoing Schemes. It is
understood by one of skill in the art that substitution in the foregoing Schemes of a starting material or
intermediate with a different regiochemistry (e.g., meta) would provide a final product with a different
regiochemistry. For example, replacement of a para-substituted starting material or intermediate in
the foregoing Schemes with a meta substituted starting material or intermediate would lead to a meta-
substituted product.
If a moiety described herein (e.g., -NH2 or -OH) is not compatible with the synthetic
methods, the moiety may be protected with a suitable protecting group that is stable to the reaction
conditions used in the methods. The protecting group may be removed at a suitable point in the
reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups
and methods for protecting or deprotecting moieties are well know in the art, examples of which can
be found in Greene and Wuts, supra. Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants employed and substituents present in
the reactants used. Solvents, temperatures and other reaction conditions may be readily selected by
one of ordinary skill in the art based on the present invention.
Other compounds of the invention can be similarly prepared according to the above-described
schemes as well as the procedures described in following examples, as appreciated by those skilled in
the art. It should be understood that the above-described embodiments and schemes and the following
examples are given by way of illustration, not limitation. Various changes and modifications within
the scope of the present invention will become apparent to those skilled in the art from the present
description.
Example compounds below were named using either ChemDraw version 9.0 or ACD version
12 (ACD vl2). Final compounds for Examples 1-50 were named using ChemDraw unless otherwise
indicated as being named using ACD vl2. Final compounds after Example 50 were named using
ACD vl2. Intermediates were named using ChemDraw, unless otherwise indicated as being named
using ACD vl2.
Certain compounds in the Examples below were purified using reverse-phase HPLC.
Purification was conducted using either a CI8 or C8 reverse-phase column. Compounds were eluted
using a gradient of about 10-100% acetonitrile in 0.1% aqueous TFA; about 60-100% methanol in 10
mM aqueous ammonium acetate; or about 10-95% methanol in 10 mM aqueous ammonium acetate.
For purifications conducted with TFA, the product thus obtained may be in the form of a TFA salt.
Compounds may be characterized as the TFA salt or as the free base following neutralization,
extraction and isolation.
Certain compounds in the Examples below were purified using normal phase silica gel
chromatography including traditional flash chromatography or an automated purification system (e.g.,
Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 [xm silica gel,
Isco gold columns)
Typical solvents for silica gel chromatography include: Ethyl acetate in hexanes, Diethyl
ether in hexanes, THF in hexanes, Ethyl acetate in methylene chloride, Methanol in methylene
chloride, Methanol in methylene chloride with NH4OH, Acetone in hexanes, and Methylene chloride
in hexanes.
Example 1
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2!2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2, l-diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxornemylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2, l-diyl)dicarbamate
Example 1A
l,4-Bis(4-nitrophenyl)butane-l,4-dione
Anhydrous zinc(II) chloride (2.73 g, 20.00 mmol) was stirred in dry benzene (15 ml) while
diethylamine (1.558 ml, 15.00 mmol) and t-butanol (1.435 ml, 15.00 mmol) were added, and the
resulting mixture was stirred at room temperature for 90 min to give a cloudy solution. To this
mixture was added 2-bromo-l-(4-nitrophenyl)ethanone (2.44 g, 10.00 mmol) and l-(4-
nitrophenyl)ethanone (2.477 g, 15.00 mmol), and the resulting mixture was stirred at room
temperature overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate
(3 x 50 ml). The combined organic layers were dried over Na2S04, filtered and concentrated. The
resulting residue was triturated with dichloromethane to give an orange solid that was collected by
filtration and dried to give the title compound (2.0 gm, 61% yield).
Example IB
l,4-Bis(4-nitrophenyl)butane- 1,4-diol
To a solution of the product from Example 1A (1.0 g, 3.05 mmol) in anhydrous THF (30 ml)
at 0°C was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at
50°C overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over
Na2S04, filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane
to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gm, 81%
yield).
Example 1C
1,4-Bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate
To a solution of the product from Example IB (0.80 g, 2.407 mmol) in dry CH2C12 (25 ml) at
0°C was added triethylamine (1.007 ml, 7.22 mmol), followed by dropwise addition of
methanesulfonyl chloride (0.469 ml, 6.02 mmol). The resulting mixture was stirred at 0°C for 30 min,
during which time the starting material slowly went into solution. After stirring an additional 1H at
0°C, a precipitate began to form. Saturated aq NH4C1 (4 ml) was added, and stirring was continued at
room temperature for 20 min. The mixture was washed with water (2 x 10 ml), and the organic layer
was treated with hexanes (10 ml) to give an orange solid that was collected by filtration to give the '
title compound (0.75 gm, 64% yield).
Example ID
l-(4-Huorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
The product from Example 1C (0.6 gm, 1.228 mmol) and 4-fluoroaniline (2.0 ml, 20.82
mmol) were combined and stirred at 50°C overnight. The resulting mixture was partitioned between
0.2 N HC1 (50 ml) and ethyl acetate (3 x 50 ml), and the combined organic layers were dried over
Na2S04, filtered and concentrated in vacuo. The crude product was purified by chromatography on
silica gel.using a solvent gradient of 0-40% ethyl acetate in hexane to give the title compound as a
mixture of cis and trans isomers (0.5 gm, 100% yield).
Example IE
4,4'-( 1 -(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline
To a solution of the product from Example ID (0.501 g, 1.23 mmol) in ethanol (5 ml) and
THF (5.00 ml) was added iron powder (0.412 g, 7.38 mmol) and a solution of ammonium chloride
(0.197 g, 3.69 mmol) in water (1.0 ml). The resulting mixture was stirred at 80°C for 45 min. The
mixture was cooled, filtered through celite, washed with ethanol, and concentrated in vacuo. The
crude product was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl
acetate in hexanes to give the title compound as a mixture of cis and trans isomers (0.135 gm, 32%).
Example IF
(2S,2'S)-tert-Butyl 2,2'-(4,4'-(l -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 -
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
To a mixture of the product from Example IE (0.13 gm, 0.374 mmol), (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.201 gm, 0.935 mmol) and HATU (0.356 gm, 0.935
mmol) in DMSO (3 ml) was added Hunig's base (0.196 ml, 1.123 mmol), and reaction mixture was
stirred at room tempertaure for 90 min. The mixture was poured into water and extracted by ethyl
acetate. The organic extract was dried over Na2S04, filtered and concentrated in vacuo to give a crude
product that was purified by column chromatography on silica gel, eluting with a solvent gradient of
5-100% ethyl acetate in hexane to give title compound (0.28 gm, 100%).
(2S,2'S)-N,N'-(4,4'-(l -(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4, l-phenylene))dipyrrolidine-2-
carboxamide
To the product from Example IF (0.28 gm, 0.377 mmol) in CH2C12 (2.0 ml) was added TFA
(2.0 ml). The reaction mixture was stirred at room temperature for 45 min and concentrated in vacuo.
The residue was partitioned between into 3:1 CH2Cl2:2-PrOH and saturated aq. NaHC03. The organic
layer was dried over Na2S04, filtered and concentrated to give the title compound (0.195 gm, 95%
yield).
Example 1H
Dimemyl(2S,2,S)44H(2S,2'S)-2,2'-(4,4'-((2S,5S)4-(4-fluorophenyl)pyrrolidine-2,5-diy^^
phenylene))bis(azanediyl)bis(oxomemylene)bis(pvrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,1 -diyl)dicarbamate
To a mixture of the product from Example 1G (0.03 gm, 0.055 mmol), (S)-2-
(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.0262 gm, 0.138 mmol) and HATU (0.0526
gm, 0.138 mmol) in DMSO (0.5 ml) was added Hunig's base (0.029 ml, 0.166 mmol), and the
resulting mixture was stirred at room temperature for 90 min. The mixture was poured into water (2
ml) and extracted by ethyl acetate (2x2 ml), and the combined organic layers were concentrated and
subjected to HPLC purification on a semi-prep CI8 reverse-phased column using a gradient of 10-
100% acetonitrile in 0.1% aq TFA. The trans-substituted pyrrolidine isomer was the first of 2
stereoisomers to elute, providing the title compound as a 1:1 mixture of diastereomers (0.014 gm,
29% yield): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.93 - 1.01 (m, 7=4.99 Hz, 18 H)
1.62 - 1.68 (m, 2 H) 1.81 - 1.93 (m, 6 H) 1.94 - 2.04 (m, 2 H) 2.09 - 2.20 (m, 2 H) 3.54 (s, 6 H) 3.59
- 3.69 (m, 2 H) 3.73 - 3.81 (m, 2 H) 4.18 - 4.24 (m, 2 H) 4.43 (dd, 7=7.81, 5.42 Hz, 2 H) 5.16 (d, 2
H) 6.20 (dd, 7=9.05, 4.39 Hz, 2 H) 6.78 (t, 7=8.89 Hz, 2 H) 7.09 (d, 7=8.89 Hz, 2 H) 7.12 (d, 4 H)
7.50 (d, 7=8.02 Hz, 4 H) 9.99 (s, 2 H). The title compound showed an EC* value of less than about
0.1 nM in HCV lb-Con 1 replicon assays in the presence of 5% FBS. The lb-Con 1 replicon assay is
described below.
Example 2
Dimethyl (2S,2'S)-l,l'-((2S,2,S)-2,2'-(4,4'-((2S,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1 -diyl)dicarbamate
To a mixture of the product from Example 1G (0.03 gm, 0.055 mmol), (S)-2-
(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.0262 gm, 0.138 mmol) and HATU (0.0526
gm, 0.138 mmol) in DMSO (0.5 ml) was added Hunig's base (0.029 ml, 0.166 mmol), and the
resulting mixture was stirred at room temperature for 90 min. The mixture was poured into water (2
ml) and extracted by ethyl acetate (2x2 ml), and the combined organic layers were concentrated and
subjected to HPLC purification on a semi-prep CI8 reverse-phased column using a gradient of 10-
100% acetonitrile in 0.1% aq TFA. The cis-substituted pyrrolidine isomer was the second of 2
stereoisomers to elute, providing the title compound (0.018 gm, 37% yield): 1H NMR (TFA salt)
(400 MHz, DMSO-D6) δ ppm 0.93 - 1.01 (m, 7=3.04 Hz, 18 H) 1.75 - 1.94 (m, 6 H) 1.94 - 2.05 (m,
2 H) 2.11 - 2.22 (m, 2 H) 2.31 - 2.35 (m, 1H) 3.54 (s, 6 H) 3.61 - 3.70 (m, 2 H) 3.74 - 3.83 (m, 2 H)
4.22 (d, 7=8.78 Hz, 2 H) 4.46 (dd, 7=8.02, 5.42 Hz, 2 H) 4.65 (t, 2 H) 6.34 (dd, 2 H) 6.86 (t, 7=8.89
Hz, 2 H) 7.08 (d, 2 H) 7.43 (d, 7=7.81Hz, 4 H) 7.60 (d, 7=8.57 Hz, 4 H) 10.05 (s, 2 H). The title
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Con 1 replicon assays in the
presence of 5% FBS.
Example 3
Dimethyl (2S,2,S)-l,r-((2S,2'S)-2,2,-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1 -diyl)dicarbamate
The product from Example 1H was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:1 mixture of hexanes:(2:1 IPA:EtOH). The title compound was the
first of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.97 (s, 18 H) 1.61 - 1.67
(m, 7=5.64 Hz, 2 H) 1.79 - 1.92 (m, 6 H) 1.93 - 2.04 (m, 7=5.86 Hz, 2 H) 2.07 - 2.20 (m, 7=6.51Hz,
2 H) 3.54 (s, 6 H) 3.59 - 3.69 (m, 2 H) 3.71 - 3.83 (m, 2 H) 4.21 (d, 7=8.89 Hz, 2 H) 4.43 (dd,
7=7.97, 5.37 Hz, 2 H) 5.15 (d, 7=6.51Hz, 2 H) 6.20 (dd, 2 H) 6.78 (t, 7=8.95 Hz, 2 H) 7.13 (d, 7=8.57
Hz, 4 H) 7.50 (d, 7=8.57 Hz, 4 H) 9.99 (s, 2 H). The title compound showed an EC50 value of less
than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 4
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1-diyl)dicarbamate
The product from Example 1H was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:1 mixture of hexanes:(2:l IPA:EtOH). The tide compound was the
second of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.96 (s, 18 H) 1.64 (d,
7=5.53 Hz, 2 H) 1.78 - 1.93 (m, 6 H) 1.94 - 2.06 (m, 2 H) 2.09 - 2.21 (m, 2 H) 3.54 (s, 6 H) 3.59 -
3.69 (m, 2 H) 3.72 - 3.83 (m, 2 H) 4.20 (d, 7=8.89 Hz, 2 H) 4.43 (dd, 7=7.92, 5.42 Hz, 2 H) 5.16 (d,
7=6.29 Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 6.77 (t, 7=8.95 Hz, 2 H) 7.12 (d, 7=8.57 Hz, 4 H)
7.50 (d, 7=8.57 Hz, 4 H) 9.99 (s, 2 H). The title compound showed an EC50 value of less than about
0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 5
Dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2,-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis( l-oxobutane-2,1 -
diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l'-((2S,2,S)-2,2'-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrroUdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis( 1 -oxobutane-2,1 -
diyl)dicarbamate
Example 5A
4,4*-((2S,5S)-l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline and 4,4'-((2R,5R)-l-(4-
Fluorophenyl)pyrrolidine-2,5-diyl)dianiline
The product from Example IE was purified by column chromatography on silica gel, eluting
with a solvent gradient of 0-100% ethyl acetate in hexanes. The title compound eluted as the first of 2
stereoisomers and was obtained as a racemic mixture of trans diastereomers. 1H NMR (400 MHz,
DMSO-D6) δ ppm 1.57 (d, 7=5.64 Hz, 2 H) 2.36 - 2.42 (m, 2 H) 4.86 - 4.91 (m, 4 H) 4.96 (d, 7=6.61Hz, 2 H) 6.17 - 6.25 (m, 2 H) 6.47 (d, 7=8.35 Hz, 4 H) 6.74 (t, 2 H) 6.82 (d, 7=8.35 Hz, 4 H).
Example 5B
(2S,2'S)-tert-Butyl2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate and (2S,2'S)-tert-Butyl 2,2'-
(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 -
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The product from Example 5A (50 mg, 0.144 mmol) was subjected to the conditions
described in Example IF to give the title compound as a 1:1 mixture of diastereomers (105 mg, 98%):
1H NMR (400 MHz, DMSO-D6) δ ppm 1.34 (d, 18 H) 1.66 (d, 7=5.10 Hz, 2 H) 1.74 - 1.89 (m, 6 H)
2.07 - 2.23 (m, 2 H) 4.15 - 4.25 (m, 2 H) 5.18 (d, 7=3.47 Hz, 2 H) 6.18 - 6.25 (m, 2 H) 6.78 (t, 7=8.95
Hz, 2 H) 7.14 (d, 7=8.24 Hz, 4 H) 7.51 (t, 7=8.29 Hz, 4 H) 9.92 (d, 2 H).
Example 5C
(2S,2,S)-N,N'-(4,4'-((2S,5S)-l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-
2-carboxamide and (2S,2'S)-N,N'-(4,4'-((2R,5R)-l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))dipyrroUdine-2-carboxamide
The product from Example 5B was subjected to the conditions described in Example 1G to
give the title compound as a 1:1 mixture of diastereomers.
Example 5D
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis( l-oxobutane-2,1 -
diyl)dicarbamate and Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-
fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis( l-oxobutane-2,1 -
diyl)dicarbamate
To a mixture of the product from Example 5C (0.102 g, 0.188 mmol), (S)-2-
(methoxycarbonyl amino)butanoic acid (0.064 g, 0.395 mmol) and HATU (0.150 g, 0.395 mmol) in
DMSO (2 ml) was added Hunig's base (0.099 ml, 0.565 mmol), and the reaction was stirred at room
temperature for 45 min. The reaction mixture was partitioned between water and ethyl acetate, and
the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel using a solvent gradient of 0-4% MeOH in
dichloromethane to give the tide compound as a 1:1 mixture of stereoisomers (0.158 gm, 94% yield):
1H NMR (400 MHz, DMSO-D6) 8 ppm 0.86 - 0.96 (m, 6 H) 1.53 (d, 7=4.34 Hz, 2 H) 1.59 -1.73 (m,
2 H) 1.80 - 1.96 (m, 7=6.29 Hz, 4 H) 1.96 - 2.06 (m, 2 H) 2.08 - 2.20 (m, 2 H) 3.52 (s, 6 H) 3.67 -
3.79 (m, 2 H) 4.12 - 4.23 (m, 2 H) 4.42 (dd, 7=8.13, 4.66 Hz, 2 H) 5.16 (d, 7=6.40 Hz, 2 H) 6.20 (dd,
7=9.22, 4.45 Hz, 2 H) 6.77 (t, 7=8.89 Hz, 2 H) 7.12 (d, 7=7.59 Hz, 4 H) 7.30 (dd, 7=7.59, 3.25 Hz, 2
H) 7.50 (d, 7=8.24 Hz, 4 H) 8.16 (s, 2 H) 9.95 (s, 2 H). The tide compound showed an EC50 value of
from about 0.1 to about 1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 6
Dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-hydroxy-3-methyl-l-
oxobutane-2,1-diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l'-((2S,2,S)-2,2'-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-hydroxy-3-methyl-l-
oxobutane-2,1-diyl)dicarbamate
To a mixture of the product from Example 5C (0.1 g, 0.185 mmol), (S)-3-hydroxy-2-
(methoxycarbonyl amino)-3-methylbutanoic acid (0.074 g, 0.388 mmol) and HATU (0.147 g, 0.388
mmol) in DMSO (2 ml) was added Hunig's base (0.097 ml, 0.554 mmol), and the reaction mixture
was stirred at room temperature for 45 min. The reaction mixture was partitioned between water and
ethyl acetate, and the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel using a solvent gradient of 0-4%
MeOH in dichloromethane to give the tide compound as a 1:1 mixture of stereoisomers (0.162 gm,
97% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.15 (d, 7=10.19 Hz, 12 H) 1.64 (d, 7=5.64 Hz, 2
H) 1.87 - 1.98 (m, 6 H) 2.09 - 2.22 (m, 2 H) 3.55 (s, 6 H) 3.58 - 3.66 (m, 2 H) 3.66 - 3.74 (m, 2 H)
3.83 - 3.92 (m, 2 H) 4.37 (s, 2 H) 4.44 - 4.50 (m, 2 H) 5.07 (s, 2 H) 5.11 (s, 2 H) 5.17 (d, 7=6.18 Hz,
2 H) 6.15 - 6.28 (m, 2 H) 6.78 (t, 7=8.89 Hz, 2 H) 7.13 (d, 7=8.13 Hz, 4 H) 7.51 (d, 7=7.81Hz, 4 H)
8.11 - 8.23 (m, 2 H) 9.67 (d, 7=9.11Hz, 2 H). The title compound showed an EC50 value of less than
about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 7
Dimethyl (2S,2,S,3R,3,R)-l,l'-((2S,2'S)-2,2,-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methoxy-1 -
oxobutane-2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S,3R,3'R)-1,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4, l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methoxy-l -
oxobutane-2,1 -diyl)dicarbamate
To a mixture of the product from Example 5C (0.025 gm, 0.046 mmol), (2S,3R)-3-methoxy-
2-(methoxycarbonylamino)butanoic acid (0.01941 gm, 0.102 mmol) and HATU (0.0439 gm, 0.115
mmol) in DMSO (0.2 ml) was added Hunig's base (0.024 ml, 0.138 mmol). The mixture was stirred
at room temperature for 2 hr, and was then poured into water and extracted with ethyl acetate. The
organic phase was dried over Na2S04, filtered and concentrated in vacu, and the crude product was
purified by chromatography on silica gel using a solvent gradient of 0-5%MeOH in CH2C12 to give
the title compound (0.040 gm, 93% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.09 - 1.31 (m, 6
H) 1.64 (d, 7=5.10 Hz, 2 H) 1.83 - 1.93 (m, 7=12.42, 12.42 Hz, 4 H) 1.93 - 2.03 (m, 2 H) 2.11 - 2.19
(m, 2 H) 3.10 - 3.18 (m, 7=6.94 Hz, 2 H) 3.24 (d, 7=4.99 Hz, 6 H) 3.42 - 3.49 (m, 7=10.84,6.72 Hz, 2
H) 3.53 (s, 6 H) 3.58 - 3.70 (m, 2 H) 3.79 - 3.89 (m, 2 H) 4.26 (t, 7=7.10 Hz, 2 H) 4.41 (dd, 7=7.97,
4.93 Hz, 2 H) 5.16 (d, 7=6.29 Hz, 2 H) 6.20 (dd, 7=9.11, 4.34 Hz, 2 H) 6.78 (t, 7=8.95 Hz, 2 H) 7.12
(d, 4 H) 7.33 (dd, 7=7.70, 3.47 Hz, 2 H) 7.50 (d, 7=8.13 Hz, 4 H) 9.95 (s, 2 H). The tide compound
showed an EC50 value of from about 0.1 to about 1 nM in HCV lb-Conl replicon assays in the
presence of 5% FBS.
Example 8
dimethyl (2S,2'S,3R,3'R)-l,l,-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrohdine-2,1 -diyl))bis(3-methoxy-1 -
oxobutane-2,1 -diyl)dicarbamate
The product from Example 7 was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:3 mixture of hexanes:(l: 1 IPA:EtOH). The title compound was the
first of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.13 (d, 7=6.18 Hz, 6 H)
1.64 (d, 7=5.64 Hz, 2 H) 1.82 - 1.93 (m, 4 H) 1.95 - 2.04 (m, 2 H) 2.10 - 2.19 (m, 2 H) 3.25 (s, 6 H)
3.44 - 3.48 (m, 2 H) 3.53 (s, 6 H) 3.62 - 3.71 (m, 2 H) 3.79 - 3.87 (m, 2 H) 4.26 (t, 7=7.75 Hz, 2 H)
4.41 (dd, 7=7.92, 4.99 Hz, 2 H) 5.16 (d, 7=6.51Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 6.78 (t,
7=8.89 Hz, 2 H) 7.13 (d, 7=8.57 Hz, 4 H) 7.34 (d, 7=7.92 Hz, 2 H) 7.50 (d, 7=8.57 Hz, 4 H) 9.95 (s, 2
H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon
assays in the presence of 5% FBS.
Example 9
dimethyl (2S,2,S,3R,3'R)-l,r-((2S,2'S)-2,2'-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methoxy-1 -
oxobutane-2,1 -diyl)dicarbamate
The product from Example 7 was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:3 mixture of hexanes:(l:l IPA:EtOH). The title compound was the
second of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.12 (d, 7=6.18 Hz, 6 H)
1.64 (d, 7=5.64 Hz, 2 H) 1.82 - 1.93 (m, 4 H) 1.95 - 2.06 (m, 2 H) 2.10 - 2.21 (m, 2 H) 3.24 (s, 6 H)
3.42 - 3.48 (m, 2 H) 3.53 (s, 6 H) 3.61 - 3.73 (m, 2 H) 3.78 - 3.88 (m, 2 H) 4.26 (t, 7=7.75 Hz, 2 H)
4.41 (dd, 7=7.92, 4.99 Hz, 2 H) 5.16 (d, 7=6.18 Hz, 2 H) 6.20 (dd, 2 H) 6.78 (t, 7=8.89 Hz, 2 H) 7.13
(d, 7=8.46 Hz, 4 H) 7.33 (d, 7=7.81Hz, 2 H) 7.49 (d, 7=8.46 Hz, 4 H) 9.95 (s, 2 H). The title
compound showed an EC50 value of from about 0.1 to about 1 nM in HCV lb-Conl replicon assays in
the presence of 5% FBS.
Example 10
Dimethyl (2S,2'S)-l,r-((2S,2'S)-2,2,-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1-
diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,r-((2S,2,S)-2,2,-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
To a mixture of the product from Example 1G (0.030 g, 0.055 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.024 g, 0.14 mmol) and HATU (0.052 g, 0.14
mmol) in DMSO (0.3 ml) was added Hunig's base (0.024 ml, 0.166 mmol), and the resulting mixture
was stirred at room temperature for 90 min. The mixture was partitioned between water and ethyl
acetate, and the organic layer was concentrated and subjected to HPLC purification on a semi-prep
CI8 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The trans-
substituted pyrrolidine isomer was the first of 2 stereoisomers to elute, providing the title compound
as a 1:1 mixture of diastereomers (9 mg, 16%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm
0.85 - 0.96 (m, 12 H) 1.64 (d, 7=5.75 Hz, 2 H) 1.82 - 1.92 (m, 6 H) 1.95 - 2.06 (m, 2 H) 2.08 - 2.20
(m, 2 H) 3.52 (s, 6 H) 3.57 - 3.68 (m, 2 H) 3.74 - 3.86 (m, 7=5.86 Hz, 2 H) 4.02 (t, 7=8.35 Hz, 2 H)
4.42 (dd, 7=7.92, 4.88 Hz, 2 H) 5.16 (d, 7=6.18 Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 6.77 (t,
7=8.89 Hz, 2 H) 7.12 (dd, 7=8.51, 1.68 Hz, 4 H) 7.31 (dd, 7=8.24, 3.36 Hz, 2 H) 7.50 (d, 7=7.26 Hz, 4
H) 9.99 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-
Conl replicon assays in the presence of 5% FBS.
Example 11
Dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2S,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
To a mixture of the product from Example 1G (0.030 g, 0.055 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.024 g, 0.14 mmol) and HATU (0.052 g, 0.14
mmol) in DMSO (0.3 ml) was added Hunig's base (0.024 ml, 0.166 mmol), and the resulting mixture
was stirred at room temperature for 90 min. The mixture was partitioned between water and ethyl
acetate, and the organic layer was concentrated and subjected to HPLC purification on a semi-prep
C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The cis-
substituted pyrrolidine isomer was the second of 2 stereoisomers to elute, providing die title
compound (11 mg, 20%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 9.35 (s, 2 H) 8.26 (s, 2
H) 7.77 - 7.83 (m, 4 H) 7.68 - 7.73 (m, 4 H) 7.01 (t, 7=8.95 Hz, 2 H) 6.61 - 6.71 (m, 2 H) 6.23 (d,
7=8.35 Hz, 2 H) 4.87 - 4.97 (m, 2 H) 4.67 - 4.78 (m, 2 H) 4.42 - 4.52 (m, 2 H) 3.99 - 4.09 (m, 2 H)
3.87 - 3.97 (m, 2 H) 3.84 (s, 6 H) 1.22 (dd, 7=6.78, 2.11Hz, 6 H) 1.15 (dd, 7=6.72, 2.06 Hz, 6 H).
The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays
in the presence of 5% FBS.
Example 12
Dimethyl (2S,2,S)-l,r-((2S,2,S)-2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrroHdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-oxobutane-2,l-
diyl)dicarbamate
The product from Example 10 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:1 mixture of hexanes:(2:l 2-PrOH:EtOH). The tide compound
eluted as the first of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.84 - 0.97 (m, 12 H)
1.64 (d, 7=5.64 Hz, 2 H) 1.88 (s, 6 H) 1.95 - 2.05 (m, 2 H) 2.08 - 2.19 (m, 2 H) 3.52 (s, 6 H) 3.58 -
3.66 (m, 2 H) 3.76 - 3.85 (m, 2 H) 4.02 (t, 7=8.51Hz, 2 H) 4.42 (dd, 7=8.02, 4.88 Hz, 2 H) 5.15 (d,
7=6.51Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 6.78 (t, 7=8.89 Hz, 2 H) 7.13 (d, 7=8.46 Hz, 4 H)
7.31 (d, 7=8.35 Hz, 2 H) 7.50 (d, 7=8.46 Hz, 4 H) 9.99 (s, 2 H). The title compound showed an EC50
value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 13
Dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2,-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
The product from Example 10 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 1:1 mixture of hexanes:(2:l 2-PrOH:EtOH). The title compound
eluted as the second of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 - 0.97 (m, 12
H) 1.65 (d, 2 H) 1.80 - 2.05 (m, 8 H) 2.08 - 2.20 (m, 2 H) 3.52 (s, 6 H) 3.57 - 3.68 (m, 2 H) 3.76 -
3.87 (m, 2 H) 4.01 (t, 2 H) 4.42 (dd, 2 H) 5.16 (d, 7=6.40 Hz, 2 H) 6.20 (dd, 7=9.22, 4.45 Hz, 2 H)
6.77 (t, 7=8.95 Hz, 2 H) 7.12 (d, 7=8.57 Hz, 4 H) 7.30 (d, 7=8.35 Hz, 2 H) 7.50 (d, 7=8.46 Hz, 4 H)
9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl
replicon assays in the presence of 5% FBS.
Example 14
Dimethyl (lS,l'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(2-oxo-1 -((R)-
tetrahydrofuran-3-yl)ethane-2,l-diyl)dicarbamate
and
Dimethyl (1S, 1 ,S)-2,2'-((2S,2,S)-2,2'-(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 -
phenylene))bis(azanediyl)bis(oxomemylene)bis(pyrrolidine-2,l-diyl))bis(2-oxo-l-((R)-
tetrahydrofuran-3 -yl)ethane-2,1 -diyl)dicarbamate
To a mixture of the product from Example 5C (0.013 g, 0.024 mmol), HATU (0.02275 gm,
0.060 mmol), and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0.0107 gm,
0.053 mmol) in DMSO (0.200 ml) was added Hunig's Base (0.013 ml, 0.072 mmol). The reaction
was stirred at room temperature for 2 hr, poured into water, and extracted with ethyl acetate. The
organic extract was dried over Na2S04, filtered and concentrated in vacuo, and the crude material was
purified on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1%
aq TFA to give the title compound (6.9 mg, 28% yield): 1H NMR (TFA salt) (400 MHz, DMSO-D6)
8 ppm 1.61 - 1.77 (m, 4 H) 1.80 - 1.94 (m, 6 H) 1.93 - 2.06 (m, 2 H) 2.08 - 2.21 (m, 2 H) 3.44 (dd,
7=8.46, 6.29 Hz, 2 H) 3.53 (s, 6 H) 3.56 - 3.68 (m, 8 H) 3.68 - 3.77 (m, 2 H) 3.80 - 3.90 (m, 2 H) 4.23
(t, 7=8.84 Hz, 2 H) 4.43 (dd, 7=8.02, 4.77 Hz, 2 H) 5.16 (d, 7=6.29 Hz, 2 H) 6.20 (dd, 7=9.11, 4.45
Hz, 2 H) 6.77 (t, 7=8.95 Hz, 2 H) 7.13 (d, 7=8.57 Hz, 4 H) 7.50 (d, 7=8.57 Hz, 4 H) 7.60 (d, 7=7.92
Hz, 2 H) 9.98 (s, 2 H). The title compound showed an EC50 value of from about 0.1 to about 1 nM in
HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 15
Dimethyl (lS,rS)-2,2,-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(2-oxo-1 -((R)-
tetrahydrofuran-3-yl)ethane-2,l-diyl)dicarbamate
The product from Example 14 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 2:3 mixture of hexanes:(l:l 2-PrOH:EtOH). The title compound
eluted as the first of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.59 - 1.78 (m, 4 H)
1.79 -1.94 (m, 6 H) 1.94 - 2.05 (m, 2 H) 2.09 - 2.23 (m, 7=5.10 Hz, 2 H) 3.44 (dd, 7=8.35, 6.40 Hz, 2
H) 3.53 (s, 6 H) 3.57 - 3.73 (m, 8 H) 3.71 - 3.80 (m, 2 H) 3.81 - 3.89 (m, 2 H) 4.23 (t, 7=8.78 Hz, 2 H)
4.43 (dd, 7=7.97, 4.83 Hz, 2 H) 5.16 (d, 7=6.07 Hz, 2 H) 6.16 - 6.24 (m, 2 H) 6.78 (t, 7=8.89 Hz, 2 H)
7.13 (d, 7=8.57 Hz, 4 H) 7.50 (d, 7=8.46 Hz, 4 H) 7.60 (d, 7=8.02 Hz, 2 H) 9.98 (s, 2 H). The tide
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the
presence of 5% FBS.
Example 16
Dimethyl (lS,l'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(2-oxo-1 -((R)-
tetrahydrofuran-3 -yl)ethane-2,1 -diyl)dicarbamate
The product from Example 14 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 2:3 mixture of hexanes:(l:l 2-PrOH:EtOH). The title compound
eluted as the second of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.61 -1.77 (m, 4 H)
1.80 -1.94 (m, 6 H) 1.93 - 2.06 (m, 2 H) 2.08 - 2.21 (m, 2 H) 3.44 (dd, 7=8.46, 6.29 Hz, 2 H) 3.53 (s,
6 H) 3.56 - 3.68 (m, 8 H) 3.68 - 3.77 (m, 2 H) 3.80 - 3.90 (m, 2 H) 4.23 (t, 7=8.84 Hz, 2 H) 4.43 (dd,
7=8.02, 4.77 Hz, 2 H) 5.16 (d, 7=6.29 Hz, 2 H) 6.20 (dd, 7=9.11, 4.45 Hz, 2 H) 6.77 (t, 7=8.95 Hz, 2
H) 7.13 (d, 7=8.57 Hz, 4 H) 7.50 (d, 7=8.57 Hz, 4 H) 7.60 (d, 7=7.92 Hz, 2 H) 9,98 (s, 2 H). The title
compound showed an EC50 value of from about 0.1 to about 1 nM in HCV lb-Conl replicon assays in
the presence of 5% FBS.
Example 17
(R,2S,2'S)-N,N'-(4,4,-((2S,5S)-l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(l-((R)-
2-phenyl-2-(piperidin-l-yl)acetyl)pyrrolidine-2-carboxamide) and
(R,2S,2'S)-N,N'-(4,4'-((2R,5R)-l-(4-Fluorophenyl)pyrroUdme-2,5-diyl)bis(4,l-phenylene))bis(l-((R)-
2-phenyl-2-(piperidin-l-yl)acetyl)pyrrolidine-2-carboxamide)
To a mixture of (R)-2-phenyl-2-(piperidin-l-yl)acetic acid TFA salt (0.0455 mg, 0.137
mmol), the product from Example 1G (0.030 gm, 0.055 mmol), and HATU (0.0526 gm, 0.138 mmol)
in DMSO (0.300 ml) was added Hunig's base (0.029.0 ml, 0.166 mmol), and the resulting mixture
was stirred at rt for 2 hr. The mixture was partitioned between water and ethyl acetate, the organic
layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was subjected to
HPLC purification on a semi-prep CI8 reverse-phased column using a gradient of 10-100%
acetonitrile in 0.1% aq TFA (8.3 mg, 11%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 1.20 -
1.42 (m, 4 H) 1.61 - 2.02 (m, 16 H) 2.62 - 2.81 (m, 4 H) 3.01 - 3.23 (m, 7=9.32 Hz, 4 H) 3.87 - 3.98
(m, 2 H) 4.40 - 4.47 (m, 7=8.24 Hz, 2 H) 5.14 - 5.24 (m, 2 H) 5.50 (d, 7=8.78 Hz, 2 H) 6.23 (dd,
7=8.89, 4.34 Hz, 2 H) 6.75 - 6.84 (m, 2 H) 7.16 (d, 7=7.81Hz, 4 H) 7.48 - 7.59 (m, 12 H) 7.62 (d,
7=3.69 Hz, 4 H) 9.89 (s, 2 H) 10.17 (s, 2 H). The tide compound showed an EC50 value of from about
0.1 to about 1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 18
(R,2S,2'S)-N,N'-(4,4'-((2S,5R)-1 -(4-fluorophenyl)pyrrondine-2,5-diyl)bis(4, l-phenylene))bis(l -((R)-
2-phenyl-2-(piperidin-1 -yl)acetyl)pyrrolidine-2-carboxamide)
To a mixture of (R)-2-phenyl-2-(piperidin-l-yl)acetic acid TFA salt (0.0455 mg, 0.137
mmol), the product from Example 1G (0.030 gm, 0.055 mmol), and HATU (0.0526 gm, 0.138 mmol)
in DMSO (0.300 ml) was added Hunig's base (0.029.0 ml, 0.166 mmol), and the resulting mixture
was stirred at rt for 2 hr. The mixture was partitioned between water and ethyl acetate, the organic
layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was subjected to
HPLC purification on a semi-prep C18 reverse-phased column using a gradient of 10-100%
acetonitrile in 0.1% aq TFA (8.7 mg, 12%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 1.22 -
1.43 (m, 4 H) 1.62 - 2.03 (m, 7=80.02 Hz, 16 H) 2.08 - 2.18 (m, 2 H) 2.62 - 2.85 (m, 4 H) 3.04 - 3.24
(m, 4 H) 3.88 - 3.99 (m, 2 H) 4.41 - 4.52 (m, 2 H) 4.64 - 4.72 (m, 2 H) 5.52 (d, 7=8.24 Hz, 2 H) 6.36
(dd, 7=9.05, 4.50 Hz, 2 H) 6.88 (t, 7=8.89 Hz, 2 H) 7.41 - 7.68 (m, 18 H) 9.89 (s, 2 H) 10.23 (s, 2 H).
The title compound showed an ECso value of less than about 0.1 nM in HCV lb-Conl replicon assays
in the presence of 5% FBS.
Example 19
Dimethyl (2S,2'S)-l,l'-((2S,2,S)-2,2,-(4,4,-(l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2, l-diyl)dicarbamate
Example 19A
l-(4-Fluorophenyl)-2,5-bis(4-nitrophenyl)-lH-pyrrole
To a slurry of the product from Example 1A (1.5 g, 4.57 mmol) in acetic acid (22.85 mL) was
added 4-fluoroaniline (4.33 ml, 45.7 mmol). The mixture was heated to 70 °C for 24 h. After cooling
to rt the mixture was diluted with water and ether and stirred vigourously, filtered and dried to provide
1.67 g (91%) of the tide compound.
Example 19B
4,4'-(l-(4-Fluorophenyl)-lH-pyrrole-2,5-diyl)dianiline
To a solution of example 19A (1.017 g, 2.496 mmol) in ethanol (15 mL) and THF (15 mL)
was added iron powder (0.836 g, 14.98 mmol) followed by ammonium chloride (0.401 g, 7.49 mmol)
and water (3.75 mL). Reaction mixture was refluxed for 45 minutes. Slurry filtered through celite,
washed with ethanol, combined filtrate was concentrated and the residue purified by column
chromatography (gradient elution from 30% to 50% EtOAc:hexanes) to provide 1.09 g (77%) of the
title compound.
Example 19C
(2S,2'S)-tert-Butyl2,2'-(4,4'-(l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
To a solution of Example 19B (1.09 g, 3.17 mmol) in DMF (15.87 mL) at rt was added
HATU (2.66 g, 6.98 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.503 g, 6.98
mmol), and Hunig's base (2.218 mL, 12.70 mmol). Stirring was continued overnight. The mixture
was partitioned between water and EtOAc added. Organic phase washed with brine, dried (Na2S04)
and concentrated. Residue purified by column chromatography (gradient elution from 20% to 50%
EtOAc/ hexanes). MS (ESI; M+H) m/z = 738.
Example 19D
(2S,2'S)-N,N'-(4,4'-(l-(4-Fluorophenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))dipyrroUdine-2-
carboxamide
To the product from Example 19C (100 mg, 0.136 mmol) in CH2C12 (2.0 mL) was added TFA
(1.0 mL) and the reaction was stirred 1H. Mixture concentrated, the residue was partitioned between
water and 25% IPA-CHCI3 and neutralized with NaHC03. The organic layer was dried over Na2S04,
filtered and concentrated to give the tide compound as a white solid used without further purification.
MS (DCI; M+H) m/z = 538.
Example 19E
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-(l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2, l-diyl)dicarbamate
To a mixture of the product from Example 19D (0.073 g, 0.136 mmol) in CH2C12 (10 mL) at
rt was added Hunig's base (0.070 mL, 0.407 mmol). To this was then added (S)-2-
methoxycarbonylamino-3,3-dimethyl-butyric acid (0.054 g, 0.285 mmol) followed by HATU (0.114
g, 0.299 mmol). Mixture stirred for 2 hrs then washed with saturated NaHC03 and the organic phase
concentrated and the residue purified by column chromatography (1% gradient elution from 0% to 3%
MeOH-CH2Cl2) to provide the desired compound as a light tan solid. MS (ESI; M+H) m/z = 881; 1H
NMR (400 MHz, DMSO-D6) δ ppm0.96 (s, 18 H), 1.81-1.89 (m, 4 H), 1.95-2.00 (m, 2 H), 2.11-2.16
(m, 2 H), 3.53 (s, 6 H), 3.61-3.65 (m, 2 H), 3.75-3.79 (m, 2 H), 4.20 (d, J=8.85 Hz, 2 H), 4.39-4.42
(m, 2 H), 6.39 (s, 2 H), 6.96 (d, J=8.69 Hz, 4 H), 7.07-7.10 (m, 4 H), 7.17 (dd, J=8.70, 8.70 Hz, 2 H),
7.41 (d, J=8.70 Hz, 4 H), 10.01 (br s, 2 H). The title compound showed an EC50 value of less than
about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 20
Dimethyl (2S,2'S)-1,1 ,-((2S,2'S)-2,2'-(4,4,-((2S,5S)-l -phenylpyrrolidine-2,5-diyl)bis(4,1-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-phenylpyrroUdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,1 -diyl)dicarbamate
A mixture of the product from Example 1C (50 mg, 0.102 mmol) and aniline (0.2 ml, 2.19
mmol) were stirred at it for 48h. The mixture was partitioned between IN aq. HC1 and ethyl acetate,
and the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate
in hexanes. The tide compound was obtained as a yellow solid (19 mg, 48%).
Example 20B
(2S,2,S)-tert-Butyl2,2'-(4,4'-(l-phenylpyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The product from Example 20A (19 mg, 0.049 mmol) was subjected to the conditions
described in Example IE. The crude product was subjected to the conditions described in Example
IF to give the title compound (33 mg, 93%).
Example 20C
Dimethyl (2S,2'S)-l,r-((2S,2'S)-2,2'-(4,4,-((2S,5S)-l-phenylpyrroUdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomemylene)bis(pyrroUdine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,1 -diyl)dicarbamate
and
Dimethyl (2S,2,S)-l,l,-((2S,2,S)-2,2'-(4,4'-((2R,5R)-l-phenylpyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1 -diyl)dicarbamate
The product from Example 20B (30 mg, 0.041 mmol) was subjected to the conditions
described in Example 1G, and the crude product was subjected to the conditions described in Example
1H. The crude product was subjected to HPLC purification on a semi-prep CI8 reverse-phased
column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The trans-substituted pyrrolidine
isomer was the first of 2 stereoisomers to elute, providing the title compound as a 1:1 mixture of
diastereomers (7 mg,' 19%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.95 (d, 7=5.31Hz,
18 H) 1.59 -1.67 (m, 2 H) 1.79 -1.91 (m, 4 H) 1.91 - 2.02 (m, 2 H) 2.08 - 2.17 (m, 2 H) 3.52 (s, 6 H)
3.58 - 3.68 (m, 2 H) 3.71 - 3.82 (m, 2 H) 4.19 (d, 7=9.00 Hz, 2 H) 4.42 (dd, 2 H) 5.17 (d, 7=5.64 Hz, 2
H) 6.24 (d, 7=8.35 Hz, 2 H) 6.39 (t, 7=7.37 Hz, 2 H) 6.90 (t, 7=7.92 Hz, 2 H) 7.07 (d, 2 H) 7.11 (d, 4
H) 7.48 (d, 7=8.24 Hz, 4 H) 9.98 (s, 2 H). The title compound showed an EC50 value of less than
about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 21
Dimethyl (2S,2'S)-l,r-((2S,2,S)-2,2'-(4,4'-((2S,5R)-l-phenylpyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,l-diyl)dicarbamate
The product from Example 20B (30 mg, 0.041 mmol) was subjected to the conditions
described in Example 1G, and the crude product was subjected to the conditions described in Example
1H. The crude product was subjected to HPLC purification on a semi-prep CI 8 reverse-phased
column using a gradient of 10-100% acetonirrile in 0.1% aq TFA. The cis-substituted pyrrolidine
isomer was the second of 2 stereoisomers to elute, providing the title compound (8.5 mg, 24%): 1H
NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.96 (d, 7=3.25 Hz, 18 H) 1.74 - 1.91 (m, 6 H) 1.93 -
2.03 (m, 2 H) 2.10 - 2.20 (m, 2 H) 3.53 (s, 6 H) 3.58 - 3.69 (m, 2 H) 3.72 - 3.83 (m, 2 H) 4.20 (d,
7=8.89 Hz, 2 H) 4.45 (dd, 7=7.97, 5.37 Hz, 2 H) 4.68 (t, 7=5.20 Hz, 2 H) 6.37 (d, 7=8.24 Hz, 2 H)
6.56 (t, 7=7.26 Hz, 2 H) 6.98 (t, 7=7.92 Hz, 2 H) 7.07 (d, 2 H) 7.42 (d, 7=8.02 Hz, 4 H) 7.58 (d,
7=8.57 Hz, 4 H) 10.03 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM
in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 22
Dimethyl (lR,l,R)-2,2,-((2S,2'S)-2,2'-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrohdine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(2-oxo-1 -
phenylethane-2, l-diyl)dicarbamate
and
Dimethyl (lR,l'R)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(2-oxo-1 -
phenylethane-2, l-diyl)dicarbamate
The product from Example 5C (25 mg, 0.046 mmol) was subjected to the conditions
described in Example 5D, substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for (S)-2-
(methoxycarbonyl amino)butanoic acid, to give the title compound as a 1:1 mixture of diastereomers
(42 mg, 48%): 1H NMR (400 MHz, DMSO-D6) δ ppm 9.83 (s, 2 H) 7.67 (d, 7=7.81Hz, 2 H) 7.51 -
7.57 (m, 4 H) 7.29 - 7.44 (m, 8 H) 7.15 (d, 7=8.46 Hz, 4 H) 6.74 - 6.83 (m, 2 H) 6.17 - 6.28 (m,
7=9.00, 4.34 Hz, 2 H) 5.48 (d, 7=7.81Hz, 2 H) 5.12 - 5.24 (m, 1H) 4.33 - 4.43 (m, 7=8.13 Hz, 2 H)
3.75 - 3.87 (m, 2 H) 3.54 (s, 6 H) 1.73 - 2.05 (m, 8 H) 1.62 - 1.70 (m, 2 H). The title compound
showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of
5% FBS.
Example 23
Dimethyl (2S,2'S)-l,l,-((2S,2,S)-2,2'-(4,4'-((2S,5S)-l-(4-(trifluoromemyl)phenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S)-1,1 ,-((2S,2'S)-2,2*-(4,4,-((2R,5R)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-
oxobutane-2,1 -diyl)dicarbamate
Example 23A
4,4'-((2S,5S)-l-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianilineand4,4'-((2R,5R)-l-(4-
(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianiline
The product from Example 1C (0.74 g, 1.5 mmol) was subjected to the conditions described
in Example ID, substituting 4-(trifluoromethyl)aniline for 4-fluoroaniline. The product thus obtained
was subjected to the conditions described in Example IE to give the title compound as a racemic
mixture of trans-substituted pyrrolidine stereoisomers (0.10 g, 17%).
Example 23B
(2S,2'S)-N,N'-(4,4,-((2S,5S)-l-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))dipyrrolidine-2-carboxamideand(2S,2'S)-N,N'-(4,4,-((2R,5R)-l-(4-
(Trifluoromemyl)phenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide
The product from Example 23A (0.95 g, 0.24 mmol) was subjected to the conditions
described in Example IF to give a solid (0.166 g, 88%), which was dissolved in 4M HC1 in 1,4-
dioxane (2 ml), and the resulting mixture was stirred at rt for 30 min. The resulting mixture was
concentrated and dried in vacuo to give an HC1 salt of the title compound as a 1:1 mixture of
stereoisomers.
Example 23C
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-
oxobutane-2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4,-((2R,5R)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-
oxobutane-2,1 -diyl)dicarbamate
The product from Example 23B (58 mg, 0.083 mmol) was subjected to the conditions
described in Example 1H to give the title compound as a colorless solid (30 mg, 39%): 1H NMR (free
base) (400 MHz, DMSO-D6) δ ppm 10.03 (s, 2 H) 7.52 (d, 7=8.46 Hz, 4 H) 7.25 (d, 7=8.89 Hz, 2 H)
7.14 (d, 7=7.48 Hz, 4 H) 7.06 - 7.11 (m, 2 H) 6.36 (d, 7=8.35 Hz, 2 H) 5.23 - 5.33 (m, 2 H) 4.39 - 4.48
(m, 2 H) 4.21 (d, 7=8.46 Hz, 2 H) 3.71 - 3.82 (m, 2 H) 3.58 - 3.69 (m, 2 H) 3.54 (s, 6 H) 2.08 - 2.21
(m, 2 H) 1.93 - 2.06 (m, 2 H) 1.76 - 1.94 (m, 4 H) 1.61 - 1.73 (m, 2 H) 0.96 (m, 18 H). The title
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Con 1 replicon assays in the
presence of 5% FBS.
Example 24
Dimethyl (2S,2'S,3S,3'S)-1, r-((2S,2,S)-2,2'-(4,4'-((2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxopentane-2,1 -diyl)dicarbamate
and
Dimethyl (2S,2'S,3S,3'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxopentane-2,1 -diyl)dicarbamate
The product from Example 1G (20 mg, 0.037 mmol) was subjected to the conditions
described in Example 1H, substituting (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid
(15.4 mg, 0.081 mmol) for (S)-2-(memoxycarbonylamino)-3,3-dimethylbutanoic acid. The title
compound was obtained as a 1:1 mixture of diastereomers (13.5 mg, 41%) after silica gel
chromatography (0-5% MeOH/CH2Cl2): 1H NMR (free base) (400 MHz, DMSO-D6) δ ppm 9.99 (s,
2 H) 7.50 (dd, 7=8.46, 1.52 Hz, 4 H) 7.36 (dd, 7=8.35, 3.04 Hz, 2 H) 7.13 (dd, 7=8.62, 1.79 Hz, 4 H)
6.78 (t, 7=8.89 Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 5.16 (d, 7=6.29 Hz, 2 H) 4.43 (dd, 7=7.92,
4.77 Hz, 2 H) 4.02 - 4.13 (m, 2 H) 3.77 - 3.89 (m, 2 H) 3.57 - 3.67 (m, 2 H) 3.52 (s, 6 H) 2.08 - 2.21
(m, 7=14.96 Hz, 2 H) 1.94 - 2.05 (m, 2 H) 1.81 -1.93 (m, 7=5.42 Hz, 4 H) 1.60 - 1.79 (m, 4 H) 1.42 -
1.57 (m, 2 H) 1.04 -1.18 (m, 2 H) 0.89 (t, 7=6.51Hz, 6 H) 0.76 - 0.85 (m, 6 H). The title compound
showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of
5% FBS.
Example 25
Dimethyl (2S,2'S,3R,3'R)-l,l,-((2S,2'S)-2,2,-(4,4'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxopentane-2, l-diyl)dicarbamate
and
Dimethyl (2S,2'S,3R,3'R)-1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomemylene)bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
oxopentane-2,1 -diyl)dicarbamate
The product from Example 1G (25 mg, 0.046 mmol) was subjected to the conditions
described in Example 1H, substituting (2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid
(19.2 mg, 0.102 mmol) for (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid. The title
compound was obtained as a 1:1 mixture of diastereomers (20.5 mg, 50%) after silica gel
chromatography (0-5% MeOH/CH2Cl2): 1H NMR (free base) (400 MHz, DMSO-D6) δ ppm 9.96 (s,
2 H) 7.49 (d, 7=8.35 Hz, 4 H) 7.14 (t, 7=7.43 Hz, 4 H) 6.77 (t, 7=8.89 Hz, 2 H) 6.20 (dd, 7=9.11, 4.45
Hz, 2 H) 5.16 (d, 7=6.40 Hz, 2 H) 4.38 - 4.48 (m, 2 H) 4.18 - 4.28 (m, 2 H) 3.69 - 3.82 (m, 2 H) 3.55 -
3.64 (m, 2 H) 3.52 (s, 6 H) 2.09 - 2.20 (m, 2 H) 1.95 - 2.05 (m, 2 H) 1.72 - 1.95 (m, 6 H) 1.58 - 1.70
(m, 7=5.64 Hz, 2 H) 1.40 - 1.55 (m, 2 H) 1.06 - 1.18 (m, 2 H) 0.79 - 0.91 (m, 12 H). The tide
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Con 1 replicon assays in the
presence of 5% FBS.
Example 26
dimediyl(2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-(4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-meuiyl-l-oxobutane-2,l-
diyl)dicarbamate
(S)-tert-butyl2-formylpyrrohdine-l-carboxylate
To an oven-dried 500-mL 3-neck flask purged with nitrogen was added oxalyl chloride (5.32
mL, 60.8 mmol) and anhydrous dichloromethane (125 mL), and the solution cooled to -78 °C. A
solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was
added dropwise from a constant-pressure addition funnel over 20-min period. A solution of (S)-tert-
butyl 2-(hydroxymethyl)pyrrolidine-l-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane
(50 mL) was added dropwise from a constant-pressure addition funnel over 20-min period, then
stirred reaction mixture at -78 °C for 30 min. Added triethylamine (32.6 mL, 234 mmol) dropwise via
syringe over a 5-min period and stirred the thick white mixture in an ice-water bath for 30 min.
Quenched reaction with 10% (w/v) aq. citric acid (30 mL), poured reaction into a separatory funnel
with Et20 (550 mL) and 10% (w/v) aq citric acid, separated layers, and washed organic phase with
water and brine. Dried the organic phase over anhydrous Na2S04, filtered, and concentrated to afford
a yellow oil (9.4 g), which was used directiy in the next reaction.
Example 26B
(S)-tert-butyl2-(lH-imidazol-2-yl)pyrrolidine-l-carboxylate
The product from Example 26A (20 g, 100 mmol) was dissolved in methanol (50.2 mL) and
ammonium hydroxide (50.2 mL) was added. To this solution glyoxal (40% in water; 24.08 mL, 211
mmol) was added, dropwise, over 10 min. The reaction was stirred at room temperature overnight.
Reaction was concentrated under reduced pressure, diluted with 50 mL of water, and then extracted
with ethyl acetate. Washed organic layer with brine, dried (Na2S04) and concentrated to a tan solid.
Solid was treated with ether and concentrated. The solid was then triturated with 2:1 diethyl
ether.hexanes (150 mL) to afford 17 g of solid, which was used directly in the next reaction.
Example 26C
(S)-tert-butyl 2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1 -carboxylate
N-bromosuccinimide (108 mmol) was added to a cold (0 °C) solution of the product from
Example 26B (12.05 g, 50.8 mmol) in dichloromethane (200 mL). Let stir in ice bath for 2 h and then
concentrated, dissolved in ethyl acetate (250 mL) washed with water (3 x 150 mL), brine (1 x 100
mL), dried (MgS04) and concentrated to very dark residue, chased with dichloromethane/hexanes
(1:1) to get brown solid (-19 g). Triturated solid with ether (-100 mL), filtered to isolate a tan solid
(13.23 g, 65% yield).
Example 26D
(S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l -carboxylate or (S)-tert-butyl 2-(4-bromo-
1H-imidazol-2-yl)pyrrolidine-1 -carboxylate
Dissolved the product from Example 26C (6.25 g, 15.82 mmol) in dioxane (200 mL) and
water (200 mL) in a 1 L round bottom flask equipped with a condenser and glass stopper, added a
solution of sodium sulfite (22.38 g, 174 mmol) in water (200 mL), and heated at reflux with heating
mantle for 16 h. Reaction was reddish-amber homogeneous solution. Cooled reaction to room
temperature, removed dioxane and some water by rotary evaporation, extracted with dichloromethane,
washed the combined organic extracts with brine (50 mL), dried over anhydrous Na2S04, filtered, and
concentrated by rotary evaporation, co-evaporating with 2:1Hexanes/dichloromethane (100 mL) to
give a beige foam (4.38 g). Dissolved foam in dichloromethane (2 mL), added hexanes (2 mL),
applied solution to column, and purified by silica gel flash chromatography eluting with 30% to 80%
ethyl acetate/hexanes to afford the title compound as a white solid (3.48 g).
Example 26E
1,4-bis(4-bromophenyl)butane-1,4-dione
To a solution of zinc(II) chloride (19.62 g, 144 mmol) in benzene (108 mL) were added
diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and the mixture
was stirred at room temperature for 2 h. 2-bromo-l-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and
l-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion, and the mixture was
stirred overnight (18 h). Quenched with 5% H2S04 (500 mL) and stirred vigorously to induce
precipitation of the product, which was collected by vacuum filtration and washed with benzene,
water, methanol, then dichloromethane, successively. The product was dried under vacuum to give the
title compound as a white solid (11.15 g, 39.1% yield).
Example 26F
2,5-bis(4-bromophenyl)-l-(4-tert-butylphenyl)-lH-pyrrole
To a solution of the product from Example 26E (4.00 g, 10.10 mmol) in toluene (40 mL) was
added 4-tert-butylaniline (1.81 g, 12.12 mmol) followed by TFA (2.30 g, 20.20 mmol). Mixture
heated to 110 °C for 2 h. Mixture cooled to room temperature and water and diethyl ether were
added. Stirred for 15 min, filtered, washed with water and diethyl ether and dried to provide the title
compound as a white solid (4.61 g; 90% yield).
Example 26G
1 -(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- lH-pyrrole
To a solution of the product from Example 26F (2.32 g, 4.56 mmol) in DMSO (26 mL) at
room temperature were added bis(pinacolato)diborane (2.54 g, 10.02 mmol), potassium acetate (5.00
g, 36.4 mmol) and PdCl2(dppf) (744 mg, 0.91 mmol). The mixture was degassed and heated to 85 °C.
After 4 h, the mixture was cooled to room temperature, diluted with dichloromethane and washed
with water followed by brine. The organic phase was dried (Na2S04) and concentrated. The residue
was taken up in 20% ethyl acetate:hexanes and filtered through a short plug of silica gel (elution with
20% ethyl acetate:hexanes) and concentrated to afford the title compound as a light yellow solid (1.62
g; 59% yield).
Example 26H
(2S,2'S)-tert-butyl2,2,-(4,4,-(4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis( lH-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
A mixture of the product from Example 26D (664 mg, 2.10 mmol), the product from Example
26G (1.48 g, 2.45 mmol), 2 M sodium carbonate (1400 μL, 2.80 mmol), and Pd(dppf)C12 (51.2 mg,
0.070 mmol) in DME (2800 jiL) was subjected to microwave irradiation at 140 °C for 20 min. The
mixture was diluted with ethyl acetate, then washed with water and brine, and dried over Na2S04.
The product was purified on silica gel eluted with 30 to 70% ethyl acetate:hexanes to provide the title
compound (140 mg; 24% yield).
Example 261
(2S,2' S)-4,4'-(4,4'-( 1 -(4-tert-butylphenyl)-l H-pyrrole-2,5-diyl)bis(4, l-phenylene))bis(2-(pyrrolidin-2-
yl)-lH-imidazole)
To a solution of the product from Example 26H (135 mg, 0.164 mmol) in dichloromethane (2
mL) at room temperature was added TFA (0.60 mL). After 3 h, the solvent was removed and the
residue partitioned between water and 25% isopropyl alcohol:CHCl3; neutralized with NaHC03. The
organic phase was dried (Na2S04), filtered and concentrated. Residue used directly in the next
reaction (98 mg; 96% yield).
Example 26J
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4,-(4,4,-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis( 1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
To a solution of the product from Example 261 (98 mg, 0.158 mmol) in DMF (2 mL) at room
temperature was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (61 mg, 0.347 mmol),
EDAC (66 mg, 0.347 mmol) and 1-hydroxybenzotriazole hydrate (53 mg, 0.347 mmol). After 3 h,
the mixture was transferred to a separatory funnel with ethyl acetate and water. The organic phase
was concentrated and the residue purified by chromatography (1% gradient elution from 0% to 4%
methanohdichloromethane) to provide the desired material as a light yellow solid (70 mg; 30% yield).
'HNMR (MeOH-d4; 400 MHz): 5 7.55-7.30 (m, 6H), 7.25-6.96 (m, 8H), 6.45 (s, 2H), 5.12 (dd,
J=5.43, 5.43 Hz, 2H), 4.20 (d, J=7.26 Hz, 2H), 4.02-3.90 (m, 2H), 3.85-3.80 (m, 2H), 3.64 (s, 6H),
2.36-1.93 (m, 10H), 1.31 (s, 9H), 0.97-0.86 (m, 12H). The title compound showed an EC50 value of
less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 27
dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-
dimemoxypyn-olidine-2,5-diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-
diyl))bis(3-methyl-l-oxobutane-2,l-diyl)dicarbamate
Example 27A
(2S,3R,4R,5S)-2,5-bis(4-bromophenyl)-l-(4-fluorophenyl)pyrrolidine-3,4-diol
A solution of 3,4-O-isopropylidene-C1-mannitol (2.24 g, 10.08 mmol) in 2:1 methanol-
dichloromethane (45 mL) was treated with iodobenzene diacetate (7.95 g, 24.19 mmol) followed by
stirring at room temperature for 5 h. The mixture was concentrated by rotary evaporation and the
residue was dissolved in 0.1M aq. sulfuric acid solution (20.6 mL) followed by stirring at room
temperature for 18 h. The mixture was adjusted to pH 6 by addition of solid sodium bicarbonate. The
mixture was then sequentially treated with 4-fluoroaniline (1.96 mL, 20.16 mmol), 4-
bromophenylboronic acid (3.64 g, 18.14 mmol), and absolute ethanol (40 mL). The mixture was then
heated in an oil bath (110 °C) at reflux for 20 h. The dark brown mixture was cooled to room
temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL), washed
with water (50 mL), 0.33M aq. potassium phosphate tribasic solution (2 x 50 mL), and brine (50 mL).
The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated by
rotary evaporation to a dark reddish-brown oil. Dissolved oil in dichloromethane-hexanes,
concentrated in vacuo, and dried in vacuo to give a dark brown foam. Purification by silica gel flash
chromatography eluting with a step gradient of 10% to 15% ethyl acetate/dichloromethane afforded
pure product as a yellow solid (1.216 g, 24%).
Example 27B
(2S,3R,4R,5S)-2,5-bis(4-bromophenyl)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine
Dissolved the product of Example 27A (237 mg, 0.467 mmol) in a mixture of THF (3 mL)
and DMF (1 mL) under a nitrogen atmosphere and cooled to 0 °C. Added 60% sodium hydride
dispersion in mineral oil (56.1 mg, 1.402 mmol) in portions and stirred the mixture at 0 °C for 15 min.
Then added neat iodomethane (65 (iL, 1.028 mmol), removed the cooling bath, and stirred the
reaction at room temperature for 14.5 h. Diluted the reaction in ethyl acetate (50 mL), washed with
saturated aq. ammonium chloride solution (25 mL), water (2 x 25 mL), and brine (25 mL). Dried the
organic phase over anhydrous sodium sulfate, filtered, and concentrated the filtrate by rotary
evaporation. The yellow residue was purified by silica gel flash chromatography eluting with 30%
hexanes/dichloromethane to afford the tide compound as a white foam (206 mg, 82%).
Example 27C
(2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)phenyl)pyrrolidine
Charged a nitrogen-purged flask with the product of Example 27B (204 mg, 0.381 mmol),
bis(pinacalato)diboron (242 mg, 0.953 mmol), potassium acetate (112 mg, 1.143 mmol), and
anhydrous dioxane (2 mL). Sparged the mixture with nitrogen for 30 min, added 1,1'-
bis(diphenylphosphino)ferrocene-palladium (IT) dichloride dichloromethane complex (31.1 mg, 0.038
mmol), sparged the mixture again with nitrogen for 5 min, and heated in an oil bath at 85 °C for 6 h.
The reaction was vacuum filtered through a small bed of celite 545, the collected solids were
thoroughly washed with 5% methanoiydichloromethane, and the filtrate concentrated in vacuo,
chasing the residue with dichloromethane/hexanes to give a tan solid. Purification by silica gel flash
chromatography eluting with 5% ethyl acetate/dichloromethane afforded the title compound as a
salmon-colored solid (238 mg, 99%).
Example 27D
(2S,2'S)-tert-butyl2,2'-(4,4'-(4,4,-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-
2,5-diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
A nitrogen-purged 5-mL microwave tube was charged with the product of Example 27C (237
mg, 0.377 mmol), the product from Example 26D (298 mg, 0.941 mmol), and a mixture of absolute
ethanol (1.5 mL) and toluene (1.5 mL). Sonicated to obtain a cloudy orange mixture, added 1M aq
sodium carbonate (0.941 mL, 0.941 mmol), and sparged with nitrogen for 20 min. Added 1,1'-
bis(diphenylphosphino)ferrocene-palladium (IT) dichloride dichloromethane complex (30.8 mg, 0.038
mmol), sparged the mixture again with nitrogen for 5 min, sealed the reaction tube with an aluminum
crimp cap, and heated in a microwave reactor with stirring at 100 °C for 1H. Cooled reaction to room
temperature, diluted in ethyl acetate (75 mL), washed with water (2 x 25 mL) and brine (25 mL),
dried the organic phase over anhydrous magnesium sulfate, filtered, and concentrated the filtrate by
rotary evaporation to a dark yellow solid. Purification by silica gel flash chromatography eluting with
4% methanol/dichloromethane afforded the title compound as a yellow solid (221 mg, 69%).
Example 27E
(S)-4,4'-(4,4'-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(2-((S)-pyrrolidin-2-yl)-lH-imidazole)
A solution of the product of Example 27D (147.5 mg, 0.174 mmol) in anhydrous
dichloromethane (2 mL) under nitrogen was treated with TFA (1 mL) and stirred at room temperature
for 30 min. The solvent was removed in vacuo and chased with 1:10 dichloromethane-hexanes (3 x
50 mL) to afford a pale yellow solid (193 mg). The solid TFA salt was dissolved in anhydrous
methanol (15 mL), treated with dry Amberlite IRA400(OH) resin (1.66 g, previously washed 10 g of
wet resin (Supelco) with deionized water (3 x 25 mL) and methanol (3 x 25 mL), then dried in vacuo),
and stirred for 2 h at room temperature. The mixture was then vacuum filtered, the collected resin
washed thoroughly with methanol, the filtrate concentrated by rotary evaporation, and the residue
chased with 1:10 dichloromethane-hexanes to afford the tide compound as a light yellow solid (94
mg, 0.145 mmol, 83%).
Example 27F
dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-
dimethoxypyrrolidine-2,5-diyl)bis(4,1 -phenylene))bis( 1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -
diyl))bis(3-methyl-l-oxobutane-2,l-diyl)dicarbamate
In an oven-dried round bottom flask, dissolved the product of Example 27E (92 mg, 0.142
mmol) in a mixture of DMF (1 mL) and DMSO (1 mL) under nitrogen and cooled the solution to 0
°C. Added sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (53.5 mg, 0.305
mmol), EDAC (61.1 mg, 0.312 mmol), 1-hydroxybenzotriazole hydrate (47.8 mg, 0.312 mmol), and
N-methylmorpholine (47 pL, 0.426 mmol). Removed the cooling bath and stirred at room
temperature for 15 h. Diluted the reaction with ethyl acetate (50 mL), washed with saturated aq.
sodium bicarbonate solution (25 mL), water (2 x 25 mL), and brine (25 mL). The organic phase was
dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated by rotary evaporation.
Purification by silica gel flash chromatography eluting with 5% methanol/dichloromethane afforded
the title compound as a pale yellow solid (78 mg, 56%). :H NMR (400 MHz, DMSO-d6) 8 ppm 0.86
(dd, J=17.67,6.72 Hz, 12 H), 0.97 -1.37 (m, 3 H), 1.41 - 2.29 (m, 11H), 3.53 (s, 6 H), 3.69 - 3.86 (m,
4 H), 4.04 (q, J=8.02 Hz, 2 H), 4.12 - 4.23 (m, 2 H), 5.07 (d, J=3.80 Hz, 2 H), 5.35 - 5.48 (m, 2 H),
6.31 (dd, J=9.16, 4.39 Hz, 2 H), 6.74 (t, J=8.89 Hz, 2 H), 7.12 - 7.71 (m, 12 H), 11.53 - 12.31 (m, 2
H); MS (ESI+) m/z 963 (M+H)+. The title compound showed an EC5o value of less than about 0.1
nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 28
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(5,5'-((2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-
o^yl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-oxobutane-2,l-
diyl)dicarbamate and dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(5,5,-((2S,5S)-l-(4-tert-
butylphenyl)pyrrolidine-2,5-diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
Zinc chloride (27.4g, 201 mmol), diethylamide (15.6 mL, 151 mmol) and t-butanol (14.4 mL,
151 mmol) were combined in benzene (151 mL) at room temperature under a nitrogen atmosphere
and stirred for 2 h. l-(4-chloro-3-nitrophenyl)ethanone (30.1 g, 151 mmol) and 2-bromo-l-(4-chloro-
3-nitrophenyl)ethanone (28 g, 101 mmol) were added. The mixture was stirred vigorously for 20 h,
and the solid product was collected by filteration and rinsed with benzene, water, methanol, and
dichloromethane. The solid was dried in a vacuum oven.
Example 28B
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol
The product of Example 28A (5.75 g, 14.48 mmol) was dissolved in ethanol (150 mL) at
room temperature and treated with sodium borohydride (1.21 g, 31.9 mmol) portionwise over 5
minutes. The solution was heated at 70 °C for 1H and then cooled to room temperature, quenched
with water, extracted into ethyl acetate, dried over sodium sulfate, and concentrated to dryness to give
4.81g (83%) of an off-white solid.
Example 28C
1,4-bis(4-chloro-3 -nitrophenyl)butane-1,4-diyl dimethanesulfonate
The product of Example 28B (4.81 g, 11.99 mmol) and triethylamine (5.85 mL, 42.0 mmol)
were dissolved in dichloromethane (80 mL) at room temperature and treated with methanesulfonyl
chloride (2.34 mL, 30.0 mmol) dropwise over 10 minutes. The resulting solution was stirred for 2 h
then concentrated to dryness and used directly in the next step.
Example 28D
l-(4-tert-butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine
The product from Example 28C (6.6 g, 11.84 mmol) was slurried in DMF (30 mL) and 4-t-
butyl aniline (18.7 mL, 118 mmol) was added and the solution was heated at 55 °C for 2 h then cooled
and poured into water and extracted into dichloromethane. The organics were concentrated and the
residue was purified by chromatography on silica gel 120g column, eluting with 0-5%ethyl
acetate/hexanes to give 4.41g (72%) of a thick oil.
Example 28E
4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)
The product from Example 28D (4.41 g, 8.57 mmol) was combined, neat, with p-methoxy
benzylamine (8.93 mL, 68.6 mmol) and heated at 145 °C for 1H. The mixture was diluted with
dichloromethane and filtered. The filtrate was washed with 0.5 M HC1, then NaHCC>3 soln, then
brine, concentrated and purified by chromatography on silica gel with an 80g column, eluting with 0-
50% ethyl acetate/hexanes to give 4.13g (67%) of an orange foamy solid.
Example 28F
4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(Nl-(4-methoxybenzyl)benzene-l,2 -diamine)
The product from Example 28E (2 g, 2.79 mmol) was dissolved in a mixture of THF (15 mL),
ethanol (15 mL), and ethyl acetate (5 mL) then platinum oxide (0.254 g, 1.12 mmol) was added via
THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to
hydrogen balloon. The mixture was stirred at room temperature for 20 h, then filtered through celite,
concentrated, and purified by chromatography on silica gel with an 80g column, eluting with 0-40%
ethyl acetate/dichloromethane to give the first peak of trans product 0.508 g (28%).
Example 28G
(2S,2'S)-tert-butyl2,2'-(5,5,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4-
methoxybenzylamino)-5,l-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate
The product from Example 28F (0.422 g, 0.643 mmol) and diisopropylethylamine (0.674 mL,
3.86 mmol) were dissolved in DMSO (6 mL) at room temperature and treated with S-Boc-proline
(0.319 g, 1.48 mmol) followed by HATU (0.514 g, 1.35 mmol). The solution was stirred for 1H at
room temperature then diluted with water and the solid product was filtered off and purified by
chromatography on silica gel with a 40g column, eluting with 0-50% ethyl acetate in dichloromethane
to give 0.565 g (84%) of a yellow solid.
Example 28H
(2S,2'S)-tert-butyl 2,2'-(5,5'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1 -
phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate
The product from Example 28G (0.565 g, 0.538 mmol) was dissolved in dichloromethane (5
mL) and water (0.25 mL) at room temperature and treated with DDQ (0.244 g, 1.076 mmol)
portionwise over 2 minutes. The mixture was diluted with sodium bicarbonate solution, extracted into
dichloromethane, concentrated and purified by chromatography on silica gel with a 40g column,
eluting with 0-15% methanol/dichloromethane to give 0.355 g (81%) of a yellow solid.
Example 281
(2S,2,S)-tert-butyl2,2'-(5,5,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(lH-
benzo[d]imidazole-5,2-diyl))dipyrrolidine-l-carboxylate
The product from Example 28H was dissolved in neat acetic acid (3 mL) and heated at 72 °C
for 2 h. The solution was concentrated and then poured into water and adjusted pH to ~7-8 with
sodium bicarbonate. The product was extracted into dichloromethane, concentrated and purified by
chromatography on silica gel with a 40g column, eluting with 0-5%methanol/dichloromethane to give
0.185 g (55%) of a light yellow solid.
Example 28J
(S)-5,5,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-
benzo[d]imidazole)
The product from Example 281 (0.204 g, 0.264 mmol) was dissolved in THF (2 mL) at room
temperature and treated with 4 M hydrochloric acid in dioxane (2 mL). The mixture was concentrated
to dryness and used direcdy in the next step.
Example 28K
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-
diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-oxobutane-2,l-
diyl)dicarbamate and dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(5,5'-((2S,5S)-l-(4-tert-
butylphenyl)pyrroudine-2,5-diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
The product from Example 28J (0.150 g, 0.261 mmol) and diisopropylethylamine (0.365 mL,
2.09 mmol) were dissolved in DMSO (3 mL) at room temperature and treated with (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.105 g, 0.601 mmol) followed by HATU (0.204 g,
0.536 mmol). The solution was stirred for 1H at room temperature then diluted with water and the
solid product was filtered off and purified by chromatography on silica gel with a 12g column, eluting
with 0-8% methanol in dichloromethane to give 0.143 g (60%) of a yellow solid.1H NMR (400
MHz, DMSO-D6) δ ppm 0.75 - 0.92 (m, 12 H) 1.07 (s, 9 H) 1.64 - 1.76 (m, 2 H) 1.85 - 2.04 (m, 6 H)
2.12 - 2.26 (m, 4 H) 2.43 (dd, J=7.75, 4.07 Hz, 2 H) 3.53 (s, 6 H) 3.76 - 3.87 (m, 4 H) 4.04 (dd,
J=11.49, 6.51Hz, 2 H) 5.12 (t, J=7.59 Hz, 2 H) 5.35 (d, J=3.25 Hz, 2 H) 6.25 (d, J=8.46 Hz, 2 H) 6.85
- 6.96 (m, 2 H) 7.07 (t, J=7.97 Hz, 2 H) 7.19 (s, 1H) 7.28 (d, J=8.35 Hz, 3 H) 7.38 (dd, J=8.19, 1.90
Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 11.97 - 12.09 (m, 2 H). The title compound showed an EC50 value
of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 29
dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(lH-
benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-l -oxobutane-2,1 -diyl)dicarbamate
anddmiethyl(2S,2,S)-l,l,-((2S,2'S)-2,2,-(5,5'-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(lH-
benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-l -oxobutane-2,1 -diyl)dicarbamate
2,5-bis(4-chloro-3-nitrophenyl)-l-(4-fluorophenyl)pyrrolidine
The product from Example 28C (2.9 g, 5.2 mmol) and 4-fluoroaniline (5.0 mL, 52.0 mmol)
were combined, neat, and heated at 45 °C for 20 h then cooled and poured into water and extracted
into dichloromethane. The organics were concentrated the residue was purified by chromatography
on silica gel with a 120g column, eluting with 0-5% ethyl acetate/hexanes to give 0.59g (24%) of a
thick oil.
Example 29B
4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nitroaniline)
The product from Example 29A (0.88 g, 1.86 mmol) was combined with 4-methoxy
benzylamine (3.64 mL, 28.0 mmol) and heated at 145 °C for 1H in a microwave reactor. The mixture
was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by
chromatography on silica gel with a 330g column, eluting with 0-60% ethyl acetate/hexanes to give
0.79g (62%) of an orange foam solid.
Example 29C
4,4'-( 1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline)
The product from Example 29B (0.78 g, 1.15 mmol) was dissolved in dichloromethane (10
mL) at room temperature and treated with TFA (1.8 mL, 23.0 mmol) for 3 h. The residue was
concentrated and partitioned between dichloromethane and sodium bicarbonate solution. The
organics were concentrated and purified by chromatography on silica gel with a 40g column, eluting
with dichloromethane to give 0.218 g (43%) of the trans isomer.
Example 29D
4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-l,2-diamine
The product from Example 29C (0.218 g, 0.50 mmol) was dissolved in DMF (5 mL) then
platinum oxide (0.226 g, 0.99 mmol) was added via THF slurry. The flask was evacuated and purged
with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room
temperature for 20 h. The solution was taken on to the next step without purification.
Example 29E
(2S,2'S)-tert-butyl2,2'<5,5'99.55 ee, 61% yield) which
was contaminated with 9.7% of the meso isomer (vs. dl isomer).
Example 34
Dimemyl(2S,2'S)4,l'K(2S,2'S)-2,2'<4,4,<(2S,5S)4<4-tert-butylphenyl)pyn:oUdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl- l-oxobutane-2,1 -
diyl)dicarbamate
and
Dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2,-(4,4,-((2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
l-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75
mmol) in DMF (40 ml) was stirred under nitrogen at 50 °C for 4 h. The resulting mixture was diluted
into ethyl acetate, treated with 1M HC1, stirred for 10 minutes and filtered to remove solids. The
filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated.
The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to
30%) to give a solid. The solid was triturated in a minimal volume of 1:9 ethyl acetate/hexane to give
a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).
Example 34B
4,4'-((2S,5S)-l-(4-^rt-butylphenyl)pyrrolidine-2,5-diyl)dianilineand4,4'-((2R,5R)-l-(4-tert-
butylphenyl)pyrrolidine-2,5-diyl)dianiline
To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and
THF (20 ml) was added Pt02 (0.22 g, 0.97 mmol) in a 50 ml pressure botde and stirred under 30 psi
hydrogen at room temperature for 1H. The mixture was filtered through a nylon membrane and
evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in
hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g,
54%).
Example 34C
(2S,2'S)-tert-Butyl2,2'-(4,4'-((2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate and (2S,2'S)-tert-Butyl 2,2'-
(4,4'-((2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
To a mixture of the product from Example 34B (250 mg, 0.648 mmol), (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 mmol) and HATU (542 mg, 1.427
mmol) in DMSO (10 ml) was added Hunig's base (0.453 ml, 2.59 mmol). The reaction mixture was
stirred at room temperature for 1H. The mixture was partitioned with ethyl acetate and water. The
organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue
was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to
give the title compound (500 mg, 99%).
Example 34D
(2S,2'S)-N,N'-(4,4'-((2S,5S)-l-(4-terf-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))dipyrrolidine-2-carboxamideand(2S,2'S)-N,N'-(4,4'-((2R,5R)-l-(4-terf-
butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide
To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was
added TFA (6 ml). The reaction mixture was stirred at room temperature for 1H and concentrated in
vacuo. The residue was partitioned between 3:1 CHCl3:isopropyl alcohol and saturated aq. NaHC03.
The aqueous layer was extracted by 3:1 CHC^isopropyl alcohol again. The combined organic layers
were dried over Na2S04, filtered and concentrated to give the title compound (345 mg, 93%).
Example 34E
Dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-«ert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
and
Dimethyl (2S,2'S)-l,l,-((2S,2,S)-2,2'-(4,4,-((2R,5R)-l-(4-fert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrroUdine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,
0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The
reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl
acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered
and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in
hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the
title compound (13 mg, 29%). :H NMR (400 MHz, DMSO-D6) δ ppm 0.85 - 0.95 (m, 12 H) 1.11 (s,
9 H) 1.59 - 1.65 (m, 2 H) 1.79 - 2.04 (m, 8 H) 2.10 - 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H)
3.57 - 3.67 (m, 2 H) 3.76 - 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 - 4.46 (m, 2 H) 5.15 (d, J=7.00
Hz, 2 H) 6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20
Hz, 2 H) 7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound
showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of
5% FBS.
Example 35
Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1 -(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 2:1 mixture of hexane:(2:l isopropyl alcohol:EtOH). The title
compound was the first of the 2 diastereomers to elute.1H NMR (400 MHz, DMSO-D6) δ ppm 0.88
(d, J=6.61Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 - 2.04 (m, 8
H) 2.09 - 2.19 (m, 2 H) 2.44 - 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 - 3.66 (m, 2 H) 3.77 - 3.84 (m, 2 H)
4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86,4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2
H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4
H) 9.98 (s, 2 H). The tide compound showed an EC5o value of less than about 0.1 nM in HCV lb-
Conl replicon assays in the presence of 5% FBS.
Example 36
Dimethyl (2S,2,S)-l,l,-((2S,2,S)-2,2'-(4,4'-((2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 2:1 mixture of hexane:(2:l isopropyl alcohol:EtOH). The title
compound was the second of 2 diastereomers to elute. 1H,NMR (400 MHz, DMSO-D6) δ ppm 0.87
(d, J=6.51Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 Hz, 2 H) 1.82 - 2.04 (m, 8
H) 2.09-2.18 (m, 2 H) 2.41 - 2.47 (m, 2 H) 3.52 (s, 6 H) 3.58 - 3.67 (m, 2 H) 3.75 - 3.84 (m, 2 H) 4.02
(t, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H)
6.94 (d, J=8.67 Hz, 2 H) 7.12 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H)
9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl
replicon assays in the presence of 5% FBS.
Example 37
Dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4,-((2S,5S)-l-(4-fert-butylphenyl)pyrroUdine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
Example 37A
(S)-2,5-dioxopyrrolidin-l-yl 2-(methoxycarbonylamino)-3-methylbutanoate
To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol)
and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture
was cooled to 0-5 °C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction
mixture was stirred at 0-5 °C for about 1Hour. The reaction mixture was warmed to room
temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The
filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the
mixture was heated to about 50 °C to obtain a homogeneous solution. Upon cooling, crystalline solids
formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the
title compound as a white solid (23.2 g, 77% yield).
Example 37B
(S)-1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid
To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA
(9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (lOg, 36.7 mmol) in
acetonitrile (20 mL) over 10 minutes. The reaction mixture was stirred overnight at room temperature.
The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water
solution was added 6N HC1 (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel
and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then
again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x
10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was
evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the
solvent was evaporated to give a foam, which was dried under high vacuum to give the title
compound (10.67g) as a white solid.
The compound of Example 37B can also be prepreared according to the following procedure:
To a flask was charged L-valine (35 g, 299 mmol), IN sodium hydroxide solution (526 ml,
526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to
dissolve solids and then cooled to 15 °C. Methyl chloroformate (29.6 g, 314 mmol) was added slowly
to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15
°C and pH adjusted to ~5.0 with concentrated HC1 solution. 100 mL of 2-methytetrahydrofuran (2-
MeTHF) was added and the adjustment of pH continued until the pH reached ~ 2.0. 150 mL of 2-
MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous
layer extracted with 100 mL of 2-MeTHF. The combined organic layer was dried over anhyd
Na2S04 and filtered, and Na2S04 cake was washed with 50 mL of 2-MeTHF. The product solution
was concentrated to ~ 100 mL, chased with 120 mL of IPAc twice. 250 mL of heptanes was charged
slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to
45 °C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min,
filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 mL). The wetcake was dried at 55 °C
for 24 h to give 47.1 g of Moc-L-Val-OH product as a white solid (90%).
Moc-L-Val-OH (150 g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 ml)
were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC
hydrochloride (172 g, 899 mmol) was charged and mixed for 20 min. The mixture was cooled to 13
°C and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g,
1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The
reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHC03 charged in 1.5 h, followed by the
addition of 1200 mL of water over 60 min. The mixture was stirred at rt for 30 min, filtered and
washed with water/DMF mixture (1:2, 250 mL) and then with water (1500 mL). The wetcake was
dried at 55 °C for 24 h to give 282 g of product as a white solid (90%).
The resulting solids (40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by
THF (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a
hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at
room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter
and concentrated to approximately 135 g solution. Heptane was added (120 mL), and the solution was
stirred until solids formed. After an addition 2-3 hours additional heptane was added drop-wise (240
mL), the slurry was stirred for approximately 1Hour, then filtered. The solids were dried to afford the
title compound.
Example 37C
(lR,4R)-l,4-bis(4-nitrophenyl)butane-l,4-diyldimethanesulfonate
The product from Example 32 (5.01 g, 13.39 mmol) was combined with 2-
methyltetrahydrofuran (70 mL) and cooled to -5 °C, and N,N-diisopropylethylamine (6.81 g, 52.7
mmol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5
mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diol slurry over 3 min.,
maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 min at -15 °C, the
cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30
minutes. After reaction completion, the crude slurry was carried immediately into the next step.
Example 37D
(2S,5S)-l-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
To the crude product solution from Example 37C (7.35 g, 13.39 mmol) was added 4-tert-
butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 h. After
completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (100
mL) and 1 M HC1 (150 mL). After partitioning the phases, the organic phase was treated with 1 M
HC1 (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (100 mL), and the phases
were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgS04,
filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2-
methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated
further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2-
methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h,
filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 °C in
a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield).
Example 37E
4,4'-((2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline
To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g,
4.49 mmol), foUowed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis))
under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig)
followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with
hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The
slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the
filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title
compound, which was dried and used directly in the next step.
Example 37F
dimethyl (2S,2'S)-l,r-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-tert-butylphenyl)pyrroUdine-2,5-diyl)bis(4,l-
phenylene)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2,1 -diyi))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
To a solution of the product from Example 37E (1.64 g, 4.25 mmol) in DMF (20 ml), the
product from Example 37B (2.89 g, 10.63 mmol), and HATU (4.04 g, 10.63 mmol) in DMF (150mL)
was added triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at room temperature for
90 min. To the reaction mixture was poured 20 mL of water, and the white precipitate obtained was
filtered, and the solid was washed with water (3x5 mL). The solid was blow dried for lh. The crude
material was loaded on a silica gel column and eluted with a gradient starting with ethyl acetate/
heptane (3/7), and ending with pure ethyl acetate. The desired fractions were combined and solvent
distilled off to give a very light yellow solid, which was dried at 45 °C in a vacuum oven with
nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 1H NMR (400 MHz, DMSO-
D6) δ ppm 0.88 (d, J=6.61Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H)
1.80 - 2.04 (m, 8 H) 2.09 - 2.19 (m, 2 H) 2.44 - 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 - 3.66 (m, 2 H) 3.77 -
3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17
(d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50
(d, J=8.35 Hz, 4 H) 9.98 (s, 2 H).
Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 mmol) and the product from
example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67
g, 144 mmol) is added and the solution is cooled to 0 °C. In a separate flask, 1-propanephosphonic
acid cyclic anhydride (T3P®) (46.0 g, 50 wt% in EtOAc, 72.2 mmol) was dissolved in EtOAc (58.5
mL), and charged to an addition funnel. The T3P solution is added to the reaction mixture drop-wise
over 3-4 h and stirred until the reaction is complete. The reaction is wanned to room temperature,and
washed with 1M HC1/7.5 wt% NaCl (100 mL), then washed with 5% NaHC03 (100 mL), then
washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL,
EtOH (300 mL) was added, and the solution was concentrated to 84 g solution.
A portion of the EtOH solution of product (29 g) was heated to 40 °C, and added 134 g 40
w% EtOH in H20. A slurry of seeds in 58 wt/wt% EtOH/H20 was added, allowed to stir at 40 °C for
several hours, then cooled to 0 °C. The slurry is then filtered, and washed with 58wt/wt% EtOH/H20.
The product is dried at 40 - 60 °C under vacuum, and then rehydrated by placing a tray of water in the
vacuum oven to give the title compound. The title compound showed an EC50 value of less than
about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 38
Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 -
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrroUdine-2,1 -diyl))bis(3,3-dimethyl-1 -oxobutane-
2,1 -diyl)dicarbamate
Example 38A
(lS,4S)-l,4-bis(4-nitrophenyl)butane-l,4-diyldimethanesulfonate
The title compound was prepared using the methods from Example 37C, substituting the
product from Example 33 for the product from Example 32.
Example 38B
(2R,5R)-1 -(4-fluorophenyl)-2,5-bis(4-nitrophenyl)pyrroUdine
The title compound was prepared using the methods from Example 37D, substituting 4-
fluoroaniline for 4-terf-butylaniline.
Example 38C
4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline
To a solution of the product from Example 38B (2.34 g, 5.74 mmol) in 1:1 ethanol:THF (60
ml) in a 250 mL stainless steel pressure bottle was added Pt02 (0.47 g, 2.06 mmol) and the resulting
mixture was placed under H2 pressure (30 psi) and stirred at rt. for 90 min. The mixture was filtered
through a nylon membrane and the filtrate was concentrated in vacuo. The crude product was purified
by column chromatography on silica gel using a solvent gradient of 0-65% ethyl acetate in hexanes to
give the title compound as a solid (0.736 g, 37%).
Example 38D
(2S,2'S)-tert-butyl2,2'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
To a solution of the product from Example 38C (3.54 g, 10.19 mmol), (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.48 g, 25.5 mmol), and HATU (9.69 g, 25.5 mmol) in
anhydrous NMP (50mL) was added N,N-diisopropylethylamine (5.29 ml, 30.6 mmol), and reaction
mixture was stirred at room temperature for 30-45 minutes. The reaction mixture diluted with water
(500mL). The precipitated product was filtered and washed with water (3xl00mL), sodium
bicarbonate solution (50mL), and water (50mL). The product dried at 40 °C for 15 h. This material
(8.5g) was passed through a pad of silica gel and eluted with ethyl acetate to afford the white solid
product (7.9g, 99%).
Example 38E
(2S,2,S)-N,N'-(4,4,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-
2-carboxamide
To a solution of the product from Example 38D (7.9 g, 10.65 mmol) in dichloromethane
(50mL), was added 5M HC1 solution in isopropyl alcohol (50mL) and the reaction mixture was stirred
at room temperature for 16 h. The solvent was evaporated by rotavap under vacuum and crude
material taken in dichloromethane containing 20% methanol (200mL). The solution was washed with
5% ammonium hydroxide solution (90mL), brine (50mL) and dried over MgS04. The solution was
filtered and concentrated to give 6.5g of crude product. This material was recrystallized from ethyl
acetate /heptane (8/2) to give the title compound (5.0 g, 87% yield).
Example 38F
Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3,3-dimethyl-l-oxobutane-
2,1 -diyl)dicarbamate
To a solution of the product from Example 38E (4.14 g, 7.64 mmol), (S)-2-
methoxycarbonylamino-3,3-dimethyl-butyric acid (3.62 g, 19.11 mmol), and EDAC (3.66 g, 19.11
mmol) in anhydrous DMF (80mL) was added N,N-diisopropylethylamine (2.96 g, 22.93 mmol) and
the solution was stirred at room temperature for 4 h. The reaction mixture poured into 400 mL of
water, and the white precipitate obtained was filtered and washed with water (3x50mL), sodium
bicarbonate (50mL), water (50ML), and dried at 45 °C in a vacuum oven with nitrogen purge for 15 h
to give 7.0 g of the crude product. The crude material was loaded on silica gel column (150g silica)
and eluted with a gradient starting with ethyl acetate/ heptane (7/3), and ending with ethyl acetate.
Desired fractions were combined and solvent distilled off to give very light yellow oil, which was
triturated MTBE /heptane(l:9) for lh. The white solid thus obtained was filtered and dried in a
vacuum oven with nitrogen purge to afford 6.1g of product. The solid 5.5 g was dissolved in 16mL of
methanol and this solution was added into water (220 mL) in a 500mL flask. The slurry was stirred
for 30 minutes, and the solid was collected by filtration, dried at 45 CC with nitrogen purge for 15 h to
give the title compound (5.4 g). :H NMR (400 MHz, DMSO-D6) δ ppm0.96 (s, 18 H) 1.64 (d, 7=5.53
Hz, 2 H) 1.78 - 1.93 (m, 6 H) 1.94 - 2.06 (m, 2 H) 2.09 - 2.21 (m, 2 H) 3.54 (s, 6 H) 3.59 - 3.69 (m,
2 H) 3.72 - 3.83 (m, 2 H) 4.20 (d, 7=8.89 Hz, 2 H) 4.43 (dd, 7=7.92, 5.42 Hz, 2 H) 5.16 (d, 7=6.29
Hz, 2 H) 6.20 (dd, 7=9.16, 4.39 Hz, 2 H) 6.77 (t, 7=8.95 Hz, 2 H) 7.12 (d, 7=8.57 Hz, 4 H) 7.50 (d,
7=8.57 Hz, 4 H) 9.99 (s, 2 H). The tide compound showed an EC50 value of less than about 0.1 nM in
HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 39
Ar-(methoxycarbonyl)-L-valyl-Af-(4-{(25,55')-l-(4-fluorophenyl)-5-[4-(2-{(25)-l-[iV-
(memoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-l//-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
and
N-(methoxycarbonyl)-L-valyl-iV-(4-{ (2R,5R)-l -(4-fluorophenyl)-5-[4-(2- {(2S)-1 -[N-
(mem6xycarbonyl)-L-valyl]pyrrolidin-2-yl}-l/7-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
l-(4-bromophenyl)-4-(4-nitrophenyl)butane-l,4-dione
Added benzene (108 mL) to anhydrous zinc(H) chloride (19.62 g, 144 mmol), followed by the
addition of diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and
stirred at room temperature for 2 h. Added 2-bromo-l-(4-bromophenyi)ethanone (20 g, 72.0 mmol)
and l-(4-nitrophenyl)ethanone (17.83 g, 108 mmol) together and stirred mixture for 18 h. Added 5%
aq. sulfuric acid (50 mL) and stirred vigorously, then the product was collected by filtration, rinsed
with benzene, water, methanol, dichloromethane and dried under vacuum to provide the product (15.0
g, 58% yield, colorless powder).
Example 39B
l-(4-bromophenyl)-4-(4-nitrophenyl)butane-l,4-diol
Dissolved the product from Example 39A (3.64 g, 10.05 mmol) in ethanol (67 mL) and added
sodium borohydride (0.837 g, 22.11 mmol) portionwise. After stirring for 1H at room temperature,
the mixture was filtered through celite and washed with methanol and ethyl acetate and the filtrate
concentrated to a solid. The solid was dissolved in ethyl acetate (200 mL) and extracted with IN aq.
HC1 (200 mL), then brine and the organic layer dried and concentrated to a colorless oil (3.68 g,
100%) that was used directly in the next reaction.
Example 39C
l-(4-bromophenyl)-4-(4-nitrophenyl)butane-l,4-diyldimethanesulfonate
Dissolved the product from Example 39B (3.68 g, 10.05 mmol) in dichloromethane (167 mL)
and cooled the solution in an ice bath followed by the addition of triethylamine (4.20 mL, 30.1 mmol)
and methanesulfonyl chloride (1.96 mL, 25.1 mmol) dropwise. After stirring for 15 min, the solution
was concentrated to a solid (5.25 g, 100%) that was used directly in the next reaction.
Example 39D
2-(4-bromophenyl)-1 -(4-fluorophenyl)-5-(4-nitrophenyl)pyrrolidine
Dissolved the product from Example 39C (5.25 g, 10.05 mmol) in DMF (31 mL) and then
added 4-fluoroaniline (9.65 mL, 101 mmol) and heated solution at 50 °C for 18 h. Solution was
cooled to room temperature and IN aq. HC1 added (100 mL) then extracted with ethyl acetate (2 x
200 mL), then combined organic extracts washed with brine, dried and concentrated to an amber oil to
which methanol (10 mL) was added and after 3 h a yellow solid (1.05 g, 24%) resulted as the title
compound as a 1/1 mixture of trans pyrrolidine isomers.
Example 39E
l-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yi)phenyi)pyrrolidine
Dissolved the product from Example 39D (1.05 g, 2.38 mmol), 4,4,4,,4',5,5,5',5'-octamethyl-
2,2'-bi(l,3,2-dioxaborolane) (0.725 g, 2.86 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(H) (0.194 g, 0.238 mmol), and potassium acetate
(0.35 g, 3.57 mmol) in dioxane (20 mL) and then bubbled nitrogen gas through the solution for 10
min, then heated at 100 °C for 1.5 h. Solution was cooled to room temperature then filtered through
celite and washed with ethyl acetate (20 mL). The filtrate was dried, concentrated and the residue
purified by column chromatography on silica gel, eluting with a solvent gradient of 10-50% ethyl
acetate in hexane to give the title compound (1.09 g, 94%) as a yellow solid and a 1/1 mixture of trans
stereoisomers.
Example 39F
(2S)-tert-butyl2-(4-(4-(l-(4-fluorophenyl)-5-(4-nitrophenyl)pyn-olidin-2-yl)phenyl)-lH-imidazol-2-
yl)pyrrolidine-1 -carboxylate
Dissolved the product from Example 39E (1.05 g, 2.15 mmol), the product from Example
26D (0.748 g, 2.365 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(n) (0.176 g,
0.215 mmol) in a mixture of toluene (10 mL), ethanol (10 mL) and a IN aq. sodium bicarbonate
solution (2.58 mL, 2.58 mmol) and bubbled nitrogen gas through the solution for 10 min, then heated
at 90°C for 3 h. Solution was cooled to room temperature and water (20 mL) added then extracted
with dichloromethane (50 mL), then dried, concentrated and the residue purified by column
chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in hexane to
give the title compound (0.28 g, 72%) as a yellow solid and a 1/1 mixture of trans stereoisomers.
Example 39G
(2S)-tert-butyl2-(4-(4-(5-(4-aminophenyl)-l-(4-fluorophenyl)pyrrolidin-2-yl)phenyl)-lH-imidazol-2-
yl)pyrrolidine-1 -carboxylate
Dissolved the product from Example 39F (300 mg, 0.502 mmol) in ethanol (5 mL) and THF
(5 mL) then added platinum(IV) oxide (22.8 mg, 0.1 mmol) and a hydrogen balloon and stirred the
solution at room temperature for 2.5 h. Solution was filtered through celite and washed with
methanol (10 mL), then concentrated to give the title compound (285 mg, 100%) as a colorless semi-
solid and a 1/1 mixture of stereoisomers.
Example 39H
(2S)4ert-butyl2-(4<5-(4<2-((S)4-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)-l-
(4-fluorophenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-l-carboxylate
Dissolved the product from Example 39G (285 mg, 0.502 mmol), (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (162 mg, 0.753 mmol), HATU (305 mg, 0.803 mmol)
and Hunig's base (0.263 mL, 1.506 mmol) in DMSO (5 mL) and stirred at room temperature for 1H.
Dichloromethane (50 mL) was added followed by extraction with water (2 x 50 mL), the organic
extract dried, concentrated and the residue dissolved in methanol (10 mL) followed by the addition of
potassium carbonate (400 mg, 2.89 mmol) and stirred the bright yellow solution at room temperature
for 30 min. The solution was then filtered and the filtrate concentrated to an oil, which was dissolved
in a 95/5 dichloromethane/methanol mixture (50 mL) and extracted with water (20 mL). The organic
extract was dried and concentrated to give the title product (350 mg, 91%) as a light yellow solid and
a 1/1 mixture of stereoisomers.
Example 391
(2S)-N-(4-(l<4-fluorophenyl)-5K4-(2<(S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)pyrroUdin-2-
yl)phenyl)pyrrolidine-2-carboxamide hydrochloride salt
Dissolved the product from Example 39H (350 mg, 0.458 mmol) in 4M hydrochloric acid in
dioxane solution (6 mL) and stirred the solution at room temperature for 30 min then concentrated the
mixture under high vacuum to a solid (approx. 310 mg) as a hydrochloride salt that was used directly
in the next reaction.
Example 39J
AT-(methoxycarbonyl)-L-valyl-iV-(4-{(25,,515)-l-(4-fluorophenyl)-5-[4-(2-{(25)-l-[N-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
and
iV-(methoxycarbonyl)-L-valyl-Ar-(4-{(2R,5^)-l-(4-fluorophenyl)-5-[4-(2-{(2lS)-l-[iV-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
To a mixture of the product from Example 391 (300 mg, 0.45 mmol), (S)-2-
(memoxycarbonylamino)-3-methylbutanoic acid (173 mg, 0.99 mmol), and HATU (428 mg, 1.125
mmol) in DMSO (5 ml) was added Hunig's base (0.786 mL, 4.5 mmol), and the reaction was stirred at
room temperature for 1H. Dichloromethane (50 mL) was added followed by extraction with water (2
x 25 mL), the organic extract dried, concentrated and the residue dissolved in methanol (15 mL)
followed by the addition of potassium carbonate (300 mg, 2.17 mmol) and stirred at room temperature
for 20 min. The solution was then filtered and the filtrate concentrated to an oil, which was dissolved
in a 95/5 dichloromethane/methanol mixture (50 mL) and extracted with water (20 mL). The organic
extract was dried and concentrated, and the residue purified by column chromatography on silica gel,
eluting with a solvent gradient of 0-25% methanol in dichloromethane to give the title compounds
(0.13 g, 33%) as a colorless solid and as a 1/1 mixture of diastereomers. :H NMR (400 MHz, DMSO-
D6) δ ppm 11.64 (s, 1H), 9.94 (s, 1H), 7.57 (d, J=8.1Hz, 2H), 7.47 (m, 3H), 7.33 (d, J=1.7 Hz, 1H),
7.24 (m, ZH), 7.08 (m, 4H), 6.72 (m, 2H), 6.17 (m, 2H), 5.15 (m, 2H), 5.01 (m, 1H), 4.38 (no, 1H), 4.0
(m, 2H), 3.75 (m, 2H), 3.56 (m, 1H), 3.48 (s, 3H), 3.47 (s, 3H), 2.06 (m, 2H), 1.87 (m, 8H), 1.63 (m,
2H), 0.82 (m, 12H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-
Conl replicon assays in the presence of 5% FBS.
Example 40
Af-(methoxycarbonyl)-L-valyl-Af-(4-{(2l?,55)-l-(4-tert-butylphenyl)-5-[4-(2-{(25)-l-[//-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
and
A?-(methoxycarbonyl)-L-valyl-N-(4-{(2i?,5R)-l-(4-ferf-butylphenyl)-5-[4-(2-{(25)-l-[^-
(memoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
2-(4-bromophenyl)-l-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidine
The product from Example 39C (10.86 g, 20.79 mmol), DMF (65 mL) and 4-tert-butylaniline
(26.5 mL, 166 mmol) was reacted according to the procedure in Example 39D to provide the title
compound (5.0 g, 50%, yellow solid) as a mixture of cis and trans pyrrolidine stereoisomers.
Example 40B
l-(4-tert-butylphenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)phenyl)pyrrolidine
The product from Example 40A (2.0 g, 4.17 mmol), 4,4,4',4',5,5,5\5'-octamethyl-2,2'-
bi(l,3,2-dioxaborolane) (1.27 g, 5.01 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.681 g, 0.834 mmol), and potassium acetate
(0.614 g, 6.26 mmol) in dioxane (35 mL) was reacted according to the procedure in Example 39E to
provide the title compound (1.5 g, 68%, yellow solid) as a mixture of stereoisomers.
Example 40C
(2S)-tert-butyl2-(4-(4-(l-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)-lH-imidazol-
2-yl)pyrrolidine-1 -carboxylate
The product from Example 40B (0.7 g, 1.33 mmol), (S)-tert-butyl 2-(4-bromo-lH-imidazol-2-
yl)pyrrolidine-l-carboxylate (0.462 g, 1.463 mmol), [1,1'-
bis(diphenylphosphhio)ferrocene]dichloropalladium(n) (0.109 g, 0.133 mmol) in a mixture of toluene
(6 mL), ethanol (6 mL) and a IN aq. sodium bicarbonate solution (1.6 mL, 1.6 mmol) was reacted
according to the procedure in Example 39F to provide the title compound (0.66 g, 78%, yellow solid)
as a mixture of stereoisomers.
Example 40D
(2S)-tert-butyl2-(4-(4-(5-(4-aminophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-yl)phenyl)-lH-
imidazol-2-yl)pyrrolidine-1 -carboxylate
The product from example 40C (1.37 g, 2.153 mmol), in ethanol (10 mL) and THF (10 mL)
then added platinum(IV) oxide (196 mg, 0.862 mmol) and a hydrogen balloon and stirred the solution
at room temperature for 48 h. The reaction was then treated according to the procedure in Example
39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers.
Example 40E
(2R)-tert-butyl2-(4-(5-(4-(2-((S)-l-(tert-butoxycarbonyl)pyrroUdin-2-yl)-m-imidazol-4-yl)phenyl)-
l-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-l-carboxylate
The product from Example 40D (1.3 g, 2.146 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-
2-carboxylic acid (1.386 g, 6.44 mmol), HATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL,
6.44 mmol) in DMSO (20 mL) was reacted according to the procedure in Example 39H to provide the
tide compound (1.01 g, 59%) as a mixture of stereoisomers.
Example 40F
(2R)-N-(4-(l-(4-tert-butylphenyl)-5-(4-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)pyrrolidin-
2-yl)phenyl)pyrrolidine-2-carboxamide hydrochloride salt
The product from Example 40E (610 mg, 0.76 mmol), in 2M hydrochloric acid in dioxane
solution (10 mL) was reacted according to the procedure in Example 391 to provide the title
compound (495 mg) as a hydrochloride salt and a mixture of stereoisomers.
Example 40G
^-(methoxycarbonyl)-L-valyl-Af-(4-{(25,55)-l-(4-fert-butylphenyl)-5-[4-(2-{(25')-l-[N-
(memoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lF4midazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
and
N-(methoxycarbonyl)-L-valyl-iV-(4- {(2R,5R> l-(4-tert-butylphenyl)-5-[4-(2- {(25)-1 -[iV-
(memoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
prolinamide (ACD vl2)
The product from Example 40F (372 mg, 0.617 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (324 mg, 1.851 mmol), HATU (821 mg, 2.16 mmol) in DMSO (6 ml) and
Hunig's base (1.078 ml, 6.17 mmol) was reacted according to the procedure in Example 39J then the
reaction was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase
chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title
compounds (68 mg, 12% yield, white solid) as a 1/1 mixture of diastereomers .1H NMR (free base)
(400 MHz, DMSO-D6) 8 ppm 0.80 - 0.96 (m, 12 H), 1.10 (s, 9 H), 1.65 (d, 7=6.07 Hz, 2 H), 1.82 -
2.04 (m, 8 H), 2.07 - 2.20 (m, 3 H), 3.52 (s, 3 H), 3.53 (s, 3 H), 3.58 - 3.66 (m, 2 H), 3.73 - 3.85 (m, 3
H), 3.99 - 4.08 (m, 2 H), 4.43 (dd, 7=7.97, 4.93 Hz, 1H), 5.06 (dd, 7=6.99, 2.87 Hz, 1H), 5.17 (d,
7=6.40 Hz, 2 H), 6.20 (d, 7=8.89 Hz, 2 H), 6.93 (d, 7=8.89 Hz, 2 H), 7.14 (dd, 7=8.51, 2.87 Hz, 4 H),
7.30 (t, 7=9.11Hz, 2 H), 7.37 (d, 7=1.84 Hz, 1H), 7.50 (d, 7=8.02 Hz, 2 H), 7.61 (d, 7=8.13 Hz, 2 H),
9.98 (s, 1H), 11.68 (s, 1H). The title compound showed an EC50 value of less than about 0.1 nM in
HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 41
Af-(methoxycarbonyl)-L-valyl-N-(4-{(21S',5R)-l-(4-tert-butylphenyl)-5-[4-(2-{(25)-l-[N-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lflr-imidazol-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-L-
To the product from Example 40F (493 mg, 0.818 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (430 mg, 2.454 mmol), HATU (1088 mg, 2.86 mmol) in DMSO (8.2 mL) and
Hunig's base (1.5 mL, 8.59 mmol) was reacted according to the procedure in Example 39J then the
residue was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase
chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title
compound (80 mg, 11 % yield, white solid). JH NMR (free base) (400 MHz, DMSO-D6) 8 ppm 0.89 -
1.04 (m, 12 H), 1.20 (s, 9 H), 1.86 - 2.12 (m, 10 H), 2.15 - 2.27 (m, 3 H), 2.43 - 2.49 (m, 2 H), 3.60 (s,
3 H), 3.61 (s, 3 H), 3.66 - 3.74 (m, 1H), 3.81 - 3.93 (m, 2 H), 4.06 - 4.15 (m, 2 H), 4.52 (dd, 7=7.86,
4.61Hz, 1H), 4.74 (d, 7=5.20 Hz, 2 H), 5.14 (dd, 7=6.99, 3.31Hz, 1H), 6.40 (d, 7=8.78 Hz, 2 H),
7.06 - 7.11 (m, 2 H), 7.32 - 7.41 (m, 2 H), 7.47 (d, 7=1.73 Hz, 1H), 7.51 (d, 7=7.81Hz, 4 H), 7.65 (d,
7=8.46 Hz, 2 H), 7.77 (d, 7=8.24 Hz, 2 H), 10.10 (s, 1H) ,11.76 (s, 1H). The tide compound showed
an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 42
dimethyl (2S,2'S)-l,l'-((2S,2,S)-2,2'-(4,4'-(4,4,-((2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-1,1 ,-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( 1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
1,4-bis(4-bromophenyl)butane-1,4-diol
The product from Example 26E (3.42 g, 8.63 mmoi) was subjected to the conditions
described in Example 39B to provide the title product (3.45 g, 100% yield, colorless oil).
Example 42B
1,4-bis(4-bromophenyl)butane-1,4-diyl dimethanesulfonate
The product from Example 42A (3.45 g, 8.63 mmoi) was subjected to the conditions
described in Example 39C to provide the title product (4.8 g, 100%).
Example 42C
2,5-bis(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidine
The product from Example 42B (5.2 g, 9.35 mmol) was subjected to the conditions described
in Example 39D, substituting 4-tert-butylaniline (11.91 mL, 74.8 mmol) for 4-fluoroaniline to provide
the title product (3.89 g, 81%) as a mixture of isomers.
Example 42D
l-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine
Dissolved the product from Example 42C (3.88 g, 7.56 mmol), 4,4,4',4',5,5,5',5'-octamethyl-
2,2'-bi(l,3,2-dioxaborolane) (6.72 g, 26.5 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(n) (0.617 g, 0.756 mmol), and potassium acetate
(3.34 g, 34.0 mmol) in dimethoxyethane (70 mL) and bubbled nitrogen gas through the solution for 10
min, then heated at 85 °C for 1H. Solution was cooled to room temperature then filtered through
celite and washed with ethyl acetate (20 mL), the filtrate dried, then concentrated and the residue
purified by column chromatography on silica gel, eluting with a solvent gradient of 0-10% ethyl
acetate in hexane followed by trituration of the resultant solid with diethyl ether to give the title
compound (1.14 g, 25%) as a 1/1 mixture of trans stereoisomers.
Example 42E
(2S,2'S)-tert-butyl2,2'-(4,4'-(4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(lH-imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
Dissolved the products from Example 42D (0.915 g, 1.506 mmol), the product from Example
26D (1.429 g, 4.52 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(n) (0.123 g,
0.151 mmol) in a mixture of toluene (7 mL), ethanol (7 mL) and a 2N aq. sodium bicarbonate solution
(2.64 mL, 5.28 mmol) and bubbled nitrogen gas through the solution for 10 min, then heated at 100 °C
for 3 h. Solution was cooled to room temperature and water (20 mL) added then extracted with
dichloromethane (50 mL), then dried, concentrated and the residue purified by column
chromatography on silica gel, eluting with a solvent gradient of 0-80% ethyl acetate in hexane to give
the title compound (0.93 g, 75%) as a 1/1 mixture of trans stereoisomers.
Example 42F
(S)-4,4'-(4,4'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 -phenylene))bis(2-((S)-pyrrolidin-2-
yl)-lH-imidazole) hydrochloride salt
To the product from Example 42E (1.11 g, 1.344 mmol), in 4M hydrochloric acid in dioxane
solution (5 mL) was reacted according to the procedure in Example 391 to provide the title compound
(1.12 g) as a hydrochloride salt and a mixture of stereoisomers.
dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2,-(4,4'-(4,4'-((2S,5S)-1 -(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-1, r-((2S,2'S)-2,2'-(4,4'-(4,4,-((2R,5R)-1 -(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
To a mixture of the products from Example 42F (1.04 g, 1.662 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.728 g, 4.15 mmol), and HATU (1.295 g, 3.41
mmol) in DMSO (20 mL) was added Hunig's base (2.322 mL, 13.29 mmol), and the reaction was
stirred at room temperature for 1H. Water (20 mL) was added to form a solid that was dissolved in
dichloromethane and purified by column chromatography on silica gel, eluting with a solvent gradient
of 0-5% methanol in dichloromethane to give a solid that was diluted with acetonitrile and water
(0.1% TFA) and further purified by reversed phase chromatography (C18), eluting with 10-100%
acetonitrile in water (0.1% TFA) to give the title compound (92 mg, 6% yield, white solid) as a 1/1
mixture of diastereomers. LH NMR (free base) (400 MHz, DMSO-D6) δ ppm 0.78 - 0.92 (m, 12 H),
1.09 (s, 9 H), 1.63 - 1.74 (m, 2 H), 1.85 - 2.00 (m, 6 H), 2.05 - 2.16 (m, 2 H), 3.44 - 3.50 (m, 4 H),
3.52 (s, 6 H), 3.70 - 3.82 (m, 4 H), 4.02 - 4.09 (m, 2 H), 5.04 (dd, J=6.67, 3.20 Hz, 2 H), 5.19 (t,
J=6.18 Hz, 2 H), 6.21 (d, J=8.57 Hz, 2 H), 6.91 (dd, J=7.16, 1.63 Hz, 2 H), 7.14 (dd, J=8.19, 2.22 Hz,
4 H), 7.20 - 7.30 (m, 2 H), 7.36 (d, J=1.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, J=4.01Hz, 2
H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon
assays in the presence of 5% FBS.
Example 43
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-(4,4'-((2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
The product from Example 42G was purified by chiral chromatography on a Chirapak IB
column eluting with a mixture of hexane/THF/MeOH (80/10/10). The title compound was the first of
2 diastereomers to elute. JH NMR (400 MHz, DMSO-D6) δ ppm 0.78 - 0.92 (m, 12 H), 1.09 (s, 9 H),
1.63 - 1.74 (m, 2 H), 1.85 - 2.00 (m, 6 H), 2.05 - 2.16 (m, 2 H), 3.44 - 3.50 (m, 4 H), 3.52 (s, 6 H),
3.70 - 3.82 (m, 4 H), 4.02 - 4.09 (m, 2 H), 5.04 (dd, J=6.67, 3.20 Hz, 2 H), 5.19 (t, J=6.18 Hz, 2 H),
6.21 (d, J=8.57 Hz, 2 H), 6.91 (dd, J=7.16, 1.63 Hz, 2 H), 7.14 (dd, J=8.19, 2.22 Hz, 4 H), 7.20 - 7.30
(m, 2 H), 7.36 (d, J=1.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, J=4.01Hz, 2 H). The tide
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the
presence of 5% FBS.
Example 44
dimethyl (2S,2,S)-l,l,-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
The product from Example 42G was purified by chiral chromatography on a Chirapak IB
column eluting with a mixture of hexane/THF/MeOH (80/10/10). The tide compound was the second
of 2 diastereomers to elute.1H NMR (400 MHz, DMSO-D6) δ ppm 0.78 - 0.92 (m, 12 H), 1.09 (s, 9
H), 1.63 - 1.74 (m, 2 H), 1.85 - 2.00 (m, 6 H), 2.05 - 2.16 (m, 2 H), 3.44 - 3.50 (m, 4 H), 3.52 (s, 6 H),
3.70 - 3.82 (m, 4 H), 4.02 - 4.09 (m, 2 H), 5.04 (dd, J=6.67, 3.20 Hz, 2 H), 5.19 (t, J=6.18 Hz, 2 H),
6.21 (d, J=8.57 Hz, 2 H), 6.91 (dd, J=7.16, 1.63 Hz, 2 H), 7.14 (dd, J=8.19, 2.22 Hz, 4 H), 7.20 - 7.30
(m, 2 H), 7.36 (d, J=1.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, J=4.01Hz, 2 H). The tide
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the
presence of 5% FBS.
Example 45
dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(4,4'-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( 1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrroUdine-2,5-
diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
2,5-bis(4-bromophenyl)-1 -(4-fluorophenyl)pyrrolidine
The product from Example 42B (5.2 g, 9.35 mmol) was subjected to the conditions described
in Example 39D to provide the title product (6.41 g, 48%) as a mixture of cis and trans isomers.
Example 45B
l-(4-fluorophenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine
The product from Example 45A (2.17 g, 4.57 mmol) was subjected to the conditions
described in Example 42D and purified by column chromatography on silica gel, eluting with a
solvent gradient of 0-15% ethyl acetate in hexane to give the title compound (1.65 g, 64%) as a
mixture of cis and trans stereoisomers.
Example 45C
(2S,2,S)-tert-butyl2,2'-(4,4'-(4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-
imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
The product from Example 45B (1.0 g, 1.756 mmol) was subjected to the conditions
described in Example 42E to provide the title product (1.0 g, 72%) as a mixture of cis and trans
isomers.
Example 45D
(S)-4,4,-(4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-2-yl)-
lH-imidazole)
Dissolved the product from Example 45C (150 mg, 0.19 mmol) in dichloromethane (1 mL)
and TFA (1 mL) and stirred the solution at room temperature for 1H then concentrated the mixture
under high vacuum to give a solid that was diluted with acetonitrile and water (0.1% TFA) and
purified by reversed phase chromatography (CI8), eluting with 10-100% acetonitrile in water (0.1%
TFA) to give the title compound (62 mg, 55% yield) as a 1/1 mixture of trans diastereomers that
eluted before the cis isomer.
Example 45E
dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4,-((2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( 1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4,-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis( lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
To a mixture of the product from Example 45D (47 mg, 0.08 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (29 mg, 0.168 mmol), and HATU (61 mg, 0.16
mmol) in DMSO (0.8 mL) was added Hunig's base (0.035 mL, 0.2 mmol) was reacted according to
the procedure in Example 39J then the residue was diluted with acetonitrile and water (0.1% TFA)
and purified by reversed phase chromatography (CI8), eluting with 10-100% acetonitrile in water
(0.1% TFA) to give the title compound (54 mg, 75% yield, white solid) as a 1/1 mixture of
diastereomers .1H NMR (free base) (400 MHz, DMSO-D6) 8 ppm 11.62 -12.13 (m, 2 H), 7.59 - 7.71
(m, 7=8.13 Hz, 3 H), 7.46 - 7.57 (m, 7=8.24 Hz, 1H), 7.38 (d, 7=1.84 Hz, 2 H), 7.10 - 7.32 (m, 6 H),
6.72 - 6.83 (m, 2 H), 6.19 - 6.31 (m, 2 H), 5.17 - 5.28 (m, 2 H), 5.02 - 5.11 (m, 7=6.72 Hz, 2 H), 4.05
(t, 7=8.40 Hz, 2 H), 3.71 - 3.85 (m, 4 H), 3.53 (s, 6 H), 2.05 - 2.21 (m, 4 H), 1.94 (s, 6 H), 1.64 - 1.78
(m, 2 H), 0.77 - 0.95 (m, 12 H). The tide compound showed an EC5o value of less than about 0.1 nM
in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 46
dimethyl (2S,2,S)-l,l'-((2S,2,S)-2,2,-(4,4'-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
The product from Example 45E was purified by chiral chromatography on a Chirapak IB
column eluting with a mixture of hexane/THF/MeOH (85/7.5/7.5). -H NMR (400 MHz, DMSO-D6) 8
ppm 11.62 -12.13 (m, 2 H), 7.59 - 7.71 (m, 7=8.13 Hz, 3 H), 7.46 - 7.57 (m, 7=8.24 Hz, 1H), 7.38 (d,
7=1.84 Hz, 2 H), 7.10 - 7.32 (m, 6 H), 6.72 - 6.83 (m, 2 H), 6.19 - 6.31 (m, 2 H), 5.17 - 5.28 (m, 2 H),
5.02 - 5.11 (m, 7=6.72 Hz, 2 H), 4.05 (t, 7=8.40 Hz, 2 H), 3.71 - 3.85 (m, 4 H), 3.53 (s, 6 H), 2.05 -
2.21 (m, 4 H), 1.94 (s, 6 H), 1.64 - 1.78 (m, 2 H), 0.77 - 0.95 (m, 12 H). The tide compound showed
an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 47
dimethyl (2S,2'S)-l,l,-((2S,2,S)-2,2,-(4,4'-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
The product from Example 45E was purified by chiral chromatography on a Chirapak IB
column eluting with a mixture of hexane/THF/MeOH (85/7.5/7.5). :H NMR (400 MHz, DMSO-D6) δ ppm 11.62 -12.13 (m, 2 H), 7.59 - 7.71 (m, 7=8.13 Hz, 3 H), 7.46 - 7.57 (m, 7=8.24 Hz, 1H), 7.38 (d,
7=1.84 Hz, 2 H), 7.10 - 7.32 (m, 6 H), 6.72 - 6.83 (m, 2 H), 6.19 - 6.31 (m, 2 H), 5.17 - 5.28 (m, 2 H),
5.02 - 5.11 (m, 7=6.72 Hz, 2 H), 4.05 (t, 7=8.40 Hz, 2 H), 3.71 - 3.85 (m, 4 H), 3.53 (s, 6 H), 2.05 -
2.21 (m, 4 H), 1.94 (s, 6 H), 1.64 - 1.78 (m, 2 H), 0.77 - 0.95 (m, 12 H). The tide compound showed
an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
Example 48
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4,-(4,4,-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-
dmiemoxypyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-irrddazole^,2-o^yl))bis(pyrrolidine-2,l-
diyl))bis(3-methyl-1 -oxobutane-2,1 -diyl)dicarbamate
(2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-l-(4-tert-butylphenyl)pyrrolidine-3,4-diol
To a solution of (lR,l'R)-l,l,-((4R,5R)-2,2-dimethyl-l,3-dioxolane-4,5-diyl)diethane-l,2-diol
(200 mg, 0.90 mmol) in methanol (6 ml) and dichloromethane (3 ml) was added iodobenzene
diacetate (696 mg, 2.16 mmol) and the solution was stirred at room temperature for 5 h. Solution was
concentrated and to the residue was added 0.1M H2S04 (4 ml) and stirring was continued at room
temperature for 18 h. The pH was adjusted to ~6 with solid NaHC03, and 4-tert-butylaniline (287 ui,
1.80 mmol) was added followed by 4-benzyloxyphenylboronic acid (369 mg, 1.62 mmol) and
hexafluoroisopropyl alcohol (4 ml) and stirred at 60 °C for 2 h. Solvent was concentrated and the
residue dissolved in ethyl acetate, washed with H20, 0.33M K3PO4, brine, dried (Na2S04), filtered and
concentrated to give crude product which was purified by chromatography on silica gel eluting with
0-20% ethyl acetate/dichloromethane to give title compound (249 mg, 46%).
Example 48B
(2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine
To a solution of the product from Example 48A (200 mg, 0.33 mmol) in THF (2.1 ml) and
DMF (0.7 ml) at 0 °C was added, in portions, sodium hydride, 60% in mineral oil (40.0 mg, 1.0
mmol) and stirring continued at 0 °C for 20 min. Iodomethane (0.046 ml, 0.734 mmol) was added and
stirring continued at room temperature overnight. Diluted with ethyl acetate, washed with saturated
NH4CI, H20, brine, dried (Na2S04), filtered and concentrated to give crude product which was
purified by chromatography on silica gel eluting with 0-20% ethyl acetate/dichloromethane to give
title compound (170 mg, 80%>
Example 48C
4,4'-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)diphenol
To a solution of the product from Example 48B (168 mg, 0.268mmol) in ethyl acetate (3 ml)
was added 10% palladium on carbon (17 mg) and the flask was evacuated and back-filled with H2 gas.
The solution was stirred under a balloon of H2 gas for 20 h, filtered through Celite, and washed with
ethyl acetate and methanol. The filtrate was concentrated and the residue was azeotroped with ether
to give title compound (120 mg, 100%) as a white solid.
Example 48D
4,4'-((2S,3R,4R,5S)-1 -(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1 -phenylene)
bis(l,l,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate)
To a solution of the product from Example 48C (117 mg, 0.261 mmol) in DMF (1.3 ml) was
added K2C03 (81 mg, 0.588 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonyl fluoride (0.101
ml, 0.575 mmol) and the solution was stirred at 100 °C for 1H. The cooled solution was diluted with
ethyl acetate, washed with H20, brine, dried (Na2SC>4), filtered and concentrated to give an oil which
was purified by chromatography on silica gel eluting with 0-20% ethyl acetate/hexane to give title
compound (195 mg, 73.7 % yield).
Example 48E
(2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)phenyl)pyrrolidine
To a pressure tube was added the product from Example 48D (193 mg, 0.191 mmol),
4,4,4',4,,5,5,5,,5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (102 mg, 0.401 mmol), dicyclohexyl(2',4',6'-
triisopropylbiphenyl-2-yl)phosphine (X-Phos) (14.55 mg, 0.031 mmol), potassium acetate (112 mg,
1.145 mmol), and dioxane (1.5 ml) and the solution was degassed with N2 gas for 30 min.
Tris(dibenzylideneacetone)dipalladium(O) (6.99 mg, 7.63 nmol) was added and degassing was
continued another 10 min. The tube was sealed and heated with stirring at 100 °C overnight. The
cooled solution was diluted with ethyl acetate, washed with H20, brine, dried (Na2S04), filtered and
the filtrate treated with 3-(mercaptopropyl) silica gel for 1H. The solution was filtered and solvent
removed to give a yellow solid which was purified by chromatography on silica gel eluting with 0-
20% ethyl acetate/hexane to give title compound (99 mg, 78 % yield) as a white solid.
Example 48F
(2S,2'S)4ert-butyl2,2'<4,4,-(4,4'-((2S,3R,4R,5S)4-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-
2,5-diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
In a sealed tube was combined the product from Example 48E (97 mg, 0.145 mmol), the
product from Example 26D (115 mg, 0.363 mmol), 1 M Na2C03 (0.363 ml, 0.363 mmol), EtOH (1.0
ml) and toluene (1.0 ml) and the solution was degassed with N2 gas for 30 min. 1,1'-
Bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (10.63 mg, 0.015
mmol) was added and degassing was continued an additional 10 min. The tube was sealed and heated
at 100 °C for 3 h. The cooled solution was diluted with ethyl acetate, filtered through Celite and the
residue washed with ethyl acetate. The filtrate was concentrated in vacuo and the resulting material
was purified chromatography on silica gel using a 12g silica gel column eluting with 0-2%
methanol/dichloromethane to give title compound (85 mg, 66.1 % yield).
Example 48G
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-(4,4,-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-
dimemoxypyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-
diyl))bis(3-methyl-l-oxobutane-2,l-diyl)dicarbamate
To a solution of the product from Example 48F (83 mg, 0.094 mmol) in dichloromethane (1.0
ml) was added TFA (1.0 ml, 12.98 mmol) and the solution was stirred at room temperature for 1H.
Solvent was concentrated and the residue was azeotroped 2 times with dichloromethane. The residue
was placed under vacuum for 1H to remove final traces of TFA. To this residue (64.2 mg, 0.094
mmol) was added DMSO (500 \il) followed by (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(41.1 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) and hunig's base (82 μL, 0.469 mmol). pH was
checked and additional Hunig's base was added to adjust pH to ~9. Stirring was continued at room
temperature for 1H. The solution was diluted with ethyl acetate, washed with H20, brine, dried
(Na2S04), filtered and concentrated to give crude residue. Purification was run by chromatography on
silica gel eluting with 0-4% methanol/dichloromethane over 60 min to give title compound (7.5 mg,
8.01 % yield). 1H NMR (400 MHz, CDC13) δ ppm 0.86 (s, 12H) 1.13 (s, 9H) 1.86-2.02 (m, 2H)
2.02-2.12 (m, 2H) 2.12-2.25 (m, 2H) 2.25-2.41 (m, 1H) 2.90-3.17 (m, 2H) 3.43 (s, 6H) 3.53-3.65 (m,
2H) 3.70 (s, 6H) 3.74-3.89 (m, 2H) 4.16-4.26 (m, 2H) 4.26-4.37 (m, 1H) 5.18-5.26 (m, 2H) 5.26-5.32
(m, 2H) 5.33-5.41 (m, 2H) 6.28 (d, J=8.78 Hz, 2H) 6.89-6.99 (m, 2H) 7.16 (s, 2H) 7.20 (s, 2H) 7.22
(s, 2H) 7.26 (s, 4H) 7.30-7.48 (br s, 1H) 7.58-7.82 (br s, 2H) 10.08-10.42 (br s, 1H). The title
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the
presence of 5% FBS.
Example 49
dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-
dimemoxypyrolidine-2,5-diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
Example 49A
(S)-tert-butyl2-(2-amino-5-bromophenylcarbamoyl)pyrrolidine-l-carboxylate
A solution of the 2-amino-4-bromoaniline (6.0 g, 32.1 mmol), Boc-Pro-OH (6.90 g, 32.1
mmol) and HATU (13.42 g, 35.3 mmol) in dry DMSO (160 mL) was treated with
diisopropylethylamine (14.0 mL, 10.4 g, 80 mmol) followed by stirring at room temperature for 18 h.
The mixture was diluted with ethyl acetate and extracted with water (3 x) and saturated sodium
chloride solution. Drying (Na2S04) and concentration in vacuo afforded a brown solid which was
used directly in the next step.
Example 49B
(S)-tert-butyl2-(5-bromo-lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate
A solution of the compound of Example 49A in glatial acetic acid (75 mL) was warmed at 60
°C for 3 h. The mixture was cooled and diluted with toluene and concentrated in vacuo. The
remainder of the acetic acid was removed by azeotroping with toluene (2 x) and the residue was
chromatographed over a 360 g silica gel cartridge, eluting with 25-75% ethyl acetate in
dichloromethane. These procedures afforded the product (10.0 g, 85%) as a light beige rigid foam.
Example 49C
(S)4ert-butyl2-(6-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-yl)pyrrolidine-
1-carboxylate
A solution of the compound of Example 49B (2.25 g, 6.14 mmol) in dry THF (25 mL) was
treated with sodium hydride (295 mg of 60% in oil, 177 mg, 7.37 mmol) followed by stirring at room
temperature for 1H. The solution was then treated with SEM-Chloride (1.20 mL, 1.13 g, 6.76 mmol)
followed by stirring at room temperature for 18 h. The mixture was quenched by addition of water
and the mixture was diluted with ethyl acetate. The mixture was extracted with water and saturated
sodium chloride solution. Drying (Na2NO4) and concentration in vacuo afforded an oil, which was
chromatographed over a 100 g silica gel cartridge, eluting with 20-75% ethyl acetate in hexanes.
These procedures afforded the product (2.24 g, 73%) as a heavy oil, which solidified after setting for
several days. This mixture of both regioisomeric SEM derivatives was not separated for use in the
next step.
Example 49D
(S)-tert-butyl2-(6-(4,4,5,5-tetramemyl-l,3,2-dioxaborolan-2-yl)-l-((2-(trimemylsnyl)emoxy)methyl)-
lH-benzo[d]imidazol-2-yl)pyrrolidine-l-carboxylate
In a resealable pressure tube, a solution of the compound of Example 49C (2.24 g, 4.51
mmol), bis(pinacolato)diboron (1.26 g, 4.96 mmol), and potassium acetate (1.33 g, 13.53 mmol) in
dry dioxane (23 mL) was degassed by nitrogen sparge for 30 min. The solution was treated with 1,1'-
bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (111 mg, 0.14
mmol) followed by degassing for another 5 min. The pressure tube was sealed and warmed at 90 °C
for 4 h. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and
saturated sodium chloride solution. The solution was dried (Na2S04) and stirred for 1H with 3-
mercaptopropyl) silica gel. After filtration and concentration in vacuo the brown oil was
chromatographed over a 100 g silica gel cartridge, eluting with 15-70% ethyl acetate in
dichloromethane. These procedures afforded the product (1.99 g, 81 %) as a white rigid foam.
Example 49E
(S)-tert-butyl2-(6-((2S,3R,4R,5S)-5-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-5-yl)-l-(4-tert-butylphenyl)-3,4-
dmydroxypyrroUdin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-
yl)pyrrolidine-l-carboxylate
A solution of 2,3-O-isopropylidene-C1-mannitol (144 mg, 0.65 mmol) and
iodobenzenediacetate (501 mg, 1.56 mmol) in 2:1 methanol-dichloromethane (3 mL) was stirred at
room temperature for 5 h. The mixture was concentrated in vacuo to a white paste and then
suspended in 0.1 M sulfuric acid solution (1.0 mL) followed by stirring at room temperature for 18 h.
The solution was adjusted to pH 6 by addition of solid sodium bicarbonate followed by addition of 4-
tert-butylaniline (206 μL, 193 mg, 1.30 mmol) the product from Example 49D (634 mg, 1.17 mmol)
and hexafluoroisopropyl alcohol (2.6 mL). The solution was then warmed at 70 °C for 5 h. The
solution was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and
extracted with 0.33 M tribasic potassium phosphate solution and saturated sodium chloride solution.
Drying (Na2S04) and concentration in vacuo afforded a brown oil, which was chromatographed over a
50 g silica gel cartridge, eluting with 15-85% ethyl acetate in dichloromethane. These procedures
afforded the recovered boronate (208 mg) as a viscous brown oil. The column was then re-eluted with
0-20% methanol in dichloromethane to afford the product (159 mg, 23%) as a brown solid.
Example 49F
(S)-tert-butyl2-(6-((2S,3R,4R,5S)-5-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-5-yl)-l-(4-tert-butylphenyl)-3,4-
dimethoxypyrrolidin-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo [d]imidazol-2-
yl)pyrrolidine-1 -carboxylate
A solution of the product from Example 49E (154 mg, 0.14 mol) in dry THF was treated with
sodium hydride (13 mg of 60% in oil, 8 mg, 0.33 mmol) followed by stirring at room temperature for
30 min. The mixture was treated with methyl iodide (19 μL, 43 mg, 0.30 mmol) followed by stirring
at room temperature for 2 h. The mixture was diluted with ethyl acetate and quenched by addition of
water. The mixture was extracted with water and saturated sodium chloride solution. Drying
(Na2S04) and concentration in vacuo afforded a brown oil, which was chromatographed over a 25 g
silica gel cartridge, eluting with 0-15% methanol in dichloromethane. These procedures afforded the
product (121 mg, 77%) as a beige foam.
Example 49G
(S)-5,5'-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrroUdine-2,5-diyl)bis(2-((S)-
pyrrolidin-2-yl)-lH-benzo[d]imidazole)
A solution of the compound of Example 49F (111 mg, 0.10 mmol) in ethanol (1 rnL) was
treated with 4 N hydrochloric acid solution (2.0 mL) followed by warming at 60 °C for 18 h. The
solution was cooled and concentrated in vacuo with ethanol-toluene mixtures (2 x) to afford the
tetrahydrochloride as a light yellow solid. This material was dissolved in methanol (3 mL) and stirred
with Amberlyte IRA 400 (OH- form, 1.4 mequiv/g, 577 mg, 0.81 mequiv) for 1H. The resin was
removed by filtration and the filtrate was concentrated in vacuo to afford the product (29 mg, 45%) as
a light amber glass.
dimethyl (2S,2,S)-l,l'-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-
dimethoxypyrrolidine-2,5-diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
A solution of the compound of Example 49G (29 mg, 0.046 mmol), HOBt hydrate (18 mg,
0.114 mmol), EDAC (22 mg, 0.114 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(20 mg, 0.114 mmol) in dry DMF (0.5 mL) at 0 °C was treated with N-methylmorpholine (15μL, 14
mg, 0.137 mmol) followed by stirring at 0 °C for 30 min and wanning to room temperature for 2 h.
The mixture was diluted with ethyl acetate and extracted with water (3 x) and saturated sodium
chloride solution. Drying (Na2S04) and concentration in vacuo afforded an oil which was dissolved
in methanol and treated with a small amount of potassium carbonate. After stirring 1H, the mixture
was filtered and concentrated in vacuo to afford a yellow oil, which was chromatographed over a 25 g
silica gel cartridge, eluting with 0-15% methanol in dichloromethane to give the product (14 mg,
32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (m, 4 H), 7.30 (m, 4 H), 7.07 (t, J = 9.1Hz, 2 H), 6.87 (m, 2 H), 6.31 (d, J = 8.9 Hz, 1H), 5.54 (m, 2 H), 5.14 (dd, J = 7.6, 4.6 Hz, 2 H), 4.14
(m, 2 H), 3.77 (m, 4 H), 3.51 (m, 6 H), 3.28 (m, 6 H), 2.15 (m, 4 H), 1.04 (s, 9 H), 0.86 (m, 12 H).
The title compound showed an EC50 value of from about 0.1 to about 1 nM in HCV lb-Con 1 replicon
assays in the presence of 5% FBS.
Example 50
dimethyl (2S,2'S)-1,1 '-((2S,2*S)-2,2,-(4,4,-(4,4'-( 1 -(4-(pentafluorothio)phenyl)- lH-pyrrole-2,5-
diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
oxobutane-2,1 -diyl)dicarbamate
2,5-bis(4-bromophenyl)-l-(4-(pentafluorothio)phenyl)-lH-pyrrole
Tide compound was prepared from the product from Example 26E using the methods from
Example 26F substituting 4-aminophenylsulfur pentafluoride for 4-tert-butylaniline to provide the
desired compound.
Example 50B
1 -(4-(pentafluorothio)phenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 1H-
pyrrole
Title compound was prepared using the methods from Example 26G substituting the product
from Example 50A for the product from Example 26F to provide the desired compound.
Example 50C
tert-butyl2,2'-(4,4'-(4,4'-(l-(4-(pentafluorothio)phenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(lH-imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
Title compound was prepared using the methods from Example 26H substituting the product
from Example 50B for the product from Example 26G to provide the desired compound.
Example 50D
4,4'-(4,4'-(l-(4-(pentafluorthio)phenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-(pyrrolidin-2-
yl)-lH-imidazole)
Title compound was prepared using the methods from Example 261 substituting the product
from Example 50C for the product from Example 26H to provide the desired compound.
Example 50E
Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-( 1 -(4-(pentafluorothio)phenyl)- lH-pyrrole-2,5-
diyl)bis(4,1 -phenylene))bis(lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1-
oxobutane-2,1 -diyl)dicarbamate
Title compound was prepared using the methods from Example 26J substituting the product
from Example 50D for the product from Example 261 to provide the desired compound. 1HNMR
(DMSO-d6; 400 MHz): 5 11.75 (br s, 2H), 7.88 (m, 2H), 7.56 (app d, J=8.35 Hz, 4H), 7.45 (br s, 2H),
7.27 (m, 4H), 6.96 (app d, J=8.35 Hz, 4H), 6.50 (s, 2H), 5.04 (m, 2H), 4.03 (m, 2H), 3.78 (m, 4H),
3.53 (s, 6H), 2.11-1.85 (m, 10H), 0.86 (d, J=6.72 Hz, 6H), 0.82 (d, J=6.72 Hz, 6H). The title
compound showed an EC50 value of less than about 0.1 nM in HCV lb-Con 1 replicon assays in the
presence of 5% FBS.
dimethyl ([ 1 -(4-fluorophenyl)- lH-pyrrole-2,5-diyl]bis{ benzene-4,1 -diylcarbamoyl(2S)pyrrolidine-
2,1 -diyl [(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Example 19D (150 mg) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were
processed using the method of Example 19E (substituting DMF as solvent) to provide the tide
compound which was purified using gradient silica gel chromatography (30-70% EtOAc in
hexanes)(70 mg). :H NMR (500 MHz, DMSO-D6) δ 9.76 (s, 2H), 7.16 (d, J== 8.7, 4H), 7.06 (d, J==
8.4, 2H), 6.92 (t, j= 8.7, 2H), 6.83 (dd, J= 5.0, 8.9, 2H), 6.71 (d, J= 8.7, 4H), 6.14 (s, 2H), 4.15 (dd,
J = 5.1, 7.9, 2H), 3.77 (t, J== 8.5, 2H), 3.59 - 3.50 (m, 2H), 3.40 - 3.31 (m, 2H), 3.27 (s, 6H), 1.95 -
1.82 (m, 2H), 1.79 - 1.52 (m, 8H), 0.67 (d, J = 6.8, 6H), 0.62 (d, J== 6.7, 6H). MS (ESI; M+H) m/z =
853.
dimethyl ([l-(4-fluoro-2-methylphenyl)-lH-pyrrole-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 1A was processed using 4-fluoro-2-methylaniline and the methods from Examples
19A, 19B, 19C, 19D, and 51 ((S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid was used) to
provide the title compound. 1H,NMR (400 MHz, DMSO-D6) δ 9.98 (s, 2H), 7.44 - 7.36 (m, 5H), 7.09
- 6.96 (m, 8H), 6.42 (s, 2H), 4.39 (dd, J = 5.5, 8.1, 2H), 4.19 (d, J = 8.7, 2H), 3.80 - 3.70 (m, 2H),
3.65 - 3.56 (m, 2H), 3.52 (s, 6H), 2.20 - 2.06 (m, 2H), 1.97 - 1.91 (m, 2H), 1.90 - 1.76 (m, 4H), 1.63
(s, 3H), 0.94 (s, 18H). MS (ESI; M+H) m/z = 895.
dimethyl ({(2S,5S)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 53A
dimethyl ({(2S,5S)-1 -[4-(trifluoromethyl)phenyl]pyrroUdine-2,5-diyl}bis {benzene-4,1 -
diylcarbamoyl(25)pyrrolidine-2,l-diylt(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate and
dimethyl ({(2i?,5R)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-4,l-
diylcarbamoyl(25)pyrrolidine-2,1 -diyl [(2S) -3 -methyl-1 -oxobutane-1,2 -diy 1]} )biscarbamate
To a solution of the product from Example 23B (84 mg, 0.142 mmol) in DMSO (1.5 mL) was
added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (62.2 mg, 0.355 mmol), HATU (135
mg, 0.355 mmol), and Hunig'sBase (0.074 mL, 0.426 mmol), and the resulting mixture was stirred at
rt for 90 min and then partitioned between H20 (1 mL) and EtOAc (2x2 mL). The combined organic
layers were dried over Na2S04, filtered and concentrated in vacuo. The drying agent was filtered off,
and the crude product was purified by column chromatography on silica gel using a solvent gradient
of 1-3% MeOH in CH2C12 to give the title compounds as a 1:1 mixture.
Example 53B
dimethyl ({(2S,5S)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 53A was separated on a Chiralpak AD-H column using 1:1
hexanes:(l:l EtOH:2-PrOH). The title compound was the first component to elute. 1H NMR (400
MHz, DMSO-D6) δ ppm 0.88 (d, 7=6.61Hz, 6 H), 0.93 (d, 7=6.61Hz, 6 H), 1.63 - 1.72 (m, 2 H),
1.78 - 2.06 (m, 8 H), 2.06 - 2.20 (m, 2 H), 3.52 (s, 6 H), 3.56 - 3.67 (m, 2 H), 3.73 - 3.86 (m, 2 H),
4.03 (t, 7=8.51Hz, 2 H), 4.42 (dd, 7=7.92, 4.88 Hz, 2 H), 5.27 (d, 7=6.61Hz, 2 H), 6.36 (d, 7=8.67
Hz, 2 H), 7.14 (d, 7=8.57 Hz, 4 H), 7.25 (d, 7=8.89 Hz, 2 H), 7.31 (d, 7=8.35 Hz, 2 H), 7.52 (d, 7=8.57
Hz, 4 H), 10.01 (s, 2 H); MS (ESI) m/z 906.3 (M+H)+.
dimethyl ({(2R,5R)-1 -[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis {benzene-4,1 -
diylcarbamoyl(2S)pyrroUdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 53A was separated on a Chiralpak AD-H column using 1:1Hexanes:(l:l EtOH:2-PrOH). The title compound was the second component to elute. 1H NMR (400
MHz, DMSO-D6) δ ppm 0.87 (d, 7=6.61Hz, 6 H), 0.92 (d, 7=6.72 Hz, 6 H), 1.64 - 1.74 (m, 2 H),
1.78 - 2.06 (m, 8 H), 2.06 - 2.22 (m, 2 H), 3.52 (s, 6 H), 3.56 - 3.67 (m, 2 H), 3.75 - 3.86 (m, 2 H),
3.97 - 4.08 (m, 2 H), 4.37 - 4.48 (m, 2 H), 5.28 (d, 7=6.51Hz, 2 H), 6.36 (d, 7=8.78 Hz, 2 H), 7.14 (d,
7=8.57 Hz, 4 H), 7.25 (d, 7=8.89 Hz, 2 H), 7.30 (d, 7=8.24 Hz, 2 H), 7.52 (d, 7=8.57 Hz, 4 H), 10.01
(s, 2 H); MS (ESI) m/z 906.3 (M+H)+.
dimethyl ([(2R,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 55A
1,4-bis(3-nitrophenyl)butane-1,4-dione
Anhydrous zinc(II) chloride (5.42 g, 39.7 mmol) was stirred in dry benzene (50 mL) under
nitrogen while diethylamine (3.10 mL, 29.8 mmol) and t-butanol (2.85 mL, 29.8 mmol) were added.
The resulting mixture was stirred at room temperature for 90 min to give a cloudy solution. To this
was added l-(3-nitrophenyl)ethanone (4.97g, 29.8mmol) followed by 2-bromo-l-(3-
nitrophenyl)ethanone (5.00g, 19.87mmol) and the resulting mixture allowed to stir at room
temperature overnight. A large portion of the benzene was subsequently removed by decantation. The
resulting mixture was then treated with 5% sulfuric acid (25mL) in a separatory funnel and the
aqueous phase drawn off. The organic phase was washed with water (2x25mL). A third washing
resulted in an emulsion. The contents of the funnel were emptied into a large volume of water
(750mL) to which was added sodium chloride and the oil in water mixture rapidly stirred. Methanol
was added (75mL) in portions to try and disperse the oil and promote solidification of the product.
After nearly forty eight hours of stirring the product solidified and was collected by vacuum filtration.
The filter cake was water washed, dried first in air and then a vacuum oven at 55 °C to provide the
title compound (5.85g, 90% yield) as a pale yellow solid that was used directly in the next step.
Example 55B
1,4-bis(3-nitrophenyl)butane- 1,4-diol
Sodium borohydride (0.6173 g, 17.74 mmol) was added to a suspension of Example 55A
(2.71 g, 8.26 mmol) in ethanol (150 mL) and stirred at ambient temperature for 3 hours. The reaction
was quenched with water (-50 mL) and concentrated to a paste which was taken up in 1:1
MeOH:THF. This suspension was filtered through a celite plug and concentrated. The residue was
taken up in toluene and heated with stirring to form a white paste which was then sonicated and
scraped until a filterable solid formed. This was filtered, rinsed with toluene and dried under vacuum
to afford 2.84 g (100%) of the title compound as an off white solid. MS (DCI) m/z 350 (M+NH4)+.
Example 55C
l,4-bis(3-nitrophenyl)butane-l,4-diyldhnethanesulfonate
Methanesulfonyl chloride (0.3 mL, 3.87 mmol) was added dropwise to a cold (0 °C) solution
of Example 55B (0.5089 g, 1.531 mmol) and triethylamine (0.65 mL, 4.66 mmol) in THF (10 mL).
The reaction was removed from the ice bath and stirred at ambient temperature for 30 minutes.
TFA (3 mL, 38.9 mmol) was added to a solution of Example 55F (0.4033 g, 0.544 mmol) in
dichloromethane (10 mL). After 90 minutes the reaction was concentrated. The residue was
sequentially dissolved in and concentrated in vacuo from the following solvents: dichloromethane
(2x), methanol (2x), and ether (lx). This semi-solid was taken up in dicholormethane and washed
with sat aq NaHC03 (2 x) water (lx) brine (lx) dried (MgS04) and filtered to provide the title
compound. LC/MS Rt 1.31 m/z 542 (M+H)+.
Example 55H
dimethyl ([(2R,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl [(2S)-3,3-dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Diisopropylethylamine (0.5 mL, 2.86 mmol) was added to a mixture of Example 55G, (S)-2-
methoxycarbonylamino-3,3-dimethyl-butyric acid (0.2600 g, 1.374 mmol) and HATU (0.4527 g,
1.191 mmol) in dichloromethane(15 mL). The reaction was stirred at ambient temperature for 18
hours. The reaction was diluted with dichloromethane, washed with water (2x), brine (lx), dried
(MgS04), concentrated and purified by flash chromatography (silica gel, 0-30%
EtOAc/dichloromethane) to afford 0.14 g (30%) of the title compound.1H NMR (400 MHz, DMSO-
d6) 8 0.96 (s, 9H), 0.98 (s, 9H), 2.06 -1.71 (m, 8H), 2.25 - 2.07 (m, 2H), 2.42 (t, J = 7.1,2H), 3.54 (d,
J = 3.2, 6H), 3.72 - 3.59 (m, 2H), 3.86 - 3.72 (m, 2H), 4.22 (d, J = 8.9, 2H), 4.51 - 4.37 (m, 2H), 4.69
(t, J = 11.9, 2H), 6.42 - 6.28 (m, 2H), 6.96 - 6.83 (m, 2H), 7.08 (t, J = 8.5, 2H), 7.39 - 7.18 (m, 4H),
7.76 - 7.54 (m, 4H), 10.03 (d, J = 9.8, 2H). MS (ESI) m/z 884 (M+H)+, 882 (M-H)+.
CI
Example 56
CI
Example 56
dimethyl ([l-(4-chlorophenyl)-lH-pyrrole-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(2S)pyrrolidine-
2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 1A was processed using 4-chloroaniline and the methods from Examples 19A, 19B,
19C, 19D, and 51 to provide the title compound (72 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s,
2H), 7.45 - 7.36 (m, 6H), 7.31 (d, J = 8.3, 2H), 7.04 (d, J= 8.4, 2H), 6.96 (d, J= 8.6, 4H), 6.39 (s,
2H), 4.44 - 4.37 (m, 2H), 4.06 - 3.99 (m, 2H), 3.85 - 3.74 (m,2H), 3.67 - 3.56 (m, 2H), 3.52 (s, 6H),
2.20 - 2.06 (m, 2H), 2.04 - 1.79 (m, 8H), 0.92 (d, J = 6.7, 6H), 0.88 (d, J= 6.7,6H). MS (ESI; M+H)
m/z = 869.
dimethyl ([l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl]bis{benzene-3,l-diylcarbamoyl(2S)pyrrolidine-
2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 55A was processed using the methods of Example 19A, 19B, 19C, 19D, and 19E to
provide the title compound. lR NMR (400 MHz, DMSO-d6) δ 0.99 - 0.84 (m, 12H), 2.05 - 1.76 (m,
8H), 2.22 - 2.05 (m, 2H), 3.53 (s, 6H), 3.70 - 3.56 (m, 2H), 3.88 - 3.71 (m, 2H), 4.11 - 3.93 (m, 2H),
4.42 (dd, J = 4.9, 7.9, 2H), 6.40 (s, 2H), 6.54 (d, J = 7.9, 2H), 7.18 - 6.98 (m, 6H), 7.34 (dd, J = 8.3,
15.4, 4H), 7.55 (s, 2H), 9.96 (d, J = 11.2, 2H). MS (ESI) m/z 852 (M+H)+.
dimethyl ({1 -[4-(trifluoromethyl)phenyl] -1H-pyrrole-2,5 -diyl }bis {benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 58A
2,5-bis(4-nitrophenyl)-l-(4-(trifluoromethyl)phenyl)-lH-pyrrole
To a slurry of the product from Example 1A (1.00 g, 3.05 mmol) in acetic acid (30 mL) was
added 4-(trifluoromethyl)aniline (1.9 mL, 15 mmol). The mixture was heated to 170 °C for 15
minutes under microwave irradiation. The cooled mixture was diluted with water and diethyl ether
and stirred vigorously for 15 minutes and then filtered. The crude product was purified by
chromatography on silica gel eluting with a solvent gradient of 0-30% ethyl acetate in hexane.
Product containing fractions were combined and concentrated under reduced pressure and then
triturated with diethyl ether to give the title compound (110 mg, 8% yield).
Example 58B
dimethyl ({1 -[4-(trifluoromethyl)phenyl] -1H-pyrrole-2,5-diyl }bis {benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 58A was processed using the methods of Examples 19B, 19C, 19D, and 51 to
provide the tide compound (44 mg). :H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 2H), 7.71 (d, 7 =
8.6, 2H), 7.42 (d, 7 = 8.7, 4H), 7.31 (d, 7 = 8.2, 2H), 7.22 (d, 7 = 8.3, 2H), 6.95 (d, 7 = 8.6, 4H), 6.43
(s, 2H), 4.39 (dd, 7 = 5.2, 8.1, 2H), 4.03 (d, 7 = 8.3, 2H), 3.85 - 3.75 (m, 2H), 3.66 - 3.56 (m, 2H),
3.52 (s, 6H), 2.18 - 2.08 (m, 2H), 2.01 - 1.79 (m, 8H), 0.92 (d, 7 = 6.7, 6H), 0.87 (d, 7 = 6.6, 6H).
MS(ESI;M+H)m/z = 903.
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl)-1 -phenylpyrrolidin-2-yl]phenyl} - 1H-
imidazol-2-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl Jcarbamate
(2S,2'S)-tert-butyl2,2,-(4,4'-(4,4'-(l-phenylpyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-imidazole-
4,2-diyl))dipyrrolidine-1 -carboxylate
Example 42B and aniline were processed using the methods of Examples 39D, 42D, and 42E
to provide the title compound as a mixture of stereoisomers. MS (ESI) rn/z 770 (M+H)+.
Example 59B
4,4'-{[(2i?,55')-l-phenylpyrrolidine-2,5-diyl]dibenzene-4,l-diyl}bis{2-[(25)-pyrroUdin-2-yl]-lff-
imidazole} (ACD vl2)
To the product of Example 59A (30 mg, 0.039 mmol) was added dimethoxyethane (1.5 mL)
and a solution of 4N hydrochloric acid in dioxane (3 mL) and the resultant solution stirred at room
temperature for 1.5 hr. The solvent was then removed under vacuum and the resultant residue was
diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18),
eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 9.8 mg (44%) of the title compound
and 8.5 mg of a mixture of the trans diastereomers (MS (ESI) m/z 570 (M+H)+) that were processed
further as described in Example 89. For the title compound: MS (ESI) m/z 570 (M+H)+.
Example 59C
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl)-1 -phenylpyrrolidin-2-yl] phenyl} - 1H-
imidazol-2-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
The product from Example 59B (9.8 mg, 0.012 mmol), (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid (5.4 mg, 0.031 mmol) and HATU (10.3 mg, 0.027 mmol) in DMSO (1 mL)
was added Hunig's base (0.017 mL, 0.098 mmol), and the reaction mixture was stirred at room
temperature for 1Hr. The reaction mixture was partitioned between water and ethyl acetate, and the
organic layer was dried over MgSC<4, filtered and concentrated in vacuo. The crude product was
purified by reversed phase chromatography (CI8), eluting with 10-100% acetonitrile in water (0.1%
TFA) to afford 4.5 mg (41%) of the title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) 5
ppm 14.50 (bs, 2 H), 7.99 (s, 2 H), 7.78 (m, 4 H), 7.65 (m, 4H), 7.32 (m, 2H), 7.02 (t, 7=8.0 Hz, 2 H),
6.63 (t, 7=7.4 Hz, 1H), 6.40 (d, 7=8.2 Hz, 2 H), 5.11 (t, 7=6.9 Hz, 2 H), 4.83 (m, 2H), 4.10 (t, 7=7.7
Hz, 2 H), 3.82 (m, 6 H), 3.48 (s, 6 H), 2.40 (m, 2 H), 2.08 (m, 2 H), 2.00 (m, 6 H), 1.85 (m, 2 H), 0.85
(m, 2 H), 0.80 (m, 12 H); MS (ESI) m/z 884 (M+H)+.
dimethyl ([(2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis {benzene-4,1-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 60A
dimethyl ([(2S,5S)-l-(4-tert-butylphenyl)pyrroUdine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-(4-tert-butylphenyl)pyrrohdine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 34D (29.0 mg, 0.05 mmol), (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid (20.81 mg, 0.110 mmol), EDC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,
Solvent was removed under vacuum to provide the title compound as a solid that was used without
purification.
Example 55D
l-(4-fluorophenyl)-2,5-bis(3-nitrophenyl)pyrrolidine
Example 55C (0.733 g, 1.5 mmol) was mixed with 4-fluoroaniline (1.5 mL, 15.63 mmol) and
DMF (3 mL). The reaction was stirred at 50 °C for 24 hours. The reaction mixture was pardoned
between EtOAc and water. The organic portion was washed with water (2 x), brine (1 x), dried
(MgS04), concentrated. Purification by flash chromatography (silica gel, 0-50% EtOAc/Hexanes).
The material was dissolved in EtOAc and washed with 1 M HC1 (2 x) to remove residual aniline,
water (1 x), sat aqueous NaHC03 (1 x) and brine (1 x) dried (MgS04) and concentrated to afford the
title compound as a mixture of trans and cis isomers (0.45 g, 73%).
Example 55E
3,3'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline
A suspension of Pd/C (0.0527 g, 0.050 mmol) in THF (2 mL) was added to a solution of
Example 55D (0.45 g, 1.105 mmol) in THF (7 mL)/EtOH (7 mL) under N2. The flask was flushed
with H2 and stirred under 1 atm H2 for 20 hours. The reaction was filtered through a celite plug, rinsed
with -100 mL (1:1 EtOH:THF) and solvent was removed under vacuum. The material was used
without purification. MS (DCI) m/z 348 (M+H)+.
Example 55F
(2S,2,S)-tert-butyl2,2'-(3,3'-((2S,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
Diisopropylethylamine (0.8 mL, 4.58 mmol) was added to a mixture of Example 55E (0.382
g, 1.1 mmol), (S)-l-(tert-butoxycarbonyl)pyrroridine-2-carboxylic acid (0.5950 g, 2.76 mmol) and
HATU (0.9196 g, 2.419 mmol) in dichloromethane (12 mL). The reaction was stirred at rt for 1Hr,
diluted with dichloromethane, washed with water (2 x), brine (1 x), dried (MgS04) and concentrated
to give a brown residue. The residue was taken up in ether, sonicated and filtered to afford the title
compound as a tan solid. The trans isomers remained in the ether solution and are described further in
Example 83. LC/MS Rt 2.27 m/z 742 (M+H)+.
Example 55G
(2S,2'S)-N,N'-(3,3'-((2S,5R)-l-(4-fluorophenyl)pyrroUdine-2,5-diyl)bis(3,l-phenylene))dipyrrolidine-
2-carboxamide
0.110 mmol) and N-methylmorpholine (0.027 mL, 0.250 mmol) were combined in DMF (2 mL). The
mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between
ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate,
filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl
acetate/hexane (50% to 80%) to give the title compound (32 mg, 69%) as a mixture of trans
diastereomers.
Example 60B
dimethyl ([(2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 60A was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 3:1 mixture of hexane:(2:l EPA:EtOH). The title compound was the
first of the 2 diastereomers to elute. :H NMR (400 MHz, DMSO-D6) δ ppm 0.97 (s, 18 H) 1.11 (s, 9
H) 1.60 -1.65 (m, 2 H) 1.79 -1.91 (m, 4 H) 1.94 - 2.03 (m, 2 H) 2.10 - 2.18 (m, 2 H) 2.44 - 2.50 (m, 2
H) 3.54 (s, 6 H) 3.59 - 3.67 (m, 2 H) 3.71 - 3.82 (m, 2 H) 4.21 (d, J=8.89 Hz, 2 H) 4.43 (dd, J=7.92,
5.42 Hz, 2 H) 5.14 (d, J=6.40 Hz, 2 H) 6.18 (d, J=8.89 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.08 (d,
J=8.78 Hz, 2 H) 7.13 (d, J=8.57 Hz, 4 H) 7.50 (d, J=8.46 Hz, 4 H) 9.99 (s, 2 H); MS (ESI+) m/z 923
(M+H)+.
dimethyl ([(2R,5R)-1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis {benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-dimethyl-1 -oxobutane-1,2-diyl] })biscarbamate
The product from Example 60A was purified by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with a 3:1 mixture of hexane:(2:l IPA:EtOH). The title compound was the
second of the 2 diastereomers to elute. !H NMR (400 MHz, DMSO-D6) δ ppm 0.96 (s, 18 H) 1.11 (s,
9 H) 1.60 -1.66 (m, 2 H) 1.78 -1.92 (m, 4 H) 1.94 - 2.04 (m, 2 H) 2.08 - 2.19 (m, 2 H) 2.42 - 2.50 (m,
2 H) 3.54 (s, 6 H) 3.59 - 3.67 (m, 2 H) 3.74 - 3.81 (m, 2 H) 4.20 (d, J=8.89 Hz, 2 H) 4.43 (dd, J=7.97,
5.37 Hz, 2 H) 5.15 (d, J=6.29 Hz, 2 H) 6.17 (d, J=8.89 Hz, 2 H) 6.94 (d, J=8.89 Hz, 2 H) 7.07 (d,
J=8.89 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.50 (d, J=8.57 Hz, 4 H) 9.99 (s, 2 H); MS (ESI+) m/z 923
(M+H)+.
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5S)-l-(4-fluorophenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl }phenyl)pyrrolidin-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
Example 62A
4,4'-{[(2^,55)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]dibenzene-4,l-diyl}bis{2-[(21S)-pyrrolidin-2-
yl]-l#-imidazole} (ACDvl2)
The product from Example 45C (0.15 g, 0.190 mmol) in CH2C12 (1 mL) was treated with
TFA (1 mL), and the resulting mixture was stirred at rt for lh and then concentrated in vacuo. The
crude product was purified by column chromatography on CI8 silica using a solvent gradient of 10-
100% CH3CN in 0.1% aq TFA. The desired cis-pyrrolidine isomer was the second of 2 components
to elute. Fractions containing pure cis-isomer were pooled and concentrated in vacuo. The residue
was partitioned between saturated aq. NaHC03 and a 3:1 mixture of CH2Cl2:2-PrOH (3x). The
combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give the tide
compound (32 mg, 28%).
Example 62B
methyl {(2S)-1 -[(2S)-2-(4-{4-[(2R,5S)-1 -(4-fluorophenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)airuno]-3-memylbutanoyl}pyn-olidin-2-yl]4H-imidazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
The product from Example 62A (32 mg, 54 mmol) was subjected to the method described in
Example 5D, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for (S)-2-
(methoxycarbonyl amino)butanoic acid, to give the title compound (34 mg, 69%). !H NMR (400
MHz, DMSO-D6) δ ppm0.78 - 0.93 (m, 12 H), 1.78 - 2.24 (m, 12 H), 2.37 - 2.46 (m, 2 H), 3.54 (s, 6
H), 3.68 - 3.87 (m, 4 H), 4.66 - 4.79 (m, 2 H), 5.02 - 5.13 (m, 2 H), 6.39 (dd, 7=9.16, 4.50 Hz, 2 H),
6.81 - 6.92 (m, 2 H), 7.23 - 7.34 (m, 2 H), 7.39 - 7.80 (m, 12 H), 11.67 - 12.12 (m, 2 H); MS (ESI)
m/z 902.7 (M+H)+.
methyl [(2S)-l-{(2S)-2-[4-(4-{(2R,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl Jphenyl)-1 - [4-(trifluoromethyl)phenyl]pyrrolidin-
2-yl }phenyl)- lH-imidazol-2-yl]pyrrolidin- 1-yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 63A
(2R,5S)-2,5-bis(4-bromophenyl)-l-(4-(trifluoromethyl)phenyl)pyrrolidine
The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (Aldrich,
32.2 g, 200 mmol) were combined in DMF (50 mL), stirred at 50 °C under nitrogen for 16 hours,
cooled and concentrated. The residue was diluted with ethyl acetate, treated with 1M HC1, stirred for
10 minutes and filtered to remove solids. The organic layer of the filtrate was washed with brine,
dried (Na2S04), filtered and concentrated. The residue was purified by flash chromatography (silica
gel, 0 to 1% ethyl acetate/hexane) to give the tide compound (1.0 g, 10 %) as the second eluting
stereoisomer. MS (ESI+) m/z 526 (M+H)+.
Example 63B
methyl [(2S)-1-{(2S)-2-[4-(4-{(2R,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrohdto-2-yl]-lH4inidazol-4-yl}phenyl)-l-[4-(trifluoromeuiyl)phenyl]pyrroUdin-
2-yl}phenyl)-lH-imida2X)l-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
The product from Example 63A (1.0 g, 1.90 mmol) was processed using die methods
described in Example 42D, 42E, 42F, and 42G to afford the title compound.1H NMR (free base) (400
MHz, DMSO-is) δ 0.80 - 0.95 (m, 12 H) 1.83 - 2.18 (m, 14 H) 3.54 (s, 6 H) 3.79 (d, J=6.18 Hz, 3 H)
3.97 - 4.15 (m, 3 H) 4.87 (d, J=4.88 Hz, 2 H) 5.02 - 5.14 (m, 2 H) 6.54 (d, J=8.67 Hz, 2 H) 7.15 - 7.80
(m, 14 H) 11.56 -12.30 (m, 2 H); MS (ESI+) m/z 953 (M+H)+.
Example 64
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)anuno]-3-memylbutanoyl}pyrrolidin-2-yl]4H-imidazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl }-lH-imida
zol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 64A
(2S,2'R)-2,2,-(4,4'-(4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-
imidazole) bis trifluoroacetate salt
Example 42C was processed using the methods of Examples 42D, 42E, and 42F to provide a
mixture of cis/trans pyrrolidine isomers. The mixture of stereoisomers was dissolved in 10 ml of 80%
(0.1% TFA/water):20% CH3CN and applied to a 13 g C18 silica column. The column was eluted
with a gradient of 0.1% TFA(aq):CH3CN; 80/20 to 50:50 over 25 minutes, giving the cis steroisomer
of the title compound as a light yellow solid trifluoroacetate salt, 88.6 mg, 58%.
Example 64B
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)pyrroUdin-
2-yl]phenyl}- lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl- l-oxobutan-2-yl Jcarbamate
The product from Example 64A was dissolved in 1 ml DMF and added dropwise to a chilled
(0-5 °C) solution containing (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.41g, 0.232
mmole), HOBt (0.036g, 0.232 mmole), EDAC (0.045 g, 0.232 mmole) and 4-methylmorpholine
(0.138g, 0.150 ml, 1.364 mmole) in 0.5 ml DMF. The pH of the solution was measured and found to
be 8. The reaction was stirred a total of 3.5 hr in the ice bath. The reaction mixture was diluted with
50 ml EtOAc and washed with 10% NaHC03, 10% NaCl, dried over anhydrous Na2S04(s), filtered
and solvent removed in vacuo leaving a pinkish oil. The oil was dissolved in 5 ml CH2C12 and applied
to a 12 g silica gel column. The column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 94/6
over 25 minutes giving the title compound as a white solid, 12.5 mg, 11%. 1H NMR (400 MHz,
DMSO-D6) d ppm 0.85 (s, 12 H) 1.13 (s, 9 H) 1.95 (s, 6 H) 2.15 (s, 4 H) 2.50 (s, 3 H) 3.43 (s, 1H)
3.54 (s, 5 H) 3.80 (s, 4 H) 4.05 (s, 2 H) 4.70 (s, 2 H) 5.07 (s, 1H) 6.36 (d, J=8.78 Hz, 2 H) 7.01 (s, 2
H) 7.28 (s, 2 H) 7.47 (s, 6 H) 7.70 (s, 4 H) 11.71 (s, 2 H) 12.09 (s, 2 H)ESI+:940.8
Example 65
methyl {(2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl }phenyl)-1 -phenyl- lH-pyrrol-2-yl]phenyl} - 1H-
imidazol-2-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl) carbamate
Example 65A
(2S,2,R)-tert-butyl2,2,-(4,4'-(4,4'-(l-phenyl-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(lH-
imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
Example 26E and aniline were processed using the methods of Examples 19 A, 26G, and 26H
to provide the title compound (150 mg).
Example 65B
(S)-4,4,-(4,4'-(l-phenyl-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-2-yl)-lH-
imidazole)
To a suspension of the product from Example 65 A (186 mg, 0.243 mmol) in dioxane (5 mL)
was added HCl/dioxane (5 mL, 20 mmol). The mixture was stirred for 30 minutes and then
concentrated under reduced pressure to provide the title compound as a hydrochloride salt.
Example 65C
methyl {(2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-imidazol-4-yl }phenyl)-l -phenyl-lH-pyrrol-2-yl]phenyl} - 1H-
imidazol-2-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
A solution consisting of Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine
hydrochloride (90 mg, 0.47 mmol), lH-benzo[d][l,2,3]triazol-l-ol hydrate (72 mg, 0.47 mmol), (S)-
2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg, 0.47 mmol) and 4-methylmorpholine
(0.28 mL, 2.6 mmol) in DMF (1.6 mL) was cooled in an icebath. To this mixture was added dropwise
a solution of the product from Example 65B (150 mg, 0.23 mmol) in DMF (0.5 mL). Additional 4-
methylmorpholine was added to the mixture until the pH was adjusted to 8. The reaction was stirred
for 3.5 hours and then the icebath was removed and the reaction was stirred for an additional 16
hours. Water was then added to the reaction mixture and the resulting precipitate was recovered by
filtration. The residue was washed with copious amounts of water followed by diethyl ether. The
crude product was purified by chromatography on silica gel eluting with a solvent gradient of 0-5%
methanol in CH2C12 to provide the tide compound. !H NMR (400 MHz, DMSO-d6) 8 12.12 - 11.64
(m, 2H), 7.57 - 7.45 (m, 4H), 7.42 - 7.36 (m, 2H), 7.36 - 7.29 (m, 3H), 7.29 - 7.05 (m,4H), 7.04 -
6.91 (m, 4H), 6.54 - 6.43 (m, 2H), 5.06 - 4.96 (m, 2H), 4.06 - 3.96 (m, 2H), 3.84 - 3.67 (m, 4H),
3.52 (s, 6H), 2.17 - 1.80 (m, 10H), 0.91 - 0.76 (m, 12H). MS (ESI; M+H) m/z = 881.
methyl [(2S)-l-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
melhylbutanoyl}pyn-oUdin-2-yl]-lH-imidazol-4-yl}phenyl)-l-[4-(trifluoromethyl)phenyl]pyrrolidin-
2-yl]phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 66A
(2R,5R)-2,5-bis(4-bromophenyl)-l-(4-(trifluoromethyl)phenyl)pyrrolidine
and
(2S,5S)-2,5-bis(4-bromophenyl)-l-(4-(trifluoromethyl)phenyl)pyrrolidine
The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (32.2 g,
200 mmol) were combined in DMF (50 mL). The mixture was stirred at 50 °C under nitrogen
overnight. The reaction mixture was evaporated and the residue was diluted with ethyl acetate, treated
with 1M HC1, stirred for 10 minutes, and filtered to remove the solid. The organic layer of filtrate was
washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with ethyl acetate/hexane (0 to 1%). The title compounds (500
mg, 5%) were eluted as the first of 2 stereoisomers and were obtained as a mixture of trans
diastereomers.
Example 66B
(2R,5R)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l-(4-
(trifluoromethyl)phenyi)pyrrolidine
and
(2S,5S)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l-(4-
(trifluoromethyl)phenyl)pyrrolidine
The products from Example 66A (500 mg, 0.952 mmol), bis(pinacolato)diboron (725 mg,
2.86 mmol), potassium acetate (374 mg, 3.81 mmol) and bis(triphenylphosphine)palladium(I[)
chloride (66.8 mg, 0.095 mmol) were combined in 1,2-dimethoxyethane (10 mL). The mixture was
purged with nitrogen for 15 minutes and stirred at 85 °C for 2 hours. The reaction mixture was
partitioned between ethyl acetate and 1M HC1. The organic layer was washed with saturated sodium
bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with hexane to ethyl acetate/hexane (10%) to give a solid which
was triturated with dichloromethane/hexane (1:3) to give the title compounds (370 mg, 63%).
Example 66C
(2S,2'S)-tert-butyl2,2,-(4,4'-(4,4'-((2R,5R)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis( lH-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
and
(2S,2,S)-tert-butyl2,2,-(4,4'-(4,4'-((2S,5S)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis( lH-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
The products from Example 66B (257 mg, 0.415 mmol), the product from Example 26D (341
mg, 1.079 mmol), potassium phosphate tribasic (352 mg, 1.660 mmol) and l,l'-bis(di-tert-
butylphosphine)ferrocene palladium dichloride (27.0 mg, 0.041 mmol) were combined in THF (4.5
mL)/ water (1.5 mL). The mixture was purged with nitrogen for 15 minutes and stirred at 70 °C for 6
hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate.
The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The
residue was purified by chromatography on silica gel eluting with methanol/dichloromethane (1% to
3%) to give the title compounds (286 mg, 82%) as a solid.
Example 66D
(S)4,4'<4,4'-((2R,5R)4<43 and a 3:1 mixture of CH2Cl2:2-PrOH (2x), and the
combined organic layers were dried over Na2S04. The drying agent was filtered off, and the solvent
was removed in vacuo to give the title compound as an amorphous solid (0.18 g, 87%).
Example 69F
methyl {(2S)-l-[(2S)-2-(4-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3,3-dimelhylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl}phenyl)pyrrolidin-2-yl]phenyl}4H-imidazol-2-yl)pyrrolidin-l-yl]-3,3-diniethyl-l-oxobutan-2-
yl} carbamate
To a mixture of the product from Example 69E (0.10 g, 0.16 mmol) and (S)-2-
(methoxycarbonylamino)-3,3-dimethylbutanoic acid (76 mg, 0.40 mmol) in anhydrous DMSO (1.6
mL) was added HATU (152 mg, 0.40 mmol) and Hunig's base (84 |iL, 0.48 mmol). The resulting
mixture was stirred at rt for 90 min, and was then partitioned between H20 (5 mL) and EtOAc (2 x
5mL). The combined organic layers were concentrated in vacuo, and the residue was dissolved in
MeOH (1 mL). To the solution was added solid K2C03 (1-2 mg) and the resulting mixture was stirred
at rt for 30 min. The mixture was filter and concentrated in vacuo, and the crude product was purified
by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH2C12 to give
the tide compound (0.12 g, 78%). !H NMR (400 MHz, DMSO-D6) 8 ppm 0.94 (s, 18 H), 1.10 (s, 9
H), 1.63 - 1.77 (m, 2 H), 1.84 - 2.25 (m, 10 H), 3.55 (s, 6 H), 3.66 - 3.87 (m, 2 H), 4.16 - 4.28 (m, 2
H), 5.03 - 5.12 (m, 2 H), 5.15 - 5.28 (m, 2 H), 6.22 (d, 7=8.46 Hz, 2 H), 6.93 (d, 7=8.67 Hz, 2 H), 7.07
(d, 2 H), 7.15 (d, 7=8.13 Hz, 4 H), 7.23 (d, 1H), 7.38 (d, 7=1.41Hz, 2 H), 7.52 (d, 1H), 7.62 (d,
7=8.02 Hz, 4 H), 11.66 - 12.10 (m, 2 H). MS (ESI) m/z 969.1 (M+H)+.
dimethyl ([(2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrroHdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 70A
Tert-butyl4,4'-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dihydroxypyrrolidine-2,5-diyl)bis(4,l-
phenylene)dicarbamate
A solution of 3,4-O-isopropylidene-C1-mannitol (444 mg, 2.0 mmol) in 2:1 methanol-
dichloromethane (8 mL) was treated with iodobenzene diacetate (1.54 g, 4.79 mmol) followed by
stirring at RT for 5 h. The mixture was concentrated in vacuo to remove organic solvents, and the
residue was suspended in 0.1 M sulfuric acid solution (4 mL) followed by stirring at RT for 18 h. The
mixture was adjusted to pH 6 by addition of solid sodium bicarbonate. The mixture was then
sequentially treated with 4-fluoroaniline (383 pL, 444 mg, 4.00 mmol), 4-(tert-
butoxycarbonylamino)phenylboronic acid (853 mg, 3.60 mmol) and hexafluoroisopropyl alcohol (8
mL). The mixture was warmed at 50 °C for 2 h. The solution was cooled and concentrated in vacuo.
The mixture was dissolved in ethyl acetate and extracted with water, 0.33 M tribasic potassium
phosphate solution, and saturated sodium chloride solution. Drying (Na2S04) and concentration in
vacuo afforded a brown solid, which was chromatographed over a 100 g silica gel cartridge, eluting
with 5-70% ethyl acetate in dichloromethane. These procedures afforded the title compound (770 mg,
67%) as a nearly white solid, :H NMR (400 MHz, CDC13) 8 7.35 (d, J = 8.3 Hz, 4 H), 7.11 (d, J = 8.4
Hz, 4 H), 6.67 (t, J = 8.8 Hz, 2 H), 6.51 (s, 2 H), 6.22 (dd, J = 9.1, 4.3 Hz, 2 H), 5.15 (d, J = 6.3 Hz, 2
H), 4.26 (d, J = 5.7 Hz, 2 H), 1.51 (s, 18 H). MS +ESI m/z (rel abundance) 580 (100, M+H), 602 (15,
M+Na), 1159(18,2M+H).
Example 70B
(2S,3R,4R,5S)-2,5-bis(4-(tert-butoxycarbonylamino)phenyl)-l-(4-fluorophenyl)pyrrolidine-3,4-diyl
diacetate
A solution of the compound of Example 70A (314 mg, 0.54 mmol), triethylamine (227 jiL,
164 mg, 1.65 mmol), and DMAP (13 mg, 0.11 mmol) in 1:1 ethyl acetate-tetrahydrofuran (2.8 mL)
was treated with acetic anhydride (128 \xL, 138 mg, 1.35 mmol) followed by stirring at RT for 1H.
The mixture was treated with water followed by stirring at RT for 30 min. The mixture was diluted
with ethyl acetate and extracted with water, saturated sodium bicarbonate solution and saturated
sodium chloride solution. Drying (Na2S04) and concentration in vacuo afforded the title compound
(330 mg, 92%) as a cream-colored solid, sufficiently pure for further use. :H NMR (400 MHz,
CDC13) δ 7.32 (d, J = 8.4 Hz, 4 H), 7.07 (d, J = 8.5 Hz, 4 H), 6.66 (t, J = 8.8 Hz, 2 H), 6.47 (s, 2 H),
6.25 (dd, J = 9.2, 4.3 Hz, 2 H), 5.53 (dd, J = 5.5, 1.9 Hz, 2 H), 5.46 (d, J = 7.2 Hz, 2 H), 1.83 (s, 6 H),
1.51 (s, 18 H). MS +ESI m/z (rel abundance) 664 (100, M+H).
Example 70C
(2S,3R,4R,5S)-2,5-bis(4-aminophenyl)-l-(4-fluorophenyl)pyrrolidine-3,4-diyl diacetate
dihydrochloride
A solution of 4 N hydrogen chloride in dioxane (8 mL) was treated with the compound of
Example 70B (136 mg, 0.21 mmol) followed by stirring at RT for 2 h. (During this time, the mono-
deprotection product started precipitating, and ca. 4 mL of dichloromethane was added to speed the
reaction by solublizing the mono-hydrochloride) The mixture was added to excess ether and the
product collected by filtration and washed with ether. After drying in a vacuum oven at 50 °C for 18
h, these procedures afforded the title compound (92 mg, 84%) as an off-white powder. :H NMR (400
MHz, DMSO-4) δ 7.28 (m, 8 H), 6.81 (t, J = 8.9 Hz, 2 H), 6.33 (m, 2 H), 5.63 (m, 2 H), 5.51 (dd, J =
5.5, 1.9 Hz, 2 H), 1.79 (s, 6 H).
Example 70D
(2S,3R,4R,5S)-2,5-bis(4-aminophenyl)-l-(4-fluorophenyl)pyrrolidine-3,4-diol
In a 25-mL round bottom flask, was dissolved Example 70C(160.5 mg, 0.299 mmol) in
MeOH (3 mL), added potassium carbonate (165 mg, 1.197 mmol), and stirred at 25 °C for 1.5 hr.
Filtered off the solids, washed with MeOH, and concentrated the filtrate by rotary evaporation to
dryness. Purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 8%
MeOH/CH2Cl2) to afford the title compound as a yellow solid (85 mg, 75%). 2H NMR (400 MHz,
DMSO-D6) δ ppm 4.10 - 4.19 (m, 2 H), 4.73 (d, 7=2.71Hz, 2 H), 4.80 - 4.88 (m, 2 H), 4.84 (s, 4 H),
6.21 (dd, 7=9.22, 4.55 Hz, 2 H), 6.45 (d, 7=8.35 Hz, 4 H), 6.72 (t, 7=8.95 Hz, 2 H), 6.77 (d, 7=8.24
Hz, 4 H); MS (DCI+) 380 (M+H)+.
Example 70E
4,4^((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimemoxypyrrohdine-2,5-diyl)dianiline
In an oven-dried 25-mL round bottom flask, dissolved the product of Example 70D (83.6 mg,
0.220 mmol) in anhydrous THF (3 mL) under nitrogen, cooled to 0 °C in an ice water bath, added 60
wt% NaH dispersion in mineral oil (18.51 mg, 0.463 mmol), and stirred at 0 °C for 15 min. Then
added iodomethane (0.028 mL, 0.441 mmol) via microsyringe and stirred at 0 °C for 1Hr, then at 25
°C for 3 hr. Removed the solvent by rotary evaporation and dried the residue in vacuo. Purified by
flash chromatography (silica gel, Alltech Extract-Clean lOg column, gradient of 1% to 2%
MeOH/CH2Cl2) to afford the title compound as a yeUow solid (59 mg, 66%). :H NMR (400 MHz,
DMSO-D6) 8 ppm 3.25 (s, 6 H), 3.92 - 4.17 (m, 2 H), 4.91 (s, 4 H), 5.07 - 5.24 (m, 2 H), 6.28 (dd,
7=9.16, 4.50 Hz, 2 H), 6.47 (d, 7=8.46 Hz, 4 H), 6.73 (t, 7=8.95 Hz, 2 H), 6.86 (d, 7=8.35 Hz, 4 H);
MS (DCI+) m/z 408 (M+H)+.
Example 70F
(2S,2'S)-tert-butyl2,2'-(4,4'-((2S,3R,3R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-
diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
fn a 10-mL round bottom flask, dissolved the product of Example 70E (57 mg, 0.140 mmol)
in anhydrous DMSO (1.2 mL) under nitrogen, added (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-
carboxylic acid (76 mg, 0.350 mmol), HATU (137 mg, 0.350 mmol), and diisopropylethylamine
(0.073 mL, 0.420 mmol), and stirred the bright yellow solution at 25 °C for 1Hr. Diluted the reaction
with EtOAc (50 mL), washed with H20 (3 x 25 mL) and brine (15 mL), dried the organic phase over
anhydrous MgS04, filtered, and concentrated by rotary evaporation to a yellow residue. Purified by
flash chromatography (silica gel, Alltech Extract-Clean lOg column, 3% MeOH/CH2Cl2) to afford the
title compound as a yellow solid (118 mg). :H NMR (400 MHz, DMSO-D6) δ ppm 1.29 (s, 11H),
1.39 (s, 7 H), 1.72 - 1.95 (m, 6 H), 2.08 - 2.25 (m, 2 H), 3.29 (s, 6 H), 3.35 - 3.49 (m, 3 H), 4.12 (d,
J=0.87 Hz, 2 H), 4.15 - 4.29 (m, 2 H), 5.30 - 5.45 (m, 2 H), 6.28 (dd, 7=9.22, 4.45 Hz, 2 H), 6.75 (t,
7=8.89 Hz, 2 H), 7.19 (d, 7=8.35 Hz, 4 H), 7.50 (t, 7=8.89 Hz, 4 H), 9.70 - 10.14 (m, 2 H); MS
(APCI+) m/z 802 (M+H)+.
Example 70G
(2S,2'S)-N,N'-(4,4'-((2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrroUdine-2,5-diyl)bis((4,l-
phenylene))dipyrrolidine-2-carboxamide
Dissolved the product of Example 70F (112 mg, 0.140 mmol) in anhydrous CH2C12 (1 mL)
under nitrogen, added TFA (1 mL), and stirred at 25 °C for 30 min. Removed the solvent by rotary
evaporation, redissolved in 1:5 v/v CH2Cl2/hexanes, and concentrated in vacuo. Took up the residue
in EtOAc (50 mL), washed with sat'd aq NaHC03 (2 x 15 mL), dried the organic phase over
anhydrous MgSC>4, filtered, and concentrated by rotary evaporation to afford the title compound as a
yellow solid (72 mg, 84%). :H NMR (400 MHz, DMSO-D6) δ ppm 1.57 - 1.69 (m, 4 H), 1.70 -1.85
(m, 2 H), 1.96 - 2.10 (m, 2 H), 2.82 - 2.95 (m, 4 H), 3.28 (s, 6 H), 3.66 (dd, 7=8.84, 5.58 Hz, 2 H),
4.07 - 4.17 (m, 2 H), 5.30 - 5.49 (m, 2 H), 6.28 (dd, 7=9.16, 4.39 Hz, 2 H), 6.75 (t, 7=8.89 Hz, 2 H),
7.18 (d, 7=8.57 Hz, 4 H), 7.56 (d, 7=8.57 Hz, 4 H), 9.90 (s, 2 H); MS (ESI+) m/z 602 (M+H)+.
Example 70H
dimemyl([(2S,3R,4R,5S)4<4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrroUdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Dissolved the product of Example 70G (69.3 mg, 0.115 mmol) in anhydrous DMF (1.2 mL)
under nitrogen, cooled to 0 °C, then sequentially added (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (50.4 mg, 0.288 mmol), HOBT monohydrate (44.1 mg, 0.288 mmol), EDAC
(56.3 mg, 0.288 mmol), and N-methylmorpholine (0.038 mL, 0.346 mmol). Removed the cooling
bath and stirred at 25 °C for 13 hr. Diluted the reaction with EtOAc (50 mL), washed with sat'd aq
NaHC03 (25 mL), H20 (2 x 25 mL), and brine (25 mL). Dried the organic phase over anhydrous
MgS04, filtered, and concentrated by rotary evaporation. Purified by flash chromatography (silica
gel, 2.5 cm x 15 cm, 6% MeOH/CH2Cl2) to afford the title compound as a white solid (48 mg, 85%).1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, 7=6.61Hz, 6 H), 0.93 (d, 7=6.72 Hz, 6 H), 1.80 -
2.05 (m, 8 H), 2.08 - 2.22 (m, 2 H), 3.28 (s, 6 H), 3.52 (s, 6 H), 3.56 - 3.69 (m, 2 H), 3.77 - 3.88 (m, 2
H), 4.03 (t, 7=8.51Hz, 2 H), 4.07 - 4.16 (m, 2 H), 4.43 (dd, 7=7.97, 4.83 Hz, 2 H), 5.29 - 5.44 (m, 2
H), 6.27 (dd, 7=9.22, 4.45 Hz, 2 H), 6.75 (t, 7=8.89 Hz, 2 H), 7.17 (d, 7=8.46 Hz, 4 H), 7.31 (d,
7=8.46 Hz, 2 H), 7.49 (d, 7=8.57 Hz, 4 H), 9.99 (s, 2 H); MS (ESI+) m/z 408 (M+H)+.
dimethyl ([(2S,3R,4R,5S)-l-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl [(2S)-3,3-dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Dissolved the product of Example 70D (58.5 mg, 0.097 mmol) in anhydrous DMF (1 mL)
under nitrogen, cooled to 0 °C, then sequentially added (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid (46.0 mg, 0.243 mmol), HOBt monohydrate (37.2 mg, 0.243 mmol), EDAC
(47.5 mg, 0.243 mmol), and 4-methylmorpholine (0.032 mL, 0.292 mmol). Removed the cooling
bath and stirred overnight at 25 °C for 16 hr . Diluted the reaction with EtOAc (50 mL), washed with
sat'd aq NaHC03 (25 mL), H20 (2 x 25 mL), and brine (25 mL). Dried the organic phase over
anhydrous MgSO^ filtered, and concentrated by rotary evaporation. Purified by flash
chromatography (silica gel, 2.5 cm x 15 cm, 4% MeOH/CH2Cl2) to afford the title compound as a
cream-colored solid (66 mg, 72%). >H NMR (400 MHz, DMSO-D6) δ ppm 0.96 (s, 18 H), 1.79 -
1.94 (m, 4 H), 1.94 - 2.06 (m, 2 H), 2.10 - 2.22 (m, 2 H), 3.28 (s, 6 H), 3.54 (s, 6 H), 3.58 - 3.70 (m, 2
H), 3.71 - 3.86 (m, 2 H), 4.06 - 4.15 (m, 2 H), 4.21 (d, 7=8.89 Hz, 2 H), 4.44 (dd, 7=7.92, 5.31Hz, 2
H), 5.31 - 5.39 (m, 2 H), 6.27 (dd, 7=9.22,4.45 Hz, 2 H), 6.75 (t, 7=8.89 Hz, 2 H), 7.08 (d, 7=8.78 Hz,
2 H), 7.17 (d, 7=8.57 Hz, 4 H), 7.49 (d, 7=8.57 Hz, 4 H), 9.99 (s, 2 H); MS (ESI+) m/z 945 (M+H)+.
dimethyl ([1 -(4-tert-butylphenyi)-1H-pyrrole-2,5 -diyljbis {benzene-4,1 -diylcarbamoyl(2S)pyrrolidine-
2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyi]})biscarbamate
Example 72A
4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)dianiline
Example 1A was processed using the methods described generally in Examples 26F and 19B
to provide the title compound. MS (ESI; M+H) m/z = 382.
Example 72B
(2S,2'S)-tert-butyl2,2'-(4,4,-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate
To a solution of the product from Example 72A (0.310 g, 0.813 mmol) in DMF (5 mL) was
added (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.385 g, 1.79 mmol) 1-
hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) and N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride (0.343 g, 1.79 mmol) and the mixture stirred overnight. The mixture
was poured into water and extracted CH2C12. The organic extract was dried (Na2S04), filtered and
concentrated to give a crude product that was purified by trituration with ether to give 325 mg (51%)
of the title compound. :H NMR (400 MHz, DMSO-D6) δ 1.25 (s, 24 H) 1.83 (s, 6 H) 2.15 (s, 2 H)
3.45 (m, 4 H) 4.18 (s, 2 H) 6.40 (s, 2 H) 6.98 (s, 6 H) 7.37 (s, 6 H) 9.98 (s, 2 H).
Example 72C
(2S,2'S)-N,N,-(4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))dipyrrolidme-2-
carboxamide
To a solution of the product from Example 72B (0.325 g, 0.419 mmol) in CH2C12 (5 mL) at rt
was added TFA (1.0 mL) and stirring continued for 5 h. The reaction was concentrated and the
residue partitioned between water and 25% isopropyl alcohol-CHCl3. The organic phase was dried
(Na2S04), filtered and concentrated to provide the title compound used directly in the next reaction.
MS (DCI; M+H) m/z = 576.
Example 72D
dimethyl ([l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(2S)pyrrolidine-
2,1 -diyl [(2S)-3-methyl-1 -oxobutane-1,2 -diyl] })biscarbamate
The product from Example 72C and the product from (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid were processed using the method described in Example 72B. The crude residue
was purified by silica gel chromatography (1% gradient elution from 0% to 4% MeOH:CH2Cl2) to
provide 129 mg (35%) of the title compound.1H NMR (400 MHz, DMSO-D6) §0.89 (s, 12 H) 1.25
(s, 9 H) 1.89 (s, 6 H) 1.98 (s, 2 H) 2.13 (s, 2 H) 3.52 (s, 6 H) 3.61 (s, 2 H) 3.80 (s, 2 H) 4.00 (s, 2 H)
4.39 (s, 2 H) 6.38 (s, 2 H) 6.95 (s, 6 H) 7.34 (s, 8 H) 9.96 (s, 2 H).
methyl [(2S)-l-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-l-{(2S)-2-t(methoxycarbonyl)amino]-3-
methylbutanoyl} pyrrolidin-2-yl] - lH-imidazol-4-yl} phenyl)-1 -[4-(methylsulfonyl)phenyl] - lH-pyrrol-
2-yl }phenylHH-iirridazol-2-yi]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 26E and 4-(methylsulfonyl)aniline were processed using the methods of Examples
26F, 26G, 26H, 65B, and 65C to provide the title compound (78 mg).1H NMR (400 MHz, DMSO-
d6) δ 12.17 - 11.67 (m, 2H), 7.92 - 7.82 (m, 2H), 7.62 - 7.49 (m, 4H), 7.48 - 7.40 (m, 2H), 7.39 -
7.15 (m, 4H), 7.08 - 6.92 (m, 4H), 6.59 - 6.47 (m, 2H), 5.08 - 4.99 (m, 2H), 4.08 - 3.98 (m, 2H),
3.84 - 3.69 (m, 4H), 3.53 (s, 6H), 3.24 (d, J= 1.9, 3H), 2.20 - 1.81 (m, 10H), 0.91 - 0.77 (m, 12H).
MS(ESI;M+H)m/z = 959.
methyl {(2S)-l-[(2S)-2-(5-{4-[l-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)aniino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
Example 74A
2,5-bis(4-bromophenyl)-1 -(4-cyclohexylphenyl)-1H-pyrrole
The product from Example 26E and 4-cyclohexylaniline (Alfa) were processed using the
method described in Example 26F to provide 1.23 g (91%) of the title compound. 1H,NMR (400
MHz, benzene-D6) §1.09 (s, 5 H) 1.60 (s, 5 H) 2.14 (s, 1H) 6.52 (s, 2 H) 6.67 (s, 4 H) 6.84 (s, 4 H)
7.11 (s, 4 H).
Example 74B
l-(4-cyclohexylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-pyrrole
The product from Example 74A was processed using the method described in Example 26G
to provide 1.58 g (60%) of the title compound. MS (ESI; M+H) m/z = 630.
Example 74C
(2S,2,S)-tert-butyl2,2'-(5,5'-(4,4'-(l-(4-cyclohexylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-
phenylene))bis(lH-imidazole-5,2-diyl))dipyrrolidine-l-carboxylate
A solution of the product from Example 74B (0.400 g, 0.635 mmol) and the product from
Example 26D (0.442 g, 1.40 mmol) in toluene (3 mL) and ethanol (3 mL) was treated with 1 M
sodium carbonate (2 mL) followed by l,r-bis(diphenylphosphino)ferrocene-palladium(H)dichloride
dichloromethane complex (0.052 g, 0.064 mmol), the mixture degassed (3 x vacuum/purge N2) and
then heated to 90 °C for 4 h. The reaction was concentrated and the residue partitioned between 25%
isopropyl alcohol-CHCl3. The organic phase was dried (Na2S04) concentrated and the residue taken
up in ether, sonicated, filtered and dried to provide 499 mg (93%) of the title compound. MS (ESI;
M+H)m/z=848.
Example 74D
(S)-5,5'-(4,4'-(l-(4-cyclohexylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-2-
yl)-lH-imidazole)
The product from Example 74C was processed using the method described in Example 19D
to provide the title compound. MS (ESI; M+H) m/z = 648.
Example 74E
methyl {(2S)-l-[(2S)-2-(5-{4-[l-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)armno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl]phenyl}-lH-irnidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
To a solution of the product from Example 74D (0.190 g, 0.293 mmol) in DMF (5 mL) was
added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.113 g, 0.645 mmol), 1-
hydroxybenzotriazole hydrate (0.099 g; 0.645 mmol) and N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride (0.124 g, 0.645 mmol) and the mixture stirred for 3 h. The mixture
was poured into water and extracted CH2C12. The organic layer was concentrated and the residue
purified by chromatography (gradient elution from 0% to 4% MeOH-CH2Cl2) to provide 100 mg
(35%) of the tide compound. 1H NMR (400 MHz, DMSO-D6) 8 0.84 (d, J=6.62 Hz, 6 H) 0.87 (d,
J=6.72 Hz, 6 H) 1.20 (m, 2 H) 1.35 (m, 4 H) 1.78 (m, 4 H) 1.92 (m, 6 H) 2.10 (m, 4 H) 3.52 (s, 6 H)
3.76 (m, 4 H) 4.02 (m, 2 H) 5.03 (m, 2 H) 6.47 (m, 2 H) 6.99 (m, 6 H) 7.18 (m, 3 H) 7.27 (m, 2 H)
7.41 (m, 2 H) 7.51 (m, 4 H) 11.74 (s, 2 H).
Example 75
methyl {(2S)-l-[(2S)-2-(5-{4-[l-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3,3-dimethylbutanoyl }pyrrolidin-2-yl]- lH-imidazol-5-yl }phenyl)- 1H-
pyrrol-2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3,3-dimethyl-1 -oxobutan-2-yl} carbamate
The product from Example 74D and (S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid
(Org. Process Res. Develop. 2008, 12, 69) was processed using the method described in Example 74E
to provide 165 mg (57%) of the title compound. :H NMR (400 MHz, DMSO-D6) δ 0.86 - 0.96 (m,
18 H) 1.23 (m, 2 H) 1.36 (m, 4 H) 1.78 (m, 4 H) 1.88 - 2.00 (m, 4 H) 2.10 (m, 4 H) 3.54 (s, 6 H) 3.77
(m, 4 H) 4.21 (m, 2 H) 5.05 (m, 2 H) 6.46 (s, 2 H) 6.96 - 7.03 (m, 6 H) 7.19 (m, 2 H) 7.38 - 7.55 (m, 7
H) 7.70 (d, J=8.35 Hz, 1H) 7.97 (d, J=8.46 Hz, 1H) 11.76 (s, 2 H).
N-(methoxycarbonyl)-L-valyl-N-(4-{l-(4-tert-butylphenyl)-5-[4-(2-{(2S)-l-[N-(methoxycarbonyl)-L-
valyl]pyrrolidin-2-yl}-lH-imidazol-5-yl)phenyl]-lH-pyrrol-2-yl}phenyl)-L-prolinamide
Example 76A
2-(4-bromophenyl)-l-(4-tert-butylphenyl)-5-(4-nitrophenyl)-lH-pyrrole
TFA (0.6 mL, 7.79 mmol) was added to a mixture of the product from Example 39A (1.2335
g, 3.41 mmol) and 4-tert-butylaniline (0.8 mL, 5.07 mmol) in toluene (30 mL) and heated at 110 °C
for 17 hours. The cooled reaction mixture was poured into ether/water and stirred until nice solid
formed. The mixture was filtered to afford the title compound.1H NMR (400 MHz, BENZENE-D6) δ 1.02 (s, 9H), 6.48 (d, J= 3.8, 1H), 6.52 (d, J = 3.8, 1H), 6.63 (d, J = 8.5, 2H), 6.80 (d, J = 8.5, 2H),
6.84 (d, J= 8.9, 2H), 6.89 (d, J= 8.5, 2H), 7.10 (d, J = 8.5, 2H), 7.70 (d, J= 8.9, 2H).
Example 76B
N-(methoxycarbonyl)-L-valyl-N-(4-{l-(4-tert-butylphenyl)-5-[4-(2-{(2S)-l-[N-(methoxycarbonyl)-L-
valyl]pyrrolidin-2-yl}-lH-irnidazol-5-yl)phenyl]-lH-pyrrol-2-yl}phenyl)-L-prolinamide
Example 76A was processed using sequentially the methods of Examples 19B, 55F, 39E
(reaction temperature = 85 °C), 39F, 55G, and 26J (reaction solvent = dichloromethane) to provide the
title compound (0.14 g). :H NMR (400 MHz, METHANOL-D4) 5.0.94 (ddd, J = 21.1, 19.5, 6.7,
12H), 1.30 (s, 10H), 2.36 - 1.92 (m, 10H), 3.63 (s, 6H), 3.76 - 3.67 (m, 1H), 3.89 - 3.78 (m, 1H), 4.02
- 3.89 (m, 2H), 4.19 (d, J = 7.9, 2H), 4.50 (dd, J = 8.1, 5.3, 1H), 5.11 (dd, J = 7.6, 5.5, 1H), 6.39 (d, J
= 3.7, 1H), 6.43 (d, J = 3.6, 1H), 7.01 (dt, J= 28.2, 8.3, 6H), 7.20 (s, 1H), 7.40 (ddd, J= 19.1, 11.9,
5.7, 6H). MS (ESI) m/z 913 (M+H)+.
N-(methoxycarbonyl)-L-valyl-N-(4- {5- [4-(2- {(2S)-1 -[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl} -
lH-imidazol-5-yl)phenyl] -1 -[4-(pentafluoro-lambda~6~-sulfanyl)phenyl]- lH-pyrrol-2-yl }phenyl)-L-
prolinamide
Example 39A and 4-aminophenylsulfurpentafluoridewere processed using sequentially the
methods of Examples 76A, 19B, 55F, 39E (reaction temperature = 85 °C), 39F, 55G, and 26J
(reaction solvent = DMF) to provide the title compound (0.36 g). ^R NMR (400 MHz, DMSO-D6) 8
0.86 (ddd, J = 6.9, 15.8, 21.6, 12H), 2.04 - 1.76 (m, 7H), 2.24 - 2.04 (m, 3H), 3.53 (d, J = 3.0, 6H),
3.61 (dd, J = 6.7, 16.0, 1H), 3.88 - 3.67 (m, 3H), 4.03 (dd, J = 8.3, 14.1, 2H), 4.40 (dd, J = 5.0, 8.0,
1H), 5.12 - 4.92 (m, 1H), 6.49 (ddd, J = 3.6, 14.2, 18.1, 2H), 7.09 - 6.84 (m, 4H), 7.38 - 7.12 (m, 4H),
7.50 - 7.38 (m, 3H), 7.58 (dd, J = 8.3, 16.7, 2H), 7.89 (t, J = 8.7, 2H), 10.01 (d, J = 20.9, 1H), 12.16 -
11.66 (m, 1H). MS (ESI) m/z 983 (M+H)+, 981 (M-H)+.
methyl {(2S)-l-[(2S)-2-(5-{3-[l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidm-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
2,4'-Dibromoacetophenone and 3'-bromoacetophenone were processed using sequentially the
methods of Examples 26E, 26F, 26G, 74C, 19D, and 74E to provide the title compound (232 rng). 'H
NMR (400 MHz, DMSO-D6) 8 0.81 - 0.91 (m, 12 H) 1.25 (s, 9 H) 1.93 (m, 4 H) 2.11 (m, 4 H) 3.53
(s, 6 H) 3.78 (m, 4 H) 4.04 (m, 2 H) 5.03 (m, 2 H) 6.49 (m, 2 H) 6.90 - 7.08 (m, 5 H) 7.11 - 7.21 (m, 1H) 7.27 - 7.55 (m, 9 H) 7.71 (d, J=8.35 Hz, 1H) 7.94 - 8.01 (m, 2 H) 11.72 (br s, 2 H).
Example 79
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxy-5-(4-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl}phenyl)pyrrolidin-2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl) carbamate
Example 79A
l,2:3,4:5,6-Tri-O-isopropylidene-L-mannitol
A solution of L-mannonic acid y-lactone (9.87 g, 55.4 mmol) in methanol (150 mL) at 0 °C
was treated with lithium borohydride (2.1 g, 97 mmol) over 30 min. After addition was complete, the
mixture was warmed to RT for 30 min. The mixture was then cautiously treated with a solution of
hydrogen chloride in dioxane (4 N, 2 mL). The solution was then concentrated in vacuo, first on the
rotary evaporator and then under high vacuum (0.3 mm Hg) while warming with a heat gun to remove
the last traces of methanol. The solid obtained was then suspended in acetone (50 mL) and treated
with 2,2-dimethoxypropane (41 mL, 34.6 g, 332 mmol) and a solution of hydrogen chloride in
dioxane (4 N, 42 mL, 166 mmol) followed by stirring at RT for 18 h. The mixture was concentrated
in vacuo to ca. 20% of original volume, and the inhomogeneous mixture was added to saturated
sodium bicarbonate solution (200 mL) followed by stirring for 48 h. The precipitate was collected by
filtration and washed with water and air dried. The white solid was dissolved in ethanol (200 proof,
175 mL) and filtered through celite to remove particulate matter. The solution was cooled to -78 °C
to effect crystallization. The solid was collected by filtration, and the mother liquors concentrated to
ca. half volume, and re-cooled to -78 °C. The second crop of crystals was collected by filtration and
washed with ethanol. After drying in a vacuum oven at 50 °C for 3 h, these procedures afforded the
title compound (9.88 g, 59%) as a fluffy white solid. 1H NMR (400 MHz, CDC13) δ 4.19 (dt, J= 6.0,
3.0 Hz, 2 H), 4.08 (dd, J = 8.3, 6.4 Hz, 2 H), 3.99 (m, 2 H), 3.95 (m, 2 H), 1.43 (s, 6 H), 1.39 (s, 6 H),
1.36 (s, 6 H). MS (+ESD m/z (rel abundance) 303 (100, M+H), 320 (43, M+NH4).
Example 79B
3,4-O-Isopropylidene-L-mannitol
The compound of Example 79A (9.88 g, 32.7 mmol) was suspended in 60% (v/v) acetic acid
in water (150 mL) in a 1 L roundbottom and the flask placed on the rotory evaporator and rotated in
the heating bath at 45 °C for 1.5 h. The heating bath was reduced in temperature to 40 °C and a line
to the vacuum pump was attached to the rotory evaporator. The mixture was concentrated under ca. 1
mm Hg pressure to a wet solid. This material was diluted with dichloromefhane (100 mL) and stirred
at RT for 10 min. The solution was filtered through celite, and the filtrate concentrated in vacuo. The
residue was dissolved in toluene and concentrated in vacuo (2 x) to remove residual acetic acid. The
white solid was then triturated with ether (60 mL) and collected by filtration. After drying in a
vacuum oven for 18 h, these procedures afforded the title compound (2.46 g, 34%) as a white solid.
1H,NMR (400 MHz, DMSO-4,) 8 5.07 (d, J= 4.5 Hz, 2 H), 4.45 (t, J = 5.7 Hz, 2 H), 3.86 (dd, J=
4.9, 1.5 Hz, 2 H), 3.54 (ddd, 7 = 10.9, 5.5, 3.1Hz, 2 H), 3.48 (d, J = 4.6 Hz, 2 H), 3.37 (m, 2 H), 1.28
(s,6H).
Example 79C
(2R,3S,4S,5R)-l-(4-tert-butylphenyl)-2,5-bis(4-(4-methoxybenzyloxy)phenyl)-pyrrolidine-3,4-diol
To a solution of Example 79B (l.Og, 4.5 mmol) in CH3OH (12.0 mL) and CH2C12 (6.0 mL)
was added iodobenzene diacetate (3.48g, 10.8 mmol) and the solution was stirred at room temperature
for 5 h. Solvent was removed in vacuo and to the residue was added 0.1 M H2S04 (4 mL) and the
solution was stirred at room temperature for 18 h. The pH was adjusted to ~6 with solid NaHC03,
and 4-tert-butylaniline (1.43 mL, 9.0 mmol) was added followed by 4-(4-
methoxybenzyloxy)phenylboronic acid (2.09g, 8.1 mmol) and hexafluoroisopropyl alcohol (8 mL).
The solution was heated at 50 °C for 2 h, cooled and solvent removed in vacuo leaving the aqueous
layer which contained quite a bit of solid material. The mixture was diluted with H20 and 0.33 M
K3PO4 was added and the mixture was stirred vigorously. The resulting white solid was collected by
filtration and dried in a vacuum oven to give title compound (1.49g, 2.26 mmol, 50%).^ NMR (400
MHz, DMSO-J6) 8 ppm 1.10 (s, 9H) 3.75 (s, 6H) 4.21 (s, 2H) 4.95 (s, 2H) 5.02 (d, J=6.9 Hz, 2H)
5.75 (s, 2H) 6.20 (d, J=8.9 Hz, 2H) 6.85-6.97 (m, 10H) 7.05 (d, J=8.6 Hz, 4H) 7.37 (d, J=8.7 Hz, 4H).
Example 79D
(2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis-(4-(4-
methoxybenzyloxy)phenyl)pyrrolidine
To a solution of Example 79C (1.49g, 2.26 mmol) in THF (17 mL) and DMF (5.7 mL) at 0 °C
was added, in portions, NaH, 60% in mineral oil (0.27g, 6.77 mmol) and the mixture was stirred at 0
°C for 20 min. Iodomethane (0.31 mL, 4.97 mmol) was added and the reaction mixture was stirred at
room temperature for 18 h, diluted with EtOAc, washed with saturated NH4CI, H20, and brine, dried
(Na2S04), filtered and solvent removed in vacuo to give an oily product. The oil was diluted with
minimal ether and the oil began to solidify and the title compound was isolated as a colorless solid
(1.55g, 2.25 mmol, 100%). 2H NMR (400 MHz, CDC13) δ ppm 1.16 (s, 6H) 3.44 (s, 6H) 3.82 (s, 6H)
4.12-4.17 (m, 2H) 4.94 (s, 4H) 5.22 (dd, J=5.2, 1.63 Hz, 2H) 6.29 (d, J=8.9 Hz, 2H) 6.88-7.00 (m,
10H) 7.12 (d, J=8.6 Hz, 4H) 7.34 (d, J=8.6 Hz, 4H). MS (ESI) m/z 688 (M+H)+.
Example 79E
4,4'-((2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)diphenol
To a solution of Example 79D (1.55g, 2.25 mmol) in CH2C12 (9 mL) was added
trifluoroacetic acid (9 mL, 117 mmol) and stirring was continued at room temperature for 1H.
Solvent was removed and the crude residue was dissolved in 1:1 EtOAc/ saturated NaHC03. The
organic layer was separated, washed with brine, dried (Na2S04), filtered and solvent removed in
vacuo to give tide compound (1.0 g, 2.23 mmol, 99%). MS (ESI) m/z 448 (M+H)+.
Example 79F
4,4'-((2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,l-
phenylene)bis( 1,1,2,2,3,3,4,4,4-nonafluorobutane-1 -sulfonate)
To a solution of Example 79E (l.Og, 2.23 mmol) in DMF (12 mL) was added K2C03 (0.695
g, 5.0 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonyl fluoride (0.86 mL, 4.9 mmol) and the
solution was stirred at 100 °C for 1H. The cooled solution was diluted with EtOAc, washed with
H20, brine, dried (Na2SC>4), filtered and solvent removed in vacuo to give crude product which was
purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexane to give the title
compound (1.63 g, 1.61 mmol, 72%). 1H NMR (400 MHz, CDC13) δ ppm 1.17 (s, 9H) 3.42 (s, 6H)
4.10 (dd, J=5.3, 1.90 Hz, 2H) 5.30 (dd, J=5.2, 1.9 Hz, 2H) 6.19 (d, J=8.8 Hz, 2H) 6.99-7.03 (m, 2H)
7.21-7.29 (m, 8H). MS (ESI) m/z 1012 (M+H)+.
Example 79G
(2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)phenyl)pyrrolidine
To a pressure tube was combined Example 79F (216 mg, 0.21 mmol), 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(l,3,2-dioxaborolane) (114 mg, 0.45 mmol), dicyclohexyl(2',4',6'-
triisopropylbiphenyl-2-yl)phosphine (16.3 mg, 0.034 mmol), potassium acetate (126 mg, 1.28 mmol)
and dioxane (2 mL) and the mixture was de-gassed with N2 gas for 30 min.
Tris(dibenzylideneacetone)dipalladium(O) (7.8 mg, 8.54 mmol) was added and de-gassing was
continued for 10 min. The tube was sealed and heated at 100 °C for 30 min. The cooled solution was
diluted with EtOAc, washed with H20, brine, dried (Na2S04), filtered and the filtrate treated with 3-
mercaptopropyl functionalized silica gel for 1H, filtered and solvent removed in vacuo to give the title
compound (143 mg, 100%).
Example 79H
(2S,2'S)-tert-butyl2,2'-(4,4'-(4,4'-((2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-
2,5-diyl)bis(4,l-phenylene)bis(lH-imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
To a pressure tube was combined Example 79G (140 mg, 0.21 mmol), (S)-tert-butyl-2-(4-
bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (Example 26D) (166 mg, 0.524 mmol), 1 M
Na2C03 (0.524 mL, 0.524 mmol), EtOH (1 mL), and toluene (1 mL) and the mixture was de-gassed
with N2 gas for 30 min. l,r-bis(diphenylphosphino)ferrocenedichloro palladiumQtt) dichloromethane
complex (15.3 mg, 0.021 mmol) was added and de-gassing was continued for 10 min. The tube was
sealed and heated at 100 °C for 3 h, then stirred at room temperature for 16 h. The solution was
diluted with EtOAc, filtered through Celite and the filtrate washed with brine, dried (Na2S04), filtered
and solvent removed in vacuo. Purified by flash chromatography on silica gel eluting with 0-100%
EtOAc/hexane to give title compound (119 mg, 0.135 mmol, 64%). 1H NMR (400 MHz, CDC13) 5
ppm 1.13 (s, 9H) 1.49 (s, 18H) 1.88-2.02 (m, 2H) 2.06-2.22 (m, 4H) 2.99 (s, 2H) 3.33-3.48 (m, 4H)
3.43 (s, 6H) 4.23 (s, 2H) 4.96 (d, J=5.3 Hz, 2H) 5.29 (d, J=6.9 Hz, 2H) 6.29 (d, J=8.9 Hz, 2H) 6.94 (d,
J=8.4 Hz, 2H) 7.13-7.29 (m, 8H). MS (ESI) m/z 886 (M+H)+.
Example 791
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,3S,4S,5R)-l-(4-tert-butylphenyl)-3,4-dimethoxy-5-(4-{2-[(2S)-1 -
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl }phenyl)pyrrolidin-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl} carbamate
To a solution of Example 79H (30 mg, 0.034 mmol) in CH2C12 (1 mL) was added
trifluoroacetic acid (1 mL) and the solution was stirred at room temperature for 1H. Solvent was
removed in vacuo and then dissolved in DMSO (0.5 mL). N,N-diisopropylethylamine was added
until pH 9-10, then (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14.8 mg, 0.085 mmol)
was added followed by HATU (32 mg, 0.085 mmol) and the solution was stirred at room temperature
for 1H. The solution was diluted with EtOAc, washed with H20, brine, dried (Na2S04), filtered and
solvent removed in vacuo. Dissolved the residue in CH3OH (2 mL), added solid K2C03 and stirred at
room temperature for 30 min. Solid was filtered off and the filtrate was concentrated in vacuo and the
residue purified by flash chromatography on silica gel eluting with 0-5% CH30H/CH2C12 to give title
compound (21.6 mg, 0.022 mmol, 63%). :H NMR (400 MHz, CDC13) 8 ppm 0.85 (s, 12H) 1.13 (s,
9H) 1.82-2.03 (m, 2H) 2.02-2.24 (m, 4H) 2.32 (br s, 2H) 3.04 (br s, 2H) 3.43 (s, 6H) 3.53-3.65 (m,
2H) 3.70 (s, 6H) 3.75-3.90 (m, 2H) 4.22 (s, 2H) 4.31 (d, J=15.7 Hz, 2H) 5.16-5.33 (m, 4H) 5.37 (d,
J=9.1Hz, 2H) 6.29 (d, J=8.9 Hz, 2H) 6.94 (s, 2H) 7.16 (s, 2H) 7.22 (d, J=8.0 Hz, 4H) 7.31-7.52 (m,
2H) 7.60-7.87 (m, 2H) 10.26 (s, 1H) 10.64 (s, 1H). MS (ESI) m/z 1000 (M+H)+.
methyl [(2S)-l-{(2S)-2-[5-(4-{l-[4-(dimethylamino)phenyl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl} phenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 26E and N,N-dimethyl-p-phenylenediamine were processed using sequentially the
methods of Examples 76A, 39E, 39F, 55G (25% isopropylalcohol/chloroform used for extraction),
and 26J (reaction solvent = dichloromethane) to provide the title compound (5.6 mg). 1H NMR (400
MHz, DMSO-d6) 8 0.94 - 0.75 (m, 12H), 2.04 - 1.78 (m, 6H), 2.21 - 2.03 (m, 4H), 2.89 (s, 6H), 3.38
(s, 1H), 3.53 (s, 6H), 3.84 - 3.68 (m, 3H), 4.10 - 3.96 (m, 2H), 5.04 (dd, J = 2.9, 6.7, 2H), 6.53 - 6.37
(m, 2H), 6.70 - 6.54 (m, 2H), 7.12 - 6.85 (m, 6H), 7.33 - 7.12 (m, 2H), 7.46 - 7.34 (m, 2H), 7.60 - 7.46
(m, 4H), 12.11 -11.64 (m, 2H). MS (ESI) m/z 923 (M+H)+.
dimethyl ([(25',55)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl[(25',45^-4-
hydroxypyrrolidine-2,1 -diyl] [(25)-3,3-dimethyl- 1-oxobutane-l ,2-diyl]} )biscarbamate
and
dimethyl ([(2R,5J?)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl[(25',41S) -4-
hydroxypyrrolidine-2,l-diyl][(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 81A
(2S,4S)-1 -(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid
To a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (3.9 g, 29.7 mmol) in THF
(26.7 mL) and water (13.3 mL) was added di-tert-butyl dicarbonate (7.14 g, 32.7 mmol) and sodium
hydroxide (2.0 N, 22.9 mL, 45.8 mmol) and the mixture stirred at room temperature overnight. The
mixture then had 10% citric acid (50 mL) added followed by EtOAc and extraction with water and
brine. The organic extract was dried, filtered and concentrated to afford 5.31 g (77%) of the tide
compound. MS (ESI) m/z 232 (M+H)+.
Example 8 IB
(2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid
To a solution of Example 81A (5.31, 22.96 mmol) and imidazole (7.82 g, 115 mmol) in
dichloromethane (106 mL) and DMF (21.3 mL) was added fert-butyldimethylsilyl chloride (7.61 g,
50.5 mmol) and the mixture stirred at room temperature overnight. The mixture then had water (425
mL) added and the solution was extracted with EtOAc and the organic extract concentrated to a
residue that was dissolved in 25% EtOAc and 75% hexanes then extracted with brine and the organic
extract concentrated to a solid. The resultant solid was dissolved in methanol (65 mL) and water (85
mL) then lithium hydroxide monohydrate (1.93 g, 46 mmol) added and the solution stirred at room
temperature for 2 h. Afterwards water (106 mL) and a solution of IN aqueous hydrochloric acid was
added until a pH of 2 was reached. The mixture was then extracted with a mixture of 25% EtOAc and
75% hexanes, the organic extract dried, filtered and concentrated to a colorless solid. MS (ESI) m/z
346 (M+H)+.
Example 81C
(3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-((2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-
phenylene))bis(azanediyl)bis(oxomemylene)bis(3-(tert-butyldimethylsilyloxy)pyrrolidine-l-
carboxylate)
and
(3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-((2R,5R)-l -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-
phenylene))bis(azanediyl)bis(oxomethylene)bis(3-(tert-butyldimethylsilyloxy)pyrroUdine-l-
carboxylate)
The product of Example 81B (149 mg, 0.432 mmol) and the product from Example 5A (50
mg, 0.144 mmol) were processed using the method described in Example IF to afford 74 mg (51%) of
the title compound as a 1:1 mixture of diastereomers. MS (ESI) m/z 1002 (M+H)+.
Example 8 ID
(2S,2'S,4S,4'S)-N,N,-(4,4,-((2S,5S)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(4-
hydroxypyrrolidine-2-carboxamide)
and
(2S,2'S,4S,4,S)-N,N,-(4,4'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(4-
hydroxypyrrolidine-2-carboxamide)
The product of Example 81C (74 mg, 0.074 mmol) was dissolved in trifluoroacetic acid (4
mL), water (0.2 mL) and dichloromethane (0.2 mL) and the mixture stirred at room temperature for 3
hours. Afterwards the mixture was concentrated to an oil which was dissolved in 75% CHC13 and
25% isopropyl alcohol then extracted with a saturated aqueous sodium bicarbonate solution, the
organic extract separated, dried, filtered and concentrated to a colorless solid. MS (ESI) m/z 574
(M+H)+.
Example 8 IE
dimethyl ([(25,55)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl[(25',45)-4-
hydroxypyrrolidine-2,l-diyl][(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl {[(2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1 -diylcarbamoyl[(2S',4S)-4-
hydroxypyrrolidine-2,1 -diyl] [(2S)-3,3 -dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
To the product from Example 8 ID (40 mg, 0.072 mmol), (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid (34.1 mg, 0.18 mmol) and HATU (60.2 mg, 0.158 mmol) in DMSO (3 mL)
was added Hunig's base (0.063 mL, 0.36 mmol), and the reaction mixture was stirred at room
temperature for 1Hr. The reaction mixture was partitioned between water and ethyl acetate, and the
organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel using a solvent gradient of 0-10% MeOH in
dichloromethane to give the title compound as a 1:1 mixture of stereoisomers (21 mg, 32% yield): 2H
NMR (400 MHz, DMSO-D6) δ ppm 9.94 (s, 2 H), 7.44 (d, 7=8.4 Hz, 4 H), 7.07 (m, 6 H) 6.74 (t,
7=8.9 Hz, 2 H), 6.15 (dd, 7=9.1, 4.4 Hz, 2 H), 5.26 (dd, 7=6.1, 3.3 Hz, 2 H), 5.11 (d, 7=5.5 Hz, 2 H),
4.33 (t, 7=7.8 Hz, 2H), 4.19 (m, 2 H), 4.07 (m, 2 H), 3.93 (m, 2 H), 3.48 (s, 6 H), 2.34 (m, 2 H), 1.66
(m, 2 H), 1.59 (m, 2 H), 1.20 (m, 2 H), 0.91 (m, 18 H).
dimethyl ([(25,55)-l-(3-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(25^)pyrrolidine-2,l-diyl[(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
dimethyl ([(2R,5R)-l-(3-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S>3,3-dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Example 1C and 3-fluoroaniline were processed using sequentially the methods of Examples
ID, IE, IF, 1G, and 1H to provide the title compounds. The trans diastereomers were separated from
the cis diastereomer at the stage of 4,4'-(l-(3-fluorophenyl)pyrrolidine-2,5-diyl)dianiline. Data for the
title compounds. :H NMR (free base) (400 MHz, DMSO-d6) δ ppm 0.96 (d, 7=2.17 Hz, 18 H), 1.75 -
1.92 (m, 7 H), 1.93 - 2.05 (m, 2 H), 2.10 - 2.21 (m, 2 H), 2.31 - 2.44 (m, 2 H), 3.43 - 3.51 (m, 4 H),
3.53 (s, 6 H), 3.59 - 3.73 (m, 6 H), 3.73 - 3.82 (m, 2 H), 4.21 (d, 7=8.89 Hz, 2 H), 4.46 (dd, 7=7.92,
5.31Hz, 2 H), 4.70 (t, 7=4.66 Hz, 2 H), 6.07 (d, 7=12.90 Hz, 1H), 6.19 (dd, 7=8.35, 1.63 Hz, 1H),
6.37 (dt, 7=8.35, 2.06 Hz, 1H), 6.97 - 7.05 (m, 2 H), 7.08 (d, 7=8.67 Hz, 2 H), 7.41 (d, 7=7.26 Hz, 4
H), 7.60 (d, 7=8.57 Hz, 4 H), 10.07 (s, 2 H). MS (ESI) m/z 885 (M+H)+.
dimethyl ([(25,55)-1 -(4-fluorophenyl)pyrrolidine-2,5 -diyfjbis {benzene-3,1 -
diylcarbamoyl(2iS)pyrrolidine-2,l-diyl[(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1 -
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl [(2S)-3,3 -dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Example 83A
(2S,2'S)-tert-butyl2,2,-(3,3,-((2S,5S)-l-(4-fluorophenyl)pyrroUdine-2,5-diyl)bis(3,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
and
(2S,2,S)-tert-butyl2,2,-(3,3,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The ether fraction from the work up of Example 55F was purified using flash chromatography
(silica gel, 0-30%EtOAc/dichloromethane) to afford the title compound as a mixture of trans
diastereomers. MS (ESI) m/z 742 (M+H)+.
Example 83B
dimethyl ([(2S,5S)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl]bis {benzene-3,1 -
diylcarbamoyl(25r)pyrrolidine-2,l-diyl[(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2i?,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(2>?)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 83A was processed using the methods described in Examples 55G
and 55H to afford the title compound (0.18 g, 27%). lU NMR (400 MHz, DMSO-D6) δ 0.97 (d, J =
4.5, 18H), 1.73 -1.60 (m, 2H), 1.92 -1.75 (m, 5H), 2.05 -1.92 (m, 3H), 2.23 - 2.05 (m, 2H), 3.54 (d, J
= 1.5,6H), 3.71 - 3.59 (m, 2H), 3.85 - 3.71 (m, 2H), 4.21 (d, J = 8.9,2H), 4.50 - 4.37 (m, 2H), 5.14 (d,
J = 5.7, 2H), 6.30 - 6.19 (m, 2H), 6.85 - 6.75 (m, 2H), 6.88 (d, J = 7.7, 2H), 7.09 (d, J = 8.7, 2H), 7.23
(t, J = 7.9, 2H), 7.40 - 7.30 (m, 2H), 7.58 (d, J = 8.1, 2H), 10.07 - 9.96 (m, 2H). MS (ESD m/z 884
(M+H)+, 882 (M-H)+.
dimethyl ([(2S,5S)-l-(4-methylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrroridine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-1 -(4-methylphenyl)pyrrolidine-2,5-diyl]bis {benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The title compound was prepared using the procedures described for the synthesis of
Examples 34A, 34B, 34C, 34D, and 34E, substituting 4-methylaniline for 4-fe/t-butylaniline. 1H
NMR (500 MHz, DMSO-D6) 8 ppm 0.85 - 0.90 (m, 6 H), 0.90 - 0.95 (m, 6 H), 1.61 - 1.65 (m, 2 H),
1.82 - 2.01 (m, 8 H), 2.03 (s, 3 H), 2.09 - 2.16 (m, 2 H), 3.52 (s, 6 H), 3.58 - 3.66 (m, 2 H), 3.77 - 3.84
(m, 2 H), 4.02 (t, 2 H), 4.40 - 4.45 (m, 2 H), 5.14 (d, 7=6.6 Hz, 2 H), 6.13 - 6.18 (m, 2 H), 6.72 (d,
7=8.4 Hz, 2 H), 7.08 - 7.14 (m, 4 H), 7.29 - 7.34 (m, 2 H), 7.46 - 7.51 (m, 4 H), 9.98 (s, 2 H); MS m/z
852.3 (M+H)+.
Example 85
dimethyl ([(2S,5S)-l-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-l -oxobutane- 1,2-diyl] })biscarbamate
and
dimethyl ([(2R,5R)-l-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyr(2S)pyrroUdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 85A
l-(4-chlorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
The product of Example IB (0.50 g, 1.51 mmol) was suspended in CH2C12 (15 mL).
Triethylamine (0.626 mL, 4.51 mmol) was added at 0 °C, the resulting mixture was stirred for 30 min,
and methanesulfonyl chloride (0.293 mL, 3.76 mmol) was added. The mixture was stirred at rt for 1Hr and then concentrated in vacuo to give a light yellow solid. The solid was dissolved in DMF (6
mL), 4-chloroaniline (1.92 g, 15.05 mmol) was added, and the resulting mixture was stirred at 50 °C
overnight. The mixture was partitioned between EtOAc and IN aq HC1, and the organic layer was
dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give the tide
compound (0.226 g, 35%).
Example 85B
4,4'-(trans-l-(4-chlorophenyl)pyrroUdine-2,5-diyl)dianiline
To a solution of the product of example 85A (0.214 g, 0.505 mmol) in EtOH (2.52 mL) and
THF (2.52 mL) was added platinum(IV) oxide (0.115 g, 0.505 mmol), and the resulting mixture was
stirred at rt under 1 atm H2 overnight. The mixture was filtered through celite, and the filtrate was
concentrated in vacuo. The crude product was purified by column chromatography on silica gel
using a solvent gradient of 0-12% EtOAc in hexane to give a-mixture of the title compound and some
dechlorinated product (4,4'-(trans-1 -phenylpyrrolidine-2,5-diyl)dianiline).
Example 85C
dimethyl ([(2S,5S)-l-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
A mixture of the product from Example 85B was subjected to the procedures described in
Examples 34C, 34D, and 34E to give the title compounds free of dechlorinated product. 1H NMR
(TFA salt) (400 MHz, DMSO-D6) δ ppm 0.84 - 0.89 (m, 6 H), 0.89 - 0.94 (m, 6 H), 1.61 - 1.66 (m, 2
H), 1.80 - 2.03 (m, 8 H), 2.06 - 2.18 (m, 2 H), 3.51 (s, 6 H), 3.56 - 3.65 (m, 2H), 3.74 - 3.84 (m, 2 H),
4.01 (t, 7=8.4 Hz, 2 H), 4.36 - 4.44 (m, 2 H), 5.16 (d, 7=6.3 Hz, 2 H), 6.21 (d, 7=8.9 Hz, 2 H), 6.93
(d, 7=9.0 Hz, 2 H), 7.08 - 7.13 (m, 4 H), 7.26 - 7.31 (m, 2 H), 7.46 - 7.51 (m, 4 H), 9.99 (s, 2 H). MS
m/z 872.3 (M+H)+.
dimethyl ([^S^SS)-1 -(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1 -
diylcarbamoyl(2iSr)pyrrolidine-2,1 -diyl[(2,S>3-mefhyl-1 -oxobutane-1,2-diyl] })biscarbamate
and
dimethyl ([(2R,5R)-l-(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1 -
diylcarbamoyl(25^pyrrolidine-2,l-diyl[(251-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 86A
l-(4-bromophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
The product from Example 1C (0.7 g, 1.433 mmol) and 4-bromoaniline (2.54 g, 14.33 mmol)
were suspended in DMF (6mL) and stirred at 50 °C overnight. The resulting mixture was partitioned
between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with IN HC1
(2x50mL) followed by a brine wash then dried over MgS04 filtered and concentrated. The crude
product was purified by chromatography on silica gel.using a solvent gradient of 2-50% ethyl acetate
in hexane to give the tide compound as a mixture of stereoisomers (74.4mg, 11% yield).
Example 86B
(2S,2'S)-N,N'-(4,4'-(l-(4-bromophenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-
carboxamide
Example 86A was processed using the methods of Examples IE, IF, and 1G to provide the
title compound as a mixture of stereoisomers.
Example 86C
dimethyl ([l-(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(2S)pyrrolidine-
2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 86B (78.0mg, 0.129mmole) was combined with EDAC (67.0mg,
0.347 mmol), 1-hydroxybenzotriazole hydrate ( 49.0mg, 0.323mmole) and (S)-2-
202
(memoxycarbonylamino)-3-methylbutanoic acid (61.0mg, 0.346mmole) in dimethylformamide
(1.4mL) at room temperature under a nitrogen atmosphere. To this solution was added
diisopropylethylamine (0.113 mL, 0.645 mmol). The mixture was allowed to stir overnight at room
temperature followed by partition between ethyl acetate (20mL) and water (5mL). The organic phase
was washed with water (3x5mL) then dried over MgS04, filtered and evaporated to dryness. The
crude product was chromatographed by reverse phase (Ci8) HPLC providing the tide compound as a
1:1 mixture of (trans) diastereomers (0.045g, 38% yield) as an off white solid. 1H NMR (free base)
(400 MHz, DMSO-D6) δ ppm 0.72 - 1.03 (m, 12 H) 1.65 (s, 2 H) 1.79 - 2.19 (m, 11H) 3.52 (s, 6 H)
3.58 - 3.67 (m, 2 H) 3.75 - 3.86 (m, 2 H) 3.95 - 4.09 (m, 2 H) 4.43 (dd, 7=7.92, 4.88 Hz, 2 H) 5.08 -
5.25 (m, 2 H) 6.19 (d, 7=8.89 Hz, 2 H) 7.06 (d, 7=8.89 Hz, 2 H) 7.12 (d, 7=7.16 Hz, 4 H) 7.31 (dd,
7=8.29, 3.96 Hz, 2 H) 7.51 (dd, 7=8.46, 1.52 Hz, 4 H) 10.00 (s, 2 H). MS ESI(+) m/z@916.6
(M+H)+.
methyl {(2S)-l-[(2S)-2-{5-[(2S,5S)-l-(4-fluorophenyl)-5-{2-[(25)-1-{(25)-2-
[(memoxycarbonyl)ammo]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-lH-benzirmdazol-5-yl}pyrrolidin-
2-yl] - l/f-benzimidazol-2-yl }pyrrolidin-l -yl] -3,3-dimethyl-1 -oxobutan-2-yl} carbamate
and
methyl {(25)-1 -[(2S)-2-[5-[(2R,5R)-l-(4-fluorophenyl)-5-{2-[(2S> 1 -{(25')-2-
[(memoxycarbonyl)ammo]-3,3-aUmethylbutanoyl}pyrrolioUn-2-yl]-lH-benzimidazol-5-yl}pyn'olidin-
2-yl]-lH-berizimidazol-2-yl}pyrrolidin-l-yl]-3,3-dimethyl-l-oxobutan-2-yl}carbamafe
The product from Example 29G (0.045 g, 0.084 mmol), (S)-2-methoxycarbonylamino-3,3-
dimethyl-butyric acid (0.037 g, 0.193 mmol), 4-methylmorpholine (0.037 mL, 0.336 mmol), 1H-
benzo[d][l,2,3]triazol-l-ol hydrate (0.028 g, 0.185 mmol) and Nl-((ethylimino)methylene)-N3,N3-
dimethylpropane-l,3-diamine hydrochloride (0.035 g, 0.185 mmol) were combined in 2 mL DMF and
stirred for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer
was washed 3 X 20 mL with brine, dried (Na2S04), filtered and concentrated. The crude material was
flash chromatographed on a 4 g Isco Gold silica cartridge eluting with 1.5-8% MeOH in methylene
chloride. A second reverse phase C-18 preparative chromatography eluting with 9:1 water/acetonitrile
--> 100% acetonitrile afforded the title compounds (29 mg, 28%; mix of trans diastereomers) as a
light tan powder. LH NMR (TFA salt) (400 MHz, DMSO-J6) δ 0.84 - 0.95 (m, 18 H) 1.21 - 1.46 (m, 4
H) 1.75 - 2.27 (m, 8 H) 3.56 (s, 6 H) 3.86 (t, J=5.26 Hz, 4 H) 4.22 (dd, J=8.57, 4.45 Hz, 2 H) 5.15 -
5.24 (m, 2 H) 5.53 (d, J=4.88 Hz, 2 H) 6.30 (dd, J=9.11, 4.34 Hz, 2 H) 6.75 - 6.83 (m, 2 H) 7.29 (d,
J=8.57 Hz, 2 H) 7.35 (d, J=8.46 Hz, 2 H) 7.48 (d, J=7.92 Hz, 2 H) 7.69 (d, J=7.37 Hz, 2 H). MS
(ESI+) m/z 879 (M+H)+.
dimethyl ([(2S,5S)-l-(4-methoxyphenyl)pyrrolidine-2,5-diyi]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-(4-methoxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The title compound was prepared using the procedures described for the synthesis of
Examples 34A, 34B, 34C, 34D, and 34E, substituting 4-methoxyaniline for 4-tert-butylaniline. 1H
NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.85 - 0.90 (m, 6 H), 0.90 - 0.95 (m, 6 H), 1.60 -1.66
(m, 2 H), 1.81 - 2.04 (m, 8 H), 2.08 - 2.19 (m, 2 H), 3.52 (s, 9 H), 3.57 - 3.66 (m, 2 H), 3.77 - 3.85 (m,
2 H), 4.02 (t, 2 H), 4.39 - 4.46 (m, 2 H), 5.12 (d, 7=6.3 Hz, 2 H), 6.18 (d, 7=9.0 Hz, 2 H), 6.56 (d,
7=9.0 Hz, 2 H), 7.09 - 7.15 (m, 4 H), 7.28 - 7.34 (m, 2 H), 7.46 - 7.52 (m, 4 H), 9.97 (s, 2 H); MS m/z
868.5 (M+H)+.
me%l{(2^-14(25)-2<4-{44(25,55)-5-(4-{2-[(2lS)-l-{(2l?)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-imidazol-4-yl }phenyl)-l -phenylpyrrolidin-2-yl] phenyl} -IH-
imidazol-2-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
and
methyl {(2^-l-[(25)-2-(4-{4-[(27?,5/?)-5-(4-{2-[(25')-l-{(21S}-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl]- l/f-imidazol-4-yl }phenyl)-l -phenylpyrrolidin-2-yl] phenyl} - 1/7-
imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
The trans diastereomers obtained in Example 59B (8.5 mg, 0.0107 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (4.67 mg, 0.027 mmol) and HATU (8.9 mg, 0.023
mmol) in DMSO (1 mL) was added Hunig's base (0.015 mL, 0.085 mmol), and the reaction mixture
was stirred at room temperature for 1Hr. The reaction mixture was partitioned between water and
ethyl acetate, and the organic layer was dried over MgS04, filtered and concentrated in vacuo. The
crude product was purified by reversed phase chromatography (CI 8), eluting with 10-100%
acetonitrile in water (0.1% TFA) to afford 5.0 mg (53%) of the title compound as a mixture of trans
diastereomers. 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 14.45 (bs, 2 H), 7.97 (s, 2 H), 7.66
(m, 4 H), 7.38 (m, 4H), 7.31 (d, 7=7.4 Hz, 2 H), 6.92 (t, 7=7.6 Hz, 2 H), 6.43 (m, 1H), 6.28 (d, 7=8.1Hz, 2 H), 5.37 (m, 2H), 5.09 (t, 7=6.7 Hz, 2 H), 4.09 (t, 7=7.7 Hz, 2 H), 3.81 (m, 6 H), 3.53 (s, 6 H),
2.40 (m, 2 H), 2.08 (m, 2 H), 2.02 (m, 6 H), 1.85 (m, 2 H), 0.85 (m, 2 H), 0.80 (m, 12 H); MS (ESI)
m/z 884 (M+H)+.
0 Of f XX^ - ^4° 9
Example 90
0 Of f XX^ - ^4° 9
Example 90
dimethyl ([(25,55)-l-(biphenyl-4-yl)pyrrolidine-2,5-diyl]bis{benzene-4,1 -
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2i?,5R)-l-(biphenyl-4-yl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(25)pyrrolidine-2,1 -diyl[(25')-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
The product from Example 86C (24.9mg, 0.027mmole) dissolved in a THF (lmL) and water
(0.3mL) solution was combined in a microwave tube with phenylboronic acid (6.90mg, 0.054mmole),
tribasic potassium phosphate (13.37mg, 0.063mmole) and l,l'-bis(di-tert-butylphosphino)ferrocene
palladium dichloride (1.42mg, 2.17umole). The tube was sealed and nitrogen bubbled through at
room temperature for five minutes. All gas lines were subsequently removed and the reaction vessel
immersed in a 50 °C oil bath and heated for two and one half hours. The contents of the tube were
partitioned between ethylacetate (5mL) and brine (lmL). The organic phase was washed with brine (2
x lmL) then dried over MgS04, filtered and concentrated. The crude product was purified by silica
gel chromatography eluting with 5% EtOAc - hexane and progressing to (75% EtOAc-hexane) + 3%
methanol to provide as a 1:1 mixture of (trans) diastereomers the title compound (18.6mg, 75% yield)
as a cream colored solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.76 - 0.99 (m, 12 H) 1.67 (s, 2 H)
1.77 - 2.19 (m, 11H) 3.52 (s, 6 H) 3.58 - 3.65 (m, 2 H) 3.74 - 3.86 (m, 2 H) 3.96 - 4.08 (m, 2 H) 4.44
(d, 7=4.99 Hz, 2 H) 5.25 (s, 2 H) 6.35 (d, 7=8.02 Hz, 2 H) 7.17 (d, 7=7.26 Hz, 5 H) 7.24 - 7.34 (m, 6
H) 7.45 (d, J=7.92 Hz, 2 H) 7.52 (d, 7=7.81Hz, 4 H) 10.00 (s, 2 H). MS ESI(+) m/z@ 915.1 (M+H)+,
m/z@ 972.3 (M+CH3CN+NH4)+.
F
\ HN—l. )—NH
H ^ <)-Example 91
F
Vo o=T
\ HN—l. )—NH
H ^ -X>Example 91
me%l{(25)-l-[(25)-2-(5-{(25,5S)-5-{2-[(2^-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -1 -[4-(trifiuoromemyl)phenyl]pyrrohdin-2-
yl} - l//-benzimidazol-2-yl)pyrrolidin-l -yl] -3-methyl-l -oxobutan-2-yl }carbamate
and
methyl {(2S)-l-[(2S)-2-(5-{(2R,5K)-5-{2-[(2S>l-{(2S>2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - l/f-benzimidazol-5-yl} -l-[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl} - l//-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
Example 91A
(2S,2,S)-2,2'(6,6'-(l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(lH-benzo[d]imidazole-
6,2-diyl))dipyrrolidinium chloride
Example 28C and 4-trifluoromethylaniline were processed using the methods of Examples
28D-28J to provide the title compound as a mixture of cis and trans stereoisomers.
Example 91B
methyl {(25)-l-[(25)-2-(5-{(25',55)-5-{2-t(25')-l-{(25)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrroHdin-2-yl]-1H-benzirmdazol-5-yl}-l-[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl} -1H-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
and
methyl {(25)-l-[(25)-2-(5-{(2JR,5^)-5-{2-[(25)-l-{(25,)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyn-oUdin-2-yl]-l//-benzimidazol-5-yl}-l-[4-(trifluoromemyl)phenyl]pyrroUdin-2-
yl} -l//-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
The product from Example 91A (1: 1 mixture of cis and trans isomers), 0.018 g, 0.027
mmole), HOBt (0.013 g, 0.082 mmole), EDAC (0.016 g, 0.082 mmole) and (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.014 g, 0.082 mmole) were combined in a 20 ml
round bottom flask and dissolved in 1 ml DMF at room temperature, added 4-methylmorpholine
(0.015 ml, 0.137 mmole) and the resulting clear slightly brown solution was stirred at room
temperature for 2 hr. The reaction mixture was analyzed by LC-MS and determined to be complete.
The reaction mixture was diluted with 50 ml EtOAc, washed with 10% NaHC03 and 10% NaCl, dried
over anhydrous Na2S04(s), filtered and solvent removed in vacuo leaving the title compound as a light
brown solid. The material was purified by preparative HPLC on a Phenomenex Luna C8(2) δ um
100A AXIA column (30mm x 75mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in
water (B) was used, at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-
95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A). The product fractions were
collected and evaporated to dryness in vacuo leaving the title compound as a tan solid, (11 mg, 44%)
and a mixture of diastereomeric trans isomers. 1H NMR (TFA salt) (400 MHz, DMSO-D6) d ppm
0.67 - 0.94 (m, 12 H) 1.95 (m, 18 H) 3.79 - 3.89 (m, 6 H) 4.10 (s, 2 H) 5.19 (s, 1H) 5.64 (s, 2 H) 6.45
(s, 2 H) 7.28 (s, 4 H) 7.47 (s, 4 H) 7.69 (s, 4 H), 12.1 (b, 2H)ESI+(m/z):900.6, ESI-(m/z):898.8.
dimethyl ([(2S,5S)-l-(4-hydroxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-(4-hydroxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrohdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
To a solution of the product from Example 88 (0.050 g, 0.058 mmol) in CH2C12 (1 mL) at -78
°C was added a 1.0 M solution of borontribromide in CH2C12 (0.29 mL, 0.29 mmol). The resulting
dark red color solution was stirred at -78 °C for 4 h, and then warmed to rt and washed with water.
The organic layer was dried over sodium sulphate, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using a solvent gradient of 0-7.5%
MeOH in CH2C12 to give the title compound (5.5 mg, 12%) as a mixture of trans diastereomers. 1H
NMR (400 MHz, DMSO-D6) 8 ppm 0.86 - 0.90 (m, 6 H), 0.90 - 0.95 (m, 6 H), 1.58 - 1.63 (m, 2 H),
1.82 - 2.04 (m, 8 H), 2.08 - 2.19 (m, 2 H), 3.52 (s, 6 H), 3.58 - 3.66 (m, 2 H), 3.77 - 3.84 (m, 2 H),
4.02 (t, 7=8.5 Hz, 2 H), 4.40 - 4.46 (m, 2 H), 5.08 (d, 7=6.3 Hz, 2 H), 6.08 (d, 7=8.8 Hz, 2 H), 6.38 (d,
7=8.8 Hz, 2 H), 7.08 - 7.13 (m, 4 H), 7.29 - 7.34 (m, 2 H), 7.45 - 7.51 (m, 4 H), 8.27 (d, 7=1.2 Hz, 1
H), 9.96 (s, 2 H); MS m/z 854.4 (M+H)+.
dimethyl ({(2S,5S)-l-[4-(propan-2-yl)phenyl]pyrrolidine-2,5-diyl }bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ({(2R,5R)-1 -[4-(propati-2-yl)phenyl]pyrrolidine-2,5-diyl}bis {benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The title compound was prepared as a mixture of trans diastereomers using the procedures
described for the synthesis of Examples 34A, 34B, 34C, 34D, and 34E, substituting 4-isopropylaniline
for 4-tert-butylaniline. 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.85 - 0.90 (m, 7=5.8, 5.8
Hz, 6 H), 0.90 - 0.96 (m, 6 H), 1.02 -1.06 (m, 6 H), 1.60 - 1.65 (m, 2 H), 1.81 - 2.04 (m, 8 H), 2.08
- 2.19 (m, 2 H), 2.56 - 2.65 (m, 1H),, 3.52 (s, 6 H), 3.58 - 3.66 (m, 2 H), 3.76 - 3.85 (m, 2 H), 4.02 (t,
7=8.3 Hz, 2 H), 4.40 - 4.45 (m, 2 H), 5.14 (d, 7=6.5 Hz, 2 H), 6.15 - 6.20 (m, 2 H), 6.79 (d, 7=8.7 Hz,
2 H), 7.09 - 7.16 (m, 4 H), 7.29 - 7.34 (m, 2 H), 7.47 - 7.52 (m, 4 H), 9.97 (s, 2 H); MS m/z 880.5
(M+H)+.
methyl {(25)-1 -[(2S)-2-(4-{4-[(25',55)-1 -(4-fluorophenyl)-5-(4-{2-[(2S> 1 -{(25)-2-
[(memoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-4-
yl }phenyl)pyrrolidin-2-yl]phenyl} - l//-imidazol-2-yl)pyrrolidin-1 -yl] -3,3 -dimethyl-1 -oxobutan-2-
yljcarbamate
and
methyl {(25^-l-[(25,)-2-(4-{4-[(2«,5R)-l-(4-fluorophenyl)-5-(4-{2-[(2S)-l-{(21S)-2-
[(memoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-4-
yl}phenyl)pyn-ohdin-2-yl]phenyl}-l//-irnidazol-2-yl)pyrrolidin-l-yl]-3,3-dimethyl-l-oxobutan-2-
yl }carbamate
The product from Example 45D (28 mg, 0.048 mmol) was subjected to the conditions
described in example 45E, substituting (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid for
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid, to give the title compound (18 mg, 41%) as a
mixture of diastereomers. 1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.86 (s, 9 H), 0.87 (s, 9
H), 1.70 - 1.81 (m, 2 H), 1.94 - 2.25 (m, 6 H), 2.34 - 2.44 (m, 2 H), 3.55 (s, 6 H), 3.72 - 3.95 (m, 4
H), 4.19 (d, 7=8.7 Hz, 2 H), 5.09 (t, 7=7.2 Hz, 2 H), 5.35 (d, 7=6.1Hz, 2 H), 6.26 (dd, 7=9.1,4.4 Hz, 2
H), 6.81 (t, 7=8.9 Hz, 2 H), 7.29 (d, 7=8.0 Hz, 2 H), 7.37 (d, 7=7.2 Hz, 4 H), 7.68 (dd, 7=7.8, 5.4 Hz, 4
H), 7.97 (s, 2 H), 14.46 (br s, 2 H); MS m/z 930.8 (M+H)+.
me±yl{(25)-l-[(25)-2-(4-{4-[(25,55)-l-(4-cyclopropylphenyl)-5-(4-{2-[(25')-l-{(25)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-4-yl}phenyl)pyrrolidiri-
2-yl]phenyl} - l//-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
and
methyl {(2S)-l-[(2S>2-(4-{4-[(2#,5#)-1 -(4-cyclopropylphenyl)-5-(4-{2-[(25> 1 -{(25)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-mediyl-l-oxobutan-2-yl}carbamate
Example 95A
(S)-4,4'-(4,4,-((2R,5R)-l-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-
pyrrolidin-2-yl)-lH-imidazole)
and
(S)-4,4'-(4,4'-((2S,5S)-l-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-
pyrrolidin-2-yl)-lH-imidazole)
The product from Example 68C (1.27 g, 1.568 mmol) was dissolved in dichloromethane (12
mL). The mixture was cooled to 0 °C and trifluroacetic acid (8 mL, 104 mmol) was added slowly. The
mixture was warmed to room temperature and stirred for lh. The solvent was evaporated and the
residue was purified by chromatography on silica gel eluting with methanol/dichloromethane (1% to
10%). The tide compound was eluted as the first of 2 stereoisomers and was obtained as a mixture of
trans diastereomers (510 mg, 53%).
Example 95B
methyl {(25)-1 -[(2S)-2-(4- {4-[(2S,5S)-1 -(4-cyclopropylphenyl)-5-(4- {2-[(25)-1 -{(25')-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyn:olidin-2-yl]-lff-imidazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl}-l//-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
and
methyl {(25)-1 -[(2S)-2-(4-{4-[(2R,5R)-1 -(4-cyclopropylphenyl)-5-(4- {2-[(2S)-l -{(25)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidm-2-yl]-1H-imidazol-4-yl)phenyl)pyrrolidin-
2-yl]phenyl} - l#-imidazol-2-yi)pyrrolidin-1 -yl] -3-methyl- l-oxobutan-2-yl Jcarbamate
The product from Example 95A (150 mg, 0.246 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (86 mg, 0.492 mmol), 4-methylmorpholine (0.216 mL, 1.968 mmol), Nl-
((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (104 mg, 0.541 mmol)
and lH-benzo[d][l,2,3]triazol-l-ol hydrate (83 mg, 0.541 mmol) were combined in DMF (10 mL).
The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate,
brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane (1% to 4%) to give the title
compound (78 mg, 34%) as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm0.35 - 0.41 (m, 2 H) 0.65
- 0.72 (m, 2 H) 0.81 - 0.92 (m, 12 H) 1.58 - 1.64 (m, 1H) 1.66 - 1.72 (m, 2 H) 1.86 - 2.03 (m, 6 H)
2.07 - 2.17 (m, 4 H) 2.24 - 2.30 (m, 2 H) 3.53 (s, 6 H) 3.74 - 3.82 (m, 4 H) 4.04 (t, J=7.86 Hz, 2 H)
5.06 (dd, J=6.72, 2.93 Hz, 2 H) 5.14 - 5.26 (m, 2 H) 6.19 (d, J=8.67 Hz, 2 H) 6.64 (d, J=8.24 Hz, 2 H)
7.10 - 7.30 (m, 6 H) 7.34 - 7.69 (m, 6 H) 11.64 -12.11 (m, 2 H); MS (ESI+) m/z 924.8 (M+H)+.
dimethyl ([(2R,5R)-l-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 38A and 4-cyclopropylaniline were processed using sequentially the methods of
Examples 34A, 34B, 34C, 66D, and 66E to provide the tide compound (62 mg).1H NMR (400 MHz,
DMSO-i6) δ 0.36 - 0.46 (m, 2 H) 0.63 - 0.77 (m, 2 H) 0.87 (d, J=6.61Hz, 6 H) 0.92 (d, J=6.72 Hz, 6
H) 1.52 - 2.46 (m, 15 H) 3.52 (s, 6 H) 3.57 - 3.66 (m, 2 H) 3.75 - 3.85 (m, 2 H) 4.02 (t, J=8.46 Hz, 2
H) 4.42 (dd, J=8.02, 4.88 Hz, 2 H) 5.14 (d, J=6.40 Hz, 2 H) 6.14 (d, J=8.78 Hz, 2 H) 6.65 (d, J=8.67
Hz, 2 H) 7.10 (d, J=8.57 Hz, 4 H) 7.30 (d, J=8.35 Hz, 2 H) 7.48 (d, J=8.57 Hz, 4 H) 9.97 (s, 2 H). MS
(APCQ m/z 878 (M+H)+.
methyl {(251-l-[(21S',45)-2-{5-[(25',55)-l-(4-fluorophenyl)-5-{2-[(2lS',45)-4-hydroxy-l-{(25)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]4//-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} -4-hydroxypyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
and
methyl {(25)-l-[(21S',45)-2-{5-[(2i?,5J?)-l-(4-fluorophenyl)-5-{2-[(25',45)-4-hydroxy-l-{(25)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidm-2-yl]-lH-benzimidaz»l-5-yl}pyrrolidin-2-
yl] - lH-benzimidazol-2-yl} -4-hydroxypyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
(2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid
(2S,4S)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96
mmol) and imidazole (7.82 g, 115 mmol) were combined in dichlorormethane (106 mL) and
dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-
butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted
with water and extracted into ethyl acetate and concentrated to provide the title compound.
Example 97B
The product from Example 29D (0.906 g, 2.62 mmol) was processed as in Examples 29E,
29F, 29G, and 29H, substituting Example 97A for S-Boc-proline in step 29E to give the title
compounds (0.012 g, 13%).1H NMR (400 MHz, DMSO-D6) δ ppm 0.69 - 0.85 (m, 12 H) 1.27 - 1.39
(m, 1H) 1.53 (dt, J=21.31, 6.64 Hz, 1H) 1.71 (s, 4 H) 1.80 - 1.90 (m, 2 H) 2.02 (d, J=7.70 Hz, 2 H)
2.54 - 2.62 (m, 2 H) 3.53 (s, 6 H) 3.68 (t, J=10.63 Hz, 2 H) 3.93 - 4.00 (m, 2 H) 4.39 (s, 2 H) 5.13 (s,
2 H) 5.38 (s, 2 H) 6.19 - 6.38 (m, 4 H) 6.74 (d, J=2.60 Hz, 2 H) 7.08 (s, 2 H) 7.21 - 7.36 (m, 4 H) 7.40
- 7.51 (m, 2 H) 12.21 -12.38 (m, 2 H); MS TFA+ m/z 882.5 (M+H)+.
dimethyl ({(2R,5R)-1 -[4-(morpholin-4-yl)phenyl]pyrrolidine-2,5-diyI}bis{benzene-4,1 -
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimediyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 98A
4-(4-((2R,5R)-2,5-bis(4-nitrophenyl)pyrrolidin-l-yl)phenyl)morpholine
The product from Example 38A and 4-morpholinoaniline were processed using the method
described in Example ID using NMP for the solvent to afford the title compound. MS (ESI) m/z 475
(M+H)+.
Example 98B
4,4'-((2R,5R)-1 -(4-morpholinophenyl)pvrrolidine-2,5-diyl)dianiline
The product from Example 98A in tetrahydrofuran (20 mL) was added to Ra-Ni (water wet,
A-7000, 0.8 g, 12.63 mmol) in a 50 mL pressure bottle and stirred for 2 hours at ambient temperature
under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated to
afford the title compound (0.31 g, 44%). MS (DCI) m/z 415 (M+H)+.
Example 98C
(2S,2'S)-tert-butyl2,2'-(4,4,-((2R,5R)-l-(4-morpholinophenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The product from Example 98B was processed using sequentially the methods of Examples
55F, 55G, and 26J (with (S)-2-(memoxycarbonylamino)-3,3-dimethylbutanoic acid) to afford the title
compound (0.13 g). !H NMR (400 MHz, DMSO-D6) δ 0.93 (d, J = 20.5, 17H), 1.92 - 1.79 (m, 4H),
2.05 -1.93 (m, 3H), 2.21 - 2.08 (m, 2H), 2.43 (t, 7 = 6.1, 3H), 2.84 - 2.75 (m, 4H), 3.54 (s, 6H), 3.68 -
3.58 (m, 6H), 3.83 - 3.70 (m, 2H), 4.20 (d, 7 = 8.9, 2H), 4.43 (dd, 7 = 7.9, 5.3, 2H), 5.12 (d, 7 = 6.3,
2H), 6.17 (d, 7 = 9.1, 2H), 6.60 (d, 7 = 9.1, 2H), 7.07 (d, 7 = 8.8, 2H), 7.11 (d, 7 = 8.5, 4H), 7.48 (d, 7
= 8.5, 4H), 9.98 (s, 2H). Impurity lR NMR (400 MHz, DMSO-D6) δ 1.63 (d, 7 = 5.6, 2H), 3.17 (d, 7
= 5.3, 3H), 4.09 (q, 7 = 5.3, 1H). MS (ESI) m/z 952 (M+H+).
dimethyl ([(2S,5S)-1 - {4-[6-(dimethylamino)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis {benzene-
4,1 -diylcarbamoyl(25r)pyrrolidine-2,1 -diyl[(25)-3-methyl-l -oxobutane- 1,2-diyl] })biscarbamate
and
dimethyl (f(2R,5R)-l-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}pyrrolidine-2,5-diyl]bis{benzene-
4J-diylcarbamoyl(2iS)pynx)lidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 99A
5-(4-(2,5-bis(4-nitrophenyl)pyrrolidin-l-yl)phenyl)-N,N-dimethylpyridin-2-amine
The product from Example 86A (25.7mg, 0.055mmole) was combined in a microwave tube
with 6-(dimethylamino)pyridine-3-ylboronic acid (17.49mg, 0.105mmole), tribasic potassium
phosphate (24.70mg, 0.116mole) and l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichlofide
(2.504mg, 3.84|imole). The tube was sealed and a solvent mixture of THF (2mL) and water (0.6mL)
added via syringe. The reaction mixture was sparged with nitrogen at room temperature for three
minutes during which time the solution turned black in color. Chromatographic analysis indicated that
the reaction was complete. The contents of the microwave tube were partitioned between brine (3mL)
and ethyl acetate (3mL). The water was drawn off and the organic phase dried over MgS04, filtered
and concentrated. The crude product was purified by chromatography on silica gel from 2 up to 20%
ethyl acetate in hexane to provide the title compound (26.8mg, 96% yield) as an orange solid as a
mixture of stereoisomers. MS ESI(+) m/z @ 510.4 (M+H)+.
Example 99B
4,4'-(l-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline
The product from Example 99A (26.8mg, 0.053mmole) was dissolved in THF (526uL) in a
round bottom flask to which was subsequently added ethanol (526nL) resulting in a yellow
precipitate. To this suspension was added platinum (IV) oxide (3.16mg, 0.014mmole). The flask was
capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a
balloon and the mixture allowed to stir at room temperature for two and one half hours. The reaction
mixture was vacuum filtered through a sand and celite plug, which was rinsed with THF and methanol
until the filtrate was u.v.(-)- The filtrate was concentrated in vacuo to provide the title compound in
quantitative yield as a white solid as a mixture of stereoisomers. MS ESI(+), m/z @ 450.7 (M+H)+.
Example 99C
(2S,2,S)4ert-butyl2,2,-(4,4'-(^(4<6-(dimemylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5-
diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
The product from Example 99B (23.83mg, 0.053mmole) was reacted with (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (27.8mg, 0.129mmole) as described in Example IF
with minor modification. The crude product was recovered by partition of the reaction mixture
between ethyl acetate(lOmL) and water(3mL). The organic phase was washed with water (3x3mL),
dried over MgS04, filtered and concentrated. Chromatography on silica gel using a solvent gradient of
2-100% ethyl acetate in hexane provided the title compound (32.6mg, 73% yield) as a cream colored
solid as a mixture of stereoisomers.
Example 99D
(2S,2'S)-N,N'-(4,4^(l<4^6?)pyrrolidme-2,l-diyl[(25^-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 99D (22.5mg, O.035mmole) was reacted with (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (19.41mg, O.lllmmole) as described in Example
86C. Chromatography on silica gel (10% ethyl acetate J90% hexane to 100% ethyl acetate J4%
methanol) provided the title compound (14.5mg, 43.3% yield), an orange yellow solid that darkened
somewhat on standing, as a 1:1 mixture of trans diastereomers. 1H NMR (400 MHz, DMSO-D6) 8
ppm 0.77 - 0.99 (m, 12 H) 1.67 (s, 2 H) 1.76 - 2.24 (m, 11H) 2.98 (s, 6 H) 3.52 (s, 6 H) 3.58 - 3.65
(m, 2 H) 3.76 - 3.90 (m, 7=9.54 Hz, 2 H) 3.95 - 4.11 (m, 2 H) 4.36 - 4.47 (m, 2 H) 5.19 - 5.27 (m, 2
H) 6.30 (s, 2 H) 6.58 (d, 7=9.00 Hz, 1H) 7.17 (t, 7=8.08 Hz, 4 H) 7.30 (d, 7=8.02 Hz, 3 H) 7.52 (d,
7=7.37 Hz, 4 H) 7.57 - 7.63 (m, 1H) 7.63 - 7.68 (m, 1H) 7.91 (s, 1H) 8.18 - 8.22 (m, 1H) 10.00 (s, 2
H). MS ESI(+) m/z @ 959.4 (M+H)+.
dimethyl ({(2R,5R)-1 -[4-(methylsulfonyl)phenyl]pyrrolidine-2,5-diyl }bis {benzene-4,1-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(25)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 38A and 4-(methylsulfonyl)aniline were processed using sequentially the methods
of Examples 98A, 98B, 55F, 55G, and 26J (with (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid; reaction solvent = dichloromethane) to provide the tide compound (55 mg). 1H NMR (400 MHz, DMSO-D6) 50.96 (d, J= 5.1, 18H), 1.24 (s, 1H), 1.69 (d, 7 = 5.7, 2H), 2.04 - 1.74
(m, 7H), 2.22 - 2.07 (m, 2H), 2.98 (s, 3H), 3.54 (s, 6H), 3.70 - 3.58 (m, 2H), 3.83 - 3.70 (m, 2H), 4.20
(d, 7 = 8.9, 2H), 4.43 (dd, 7 = 7.8, 5.4, 2H), 5.32 (d, 7 = 6.1, 2H), 6.39 (d, 7 = 9.0, 2H), 7.08 (d, 7 =
8.8, 2H), 7.15 (d, J= 8.6,4H), 7.43 (d, 7 = 9.0, 2H), 7.53 (d, 7= 8.6, 4H), 10.03 (s, 2H). MS (ESI) m/z
966 (M+Na)+, 943 (M-H)+.
dimethyl ([(2S,5S)-1 - {4- [6-(morpholin-4-yl)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis {benzene-
4,1 -diylcarbamoyl(2S)pyrrolidine-2,1 -diyl [(2S)-3-methyl-1 -oxobutane-1,2-diyl] })biscarbamate
and
dimethyl ([(2R,5R)-l-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-2,5-diyl]bis{benzene-
4,l-diylcarbamoyl(25r)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 86A and 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
were processed using sequentially the methods of Examples 99A, 99B, IF, 1G, and 86C to provide
the title compound as a 1:1 mixture of trans diastereomers. 1H NMR (free base) (400 MHz, DMSO-
D6) 8 ppm 0.78 - 1.00 (m, 12 H) 1.67 (s, 2 H) 1.75 - 2.20 (m, 11H) 3.36 - 3.41 (m, 4 H) 3.52 (s, 6 H)
3.57 - 3.65 (m, 2 H) 3.65 - 3.72 (m, 4 H) 3.79 (s, 2 H) 4.02 (s, 2 H) 4.36 - 4.48 (m, 2 H) 5.24 (s, 2 H)
6.32 (d, 7=7.70 Hz, 2 H) 6.78 (d, 7=9.00 Hz, 1H) 7.12 - 7.18 (m, 4 H) 7.21 (d, 7=8.78 Hz, 2 H) 7.31
(d, 7=8.35 Hz, 2 H) 7.52 (d, 7=7.48 Hz, 4 H) 7.63 - 7.69 (m, 1H) 8.22 - 8.27 (m, 1H) 10.00 (s, 2 H).
MS ESI(+) m/z@ 1000.6 (M+H)+.
dimethyl ({(2S,5S)-l -[4-(pyridin-3-yl)phenyl]pyrrolidine-2,5-diyl }bis{benzene-4,1-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ({(2R,5/?)-l-[4-(pyridin-3-yl)phenyl]pyrroIidine-2,5-diyl}bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Example 86A and pyridin-3-ylboronic acid were processed using sequentially the methods of
Examples 99A, 99B, IF, 1G, and 86C to provide the title compound as a 1:1 mixture of trans
diastereomers ( 35.8mg). 1H NMR (free base) (400 MHz, DMSO-D6) δ ppm0.71 - 1.05 (m, 11H)
1.68 (s, 2 H) 1.87 (s, 8 H) 2.06 - 2.21 (m, 2 H) 3.52 (s, 6 H) 3.56 - 3.67 (m, 2 H) 3.80 (s, 2 H) 4.02 (d,
7=1.73 Hz, 2 H) 4.43 (dd, 7=7.97, 4.93 Hz, 2 H) 5.26 (d, 7=6.29 Hz, 2 H) 6.37 (d, 7=7.92 Hz, 2 H)
7.17 (dd, 7=8.57, 1.95 Hz, 4 H) 7.28 - 7.36 (m, 5 H) 7.52 (d, 7=7.81Hz, 4 H) 7.82 - 7.87 (m, 1H)
8.36 (dd, 7=4.72, 1.36 Hz, 1H) 8.69 (s, 1H) 10.00 (s, 2 H). MS ESI(+) m/z @ 915.6 (M+H)+
methyl [(2S,3S)-1 -{(2S>2-[5-(4-{(2S,5S)-l-(4-tert-butylphenyl)-5-[4-(2-{(25)-1 -[N-
(methoxycarbonyl)-O-methyl-C1-threonyl] pyrrolidin-2-yl} -1 //-imidazol-5-yl)phenyl]pyrrolidin-2-
yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methoxy-l-oxobutan-2-yl]carbamate
and
methyl [(25,,3>S,)-l-{(25)-2-[5-(4-{(2i?,5R)-l-(4-tert-butylphenyl)-5-[4-(2-{(2>S)-l-[N-
(methoxycarbonyl)-O-methyl-C1-threonyl]pyrrolidin-2-yl} - l/f-imidazol-5-yl)phenyl]pyrrolidin-2-
yl }phenyl)- l#-imidazol-2-yl]pyrrolidin-1 -yl} -3-methoxy-1 -oxobutan-2-yl] carbamate
The product from Example 201A (0.122 g, 0.639 mmol), and HOBt ( 0.098 g, 0.639 mmole)
were combined and dissolved in 2 ml DMF then cooled in an ice bath between 0-5 °C. To this
solution was added EDAC (0.123g, 0.639 mmol) followed by 4-methylmorpholine (0.211 ml, 1.917
mmole) and the mixture was stirred 5 minutes, then added dropwise the mixture of the products from
Example 42F (0.2 g, 0.320 mmol), in DMF (2 ml) with a DMF wash (1 ml). The pH of the solution
was adjusted with additional 4-methylmorpholine (0.1 ml, 0.96 mmole) and the mixture was stirred a
total of 90 minutes in the ice bath. The reaction mixture was analyzed by LC-MS at 90 min and
determined the reaction to be complete. The reaction mixture was diluted with 100 ml EtOAc and
washed with 25 ml water. The layers were separated and the aqueous layer was extracted with
another 100 ml EtOAc. The combined organic extracts were washed with 10% NaHC03 and 10%
NaCl, dried over anhydrous Na2S04(s), filtered and solvent removed in vacuo leaving a purple oil.
The oil was dissolved in 10 ml CH2C12 and applied to a 12 g silica gel column. The column was
eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over 25 minutes. The title compounds were
isolated as a light yellow solid, 60 mg, 19%. 1H NMR (400 MHz, DMSO-D6) d ppm 0.86 (m, 2 H)
1.00 - 1.18 (m, 15 H) 1.27 (m, 2 H) 1.70 (m, s H) 1.99 (m, 2H) 2.15 (m, 4 H) 3.18 (d, J=10.08 Hz, 6
H) 3.54 (s, 6 H) 3.81 (m, 4 H) 4.27 (m, 2 H) 5.06 (m, 2 H) 5.21 (d, 2 H) 6.21 (d, 2 H) 6.94 (d, 2 H)
7.17 (d, 2 H) 7.29 (d, 2 H) 7.38 (d, J=1.73 Hz, 2 H) 7.51 (d, 2 H) 7.62 (d, J=8.02 Hz, 2 H) 11.68 (s, 2
H), 12.01 (m, 2H);ESI+:972.6
HN—N \^* N—NH
vc >-{
/ NH N r Example 105
HN—N \^* N—NH
vc >-{
/ NH N r Example 105
methyl {(25)-l-[(25)-2-(3-{4-[(25',55)-l-(4-tert-butylphenyl)-5-(4-{5-[(21S,)-l-{(2^-2-
[(memoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-pyrazol-3-yl}phenyl)pyrroUdin-2-
yl]phenyl}-l//-pyrazol-5-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
and
methyl {(25)-1-[(25)-2-(3-{4-[(2R,5R)-l-(4-fert-butylphenyl)-5-(4-{5-[(25> 1 -{(25)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl)pyrrolidin-2-yl]-l//-pyrazol-3-yl}phenyl)pyrrohdin-2-
yl]phenyl} - l/7-pyrazol-5-yi)pyrrolidin- l-yl]-3-methyl- l-oxobutan-2-yl} carbamate
Example 105 A
l-(4-tert-butylphenyl)-2,5-bis(4-((trimeihylsilyl)ethynyl)phenyl)pyrrolidine
To an oven-dried microwave tube (Size M, 5 mL) purged with nitrogen, added the product of
Example 42C (340 mg, 0.662 mmol), bis(triphenylphosphine)palladium(n) dichloride (18.60 mg,
0.026 mmol), THF (2 mL), and triethylamine (2 mL). Stirred at room temperature for 5 min, then
added copper(I) iodide (2.52 mg, 0.013 mmol), stirred the yellow mixture for 2 min, then nitrogen
bubbled through for 15 min. Added trimethylsilylacetylene (0.374 mL, 2.65 mmol), sealed the tube
with an aluminum crimp cap, and heated in an oil bath at 70 °C for 20 hr. Cooled the reaction to
room temperature, added fresh bis(triphenylphosphine)palladium(II) dichloride (18.60 mg, 0.026
mmol) and copper(I) iodide (2.52 mg, 0.013 mmol), added additional trimethylsilylacetylene (0.374
mL, 2.65 mmol), and continued heating at 80 °C for 24 hr. Cooled the reaction to room temperature,
diluted with Et20 (50 mL), washed with H20 (2 x 25 mL) and brine (25 mL), dried the organic phase
over anhydrous MgS04, filtered, and concentrated by rotary evaporation to a light tan foam (470 mg).
Purified by flash chromatography (silica gel, 2.5 cm x 10 cm, 2% Et20/hexanes) to afford the title
product as a yellow foam (324 mg, 89%) as a mixture of stereoisomers. MS (ESI+) m/z 548 (M+H)+.
Example 105B
l-(4-tert-butylphenyl)-2,5-bis(4-ethynylphenyl)pyrrolidine
Dissolved the product of Example 105A (322 mg, 0.588 mmol) in anhydrous THF (5 mL)
under nitrogen, added 1M TBAF in THF (1.322 mL, 1.322 mmol), and stirred at 25 °C for 30 min.
The reaction darkened immediately upon addition and remained a brown color throughout the
reaction. Removed solvent by rotary evaporation, dissolved the residue in Et20 (50 mL), washed with
H20 (2 x 25 mL) and brine (25 mL), dried the organic phase over anhydrous MgS04, filtered, and
concentrated by rotary evaporation to a light tan foam (289 mg). Purified by flash chromatography
(silica gel, 3.8 cm x 14 cm, 20% CH^l^exanes) to the title compound as a light yellow foam (176
mg, 74%) as a mixture of stereoisomers. MS (ESI+) m/z 404 (M+H)+.
Example 105C
(S)-3,3'-(4,4,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(l-(4,l-phenylene))bis(l-(N-Boc-(S)-
pyrrolidin-2-yl)prop-2-yn-1 -one
In a flame-dried 10-mL round bottom flask, dissolved the product of Example 105B (94.3 mg,
0.234 mmol) in anhydrous THF (2 mL) under nitrogen and cooled to -78 °C, added 1.6 M n-BuL1 in
hexanes (0.365 mL, 0.584 mmol) slowly in a dropwise manner via gas-tight syringe, and stirred the
greenish-yellow solution for 1Hr at -78 °C. In a separate flame-dried 10-mL round bottom flask
purged with nitrogen, was prepared a solution of N-(tert-butoxycarbonyl)-L-proline N'-methoxy-N'-
methylamide (166 mg, 0.631 mmol) in anhydrous THF (1 mL), and cooled to -78 °C. Added the
dianion mixture dropwise via a gas-tight syringe fitted with a 16G needle to the Weinreb amide
solution and stirred at -78 °C for 30 min, replaced the dry ice-acetone bath with an ice-water bath, and
stirred at 0 °C for 1Hr. Removed the cooling bath and stirred at room temperature for 1Hr, the cloudy
yellow mixture became a dark yellow solution. Quenched the reaction with sat'd aq NH4C1 (10 mL),
extracted with Et20 (2 x 25 mL), washed the combined ethereal extracts with H20 (2 x 25 mL) and
brine (25 mL), dried the organic phase over anhydrous MgS04, filtered, and concentrated by rotary
evaporation to a yellow oil (214 mg). Purified by flash chromatography (silica gel, Alltech Extract-
Clean lOg column, gradient of 5% to 7% EtOAc/CH2Cl2) to afford the title compound as a yellow
solid (77 mg, 41%) as a mixture of stereoisomers. MS (ESI+) m/z 798 (M+H)+, 1595 (2M+H)+.
Example 105D
(2S,2' S)-tert-butyl 2,2' -(3,3' -(4,4' -(1 -(4-tert-butylphenyl)pyrroUdine-2,5-diyl)bis(4,1 -
phenylene))bis(l//-pyrazole-5,3-diyl))dipyrrolidine-l-carboxylate
Dissolved the product of Example 105C (75 mg, 0.094 mmol) in anhydrous absolute EtOH (1
mL) under nitrogen, added hydrazine hydrate (0.023 mL, 0.235 mmol), and stirred the yellow
solution at room temperature for 1Hr. Removed the solvent by rotary evaporation, azeotroped the
yellow oil with toluene (2x5 mL), redissolved in 1:5 v/v CH2Cl2/hexanes, concentrated, and dried the
light yellow solid in vacuo. Purified by flash chromatography (silica gel, 2.5 cm x 15 cm, 4%
MeOH/CH2Cl2) to afford the title compound as a white solid (59 mg, 76%) as a mixture of
stereoisomers. MS (ESI+) m/z 826 (M+H)+, 848 (M+Na)+.
Example 105E
(S)-3,3'-(4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(5-((S)-pyrrolidin-2-
yl)-1H-pyrazole
Dissolved the product of Example 105D (57.5 mg, 0.070 mmol) in anhydrous CH2C12 (2 mL)
under nitrogen, added TFA (1 mL, 12.98 mmol), and stirred at 25 °C for 30 min. Removed the
solvent by rotary evaporation, took up the residue in 1:5 v/v CEtCl^exanes, concentrated to a yellow
residue, and dried in vacuo (83 mg). The TFA salt was dissolved in anhydrous MeOH (7 mL) under
nitrogen, treated with pre-washed (H20 and MeOH) and dried Amberlite IRA-400(OH) resin (750
mg, 15 equivs of OH" based on 1.4 mequiv/g dry resin) and stirred at 25 °C for 2 hr. Vacuum
filtered in a Buchner funnel and washed the resin thoroughly with MeOH. The filtrate was
concentrated by rotary evaporation, the residue taken up in 1:5 v/v CH2Cl2/hexanes, and concentrated
in vacuo to give the title compound as a light yellow solid (41 mg, 94%) as a mixture of
stereoisomers. MS (ESI+) m/z 626 (M+H)+, 1251 (2M+H)+.
Example 105F
methyl {(2^4-[(2^-2<3-{4-[(25^5)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(25)-2-
[(memoxycarbonyl)ammo]-3-metliylbutanoyl}pyrrolidiii-2-yl]-lff-pyrazol-3-yl}phenyl)pyrrolidiri-2r
yl]phenyl} - lff-pyrazol-5-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
and
methyl {(25)-l-[(25)-2-(3-{4-[(2R,5R> 1 -(4-tert-butylphenyl)-5-(4-{5-[(2S> 1 -{(25)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]-1H-pyrazol-3-yl}phenyl)pyrrolidin-2-
yl]phenyl}-lH-pyrazol-5-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
In an oven-dried 10-mL round bottom flask purged with nitrogen, dissolved the product of
Example 105E (39.7 mg, 0.063 mmol) in anhydrous DMF (1 mL) and cooled to 0 °C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (23.89 mg, 0.136 mmol), HOBt
hydrate (21.37 mg, 0.140 mmol), EDAC (27.3 mg, 0.140 mmol), and N-methylmorpholine (0.021
mL, 0.190 mmol). Removed the cooling bath and stirred the dark yellow solution at 25 °C for 1Hr.
Diluted the reaction with EtOAc (50 mL), washed with H20 (3 x 25 mL) and brine (25 mL), dried the
organic phase over anhydrous MgS04, filtered, and concentrated by rotary evaporation to a light
peach solid (63 mg). Dissolved the crude material in CH2C12 and purified by flash chromatography
(silica gel, 2.5 cm x 10 cm, 5% MeOH/CH2Cl2) to afford a 1:1.25 trans:cis product mixture (34 mg,
94% purity). Dissolved the residue in 1:1 v/v DMSO/MeOH (2 mL) and purified by RP-C18 HPLC
(Waters Prep LC, 40mm Module with Nova Pak HR Ci8 6μm 40x100mm Prep Pak cartridge) eluting
with a 30 min gradient of 90:10 0.1% TFA in H20/AcCN to 100% AcCN at 20 mL/min. Fractions
containing a mixture of the trans diastereomers were concentrated by rotary evaporation, the residue
taken up in 1:5 v/v CH2Cl2/hexanes and evaporated (5 times), and dried in vacuo to afford the title
compounds as a cream-colored solid (12 mg, 16%). !H NMR (TFA salt) (400 MHz, DMSO-D6) 8
ppm 0.76 - 0.94 (m, 12 H), 1.10 (s, 9 H), 1.13 - 1.31 (m, 3 H), 1.71 (d, 7=5.42 Hz, 2 H), 1.82 - 2.17
(m, 9 H), 3.53 (s, 6 H), 3.70 - 3.85 (m, 4 H), 4.05 (t, 7=8.08 Hz, 2 H), 5.09 - 5.19 (m, 2 H), 5.26 (d,
7=5.96 Hz, 2 H), 6.22 (d, 7=8.78 Hz, 2 H), 6.39 (d, 7=1.30 Hz, 2 H), 6.94 (d, 7=8.67 Hz, 2 H), 7.20 -
7.31 (m, 6 H), 7.62 (d, 7=7.92 Hz, 4 H); MS (ESI+) m/z 940 (M+H)+.
methyl {(2S)-l-[(2S)-2-(3-{4-[(2R,5S)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-pyrazol-3-yl}phenyl)pyrrolidin-2-
yl]phenyl}-lH-pyrazol-5-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
From the preparative HPLC separation of Example 105F was obtained the title compound
(cis) as a yellow solid (16 mg, 21%).1H NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.77 - 0.93
(m, 12 H), 1.14 (s, 9 H), 1.17 - 1.31 (m, 2 H), 1.80 - 2.18 (m, 11H), 3.35 (d, 7=8.02 Hz, 1H), 3.54 (s,
6 H), 3.72 - 3.85 (m, 4 H), 4.06 (t, 7=8.29 Hz, 2 H), 4.71 - 4.79 (m, 2 H), 5.13 - 5.20 (m, 2 H), 6.35 (d,
7=8.78 Hz, 2 H), 6.43 (s, 2 H), 7.03 (d, 7=8.78 Hz, 2 H), 7.28 (d, 7=8.35 Hz, 2 H), 7.55 (d, 7=8.24 Hz,
4 H), 7.71 (d, 7=7.59 Hz, 4 H); MS (ESI+) m/z 940 (M+H)+.
methyl {(2S)-l-[(2S)-2-(3-{4-[l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-pyrazol-3-yl}phenyl)-lH-pyrrol-2-
yl]phenyl} -lH-pyrazol-5-yl)pyrrolidin-1 -yl]-3-methyl- l-oxobutan-2-yl Jcarbamate
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of
Example 105E (5.1 mg, 8.15 jimol) in anhydrous DMF (400 \iL) and cooled to 0 °C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (3.07 mg, 0.018 mmol), HOBt
hydrate (2.75 mg, 0.018 mmol), ED AC (3.51 mg, 0.018 mmol), and N-methylmorpholine (2.69 \iL,
0.024 mmol). Removed the cooling bath and stirred the dark yellow solution at 25 °C for 18 hr.
Diluted the reaction in ErOAc (50 mL), washed with H20 (2 x 10 mL) and brine (10 mL), dried the
organic over anhydrous MgS04, filtered, and concentrated by rotary evaporation to a yellow solid (9.6
mg). Dissolved in 1:1 v/v MeOH/DMSO (1.5 mL) and purified by RP-C18 HPLC (Waters Prep LC,
40mm Module with Nova Pak HR Ci8 6μm 40x100mm Prep Pak cartridge) eluting with a 30 min
gradient of 90:10 0.1% TFA in H20/AcCN to 100% AcCN at 20 rnL/min. Pure fractions were
concentrated by rotary evaporation, azeotroped with toluene (25 mL), the residue was taken up in 1:5
v/v CH2Cl2/hexanes and evaporated (3 times), then dried in vacuo to afford the title compound as an
off-white solid (2.5 mg, 25%).1H NMR (TFA salt) (400 MHz, DMSO-D6) δ ppm 0.76 - 0.92 (m, 12
H), 1.27 (s, 9 H), 1.80 - 2.15 (m, 10 H), 3.53 (s, 6 H), 3.69 - 3.84 (m, 4 H), 4.05 (t, 7=8.24 Hz, 2 H),
5.08 - 5.16 (m, 2 H), 6.39 (s, 2 H), 6.53 (s, 2 H), 7.06 (dd, 7=8.29, 2.87 Hz, 6 H), 7.26 (d, 7=8.35 Hz,
2 H), 7.37 (d, 7=8.46 Hz, 2 H), 7.44 - 7.55 (m, 4 H), 12.92 (s, 2 H); MS (ESI+) m/z 936 (M+H)+.
N-(methoxycarbonyl)-L-valyl-N-{4-[(25,5R)-5-(4-{[N-(methoxycarbonyl)-L-valyl]amino}phenyl)-l-
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
and
N-(methoxycarbonyl)-L-valyl-Ar-{4-[(2R,55,)-5-(4-{[N-(methoxycarbonyl)-L-valyl]amino}phenyl)-l-
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
Example 108A
4-(5 -(4-(2,5-bis(4-nitrophenyl)pyrrolidin-1 -yl)phenyl)pyridin-2-yl)morpholine
In a microwave tube (size L, 20 mL) purged with nitrogen and sealed with a rubber septum,
dissolved the product of Example 86A (160 mg, 0.342 mmol) and 4-[5-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)pyridin-2-yl]morpholine (153 mg, 0.512 mmol) in THF (6 mL), added a solution of
potassium phosphate (176 mg, 0.803 mmol) in water (2 mL), and sparged the reaction solution with
nitrogen for 5 min. Added l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (12.02 mg,
0.018 mmol) and stirred at 25 °C for 15 min . During this process, the reaction darkened quickly to a
brown color. Diluted the reaction with EtOAc (50 mL), washed with brine (10 mL), dried the organic
phase over anhydrous MgSCU, filtered, and concentrated by rotary evaporation. Dissolved the residue
in CH2C12 and purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 20%
EtOAc/CH2Cl2) to afford the title compound as a solid (176 mg, 93%) as a mixture of stereoisomers.
:H NMR (400 MHz, DMSO-D6) 8 ppm 1.82 - 1.94 (m, 2 H), 2.53 - 2.62 (m, 2 H), 3.37 - 3.47 (m, 4
H), 3.64 - 3.74 (m, 4 H), 5.03 (t, 7=5.37 Hz, 2 H), 6.40 (d, 7=8.89 Hz, 2 H), 6.82 (d, 7=9.00 Hz, 1H),
7.34 (d, 7=8.78 Hz, 2 H), 7.69 (dd, 7=8.84, 2.55 Hz, 1H), 7.83 (d, 7=8.78 Hz, 4 H), 8.28 (d, 7=8.78
Hz, 4 H), 8.29 - 8.31 (m, 1H); MS (ESI+) m/z 552 (M+H)+.
Example 108B
4,4'-(l-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline
Charged a 100-mL round bottom flask with the product of Example 108A (174.7 mg, 0.317
mmol), partially dissolved in THF (12.50 mL) and absolute EtOH (2.50 mL), evacuated on house
vacuum and filled flask with nitrogen, then added platinum (IV) oxide (14.38 mg, 0.063 mmol),
evacuated flask on house vacuum and filled with hydrogen from a balloon, repeated evacuation/filling
cycle 3 times, and stirred heterogeneous reaction mixture vigorously under hydrogen (1 arm). After 2
hr, charged reaction with additional platinum (IV) oxide (14.38 mg, 0.063 mmol) and continued to
vigorously stir under hydrogen at 25 °C. After 5 hr, added additional platinum (IV) oxide (14.38 mg,
0.063 mmol). The reaction mixture was then vacuum filtered through a bed of Celite 545 in a
Biichner funnel, the filter pad was washed with CHC13 (100 mL) and hot CHC13 (2 x 50 mL), and the
filtrate concentrated by rotary evaporation to give the title compound as a yellow solid (101 mg, 65%)
as a mixture of stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.71 - 1.87 (m, 2 H), 2.24 -
2.31 (m, 1H), 3.37 - 3.45 (m, 4 H), 3.64 - 3.74 (m, 4 H), 4.57 (t, 7=4.99 Hz, 2 H), 4.95 (s, 4 H), 6.42 -
6.53 (m, 3 H), 6.57 (d, 7=8.35 Hz, 4 H), 6.76 - 6.89 (m, 2 H), 7.15 (d, 7=8.35 Hz, 4 H), 7.26 (d,
7=8.78 Hz, 2 H), 7.68 (dd, 7=8.84, 2.44 Hz, 1H), 8.29 (d, 7=2.39 Hz, 1H); MS (ESI+) m/z 492
(M+H)+.
methyl (2S)-l-(4-(5-(4-aminophenyl)-l-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidin-2-
yl)phenylamino)-3-methyl-1 -oxobutan-2-ylcarbamate
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of
Example 108B (70 mg, 0.142 mmol) and (S)-2-(methoxycarbonylamino)-3-mediylbutanoic acid (26.2
mg, 0.150 mmol) in anhydrous DMSO (1.5 mL), added HATU (58.6 mg, 0.150 mmol) and
diisopropylethylamine (0.050 mL, 0.285 mmol), and stirred dark yellow solution at 25 °C for 15 min.
Diluted the reaction with MeOH (1.5 mL) and purified by RP-Ci8 HPLC (Waters Prep LC, 40mm
Module with Nova Pak HR Ci8 6^m 40x100mm Prep Pak cartridge) eluting with a 30 min gradient of
95:5 0.1% TFA in H20/AcCN to 25:75 0.1% TFA in H20/AcCN, then 10 min to 100% AcCN at 20
mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume,
partitioned between 20% iPrOH/CHCU. (50 mL), and sat'd aq NaHC03 (15 mL), separated layers,
dried organic extract over anhydrous MgS04, filtered, and concentrated by rotary evaporation to
afford the title compound as a light yellow solid (48 mg, 52%). 1H NMR showed the material to be
3:1 transis mixture; MS (ESI+) m/z 649 (M+H)+, 1297 (2M+H)+.
Example 108D
N(methoxycarbonyl)-L-valyl-iV-{ 4-[(2S,5R)-5-(4- {[N-(methoxycarbonyl)-L-valyl] amino }phenyl)-l -
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide-ACD vl2
and
N-(methoxycarbonyl)-L-valyl-iV- [4-[(2R,5S)-5-(4- {[N-(methoxycarbonyl)-L-valyl] amino }phenyl)-l -
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide ACD vl2
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved 3:1 trans/cis
mixture of Example 108C (44 mg, 0.068 mmol) and the product of Example 37B (20.31 mg, 0.075
mmol) in anhydrous DMSO (1 mL), added HATU (29.2 mg, 0.075 mmol) and diisopropylethylamine
(0.024 mL, 0.136 mmol), and stirred yellow solution at 25 °C for 30 min. Diluted the reaction with
MeOH (1 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40mm Module with Nova Pak HR C18
6μm 40x100mm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H20/AcCN
to 25:75 0.1% TFA in H20/AcCN, then 10 min to 100% AcCN at 20 mL/rnin. The earlier eluting
compound (18.8 mg, 31%) was determined by1H NMR to be the trans diastereomers. The fractions
of the later eluting peak were concentrated by rotary evaporation (water bath 35 °C) to small volume,
partitioned between 20% iPrOH/CHCl3 (50 mL) and sat'd aq NaHC03 (15 mL), separated layers,
dried the organic phase over anhydrous MgSCv, filtered, and concentrated by rotary evaporation to
afford a 2:3 transxis mixture as an off-white solid (10 mg). The mixture was dissolved in 1:1 v/v
MeOH/DMSO (1.5 mL) and purified by RP-C18 HPLC (Phenomenex Luna C8(2) δ nm 100A AXIA
column (30mm x 75mm)) eluting with a gradient of 90:10 10 mM NELOAcMeOH to 100%) MeOH
to afford the title cis compounds as a light beige solid (2 mg, 3%).1H NMR (400 MHz, DMSO-D6) δ ppm0.85 - 0.98 (m, 12 H), 1.77 - 2.06 (m, 7 H), 2.09 - 2.21 (m, 1H), 2.36 - 2.45 (m, 1H), 3.37 - 3.42
(m, 4 H), 3.51 (s, 3 H), 3.53 (s, 3 H), 3.59 - 3.70 (m, 6 H), 3.75 - 3.86 (m, 1H), 3.95 (t, 7=8.13 Hz, 1H), 4.02 (t, 7=8.57 Hz, 1H), 4.44 (dd, 7=8.19, 4.72 Hz, 1H), 4.73 (s, 2 H), 6.43 (d, 7=8.89 Hz, 2 H),
6.80 (d, 7=8.89 Hz, 1H), 7.27 (d, 7=8.78 Hz, 2 H), 7.29 - 7.38 (m, 2 H), 7.44 (dd, 7=8.57, 2.71Hz, 4
H), 7.54 - 7.64 (m, 4 H), 7.67 (dd, 7=8.89, 2.49 Hz, 1H), 8.27 (d, J=2.49 Hz, 1H), 10.04 (s, 2 H); MS
(ESI+) m/z 903 (M+H)+, 920 (M+NH4)+, 961 (M+AcCN+NH4)+.
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arnino]-3-methylbutanoyl}pyrrohdin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2-yl} carbamate
Example 109 A
2-bromo-l-(4-chloro-3-nitrophenyl)ethanone
Method A:
To a flask equipped with a magnetic stir bar and under an atmosphere of N2 was added 4'-
chloro-3'-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was
added portion-wise phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes
time period. The resultant mixture was then stirred with monitoring every hour via LCMS. After 3 hr
the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then
concentrated, H20 and 10% aq. NaHC03 added and washed with EtOAc (2 x 300 mL). The
combined organic layers were then washed with Brine, dried (MgSO4), filtered and concentrated.
The residue material was then subjected to purification via crystallization (dissolved material in 100
mL EtOAc and slowly added hexanes until cloudy - let stand for a few hours) to yield 9.81 g (70%) of
2-bromo-l-(4-chloro-3-nitrophenyl)ethanone as an off white colored solid product. 1H NMR (500
MHz, DMSO-D6) 8 ppm 5.00 (s, 2 H) 7.98 (d, J=8.54 Hz, 1H) 8.24 (dd, J=8.54,2.14 Hz, 1H) 8.61
(d,J=1.98Hz, 1H).
Method B:
In a 500 mL round-bottomed flask was added l-(4-chloro-3-nitrophenyl)ethanone (11.98 g,
60 mmol) in benzene (75 ml) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added
dropwise over 5 minutes to give a deep red solution. Stirred for 1Hour to give a yellow solution that
was concentrated in vacuo to a yellow solid. Recrystallized from 9:1Hexane/ethyl acetate to give 2-
bromo-l-(4-chloro-3-nitrophenyl)ethanone as yellow needles.
Example 109B
l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-dione
Zinc (IT) chloride (14.68 g, 108 mmol) was added to toluene (81 mL), then diethylamine (8.35
mL, 81 mmol) and tert-butanol (7.73 mL, 81 mmol) were added and the resultant heterogenous
solution stirred at rt for approx. 2 h. Afterwards Example 109A (15.0 g, 53.9 mmol) and 4'-chloro-3'-
nitroacetophenone (16.13 g, 81 mmol) were added to the solution in one portion, and the resultant
mixture stirred at rt for 42 h). The reaction was then quenched with 5% aqueous sulfuric acid (500
mL) and stirred vigorously to induce solid formation. The resultant solid was vacuum filtered, then
washed with toluene, water, and methanol successively. Then the solid was added to a solution of hot
ethyl acetate and resulting heterogeneous solution was stirred for 30 minutes and then the solid was
collected and dried overnight in a vacuum oven to provide 16.6 g (78%) of the title compound. 1H
NMR (400 MHz, DMSO-d6) 8 8.61 (d, J = 1.9 Hz, 2H), 8.27 (dd, J = 8.4, 1.9 Hz, 2H), 7.96 (d, J = 8.3
Hz, 2H), 3.48 (s, 4H).
Example 109C
(lS,4S)-l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-diol
(R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08g, 4.28mmol) was dissolved in 70
mL of THF at ambient temperature in a dry flask under nitrogen and the timethyl borate (650 μL, 5.54
mmol) was added dropwise. The resulting solution was stirred for 1Hr. The solution was cooled in a
cold bath to ~ 10 °C and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise
with some bubbling. After 15 min, this solution was transferred to an addition funnel and added
dropwise to l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-dione (Example 109B) (lO.Og, 25.2 mmol)
suspended in 200 mL of THF and cooled to ~ 10 °C. Bubbling was observed. After the addition,
mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30
mL MeOH was added dropwise till bubbling stopped, then the mixture was let stir at ambient
temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The
filtrate was concentrated, poured into 1 M HC1 and extracted into ethyl acetate, dried over sodium
sulfate; concentrated to give the title compound (9.9g, 99%) as a yellow waxy solid. Chiral HPLC e.e.
>99.9% (RR diol was undetectable). JH NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 1.9 Hz, 2H), 7.69
(d, J = 8.4 Hz, 2H), 7.60 (dd, J = 8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Example 109D
The product of Example 109C was processed as in Example 113A, 113B, 113C, and 113D,
substituting 4-t-butylaniline for 4-cyclohexylaniline in the step 113A procedure to give 0.212 g (22%)
of the title compound. 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.74 - 0.92 (m, 12 H) 1.07 (s, 9 H)
1.69 (d, J=4.01Hz, 2 H) 1.86 - 2.05 (m, 6 H) 2.13 - 2.24 (m, 4 H) 2.54 (d, J=2.60 Hz, 2 H) 3.51 - 3.56
(m, 6 H) 3.81 (s, 4 H) 4.05 (t, J=8.13 Hz, 2 H) 5.09 - 5.18 (m, 2 H) 5.35 (d, J=3.47 Hz, 2 H) 6.25 (d,
J=8.78 Hz, 2 H) 6.86 - 6.96 (m, 2 H) 7.07 (t, J=7.81Hz, 2 H) 7.20 (s, 1H) 7.26 - 7.32 (m, 3 H) 7.38
(d, J=8.24 Hz, 1H) 7.46 (d, J=8.24 Hz, 1H) 11.98 -12.08 (m, 2 H); MS TFA+ m/z 889.
methyl {(2S)-l-[(2S)-2-{5-[(2S,5S)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
The product from Example 28K was purified by chiral chromatography on a Chirapak IA
column eluting with a mixture of hexane/methanol/tetrahydrofuran (3:1:1) to give the title compound.
1H NMR (400 MHz, DMSO-D6) 8 ppm0.78 - 0.91 (m, 12 H) 1.07 (s, 9 H) 1.64 -1.73 (m, 2 H) 1.89 -
2.00 (m, 6 H) 2.12 - 2.23 (m, 4 H) 3.14 - 3.24 (m, 2 H) 3.52 (s, 6 H) 3.76 - 3.85 (m, 4 H) 4.05 (td,
J=8.38, 2.33 Hz, 2 H) 5.07 - 5.16 (m, 2 H) 5.30 - 5.39 (m, 2 H) 6.23 (d, J=8.78 Hz, 2 H) 6.90 (ddd,
J=8.95,4.72, 4.55 Hz, 2 H) 7.06 (t, J=9.22 Hz, 2 H) 7.17 (s, 1H) 7.23 - 7.31 (m, 3 H) 7.37 (d, J=8.13
Hz, 1H) 7.44 (d, J=8.24 Hz, 1H) 12.02 (d, J=23.42 Hz, 2 H); MS ESI+ m/z 888 (M+H)+.
dimethyl ([(2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(3S)-2-
azabicyclo[2.2.1]heptane-3,2-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
(3S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic
acid
(3S)-ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (1.25 g, 7.39 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (1.42 g, 8.13 mmol), diisopropylethylamine (6.45
mL, 36.9 mmol), and HATU (2.95 g, 7.76 mmol) were combined in dimethylformamide (40 mL) at
ambient temperature and stirred for 2 hours. The solution was diluted with water and the product
filtered and dried. The dried ester (l.Og, 3.06 mmol) was taken up in water (15 mL) and ethanol (15
mL) and treated with sodium hydroxide (0.5 g, 12.5 mmol) at ambient temperature for 17 hours. The
solution was washed with ether then the aqueous was neutralized with concentrated HC1 to pH 7 and
the product extracted into ethyl acetate, dried over sodium sulfate, and concentrated to give the title
compound as a waxy solid.
Example 111B
dimethyl ([(2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(3S)-2-
azabicyclo[2.2.1]heptane-3,2-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 37E (0.05g, 0.13 mmol), the product from example 111A (0.097
g, 0.324 mmol), diisopropylethylamine (0.113 mL, 0.648 mmol), and HATU (0.104 g, 0.272 mmol)
were combined in dimethylformamide (2 mL) at ambient temperature and stirred for 3 hours. The
solution was poured into brine, extracted into ethyl acetate, concentrated, and purified by combi-flash
12g silica column, eluting with 0-6% methanol in dichloromethane to give the title compound as a
solid. 1H NMR (400 MHz, DMSO-D6) 8 ppm0.91 (d, J=6.72 Hz, 6 H) 0.98 (d, J=6.72 Hz, 6 H) 1.11
(s, 9 H) 1.32 (d, J=8.89 Hz, 2 H) 1.36 - 1.46 (m, 2 H) 1.59 - 1.74 (m, 6 H) 1.76 - 1.84 (m, 2 H) 1.90
(td, J=13.88, 6.94 Hz, 2 H) 2.01 - 2.09 (m, 2 H) 2.40 - 2.47 (m, 2 H) 2.60 (d, J=1.19 Hz, 2 H) 3.52 (s,
6 H) 3.94 (s, 2 H) 4.04 - 4.15 (m, 2 H) 4.46 (s, 2 H) 5.15 (d, J=6.51Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H)
6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.57 Hz, 4 H) 7.22 (d, J=8.46 Hz, 2 H) 7.49 (d, J=8.57 Hz, 4 H)
9.94 (s, 2 H)
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)(methyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl }phenyl)pyrrolidin-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl} methylcarbamate
The product from Example 126H was processed as in Example 42B-42G, substituting (S)-2-
(methoxycarbonyl(methyl)amino)-3-methylbutanoic acid for (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid in step 42G, to give 0.07 g (40%) of the tide compound as a white solid. 1H
NMR (free base) (400 MHz, DMSO-D6) δ ppm 0.76 (d, J=6.61Hz, 6 H) 0.83 (d, J=6.51Hz, 6 H)
1.09 (s, 9 H) 1.63 - 1.75 (m, 2 H) 1.86 - 2.00 (m, 4 H) 2.03 - 2.21 (m, 6 H) 2.77 (s, 6 H) 3.10 - 3.22
(m, 4 H) 3.63 (s, 6 H) 3.74 - 3.84 (m, 2 H) 4.98 - 5.07 (m, 2 H) 5.16 - 5.23 (m, 2 H) 6.21 (d, J=8.78
Hz, 2 H) 6.88 - 6.96 (m, 2 H) 7.15 (d, J=8.24 Hz, 4 H) 7.22 (d, J=8.35 Hz, 1H) 7.36 (d, J=1.52 Hz, 2
H) 7.51 (d, J=8.24 Hz, 1H) 7.61 (d, J=8.13 Hz, 4 H) 11.70 (s, 2 H); MS ESI+ m/z 968.7 (M+H)+; MS
ESI+ m/z 968.7 (M+H)+.
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-cyclohexylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 113A
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-cyclohexylphenyl)pyrrolidine
The product of Example 109C (2.0g, 4.99mmol) and triethylamine (1.51 mL, 14.96 mmol)
were dissolved in dichloromethane (50 mL) and cooled in an ice bath. Methanesulfonyl chloride
(0.855 mL, 10.97 mmol) in dichloromethane (2 mL) was added dropwise and the resulting mixture
was stirred at ambient temperature for 2 hours. The solution was concentrated to dryness and
dissolved in dimethylformamide (8 mL). 4-Cyclohexylaniline (5.24 g, 29.9 mmol) was added and the
solution was heated at 65 °C for 2 hours then poured into 1 M HC1 and extracted into
dichloromethane, concentrated, and purified by combi-flash 80g silica column, eluting with 0-20%
ethyl acetate in hexanes to give 1.38 g (51%) of the title compound.
(2S,2,S)-tert-butyl2,2'-(4,4'-((2R,5R)-l-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The product from Example 113A (1.29 g, 2.39 mmol), (S)-tert-butyl 2-carbamoylpyrrolidine-
1-carboxylate (1.53 g, 7.16 mmol), cesium carbonate (2.33g, 7.16 mmol), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (0.33 g, 0.573 mmol), and
tris(dibenzylideneacetone)dipalladium(O) (0.328 g, 0.358 mmol) were combined in dioxane (18 mL)
and nitrogen was bubbled through the solution for 15 min, then the flask was capped with a reflux
condenser and the solution heated at 100 °C for 8 hours. After filtering through celite and
concentrating, the residue was purified by combi-flash 80g silica column, eluting with 0-20% ethyl
acetate in dichloromethane to give 1.71 g (80%) of the title compound.
(2S,2'S)-tert-butyl2,2'-(4,4'-((2R,5R)-l-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
The product from Example 113B (1.71 g, 1.91 mmol) was dissolved in tetrahydrofuran (10
mL) and ethanol (10 mL) at ambient temperature and treated with Platinum (IV) oxide (0.11 g, 0.48
mmol). The flask was evacuated and opened to a hydrogen balloon and stirred for 18 hours then
filtered through celite and concentrated to give the title compound.
Example 113D
methyl {(2S)-1 -[(2S)-2- {5-[(2R,5R)-1 -(4-cyclohexylphenyl)-5-{2-[(2S)-1 - {(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyn:olidin-2-yl]-lH-benzimidazol-5-yl}pyrro]idin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 113C was processed using the methods of Examples 281, 28J, and 28K to provide
the tide compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.76 - 0.91 (m, 12 H) 1.03 - 1.29 (m, 6
H) 1.55 -1.74 (m, 7 H) 1.84 - 2.06 (m, 6 H) 2.11 - 2.25 (m, 6 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 4.02 - 4.13
(m, 2 H) 5.08 - 5.18 (m, 2 H) 5.32 - 5.38 (m, 2 H) 6.24 (d, J=8.57 Hz, 2 H) 6.68 - 6.77 (m, 2 H) 7.06
(t, J=7.54 Hz, 2 H) 7.19 (s, 1H) 7.26 - 7.32 (m, 3 H) 7.37 (d, J=8.24 Hz, 1H) 7.45 (d, J=8.35 Hz, 1
H) 11.98 -12.05 (m, 2 H); MS ESI+ m/z 914.5.
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}-l-[4-(4-methylpiperazin-l-
yl)phenyl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl}carbamate
The product of Example 109C (l.Og, 2.49mmol) was processed as in Examples 113A-113D,
substituting 4-(4-methylpiperazin-l-yl)aniline for 4-cyclohexylaniline in the procedure of Example
113A and substituting Raney Nickel in tetrahydrofuran for platinum(IV) oxide in tetrahydrofuran and
ethanol in the procedure of Example 113C to give 0.028 g (50%) of the title compound as a solid. 1H
NMR (400 MHz, DMSO-D6) δ ppm 0.77 - 0.90 (m, 12 H) 1.65 - 1.72 (m, 2 H) 1.85 - 2.04 (m, 8 H)
2.13 (s, 3 H) 2.15 - 2.23 (m, 4 H) 2.32 (s, 2 H) 2.77 (s, 6 H) 3.54 (s, 6 H) 3.82 (d, J=4.66 Hz, 4 H)
4.02 - 4.08 (m, 2 H) 5.09 - 5.18 (m, 2 H) 5.28 - 5.37 (m, 2 H) 6.23 (d, J=8.78 Hz, 2 H) 6.54 (ddd,
J=9.00, 4.66, 4.55 Hz, 2 H) 7.02 - 7.08 (m, 2 H) 7.19 (s, 1H) 7.26 - 7.31 (m, 3 H) 7.36 (d, J=8.13 Hz,
1H) 7.44 (d, J=8.35 Hz, 1H) 12.01 (s, 2 H); MS ESI+ m/z 556 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(l,3-benzothiazol-2-yl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 115A
(2R,5R)-l-allyl-2,5-bis(4-chloro-3-nitrophenyl)pyrrohdine
The product from Example 109C (5.0 g , 12.46 mmol) and allylamine were processed as in
Example 113A to give 1.5 g (39%) of the title compound as a thick oil.
Example 115B
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine
The product from Example 115 A (2.0 g, 4.74 mmol) was dissolved in acetonitrile (40 mL)
and water (4 mL) and treated with Tris(triphenylphosphine)rhodium(I) chloride (0.219 g, 0.237
mmol). The mixture was heated at 100 °C and nitrogen was bubbled through the solution for 3 hours.
The mixture was partitioned between 5% sodium bicarbonate solution and ethyl acetate, then the
organics were concentrated and the product purified by combiflash 80g silica column eluting with
dichloromethane to give 1.33 g (74%) of the title compound.
Example 115C
2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)benzo[d]thiazole
The product from Example 115B (0.335 g, 0.877mmol), 2-bromobenzo[d]thiazole (0.281 g,
1.32 mmol), tris(dibenzylideneacetone)dipalladium(O) 0.08 g (0.088 mmol), BINAP (0.055 g, 0.088
mmol), and sodium tert-butoxide (0.126 g, 1.32 mmol) were combined in dioxane (8 mL) and
nitrogen was bubbled through the solution for 10 minuets. The tube was sealed and heated at 100 °C
for 18 hours. The reaction mixture was partitioned between brine and dichloromethane and the
organics were concentrated and purified by combi-flash 24 g silica column, eluting with 1:1Hexanes:
dichloromethane, followed by 100% dichloromethane to give 0.165 g (37%) of the tide compound.
Example 115D
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(l,3-benzothiazol-2-yl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)anuno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benziniidazol-5-yl}pyTTolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
The product from Example 115C was processed as in Examples 113B, 113C, and 113D to
give 0.040 g (38%) of the tide compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.74 - 0.88 (m, 12
H) 1.76 -1.84 (m, 2 H) 1.85 -1.94 (m, 3 H) 1.95 - 2.07 (m, 4 H) 2.14 - 2.26 (m, 4 H) 2.61 - 2.71 (m, 2
H) 3.53 (s, 6 H) 3.76 - 3.85 (m, 4 H) 4.05 (t, J=8.51Hz, 2 H) 5.10 - 5.18 (m, 2 H) 6.90 (t, J=7.54 Hz,
2 H) 7.07 - 7.16 (m, 3 H) 7.22 - 7.35 (m, 4 H) 7.40 (d, J=8.13 Hz, 2 H) 7.47 (d, J=8.35 Hz, 1H) 7.52 -
7.59 (m, 1H) 12.07 (s, 2 H); MS ESI+ m/z 889.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-t(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}-l-(4,5,6,7-tetrahydro-l,3-benzothiazol-2-
yl)pyrrolidin-2-yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
Example 116A
(S)-pyrrolidine-2-carboxamide hydrochloride salt
To (S)-tert-butyl 2-carbamoylpyrrolidine-l-cafboxylate (29.8 g, 139 mmol) was added a
solution of 4N HC1 in dioxane (209 mL, 836 mmol) and the resultant mixture stirred at room
temperature for 18 hrs. The mixture was then concentrated and triturated with diethyl ether then
vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the tide product as a colorless
solid.
Example 116B
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
To (S)-2-amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved in dioxane (277 mL) was
added a 2N aqueous sodium hydroxide solution (803 mL, 1606 mmol) followed by the dropwise
addition of methyl chloroformate (75 mL, 973 mmol) over 1Hr which caused warming of the solution
to occur. After the addition, the mixture was heated at 60 °C for 22 hrs, then cooled and extracted
with dichloromethane (400 mL). The resultant aqueous layer was cooled in an ice bath then 12N
hydrochloric acid was added dropwise until the pH was 2. The resultant mixture was stirred at 0 °C
for 2 hrs then the resultant solid was vacuum filtered and dried in a vacuum oven to provide 80g
(94%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 12.50 (bs, 1H),
7.34 (d, J = 8.6 Hz, 1H), 3.84 (dd, J = 8.6, 6.0 Hz, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J = 7.0 Hz,
6H).
memyl(S)-l-((S)-2-carbamoylpyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate
To the product of Example 116A (21.6 g, 144 mmol), the product of Example 116B (29.1 g,
166 mmol), lH-benzo[d][l,2,3]triazol-l-ol hydrate (27.6 g, 180 mmol), Nl-((ethylimino)methylene)-
N3,N3-dimethylpropane-l,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine
(63.5 mL, 578 mmol) was dissolved in dichloromethane (960 mL) and stirred at room temperature for
18 hrs. The resultant solution was then concentrated to a residue, water was then added and the
solution extracted with a 25% isopropanol in chloroform solution (2 x 2000 mL) the organic layer
washed with brine then the organic extract dried over MgS04, then concentrated to a yellow oil which
was purified by column chromatography eluting with a gradient of 0-10% methanol in
dichloromethane to provide 25 g (64%) of the title coompound as a colorless solid. 1H NMR (400
MHz, DMSO-d6) 8 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J = 8.1, 4.4 Hz, 1H), 4.00 (t, J = 8.4 Hz, 1H),
3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J = 6.7
Hz, 3H), 0.86 (d, J = 8.6 Hz, 3H).
2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole
The product from Example 109C (0.80 g, 1.489mmol) and 4,5,6,7-tetrahydrobenzo[d]thiazol-
2-amine were processed using the method of Example 113A to give 0.375 g (50%) of the tide
compound
dimemyl([(2i?,5/?)4-(4,5,6,7-tetrahydro-l,3-benzothiazol-2-yl)pyrrolidine-2,5-diyl]bis{(2-
nitrobenzene-4,1 -diyl)carbamoyl(2S)pyrrolidine-2,1 -diyl[(2i!0-3-methyl-1 -oxobutane-1,2-
diyl] })biscarbamate (ACD vl2))
The product from Example 116D (0.375 g, 0.722 mmol) was processed as in Example 113B,
substituting the product from Example 116C for (S)-tert-butyl 2-carbamoylpyrrolidine-l-carboxylate
to give 0.59 g (83%) of the title compound.
dime%l([(2^,5R)4-(4,5,6,7-tetrahydro-l,3-benzomiazol-2-yl)pyrroUdine-2,5-diyl]bis{(2-
aminobenzene-4,l-diyl)carbamoyl(25)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-
diyl] })biscarbamate (ACD vl2))
The product from Example 116E (0.59 g, 0.596 mmol) was dissolved in tetrahydrofuran (15
mL) and treated with Raney Nickel slurry in water (0.25 mL). The flask was evacuated and opened to
a hydrogen balloon and stirred at ambient temperature for 1Hour. The solution was filtered through a
silica plug and concentrated to dryness to give the title compound.
Example 116G
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -1 -(4,5,6,7-tetrahydro-1,3-benzothiazol-2-
yl)pyrrolidin-2-yl] -1H-benzimidazol-2-yl }p yrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl} carbamate
The product from Example 116F (0.55 g, 0.592 mmoi) was dissolved in toluene (6 mL) and
treated with acetic acid (0.34 mL, 5.92 mmol) and heated to 65 °C for 4 hours. The solution was
. concentrated to dryness and purified by combi-flash 12g silica column, eluting with 0-6% methanol in
dichloromethane to give 0.245 g (48%) of the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.78 - 0.92 (m, 12 H) 1.53 - 1.61 (m, 4 H) 1.67 - 1.75 (m, 2 H) 1.88 - 2.07 (m, 6 H) 2.15 - 2.27
(m, 6 H) 2.41 - 2.47 (m, 2 H) 2.59 (d, J=1.63 Hz, 2 H) 3.54 (s, 6 H) 3.79 - 3.87 (m, 4 H) 4.07 (t,
J=8.57 Hz, 2 H) 5.12 - 5.20 (m, 2 H) 5.38 - 5.46 (m, 2 H) 7.05 (dd, J=12.79, 9.00 Hz, 2 H) 7.22 - 7.33
(m, 4 H) 7.39 (d, J=8.46 Hz, 1H) 7.46 (d, J=8.46 Hz, 1H) 12.06 (d, J=6.83 Hz, 2 H); MS ESI+ m/z
893.5.
methyl {(2S)-l-[(2S)-2-(4-{4-[(2S,3R,4R,5S)-l-(4-tert-butylphenyl)-3,4-diethoxy-5-(4-{2-[(2SM-
{(2S)-2-[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl}phenyl)pyrrolidin-2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl} carbamate
3.4-O-isopropylidene-C1-mannitol was processed using the methods of Examples 79C, 79D,
79E, 79F, 79G, 79H, and 791 to provide the title compound, wherein iodoethane was used in the O-
alkylation step (method of Example 79D) instead of iodomethane. :H NMR (400 MHz, CDC13) δ ppm
0.86 (t, J=7.4 Hz, 12H) 1.04 (t, J=7.0 Hz, 6H) 1.13 (s, 9H) 1.85-2.03 (m, 4H) 2.03-2.13 (m, 2H) 2.13-
2.24 (m, 2H) 2.24-2.40 (m, 2H) 3.03 (m, 2H) 3.54-3.89 (m, 9H) 3.69 (d, J=1.7 Hz, 6H) 4.25 (d, J=5.3
Hz, 2H) 4.31 (br s, 2H) 5.19-5.29 (m, 4H) 5.36 (br s, 2H) 6.28 (d, J=8.8 Hz, 2H) 6.90-6.98 (m, 4H)
7.12-7.23 (m, 6H). MS (ESI) m/z 1029 (M+H)+.
methyl {(2S)-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-5 -yl} -1 -[6-(pyrrolidin-1 -yi)pyridin-3 -
yl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 118A
5-nitro-2-(pyrrolidin-l-yl)pyridine
To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room
temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70 °C for 18
h. The cooled solution was concentrated in vacuo and the residue partitioned between CH2C12 and
1M NaOH. The organic layer was dried (Na2S04), filtered and solvent removed in vacuo to give title
compound (9.52g, 78%). MS (ESI) m/z 194 (M+H)+.
Example 118B
6-(pyrrolidin- l-yl)pyridin-3-amine
Material from Example 118A (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and DMF
(40 mL) and added to a pressure bottle containing Raney Nickel 2800, water slurry (45%) (9.52g, 162
mmol) stirred for 2 h at 30 psi under H2 gas. The solution was filtered through a nylon membrane,
washed with CH3OH and the filtrate concentrated in vacuo to give the title compound (7.78 g, 97%).
1H,NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.91 (m, 4H) 3.17-3.29 (m, 4H) 4.30 (s, 2H) 6.25 (d,
J=8.7, 1H), 6.90 (dd, J=2.8, 8.7, 1H), 7.55 (d, J=2.6, 1H). MS (ESI) m/z 164 (M+H)+.
Example 118C
(2S,2' S)-tert-butyl 2,2' -(5,5' -((2R,5R)-1 -(6-(pyrrolidin-1 -yl)pyridine-3-yl)pyrrolidine-2,5-
diyl)bis( 1H-benzo [d] imidazole-5,2-diyl)dipyrrolidine-1 -carboxylate
Example 118B and Example 109C were processed using sequentially the methods of
Examples 113A, 113B, 116F, and 281 to provide the tide compound.
Example 118D
methyl {(2S)-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-5-yl} -1 -[6-(pyrrolidin-1 -yl)pyridin-3-
yl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
To a solution of Example 118C (741 mg, 0.94 mmol) in dioxane (4 mL) was added 4 M HC1
in dioxane (4.0 mL) and the solution was stirred at room temperature for 30 min. Solvent is removed
in vacuo and the residue is dissolved in DMF (9.4 mL). Added N,N-diisopropyethylamine (0.99 mL,
5.65 mmol) followed by (S)-2-(methoxycarbonyl-amino)-3-methylbutanoic acid (379 mg, 2.16
mmol), HOBT (331 mg, 2.16 mmol), and EDC (415 mg, 2.16 mmol) and stirred at room temperature
for 18 h. Poured into EtOAc, washed with H20, brine, dried (Na2S04), filtered and removed solvent
in vacuo to give crude product which was purified by flash chromatography on silica gel eluting with
0-6% CH30H/CH2C12 to give the title compound (165 mg, 0.183 mmol, 19%). 1H NMR (400 MHz,
DMSO-d6) δ 0.73-0.95 (m, 12H) 1.66-2.27 (m, 12H) 3.09 (br s, 5H) 3.53 (s, 6H) 3.81 (br s, 4H) 4.06
(t, J=8.4 Hz, 2H) 5.13 (br s, 2H) 5.33 (br s, 2H) 6.12 (br s, 1H) 6.64 (br s, 1H) 7.00-7.47 (m, 10H)
12.02 (s, 2H). MS (ESI) m/z 903 (M+H)+.
methyl 4-{4-[(2R,5R)-2,5-bis(2-{(2S)-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-
benzimidazol-5-yl)pyrrolidin-l -yl] -2-fluorophenyl Jpiperazine-1 -carboxylate
Example 119A
l-(2-fluoro-4-nitrophenyl)piperazine
To a warm solution of piperazine (7.78 g, 90 mmol) in DMSO (40 mL) was added dropwise
l,2-difluoro-4-nitrobenzene (2.0 mL, 18.07 mmol). The solution was stirred at 70 °C for 2 h, cooled
to room temperature, diluted with EtOAc, washed with H20, brine, dried (Na2S04), filtered and
solvent removed in vacuo to give the title compound (4.05 g, 17.98 mmol, 100%). 1H NMR (400
MHz, CDC13) δ ppm 3.03-3.09 (m, 4H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, 1H) 7.91 (dd, J=13.1, 2.6
Hz, 1H) 7.96-8.01 (m, 1H). MS (ESI) m/z 226 (M+H)+.
Example 119B
Methyl 4-(2-fluoro4-nitrophenyl)piperazine-1 -carboxylate
To a solution of Example 119A (4.0 g, 17.76 mmol) in dioxane (40 mL) at 0 °C was added 2
M NaOH (29.3 mL, 58.6 mmol) followed by dropwise addition of methyl chloroformate (2.75 mL,
35.5 mmol). The solution was warmed to room temperature and stirred for 2 h. Diluted with EtOAc
and added 1 N HC1 until all solid had dissolved, separated the phases and washed the organic phase
with 1 N HC1, H20, brine, dried (Na2S04), filtered and removed solvent in vacuo to give the title
compound (4.69 g, 16.56 mmol, 93%). ]H NMR (400 MHz, CDC13) 8 ppm 3.20-3.31 (m, 4H) 3.62-
3.71 (m, 4H) 3.75 (s, 3H) 6.92 (t, J=8.8 Hz, 1H) 7.93 (dd, J=12.9, 2.6 Hz, 1H) 7.98-8.02 (m, 1H). MS
(ESI) m/z 284 (M+H)+.
Example 119C
Methyl 4-(4-amino-2-fluorophenyl)piperazine-1 -carboxylate
To a solution of Example 119B (3.0 g, 10.59 mmol) in EtOAc (40 mL) was added 10%
palladium on carbon (300 mg) and the solution was stirred under a balloon of H2 gas for 1.5 h. The
solution was filtered through Celite, the catalyst washed with EtOAc, and the filtrate concentrated in
vacuo to give the title compound (2.68g, 10.59 mmol, 100%).
Example 119D
methyl 4-{4-[(2R,5R)-2,5-bis(2-{(2S)-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-
benzimidazol-5-yl)pyrrolidin-1 -yl] -2-fluorophenyl} piperazine-1 -carboxylate
Example 119C and Example 109C were processed using sequentially the methods of
Examples 113A-113C, 261, and 118D to provide the tide compound. 1H NMR (400 MHz, DMSO-i(5)
5 ppm 0.75-0.93 (m, 12H) 1.69 (br s, 2H) 1.82-2.07 (m, 7H) 2.10-2.28 (m, 4H) 2.61-2.73 (m, 5H)
3.54 (s, 6H) 3.56 (s, 3H) 3.82 (br s, 4H) 3.99-4.11 (m, 2H) 5.09-5.19 (m, 2H) 5.29-5.41 (m, 2H) 6.01-
6.13 (m, 2H) 6.61-6.72 (m, 1H) 7.06 (s, 2H) 7.20 (s, 1H) 7.29 (d, J=9.1Hz, 3H) 7.38 (d, J=8.1Hz,
1H) 7.46 (d, 1H) 12.04 (s, 2H). MS (ESI) m/z 993 (M+H)+.
methyl {(2S)-1 -[(2S)-2-{5-[(2R,5R)-l-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 120A
4-(2-Fluoro-4-nitrophenyl)morpholine
A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and dibasic potassium phosphate
(9.44 g, 54.2 mmol) in DMSO (27 mL) was treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g,
27.1 mmol) was warmed at 60 °C for 18 h. The solution was cooled and diluted with ethyl acetate
and extracted with water (3 x) and saturated sodium chloride solution. Drying (Na2S04) and
concentration in vacuo afforded the tide compound (6.32 g, ca. 100%) as a yellow solid. 1H NMR
(400 MHz, CDC13) δ 8.00 (ddd, J = 9.0, 2.6, 0.9 Hz, 1H), 7.92 (dd, J = 13.1, 2.6 Hz, 1H), 6.92 (t, J =
8.8 Hz, 1H), 3.88 (m, 4 H), 3.29 (dd, J = 5.5, 4.0 Hz, 4 H). MS +DCI m/z (rel abundance) 227 (10,
M+H), 244 (100, M+NH4).
Example 120B
3-Fluoro-4-morpholinoaniline
A solution of the compound of Example 120A (2.26 g, 10.00 mmol) in ethyl acetate (35 mL)
was treated with 10% palladium on carbon (300 mg) followed by hydrogenation under one
atmosphere pressure for 6 h. The mixture was filtered through celite and concentrated in vacuo to
afford the title compound as a white solid.
Example 120C
4-(4-((2R,5/?)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-fluorophenyl)morpholine
A solution of the compound of Example 109C (2.00 g, 4.99 mmol) and triethylamine (4.17
mL, 3.03 g, 29.9 mmol) in dry dichloromethane (25 mL) at 0 °C was treated with methanesulfonyl
chloride (1.17 mL, 1.71 g, 14.96 mmol) followed by stirring at 0 °C for 30 min. The solution was
warmed to RT and then concentrated in vacuo. The residue was combined with the compound of
Example 120B and N,N-dimethylardline (1.26 mL, 1.21 g, 9.98 mmol) and dissolved in dry DMF (14
mL) followed by warming at 50 °C for 2 h. The solution was cooled and diluted with ethyl acetate,
followed by extraction with water (3 x) and 1 N hydrochloric acid solution (2 x) and saturated sodium
chloride solution. Drying (Na2S04) and concentration in vacuo afforded an orange oil, which was
chromatographed over a 340 g silica gel cartridge, eluting with 10-80% ethyl acetate in hexanes.
These procedures afforded the title compound (1.39 g, 50%) as an orange rigid foam. 1H NMR (400
MHz, CDC13) δ 7.92 (m, 2 H), 7.58 (m, 9 H), 7.31 (dd, J = 8.3, 2.1Hz, 2 H), 6.69 (s, 1H), 5.99 (m, 2
H), 5.20 (d, J= 7.1Hz, 2 H), 3.79 (m, 4 H), 2.92 (m, 6 H), 2.54 (m, 2 H), 1.88 (m, 2 H).
Example 120D
Dimethyl (2R,2'R)-l,V -{{2S,2 'S)-2,2'-(4A'-((2R,5R)-1 -(3-fluoro-4-morpholinophenyl)pyrrolidin-2,5-
diyl)bis(2-nitro-4,1 -phenylene))bis(azanediyl)bis(oxomemylene)bis(pyrrolidine-2,1 -diyl))bis(3-
metbyl-1 -oxobutane-2,1 -diyl)dicarbamate
In a microwave tube, a suspension of the Example 120C (1.39 g, 2.48 mmoL), the compound
of Example 116C (2.02 g, 7.43 mmol), XantPhos (129 mg, 0.22 mmol) and cesium carbonate (2.42 g,
7.43 mmoL) in dioxane (14 mL) was degassed by nitrogen sparge for 30 min. The mixture was
treated with tris(dibenzylideneacetone)dipalladium (O) (68 mg, 0.074 mmol) followed by degassing
for another 5 min. The microwave tube was sealed and the mixture was warmed at 100 °C for 2 h.
The mixture was cooled and diluted with ethyl acetate and extracted with water (3 x) and saturated
sodium chloride solution. The solution was dried (Na2S04) and stirred overnight with 3-
(mercaptopropyl) silica gel. Filtration and concentration in vacuo afforded a solid, which was
chromatographed over a 340 g silica gel cartridge, eluting with 0-10% methanol in dichloromethane.
These procedures afforded the title compound as an orange solid. lR NMR (400 MHz, DMSCW6) 8
ppm 0.80-0.90 (m, 12H) 1.74 (br s, 2H) 1.82-2.03 (m, 10H) 2.08-2.20 (m, 2H) 2.71-2.81 (m, 4H) 3.52
(s, 6H) 3.62 (m, 4H) 3.76 (s, 2H) 4.02 (m, 2H) 4.50 (d, J=4.4 Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H)
6.72-6.81 (m, 1H) 7.32 (d, J=8.4 Hz, 2H) 7.47-7.60 (m, 4H) 7.80 (d, J=1.5 Hz, 2H) 10.41 (s, 2H). MS
(ESI) m/z 1031 (M+H)+.
Example 120E
Dimethyl (2S,2' S)-1,1' -((2S,2' S)-2,2'-(4,4' -((2R,5R)- l-(3-fluoro-4-morpholinophenyl)pyrrolidine-
2,5-diyl)bis(2-amino-4,l-phenylene)bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,ldiyl)bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
To a solution of Example 120D (640 mg, 0.621 mmol) in EtOH (4 mL) and THF (4 mL) was
added Pt02 (35 mg) and the solution was stirred under a balloon of H2 gas for 16 h. The solution was
filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the
title compound (322 mg, 0.332 mmol, 53%).
Example 120F
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-{2-[(2S)-1 -{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
To a solution of Example 120E (320 mg, 0.33 mmol) in toluene (1.5 mL) was added glacial
acetic acid (0.057 mL, 0.99 mmol) and the solution was stirred at 50 °C for 3 h. The cooled solution
was concentrated in vacuo and azeotroped 2 times with toluene. The crude product was purified by
flash chromatography on silica gel during with 0-4% CH3OH/CH2C12 to give the title compound (100
mg, 0.107 mmol, 32%). :H NMR (400 MHz, DMSO-<2<5) δ ppm 0.72-0.92 (m, 12H) 1.69 (br s, 2H)
1.81-2.10 (m, 8H) 2.11-2.28 (m, 4H) 2.64-2.78 (m, 4H) 3.54 (s, 6H) 3.59 (s, 4H) 3.73-3.92 (m, 4H)
4.06 (s, 2H) 5.02-5.21 (m, 2H) 5.36 (s, 2H) 6.03-6.14 (m, 2H) 6.60-6.73 (m, 1H) 7.00-7.15 (m, 2H)
7.15-7.37 (m, 4H) 7.36-7.61 (m, 2H) 12.06 (br s, 2H). MS (ESI) m/z 935 (M+H)+.
methyl [(2S)-l-{(2S)-2-[5-(4-{(2S,3R,4R,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-irnidazol-5-yl}phenyl)-3,4-bis[2-
(2-memoxyethoxy)emoxy]pyiTolidin-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-
oxobutan-2-yl] carbamate
3.4-O-isopropylidene-C1-mannitol was processed using sequentially the methods of Examples
79C, 79D (l-bromo-2-(2-methoxyethoxy)ethane as the alkyating agent with added sodium iodide),
79E-79G, 79H (18 hour reaction time), 66D, and 66E to provide the tide compound (46 mg) as a light
yellow solid. 1H NMR (400 MHz, DMSO-4?) δ 7.60 (d, J = 7.9 Hz, 4 H), 7.50 (d, J = 8.4 Hz, 2 H),
7.38 (s, 2 H), 7.29 (d, J= 8.6 Hz, 2 H), 7.19 (s, 4 H), 6.90 (m, 2 H), 6.27 (d, 7 = 8.6 Hz, 2 H), 5.37 (s,
2 H), 5.07 (d, J = 3.6 Hz, 2 H), 4.32 (s, 2 H), 4.06 (m, 2 H), 3.78 (d, J = 6.0 Hz, 2 H), 3.66 (d, J= 4.2
Hz, 4 H), 3.53 (s, 6 H), 3.17 (s, 6 H), 2.10 (m, 4 H), 1.93 (m,4 H), 1.07 (s, 9 H), 0.86 (m, 12 H). MS
(+ESI) m/z (rel abundance) 1177 (100, M+H), 1199 (5, M+Na).
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,3R,4R,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-3,4-bis(3-
methoxypropoxy)pyrrolidin-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl}carbamate
3.4-O-isopropylidene-C1-mannitol was processed using sequentially the methods of Examples
79C, 79D (l-bromo-3-methoxypropane as the alkyating agent with added sodium iodide), 79E-79H,
66D, and 66E to provide the title compound. 1H NMR (400 MHz, DMSO-ds) 8 7.60 (s, 4 H), 7.52
(m, 2 H), 7.37 (m, 2 H), 7.30 (m, 4 H), 7.18 (d, J = 7.1Hz, 4 H), 6.91 (m, 2 H), 6.24 (m, 2 H), 5.40
(m, 2 H), 5.06 (m, 2 H), 4.31 (m, 2 H), 4.11 (m, 2 H), 3.78 (s, 4 H), 3.66 (m, 4 H), 3.56 (m, 10 H),
3.14 (m, 14 H), 2.14 (m, 6 H), 1.94 (d, J = 3.5 Hz, 8 H), 1.43 (m, 6 H), 1.07 (s, 10 H), 0.89 (d, J = 6.1Hz, 6 H), 0.84 (d, J = 5.9 Hz, 6H).
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,3R,4R,5S)-l-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)armno]-3-memylbutanoyl}pyrroUdin-2-yl]-lH-imidazol-5-yl}phenyl)-3,4-bis(2-
methoxyethoxy)pyrrolidin-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yljcarbamate
3.4-O-isopropylidene-C1-mannitol was processed using sequentially the methods of Examples
79C, 79D (l-bromo-2-methoxyethane as the alkyating agent with added sodium iodide), 79E, 79F,
79G, and 79H, wherein Example 126G replaced (S)-tert-butyl-2-(4-bromo-lH-imidazol-2-
yl)pyrrolidine-l-carboxylate in applying the method of Example 79H, to provide the title compound
(43 mg) as a light beige solid. :H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 8.0 Hz, 4 H), 7.47 (m, 2
H), 7.37 (m, 2 H), 7.27 (m, 4 H), 7.19 (s, 4 H), 6.90 (d, J = 8.6 Hz, 2 H), 6.26 (d, J = 8.7 Hz, 2 H),
5.37 (s, 2 H), 5.06 (d, J= 3.7 Hz, 2 H), 4.30 (s, 2 H), 4.03 (m, 2 H), 3.79 (s, 4 H), 3.66 (m, 6 H), 3.53
(s, 6 H), 3.25 (m, 6 H), 3.12 (s, 6 H), 2.13 (m, 4 H), 1.94 (m, 6 H), 1.07 (s, 9 H), 0.89 (d, J = 6.6 Hz, 6
H), 0.84 (d, J =6.6 Hz, 6 H). MS +ESI m/z (rel abundance) 1088 (100, M+H).
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}-l-[6-(morpholin-4-yl)pyridin-3-
yl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 109C and Example 154B were processed using the methods of Examples 113A,
113B, 116F, 281 (reaction conducted at 50 °C for 4 h), 66D, and 66E to provide the tide compound
(120 mg) as a light beige solid. :H NMR (400 MHz, DMSO-^) δ 12.03 (s, 1H), 7.46 (d, J= 8.2 Hz,
1H), 7.45 (s, 1H), 7.31 (d, J = 6.4 Hz, 3 H), 7.21 (s, 1H), 7.06 (t, J= 8.0 Hz, 2 H), 6.64 (m, 1H),
6.49 (m, 1H), 5.36 (d, J= 6.2 Hz, 2 H), 5.13 (s, 2 H), 4.04 (m, 2 H), 3.77 (m, 3 H), 3.55 (m, 9 H),
3.04 (s, 4 H), 2.19 (s, 3 H), 1.95 (m, 5 H), 1.73 (s, 3 H), 0.82 (m, 12 H). MS +ESI mJz (rel
abundance) 918 (100, M+H).
methyl {(2S)-l-[(2S)-2-(5-{4-[l-(2,3-dihydro-lH-inden-5-yl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 26E and 5-aminoindan were processed using the methods of Examples 76A, 39E,
39F, 55G, and 26J (reaction solvent = dichloromethane) to provide the title compound (0.1446 g).1H NMR (400 MHz, DMSO-D6) δ 0.91 - 0.79 (m, 12H), 2.18 - 1.87 (m, ITS), 2.1 A (t, 7= 6.7, 2H), 2.86
(t, J= 6.8, 2H), 3.53 (s, 6H), 3.84 - 3.68 (m, 4H), 4.10 - 3.98 (m, 2H), 5.03 (dd, J= 6.8, 2.9, 2H), 6.54
- 6.40 (m, 2H), 7.10 - 6.86 (m, 5H), 7.22 - 7.13 (m, 2H), 7.33 - 7.22 (m, 2H), 7.45 - 7.35 (m, 2H), 7.53
(dd, J= 13.7, 8.5, 4H), 11.70 (s, 1H), 12.07 -11.96 (m, 1H). MS (ESI) mJz 920 (M+H)+, 918 (M-H)+.
methyl [(2S)-l-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-[4-(pentafluoro-lambda~6~-
sulfanyl)phenyl]pyrrolidin-2-yl } phenyl)- lH-imidazol-2-yl] pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-
yl]carbamate
Example 126A
(S)-2-(methoxycarbonylamino)-3-methylbutanoicacid
A mixture of (S)-2-amino-3-methylbutanoic acid (10.0 g, 85.0 mmol), NaOH (3.41 g, 85.0
mmol) and NaHC03 (4.7 g, 44.4 mmol) in H20 (85 mL) was cooled to 0 °C. A mixture of methyl
chloroformate (7.3 mL, 94.0 mmol) dissolved in Et20 (40 mL) was slowly added to the aqueous
mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pH 2.0 with
HC1 (cone). The mixture was extracted with CH2C12 (3 x 100 mL) and then dried (MgS04), filtered
and concentrated to afford 7.5 g (50%) of the tide compound. MS (ESI) m/z 176 (M+H)+.
Example 126B
(S)-tert-butyl2-formylpyrrolidine-l-carboxylate
A mixture of oxalyl chloride (14.1 mL, 161 mmol) in CH2C12 (331 mL) was cooled to -75 °C.
Dimethylsulfoxide (19.4 mL, 273 mmol) in CH2C12 (70 mL) was slowly added over 30 minutes
followed by stirring at -75 °C for an additional 15 minutes. At -75 °C (S)-tert-butyl 2-
(hydroxymethyl)pyrrolidine-l-carboxylate (25.0 g, 124 mmol) in CH2C12 (132 mL) was added slowly
over one hour, followed by a further 15 minutes of stirring. Then, still at -75 °C, Et3N (87 mL, 621
mmol) was added over 30 minutes followed by another 15 minutes of stirring. Mixture was then
allowed to stir at 0 °C for 90 minutes. Mixture was quenched with 10% aqueous Citric acid at 0 °C.
The mixture was diluted with 10% aqueous Citric acid and partitioned. Organic was washed with
H20 (5 x 150 mL) and Brine. The organic was then dried (MgS04), filtered and concentrated to
afford 24.7g (100%) of the title compound. MS (ESI) m/z 200(M+H)+.
Example 126C
(S)-tert-butyl 2-( 1H-imidazol-2-yl)pyrrolidine-1 -carboxylate
A mixture of Example 126B (24.7g, 124.0 mmol) and NH4OH (62.0 mL, 497 mmol) in
methanol (62 mL) was stirred at 0 °C followed by slow addition of glyoxal hydrate (29.9 mL, 262
mmol) over 10 minutes. Mixture was stirred for 16 hours at ambient temperature. The mixture was
concentrated, diluted with H20 and extracted with EtOAc (3 x 200 mL). The organic was then dried
(MgS04), filtered and concentrated. Purification by trituration with tBuOMe afforded 15.5g (53%) of
the title compound. MS (ESI) m/z 238 (M+H)+.
Example 126D
(S)-tert-butyl 2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1 -carboxylate
A mixture of Example 126C (15.5 g, 65.4 mmol) in CH2C12 (260 mL) was stirred at 0 °C
followed by portion-wise addition of l-bromopyrrolidine-2,5-dione (24.5, 137.0 mmol) over 10
minutes. Mixture was stirred 0 °C for 90 minutes. Mixture was concentrated, diluted with EtOAc
(600 mL) and washed with H20 (3 x 200 mL) and brine. The organic was then dried (MgS04),
filtered and concentrated. Purification by trituration with Et20 afforded 24.9 g (96%) of the tide
compound. MS (ESI) m/z 396 (M+H)+.
Example 126E
(S)-tert-butyl2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate
A mixture of Example 126D (12.5 g, 31.5 mmol) in dioxane (400 mL) and H20 (400 mL) had
a solution of Na2S03 (43.7 g, 347 mmol) in H20 (400 mL) added and was heated to reflux for 21Hours. The mixture was concentrated to half volume and extracted with CH2C12 (3 x 200 mL). The
organic was then washed with brine, dried (MgS04), filtered and concentrated. Purification by
trituration (CH2C12, ffiuOMe, and Hexanes). afforded 5.2 g (52%) of the title compound. MS (ESI)
m/z 317(M+H)+.
Example 126F
(S)-5-bromo-2-(pyrrolidin-2-yl)-lH-imidazole hydrochloride
A mixture of Example 126E (5.0g, 15.8 mmol) in 4M HCl/Dioxane (40 mL) was allowed to
stir for one hour. The mixture was concentrated to afford 3.99g (100%) of die title compound. MS
(ESI) m/z 217 (M+H)+.
Example 126G
methyl (S)-l-((S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate
A mixture of Example 126F (3.99g, 15.8 mmol), Example 126A (2.77 g, 15.8 mmol), N-(3-
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.63 g, 19.0 mmol), 1-Hydroxy-
benzotriazole hydrate (2.90 g, 19.0 mmol) and N-methylmorpholine (12.2 mL, 111.0 mmol) in DMF
(150 mL) were allowed to stir overnight. Mixture was diluted with H20 and extracted with EtOAc (3
x 300 mL). The organic was washed with H20 and Brine. The organic was then dried (MgS04),
filtered and concentrated. Purification by chromatography (silica gel, 75% EtOAc in Hexanes)
afforded 5.2 g (88%) of the tide compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (dd, 7=6.67,
3.63 Hz, 6 H), 1.84 - 1.96 (m, 3 H), 2.02 - 2.14 (m, 2 H), 3.51 (s, 3 H), 3.66 - 3.80 (m, 2 H), 3.96 -
4.03 (m, 1H), 4.91 - 4.99 (m, 1H), 7.06 (d, 7=1.52 Hz, 1H), 7.26 (d, 7=8.46 Hz, 1H), 12.01 (s, 1H).
MS (ESI) m/z 373 (M+H)+.
Example 126H
(1 S,4S)-1,4-bis(4-bromophenyl)butane-1,4-diol
(lS,4S)-l,4-bis(4-bromophenyl)butane-l,4-diol was prepared using the method of Example
69A and (R)-alpha, alpha-diphenyl-2-pyrrolidinemethanol).
(2R,5R)-2,5-bis(4-bromophenyi)-1 -(4-sulfur pentafluoride phenyl)pyrrolidine
A solution of methanesulfonic anhydride (2.95 mL, 23.02 mmol) in 2-Me THF (15 mL) was
cooled in ice/salt bath to ~0°C. To this cold solution a solution of Example 126H (4.0524 g, 10.13
mmol) and N,N-diisopropylethylamine (5.5 mL, 31.8 mmol) in 2-Me THF (40 mL) was added
dropwise over 40 minutes. The reaction was slowly warmed to 20 °C. At this time 4-
aminophenylsulfur pentafluoride (7.1238 g, 32.5 mmol) was added and the mixture was warmed to 38
°C for 17 hours. The reaction was cooled and partioned between EtOAc and water. The organic
fraction was washed with water (2 x) brine (1 x) and concentrated. Purification by flash
chromatography (silica gel, EtOAc/hexane) afforded the tide compound (1.95 g, 33%). LC/MS Rt
2.38 m/z 584 (M+H)+.
Example 126J
(2R,5R)-l-(4-sulfurpentafluoridephenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)phenyl)pyrrolidine
The product from Example 1261 was processed using the method described in Example 39E
to afford the title compound (1.67 g, 74%). MS (ESI) m/z 678 (M+H)+.
Example 126K
methyl [(2S)-1 -{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-[4-(pentafluoro-lambda~6~-
sulfanyl)phenyl]pyrrolidin-2-yl Jphenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl }-3-methyl- l-oxobutan-2-
yl]carbamate
The product from Example 126J and Example 126G were processed using the method
described in Example 39F to afford the title compound (0.75 g, 30%). 1H,NMR (400 MHz, DMSO-
d6) δ 0.85 (dd, J= 6.7, 15.8, 12H), 2.26 - 1.66 (m, 14H), 3.53 (s, 6H), 3.87 - 3.63 (m, 4H), 4.14 -
3.91 (m, 2H), 5.06 (dd, J= 3.0, 6.7, 2H), 5.34 (s, 2H), 6.34 (d, J= 9.1,2H), 7.17 (d, J= 8.2, 4H), 7.26
(dd, 7= 8.4, 17.3, 2H), 7.75 - 7.34 (m, 8H), 12.22 - 11.46 (m, 2H). MS (ESI) m/z 1010 (M+H)+, 1008
(M-H)+.
methyl [(2S)-l-{(2S)-2-[5-(4-{l-[4-(azepan-l-yl)phenyl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arruno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl }phenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-l -oxobutan-2-yl]carbamate
Example 26E and 4-(l-azepanyl)aniline were processed using the methods of Examples 76A,
39E, 39F, 55G, and 26J (reaction solvent = dichloromethane) to provide the title compound (6.1 mg).
MS (ESI) m/z 977 (M+H)+.
methyl {(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-l-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidm-2-yl]-lH4midazol-5-yl}phenyl)pyrrolidin-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
Example 126H and 4-cyclohexylaniline were processed using the methods of Examples 1261,
126J, and 126K to provide the tide compound (0.14 g).^ NMR (400 MHz, DMSO-D6) δ 0.85 (dd, J
= 16.6, 6.9, 12H), 1.32 -1.06 (m, 8H), 1.65 (dd, J= 19.1, 6.2, 7H), 2.27 -1.82 (m, 13H), 3.53 (s, 6H),
3.78 (d, 7 = 6.8, 2H), 4.10 - 3.95 (m, 2H), 5.06 (dd, J= 6.9, 3.1, 2H), 5.19 (t, J= 6.7, 2H), 6.21 (d, J =
8.7, 2H), 6.76 (dd, J= 8.6, 3.7, 2H), 7.19 - 7.08 (m, 4H), 7.34 - 7.19 (m, 2H), 7.37 (d, J = 1.8, 1H),
7.50 (t, J= 11.3, 1H), 7.65 - 7.57 (m, 3H), 11.68 (s, 1H), 12.10 - 11.93 (m, 1H). MS (ESI) m/z 966
(M+H)+.
methyl {(2S)-l-[(2S)-2-(4-chloro-5-{4-[(2R,5R)-5-(4-{4-chloro-2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-(4-
cyclohexylphenyl)pyrrolidin-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yljcarbamate
N-Chlorosuccinimide (0.046 g, 0.342 mmol) was added to a solution of the product from
Example 128 (0.1435 g, 0.149 mmol) in dichloromethane (7 mL) and stirred at ambient temperature
for 17 hours. The reaction was diluted with dichloromethane and washed with sat aq NaHC03 (2 x)
and concentrated. The residue was purified by flash chromatography (silica gel,
MeOH/dichloromethane) then by prep HPLC to afford the title compound (20.4 mg, 13%). % NMR
(free base) (400 MHz, DMSO-D6) 8 0.94 - 0.73 (m, 12H), 1.39 - 0.99 (m, 8H), 1.75 - 1.41 (m, 6H),
2.27 -1.77 (m, 12H), 3.53 (s, 6H), 3.86 - 3.66 (m, 3H), 4.08 - 3.96 (m, 2H), 5.11 - 4.89 (m, 2H), 5.30
- 5.12 (m, 1H), 5.55 - 5.33 (m, 1H), 6.21 (d, J = 8.7, 1H), 6.88 - 6.67 (m, 2H), 6.94 (dd, J = 4.3, 8.4,
1H), 7.42 - 7.02 (m, 6H), 7.56 - 7.42 (m, 3H), 7.61 (t, J = 8.5, 1H), 11.68 (d, J = 10.7, 1H), 12.49 -
12.26 (m, 1H). MS (ESI) mJz 1034 (M+H)+.
methyl [(2S)-l-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
metbylbutanoyl]pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-t4-(morpholin-4-yl)phenyl]pyrrolidin-
2-yl} phenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 126H and 4-morpholinoaniline were processed using sequentially the methods of
Examples 1261, 39E, 39F, 391, and 26J (reaction solvent = dichloromethane) to provide the tide
compound (0.16 g). 1H,NMR (300 MHz, DMSO-D6) 8 0.86 (dd, J = 12.2, 6.6, 12H), 1.77 - 1.55 (m,
2H), 2.03 -1.77 (m, 6H), 2.21 - 2.03 (m, 4H), 2.45 - 2.39 (m, 1H), 2.58 - 2.54 (m, 1H), 2.82 - 2.74 (m,
4H), 3.53 (s, 6H), 3.67 - 3.57 (m, 4H), 3.77 (d, J= 6.1, 3H), 4.04 (t, 7 = 8.3, 2H), 5.06 (dd, J = 6.7,
3.0, 2H), 5.18 (t, J = 5.0, 2H), 6.22 (d, J = 9.0, 2H), 6.58 (dd, J= 9.0, 1.9, 2H), 7.14 (d, J= 8.4, 4H),
7.32 - 7.17 (m, 3H), 7.37 (d, J = 1.8, 2H), 7.55 - 7.41 (m, 1H), 7.63 (t, J = 10.0, 4H), 11.68 (s, 1H),
12.15 -11.90 (m, 1H). MS (ESI) m/z 969 (M+H)+.
methyl [(2S)-1-{(2S)-2-[4-chloro-5-(4-{(2R,5R)-5-(4-{4-chloro-2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arm^o]-3-memylbutanoyl}pyrrohdin-2-yl]-lH-imidazol-5-yl}phenyl)-l-[4-
(pentafluoro4ambda~6~-sulfanyl)phenyl]pyrrolidin-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-
3-methyl-1 -oxobutan-2-yl] carbamate
The product from Example 126K was processed using the method described in Example 129.
The mixture of mono and dichlorinated products was purified via reverse phase HPLC to afford the
title compound (90.9 mg, 19%). :H NMR (free base) (500 MHz, DMSO-D6) δ 0.84 (dd, J= 6.8,16.1,
12H), 2.23 - 1.70 (m, 13H), 3.53 (s, 6H), 3.85 - 3.66 (m, 4H), 4.02 (ddd, J = 4.8,10.8, 16.1, 3H),
5.05-4.91 (m, 2H), 5.43 (d, 7 = 5.8, 2H), 6.36 (d, J = 9.1, 2H), 7.28 (d, J= 8.4,2H), 7.34 (d, J= 8.3,
4H), 7.46 (d, J = 9.4,2H), 7.72 - 7.58 (m, 4H), 12.43 (s, 2H). MS(ESI) m/z 1078 (M+H)+.
methyl [(2S)-l-{(2S)-2-[4-chloro-5-(4-{(2R,5R)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-
3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-5-yl} phenyl)-1 - [4-(pentafluoro-lambda~6~-
sulfanyl)phenyl]pyrrolidin-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-
yl]carbamate
The product from Example 126K was processed using the method described in Example 129.
The mixture of mono and dichlorinated products was purified via reverse phase HPLC to afford the
title compound (33.3 mg, 7%). 1H NMR (free base) (500 MHz, DMSO-D6) δ 0.94 - 0.76 (m, 12H),
2.24 - 1.63 (m, 13H), 3.53 (d, J= 1.2, 6H), 3.86 - 3.68 (m, 4H), 4.10 - 3.98 (m, 2H), 5.02 - 4.93 (m,
1H), 5.06 (dd, J= 3.2,7.1, 1H), 5.48-5.30 (m, 2H), 6.35 (d, J = 9.1, 2H), 7.21-7.10 (m, 2H), 7.36 -
7.21 (m, 4H), 7.58 - 7.38 (m, 4H), 7.73 - 7.59 (m, 4H), 12.50 - 11.65 (m, 2H). MS (ESI) m/z 1044
(M+H)+, 1042 (M-H)+.
methyl [(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1 -{(2S)-2-t(melhoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl]- lH-imidazol-5-yl }phenyl)-l -[6-(piperidin-1 -yl)pyridin-3-
yl]pyrrolidm-2-yl}phenyl)4H-imidazoI-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 126H and 6-(piperidin-l-yl)pyridine-3-amine were processed using sequentially the
methods of Examples 1261, 39E, 39F, 391, and 26J (reaction solvent = dichloromethane) to provide
the title compound (91.4 mg). 1H NMR (400 MHz, DMSO-D6) 8 0.85 (dt, J= 7.1,14.3, 12H), 1.24
(s, 2H), 1.44 (s, 6H), 1.70 (d, J = 5.2, 2H), 2.04 - 1.82 (m, 6H), 2.23 - 2.04 (m, 4H), 3.21 - 3.03 (m,
4H), 3.53 (s, 6H), 3.87 -3.67 (m, 4H), 4.12- 3.96 (m, 2H), 5.06 (dd, J= 3.2, 7.0,2H), 5.20 (t, J=
6.8, 2H), 6.49 (dd, J= 3.1, 9.1, 1H), 6.60 (dd, J = 2.9, 9.2,1H), 7.20 - 7.10 (m, 4H), 7.33 - 7.20 (m,
3H), 7.38 (d, J= 1.8,2H), 7.51 (t, J= 10.4, 1H), 7.64 (dd, 7= 8.1,15.7, 3H), 11.69 (s, 1.4H), 12.06 (t, J=32.1,0.6H).
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-t(methoxycarbonyl)amino]-3-
methylbutanoyl} pyrrolidin-2-yl]- lH-benzimidazol-6-yl} -1 - [6-(piperidin-1 -yl)pyridin-3-yl]pyrrolidin-
2-yl} -1H-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 109C and 6-(piperidin-l-yl)pyridine-3-amine were processed using sequentially the
methods of Examples 113A, 113B, 116F (Ra-Ni reduction conducted in an SS pressure bottle for 120
min at 30 psi at room temperature), 281 (reaction conducted at 50 °C for 4 hours), 391, and 26J
(reaction solvent = dichloromethane) to provide the title compound (71 mg). 1H NMR (400 MHz,
METHANOL-D4) δ 0.89 (ddd, J = 6.5,20.7,26.0,12H), 1.62 - 1.43 (m, 6H), 2.48 - 1.80 (m, 13H),
2.72 - 2.60 (m, 2H), 3.10 - 2.97 (m, 4H), 3.64 (s, 6H), 3.93 - 3.78 (m, 2H), 4.09 - 3.94 (m, 2H), 4.22
(d, J = 7.3, 2H), 5.21 (dd, J = 5.2, 7.6, 1H), 5.44 - 5.30 (m, 2H), 6.50 (d, J= 9.1, 1H), 6.83 - 6.71 (m,
1H), 7.59 - 7.15 (m, 7H). MS (ESI) mJz 916 (M+H)+, 914 (M-H)+.
methyl [(2S)-1 -{(2S)-2-[5-(4-{l-[6-(4,4-difluoropiperidin-l-yl)pyridin-3-yl]-5-(4-{2-[(2S)-1-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-lH-pyrrol-
2-yl}phenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-l -oxobutan-2-yl]carbamate
Example 135A
2-(4,4-difluoropiperidin-1 -yl)-5-nitropyridine
To a slurry of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and 4,4-difluoropiperidine
hydrochloride (4.97 g) in ethanol (40 mL) at ambient temperature was added N,N-
diisopropylethylamine (12.00 mL, 69.4 mmol) and the mixture heated to 70 °C for 18 hours. The
reaction was concentrated, partitioned between CH2C12 and 1M NaOH. The organic phase
concentrated and purified by chromatography (elution with 2% MeOH-CH2C12 then 3% MeOH-
CH2C12) to provide the title compound as a yellow oil. MS (DCI) m/z 261 (M+NH4)+.
Example 135B
6-(4,4-difluoropiperidin-l-yl)pyridin-3-amine
The product from Example 135A (4.56 g, 18.75 mmol) and solvent THF (20 mL)/DMF were
added to Ra-Ni 2800, water slurry (4.56 g, 78 mmol) in a 250 mL SS pressure bottle and stirred for 2
hr at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and washed
with MeOH. The filtrate was concentrated and dried under vacuum to afford the title compound (3.40
g, 85%). :H NMR (400 MHz, DMSO-D6) δ 2.03 - 1.88 (m, 4H), 3.49 - 3.38 (m, 4H), 4.61 (s, 2H),
6.73 (d, 7 = 8.8, 1H), 6.93 (dd, J = 2.9, 8.8, 1H), 7.61 (d, J= 2.6, 1H). MS (ESI) m/z 214 (M+H+).
Example 135C
5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-5-yl)phenyl)-lH-pyrrol-l-yl)-2-(4,4-
difluoropiperidin-1 -yl)pyridine
TFA (0.046 mL, 0.596 mmol) was added to a mixture of the product from Example 138B
(0.2114 g, 0.298 mmol) and the product from Example 135B (0.095 g, 0.447 mmol) in toluene (2.98
mL). The mixture was heated at 110 °C for 18 hours. The reaction was cooled and additional TFA
(0.023 mL, 0.298 mmol) was added and stirred for another hour. The solvent was removed under
reduced pressure and azatroped with toluene to afford the title compound.
Example 135D
methyl [(2S)-1 -{(2S)-2-[5-(4-{l-[6-(4,4-difluoropiperidin-l-yl)pyridin-3-yl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-5-yl Jphenyl)-1H-pyrrol-
2-yl}phenyl)4H-irnidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
The product from Example 135C was processed using the method described in Example 26J
to afford the title compound. :H NMR (400 MHz, DMSO-D6) δ 0.94 - 0.73 (m, 12H), 2.03 -1.82 (m,
10H), 2.20 - 2.04 (m, 4H), 3.53 (s, 6H), 3.64 (s, 4H), 3.86 - 3.69 (m, 4H), 4.04 (dd, 2H), 5.04 (dd, J=
3.0, 7.0, 2H), 6.53 - 6.39 (m, 2H), 6.93 - 6.79 (m, 1H), 7.06 (d, J= 8.4, 3H), 7.13 (dd, 7= 10.9, 19.3,
1H), 7.30 - 7.21 (m, 2H), 7.39 - 7.30 (m, 1H), 7.42 (d, J= 1.7, 1H), 7.48 - 7.43 (m, 1H), 7.66 - 7.49
(m, 4H), 7.85 (dd, J= 2.7, 9.7,1H), 12.16 -11.64 (m, 2H). MS (ESI) rn/z 1000 (M+H)+, 998 (M-H)+.
methyl {(2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -lH-imidazol-4-yl }phenyl)-l - {4-[(trifluoromethyl)sulfonyl]phenyl} -
lH-pyn-ol-2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
Example 136A
2,5-bis(4-bromophenyi)-1 -(4-(trifluoromethylsulfonyl)phenyl)-1H-pyrrole
To a slurry of the product from Example 26E (0.60 g, 1.52 mmol) and 4-
(trifluoromethylsulfonyl)aniline (0.51 g, 2.27 mmol) in toluene (12 mL) was added a IN solution of
titanium(IV) chloride (1.6 mL, 1.6 mmol) in toluene. The mixture was stirred overnight at room
temperature and then heated to reflux for 3 hours. The cooled mixture was filtered and the solid
residue was suspended in a mixture of water and diethyl ether. The solid was diluted with water and
ether and stirred vigorously for 15 minutes. The mixture was filtered and then washed thoroughly
methyl {(2S)-l-[(2S)-2-(4-{4-[l-(3-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-pyrrol-
2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
Example 138A
l,4-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)butane-l,4-dione
To a solution of die product from Example 26E (2.00 g, 5.05 mmol), bis(pinacolato)diborane
(3.85 g, 15.15 mmol), potassium acetate (1.982 g, 20.20 mmol) in dimethoxyethane (50 mL) at room
temperature was added PdCl2(dppf)-CH2Cl2 adduct (0.412 g, 0.505 mmol) and the mixture degassed
(purge with N2). The mixture was heated to reflux for 1Hour. The cooled mixture was filtered
through celite and washed with ethyl acetate. The filtrate was washed with water, brine and dried
(Na2S04). After filtration and removal of solvent, the residue was purified by chromatography (80 g
column; gradient elution from 0% to 40% ethyl acetate-hexanes) to provide the title compound (2.22
g; 90%) as a white solid. 1HNMR (CDC13; 400 MHz): 5 8.02 (AA'XX', J=8.24 Hz, 4H), 7.91
(AA'XX', J=8.13 Hz, 4H), 3.47 (s, 4H), 1.36 (s, 24H).
di-tert-butyl(25',2'1S,)-2,2'-[(l,4-dioxobutane-l,4-diyl)bis(benzene-4,l-diyl-l//-imidazole-5,2-
diyl)]dipyrrolidine-l-carboxylate
A solution of the product from Example 138A (2.22 g, 4.53 mmol), PdCl2(dppf)-CH2Cl2
adduct (0.37 g, 0.45 mmol), 1 M sodium carbonate (18 mL, 18 mmol) and the product from Example
26D (4.30 g, 13.6 mmol) in ethanol (23 mL)/toluene (23 mL) was degassed (purge N2) and heated in
oil bath at 90 °C overnight. The cooled mixture was concentrated and the residue partitioned between
water and ethyl acetate. The organic phase was concentrated and the residue was purified by
chromatography (gradient elution from 30% to 100% ethyl acetate-hexane) to provide the title
compound (1.90 g, 59%) as a light tan solid. 1HNMR (DMSO-d6; 400 MHz): 5 12.06 (m, 2H), 8.04-
7.96 (m, 4H), 7.89-7.78 (m, 4H), 7.69 (m, 2H), 4.85-4.75 (m, 2H), 3.53 (m, 2H), 3.35 (m, 4H), 2.24-
1.87 (m, 10H), 1.39 (br s, 8H), 1.14 (br s, 10H). MS (ESI; M+H) m/z = 709.
Example 138C
(S)-4,4'-(4,4'-(l-(3-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-2-
yl)-lH-imidazole)
To a solution of the product from Example 138B (180 mg, 0.25 mmol) and 3-tert-butylaniline
(57 mg, 0.38 mmol) in toluene (2.0 mL) was added trifluoroacetic acid (39 \iL 0.50 mmol). The
mixture was heated to 110 °C overnight. To the cooled mixture was added trifluoroacetic acid (0.4
mL) and the mixture was stirred for 1Hour at room temperature. The mixture was concentrated under
reduced pressure. The residue was partitioned between 25% isopropyl alcohol in CHC13 and saturated
sodium bicarbonate solution. The organic layer was separated and dried over Na2S04, filtered and
concentrated under reduced pressure to provide the title compound.
Example 138D
methyl {(2S)-l-[(2S)-2-(4-{4-[l-(3-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-pyrrol-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
A solution consisting of Nl-((ethyUmino)methylene)-N3,N3-dimethylpropane-l,3-diamine
hydrochloride (109 mg, 0.57 mmol), lH-benzo[d][l,2,3]triazol-l-ol hydrate (87 mg, 0.57 mmol), (S)-
2-(methoxycarbonylamino)-3-methylbutanoic acid (100 mg, 0.57 mmol) and 4-methylmorpholine
(0.14 mL, 1.0 mmol) in DMF (2.6 mL) was cooled in an icebath. To this mixture was added the
product from Example 138C (161 mg, 0.26 mmol). Additional 4-methylmorpholine was added to the
mixture until the pH was adjusted to 8. The reaction was stirred for 3.5 hours and then the icebath
was removed and the reaction was stirred for an additional 16 hours. Water was then added to the
reaction mixture and the resulting precipitate was recovered by filtration. The residue was washed
with copious amounts of water followed by diethyl ether. The crude product was purified by
chromatography on silica gel eluted with a solvent gradient of 0-5% methanol in CH2C12 to provide
the title compound (15 mg, 6% yield). 1H NMR (400 MHz, DMSO-D6) δ 12.04 - 11.65 (m, 2H), 7.57
- 7.45 (m, 4H), 7.43 - 7.35 (m, 2H), 7.33 - 7.08 (m, 5H), 7.05 - 6.91 (m, 4H), 6.79 (t, J = 7.5, 1H),
6.53 - 6.40 (m, 2H), 5.05 - 4.99 (m, 2H), 4.02 (t, J= 8.3, 2H), 3.82 - 3.68 (m, 4H), 3.56 - 3.47 (m,
6H), 2.18 - 1.79 (m, 10H), 1.09 (s, 9H), 0.89 - 0.75 (m, 12H). MS (ESI; M+H) m/z = 937.
methyl {(2S)-1 -[(2S)-2-(4- {4-[ 1 -(4-cyclopropylphenyl)-5-(4- {2-[(2S)-1 - {(2S)-2-
[(methoxycarbonyl) amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl Jphenyl)-1H-pyrrol-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 139A
(S)-4,4'-(4,4,-(l-(4-cyclopropylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-
2-yl)- lH-imidazole) tetraMs(2,2,2-trifluoroacetate)
To a solution of the product from Example 138B (0.30g 0.43 mmol) and 4-cyclopropylaniline
(85 mg, 0.64 mmol) in toluene (3.4 mL) was added trifluoroacetic acid (65 \ih 0.85 mmol). The
mixture was heated to 110 °C overnight. To the cooled mixture was added trifluoroacetic acid (1.0
mL) and the mixture was stirred for 1Hour at room temperature. The mixture was concentrated under
reduced pressure and then triturated with diethyl ether to provide the title compound (0.42g, 28%
yield).
Example 139B
methyl {(2S)-l-[(2S)-2-(4-{4-[l-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl Jphenyl)-1H-pyrrol-
2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
The title compound was prepared using the methods from Example 138D substituting the
product from Example 139A for the product from Example 138C to provide the title compound (150
mg, 40% yield). lR NMR (400 MHz, DMSO-D6) δ 12.09 - 11.63 (m, 2H), 7.56 - 7.46 (m, 4H), 7.44
- 7.35 (m, 2H), 7.30 - 7.11 (m, 2H), 7.07 - 6.88 (m, 8H), 6.54 - 6.39 (m, 2H), 5.07 - 4.97 (m, 2H),
4.03 (t, J= 8.3, 2H), 3.83 - 3.66 (m, 4H), 3.52 (s, 6H), 2.18 - 1.79 (m, 10H), 1.26 - 1.19 (m, 1H),
0.98 - 0.90 (m, 2H), 0.90 - 0.74 (m, 12H), 0.69 - 0.60 (m, 2H). MS (ESI; M+H) m/z = 921.
with diethyl ether to give the title compound as a crude mixture that was used in subsequent reactions
without further purification (0.60g, 68% yield crude).
Example 136B
methyl {(2S)-1 -[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]4H-imidazol-4-yl}phenyl)-l-{4-[(trifluoromethyl)sulfonyl]phenyl}-
lH-pyrrol-2-yl]phenyl}4H-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
Example 136A was processed using sequentially the methods of Examples 26G, 26H, 65B,
and 65C to provide the title compound (90 mg). JH NMR (400 MHz, DMSO-D6) 8 12.20 - 11.68 (m,
2H), 8.17 - 8.04 (m, 2H), 7.63 - 7.42 (m, 8H), 7.31 - 7.15 (m, 2H), 7.02 - 6.90 (m, 4H), 6.64 - 6.53
(m, 2H), 5.08 - 4.97 (m, 2H), 4.05 - 3.97 (m, 2H), 3.83 - 3.69 (m, 4H), 3.53 (s, 6H), 2.18 - 1.79 (m,
10H), 0.90 - 0.78 (m, 12H). MS (ESI; M+H) m/z = 1013.
methyl [(2S)-l-{(2S)-2-[4-(4-{l-[4-(2-cyanopropan-2-yI)phenyl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyn:olidm-2-yl]-lH4midazol-4-yl}phenyl)-lH-pyrrol-
2-yl} phenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 26E and 2-(4-aminophenyl)-2-methylpropanenitrile were processed using
sequentially the methods of Examples 26F, 26G, 26H, 65B, and 65C to provide the title compound
(100 mg). 1H NMR (400 MHz, DMSO-D6) δ 12.15 - 11.68 (m, OH), 7.58 - 7.44 (m, OH), 7.44 - 7.36
(m, OH), 7.30 - 7.12 (m, OH), 7.07 - 6.91 (m, OH), 6.55 - 6.42 (m, OH), 5.06 - 4.96 (m, OH), 4.02 (t, J
= 8.3, OH), 3.81 - 3.67 (m, OH), 3.52 (s, OH), 2.15 - 1.82 (m, OH), 1.65 (s, OH), 0.90 - 0.74 (m, 1H).
MS (ESI; M+H) m/z = 948.
methyl [(2S)-l-{(2S)-2-[5-bromo-4-(4-{ l-(4-cyclopropylphenyl)-5-[4-(2-{(2S)-l-[N-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-lH-imidazol-4-yl)phenyl]-lH-pyrrol-2-yl}phenyl)-lH-
imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
To a suspension of the product from Example 139 (47 mg, 0.051 mmol) in CH2C12 (0.5 mL)
was added a mixture of l-bromopyrrolidine-2,5-dione (9.1 mg, 0.051 mmol) in CH2C12 (0.5 mL). The
mixture was stirred overnight at room temperature then concentrated under reduced pressure and
triturated with diethyl ether to provide a mixture of brominated compounds that was subjected to
reverse phase HPLC purification eluted with a gradient of 10-100% CH3CN in 0.1% aqueous
trifluoroacetic acid to afford the tide compound (8 mg, 13% yield). lU NMR (TFA salt) (400 MHz,
DMSO-D6) δ 14.32 (s, 1H), 12.44 (s, 1H), 7.97 (s, 1H), 7.62 - 7.48 (m, 4H), 7.31 (d, J= 8.4, 1H),
7.24 (d, J= 8.5, 1H), 7.18 - 7.08 (m, 4H), 7.09 - 7.00 (m, 4H), 6.61 (d, J = 3.7, 1H), 6.57 (d, J = 3.7,
1H), 5.07 (t, J= 7.0, 1H), 4.98 - 4.91 (m, 1H), 4.08 (t, J= 7.9, 1H), 4.02 (t, J = 8.3, 1H), 3.90 - 3.67
(m, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 2.18 - 1.83 (m, 10H), 1.22 (s, 1H), 1.01 - 0.93 (m, 2H), 0.89 -
0.72 (m, 12H), 0.70 - 0.62 (m, 2H). MS (ESI; M+H) m/z = 1000.
methyl {(2S)-l-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-bromo-2-t(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-(4-
cyclopropylphenyl)-1H-pyrrol-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-
2-yl}carbamate
The title compound was formed as an additional product in Example 140. The mixture of
products was subjected to reverse phase HPLC purification eluted with a gradient of 10-100% CH3CN
in 0.1% aqueous trifluoroacetic acid to afford the title compound (15 mg, 23% yield). 1H NMR (TFA
salt) (400 MHz, DMSO-D6) δ 12.43 (s, 2H), 7.54 (dd, 4H), 7.25 (d, 7 = 8.4, 2H), 7.15 - 7.08 (m, 4H),
7.08 - 7.00 (m, 4H), 6.55 (s, 2H), 4.99 - 4.89 (m, 2H), 4.02 (t, 7= 8.3, 2H), 3.82 - 3.68 (m, 4H), 3.51
(s, 6H), 2.22 - 2.03 (m, 4H), 2.00 - 1.81 (m, 6H), 1.27 - 1.19 (m, 1H), 1.02 - 0.92 (m, 2H), 0.90 -
0.77 (m, 12H), 0.70 - 0.61 (m, 2H). MS (ESI; M+H) m/z = 1078.
memyl{(2S)4-[(2S)-2-(4-{445-(4-{2-[(2S)4-{(2S)-2-[(memoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-(4-tritylphenyl)-lH-pyrrol-2-
yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1-yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 142 A
(S)-4,4'-(4,4'-(l-(4-tritylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l-phenylene))bis(2-((S)-pyrrolidin-2-yl)-
lH-imidazole) tetrakis(2,2,2-trifluoroacetate)
The tide compound was prepared using the methods from Example 139A substituting 4-
tritylaniline for 4-cyclopropylaniline to provide the tide compound.
Example 142B
methyl {(2S)-l-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-bromo-2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl )pyrrolidin-2-yi] - lH-imidazol-4-yl Jphenyl)-1 -(4-
cyclopropylphenyl)-1H-pyrrol-2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-
2-yl}carbamate
The tide compound was prepared using the methods from Example 138D substituting the
product from Example 142A for the product from Example 138C to provide the tide compound (71
mg, 43% yield). lR NMR (400 MHz, DMSO-D6) 8 12.15 - 11.69 (m, 2H), 7.61 - 7.48 (m, 4H), 7.46
- 7.37 (m, 2H), 7.35 - 7.15 (m, 11H), 7.10 - 6.91 (m, 14H), 6.55 - 6.44 (m, 2H), 5.11 - 5.00 (m, 2H),
4.03 (t, J= 8.5, 2H), 3.86 - 3.70 (m, 4H), 3.52 (s, 6H), 2.21 - 1.83 (m, 10H), 0.92 - 0.76 (m, 12H).
MS(ESI;M+H)m/z=1123.
methyl {(2S)-l-[(2S)-2-(5-bromo-4-{4-[4-bromo-5-(4-{5-bromo-2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -lH-imidazol-4-yl Jphenyl)-1 -(4-
cyclohexylphenyl)- lH-pyrrol-2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-
2-yl} carbamate
To a suspension of the product from Example 74 (100 mg, 0.10 mmol) in CH2C12 (1.0 mL) at
-78 °C was added a mixture of l-bromopyrrolidine-2,5-dione (59 mg, 0.33 mmol) in CH2C12 (1.0
mL). The mixture was stirred for 3 hours, warming to room temperature then concentrated under
reduced pressure and triturated with diethyl ether to provide the title compound (103 mg, 83% yield).
1H NMR (400 MHz, DMSO-D6) δ 12.47 (s, 1H), 11.02 (s, 1H), 7.54 (d, J= 26.1, 4H), 7.29-6.98 (m,
10H), 6.71 (s, 1H), 5.01 - 4.90 (m, 2H), 4.02 (t, J = 8.1, 2H), 3.86 - 3.67 (m, 4H), 3.52 (s, 6H), 2.18 -
1.58 (m, 16H), 1.35 - 1.20 (m, 5H), 0.90 - 0.76 (m, 12H). MS (ESI; M+H) m/z = 1200.
methyl [(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH4midazol-4-yl}phenyl)-l-[6-(piperidin-l-yl)pyridin-3-yl]-lH-
pyrrol-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 144 A
5-nitro-2-(piperidin-1 -yl)pyridine
To a slurry of 2-chloro-5-nitropyridine (100 g, 632 mmol) in ethanol (2000 mL) at room
temperature was added piperidine (206 mL, 2.08 mol) and the mixture heated to 60 °C for 30 minutes.
The cooled mixture was concentrated and the residue taken up in CH2C12 then washed with saturated
NaHCO3 and brine. The mixture was dried (Na2SO4), filtered, and concentrated to provide the tide
compound as a yellow solid (130.4g, 99% yield). 1H NMR (400 MHz, DMSO-D6) δ 8.94 (d, J= 2.9,
1H), 8.17 (dd, J = 9.6, 2.9, 1H), 6.93 (d, 7 = 9.6, 1H), 3.79 - 3.73 (m, 4H), 1.69 - 1.64 (m, 2H), 1.61 -
1.51 (m,4H).
Example 144B
tert-butyl 6-(piperidin-1 -yl)pyridin-3-ylcarbamate
To a solution of the product from Example 144A (130.4g, 629 mmol) and di-fert-butyl
dicarbonate (165g, 755 mmol) in ethanol (750 mL) was added Pt02 (5.4g, 24 mmol). The mixture
was pressurized at 40 psi with H2 and stirred overnight at room temperature. To ensure complete
reaction additional Pt02 (3.2g, 14 mmol) was added and the pressurized mixture was heated to 50 °C
for 1Hour. The mixture was then filtered, concentrated under reduced pressure and absorbed onto
silicagel and placed on top of a 4 to 5" plug of silica in a 3000 mL sintered glass funnel. Material was
eluted with 15% diethyl ether in CH2C12 and the filtrate was concentrated under reduced pressure and
the residue triturated with boiling hexanes. Additional product was recovered upon concentration of
the filtrate, which was then chromatographed on silica gel etuled with 10% diethyl ether in CH2C12.
The appropriate fractions were collected and concentrated then triturated with boiling hexanes. The
two lots of lavender solids were combined to provide the title compound (100g, 57% yield). :H NMR
(400 MHz, DMSO) δ 9.02 (bs, 1H), 8.11 (s, 1H), 7.63 - 7.54 (m, 1H), 6.74 (d, J= 9.1, 1H), 3.42 -
3.37 (m, 4H), 1.57 - 1.49 (m, 6H), 1.45 (9, 1H).
Example 144C
6-(piperidin-1 -yl)pyridin-3 -amine dihydrochloride
The product from Example 144B (1.00 g, 3.62 mmol) was added slowly to 4 M hydrochloric
acid (10 mL, 40 mmol) and stirred at room temperature. After stirring overnight, ether was added and
the solid filtered. Dried in vacuum oven to a white solid (0.817 g; 84%). 1H NMR (400 MHz,
methanol-d4) 8 1.77 (s, 6H), 3.65 (s, 4H), 7.41 (d, J=9.8 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.79 (dd,
J=2.7, 9.8 Hz, 1H).
Example 144D
5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)-lH-pyrrol-l-yl)-2-(piperidin-l-
yl)pyridine
To a solution of the product from Example 138B (0.20 g, 0.28 mmol) and the product from
Example 144C (0.11 g, 0.42 mmol) in toluene (2.8 mL) was added TFA (22 \iL, 0.28 mmol). The
mixture was stirred at 110 °C for 3 hours. To the cooled mixture was added TFA (0.5 mL) and the
mixture was stirred for 1H at rt. The solvent was then removed under reduced pressure and triturated
with diethylether and dried to provide 0.31 g of the desired compound as a TFA salt. 1HNMR
(DMSO-d6; 400 MHz): 5 9.78 (br s, 2H), 7.84 (d, J=2.71Hz, 1H), 7.75 (s, 2H), 7.67 (AA'XX', J=8.34
Hz, 4H), 7.35 (dd, J=9.11, 2.71Hz, 1H), 7.18 (AA'XX', J=8.46 Hz, 4H), 6.79 (d, J=9.11Hz, 1H),
6.53 (s, 2H), 4.79 (app t, J=7.81Hz, 2H), 3.4-3.2 (m, 4H), 2.44-2.36 (m, 2H), 2.25-1.98 (m, 6H),
1.65-1.45 (m,6H).
Example 144E
me%l[(2S)-l-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(memoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -lH-imidazol-4-yl }phenyl)-l -[6-(piperidin-1 -yl)pyridin-3-yl] -1H-
pyrrol-2-yl }phenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl} -3 -methyl-1 -oxobutan-2-yl]carbamate
To a solution of Nl-((ethyUmino)methylene)-N3,N3-dimethylpropane-l,3-diamine
hydrochloride (0.17 g, 0.89 mmol), lH-benzo[d][l,2,3]triazol-l-ol hydrate (0.14 g, 0.89 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (0.16 g, 0.89 mmol) in DMF (1.0 mL) was added 4-
methylmorpholme (0.3 mL, 2.7 mmol). This mixture was stirred at room temperature for 15 minutes
and then added to a solution of the product from Example 144D (0.31 g, 0.25 mmol) and 4-
methylmorpholine (0.2 mL, 1.8 mmol) in DMF (0.7 mL). After stirring 4 h, water was added to this
mixture and the solid collected by filtration then washed with water and diethylether. The residue was
purified on silica gel eluted with 60% THF/Hexanes to provide 100 mg of the title compound. :H
NMR (400 MHz, DMSO) δ 12.17 - 11.70 (m, 2H), 7.84 - 7.76 (m, 1H), 7.64 - 7.50 (m, 4H), 7.49 -
7.40 (m, 2H), 7.31 - 7.02 (m, 7H), 6.76 - 6.69 (m, 1H), 6.52 - 6.41 (m, 2H), 5.09 - 5.01 (m, 2H),
4.04 (t, J= 8.3, 2H), 3.83 - 3.71 (m, 4H), 3.53 (s, 6H), 3.50 - 3.44 (m, 4H), 2.18 - 2.04 (m, 4H), 2.03
- 1.86 (m, 6H), 1.61 - 1.46 (m, 6H), 0.90 - 0.79 (m, 12H). MS (ESI; M+H) m/z = 965.
methyl {(2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-{4-[(trifluoromethyl)sulfanyl]phenyl}-
lH-pyrrol-2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 138B and 4-(trifluoromethylthio)aniline were processed using the methods of
Examples 139A and 138D to provide the title compound (19 mg). 1H NMR (400 MHz, DMSO-D6) δ 12.18 - 11.65 (m, 2H), 7.73 - 7.63 (m, 2H), 7.60 - 7.48 (m, 4H), 7.45 - 7.39 (m, 2H), 7.31 - 7.15 (m,
4H), 7.06 - 6.92 (m, 4H), 6.58 - 6.46 (m, 2H), 5.08 - 5.00 (m, 2H), 4.03 (t, J = 8.4, 2H), 3.85 - 3.69
(m, 4H), 3.53 (s, 6H), 2.23 - 1.79 (m, 10H), 0.93 - 0.77 (m, 12H). MS (ESI; M+H) m/z = 981.
methyl {(2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-(2-methyl-l,3-benzothiazol-5-yl)-lH-
pyrrol-2-yl] phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 138B and 2-methylbenzo[d]thiazol-5-amine dihydrochloride were processed using
the methods of Examples 139A and 138D to provide the tide compound (19 mg). JH NMR (400
MHz, DMSO-D6) δ 12.04 - 11.63 (m, 2H), 8.02 - 6.85 (m, 15H), 6.58 - 6.45 (m, 2H), 5.07 - 4.96
(m, 2H), 4.02 (t, J = 8.4, 2H), 3.86 - 3.67 (m, 4H), 3.53 (s, 6H), 2.75 (s, 3H), 2.21 - 1.78 (m, 10H),
0.93 - 0.76 (m, 12H). MS (ESI; M+H) m/z = 952.
diethyl (4-{2,5-bis[4-(2-{(2S)-l-tN-(methoxycarbonyl)-L-valyl]pyrroUdin-2-yl}-lH-imidazol-4-
yl)phenyl]- lH-pyrrol-1 -yl }benzyl)phosphonate
Example 138B and diethyl 4-aminobenzylphosphonate were processed using the methods of
Examples 139A and 138D to provide the title compound. 1H NMR (400 MHz, DMSO-D6) δ 12.19 -
11.63 (m, 2H), 7.56 - 7.44 (m, 4H), 7.42 - 7.34 (m, 2H), 7.32 - 7.10 (m, 4H), 7.10 - 6.91 (m, 6H),
6.53 - 6.40 (m, 2H), 5.10 - 4.98 (m, 2H), 4.03 (t, J= 8.4, 2H), 3.91 - 3.67 (m, 8H), 3.53 (s, 6H), 3.23
(d, J= 21.8, 2H), 2.22 - 1.80 (m, 10H), 1.15 - 1.04 (m, 6H), 0.92 - 0.77 (m, 12H). MS (ESI; M+H)
m/z=1031.
methyl {(2S)-l-[(2S)-2-(4-{4-[l-(lH-indazol-6-yl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)armno]-3-memylbutanoyl}pyrrolidm-2-yl]-lH-imidazol-4-yl}phenyl)-lH-pyrrol-
2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-l-oxobutan-2-yl Jcarbamate
Example 138B and lH-indazol-6-amine were processed using the methods of Examples 139A
and 138D to provide the tide compound (24 mg). 2H NMR (400 MHz, DMSO-D6) δ 13.08 - 12.99
(m, 1H), 12.05 - 11.62 (m, 2H), 8.13 - 8.04 (m, 1H), 7.74 - 7.66 (m, 1H), 7.54 - 7.42 (m, 4H), 7.41 -
7.34 (m, 2H), 7.31 - 7.09 (m, 3H), 7.05 - 6.77 (m, 5H), 6.58 - 6.47 (m, 2H), 5.06 - 4.97 (m, 2H),
4.02 (t, J = 8.4, 2H), 3.83 - 3.66 (m, 4H), 3.53 (s, 6H), 2.20 - 1.78 (m, 10H), 0.89 - 0.76 (m, 12H).
MS(ESI;M+H)m/z = 921.
methyl [(2S)-l-{(2S)-2-[4-(4-{l-[3-fluoro-4-(piperidin-l-yl)phenyl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl Jphenyl)-1H-pyrrol-
2-yl} phenyl)-1H-imidazol-2-yl]pyrrolidm-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 138B and 3-fluoro-4-(piperidin-l-yl)aniline were processed using the methods of
Examples 139A and 138D to provide the title compound. !H NMR (400 MHz, DMSO-D6) δ 12.15 -
11.69 (m, 2H), 7.62 - 7.49 (m, 4H), 7.48 - 7.39 (m, 2H), 7.32 - 7.15 (m, 2H), 7.12 - 6.77 (m, 7H),
6.52 - 6.42 (m, 2H), 5.08 - 4.99 (m, 2H), 4.04 (t, J= 8.4, 2H), 3.84 - 3.70 (m, 4H), 3.53 (s, 6H), 3.01
- 2.89 (m, 4H), 2.19 - 1.82 (m, 10H), 1.68 - 1.43 (m, 6H), 0.92 - 0.75 (m, 12H). MS (ESI; M+H)
m/z = 982.
methyl t(2S)-l-{(2S)-2-[4-(4-{l-[4-(hexyloxy)phenyl]-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-pyrrol-
2-yl} phenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
Example 138B and 4-(hexyloxy)aniline were processed using the methods of Examples 139A
and 138D to provide the tide compound (15 mg). 1H NMR (400 MHz, DMSO-D6) δ 12.12 - 11.67
(m, 2H), 7.59 - 7.48 (m, 4H), 7.45 - 7.39 (m, 2H), 7.30 - 7.13 (m, 2H), 7.08 - 6.96 (m, 6H), 6.90 -
6.83 (m, 2H), 6.52 - 6.42 (m, 2H), 5.07 - 5.01 (m, 2H), 4.04 (t, J = 8.5, 2H), 3.92 (t, J= 6.4, 2H),
3.83 - 3.70 (m, 4H), 3.53 (s, 6H), 2.19 - 1.83 (m, 10H), 1.73 - 1.63 (m, 2H), 1.45 - 1.21 (m, 6H),
0.92 - 0.77 (m, 15H). MS (ESI; M+H) m/z = 981.
diethyl (4-{3-tert-butyl-2,5-bis[4-(2-{(2S)-1 -[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}- 1H-
imidazol-4-yl)phenyl] - lH-pyrrol-1 -yl }benzyl)phosphonate
The title compound was formed as an additional product from Example 147. The mixture of
products was purified by chromatography on silica gel eluted with a solvent gradient of 0-5%
methanol in CH2C12 to provide the title compound. 1H NMR (400 MHz, DMSO-D6) δ 11.68 (d, J =
13.5, 2H), 7.55 - 7.39 (m, 5H), 7.37 - 7.23 (m, 3H), 7.21 - 6.90 (m, 8H), 6.43 (s, 1H), 5.07 - 4.99 (m,
2H), 4.06 - 3.97 (m, 2H), 3.83 - 3.58 (m, 8H), 3.53 (s, 6H), 3.07 (d, J= 21.5, 2H), 2.20 - 1.81 (m,
10H), 1.15 (s, 9H), 0.98 (t, J= 7.0,6H), 0.90-0.78 (m, 12H). MS (ESI; M+H) m/z= 1087.
Example 152
methyl [(2S)-l-{(2S)-2-[4-(4-{l-[4-(2,2-dichloro-l-methylcyclopropyl)phenyl]-5-(4-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)arruno]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-
1H-pyrrol-2-yl Jphenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -oxobutan-2-yl] carbamate
Example 138B and 4-(2,2-dichloro-l-methylcyclopropyl)aniline were processed using the
methods of Examples 139A and 138D to provide the title compound (36 mg). :H NMR (400 MHz,
DMSO-D6) δ 12.18 - 11.68 (m, 2H), 7.55 - 7.42 (m, 4H), 7.41 - 7.22 (m, 6H), 7.17 - 6.90 (m, 6H),
6.57 - 6.44 (m, 2H), 5.08 - 5.00 (m, 2H), 4.03 (t, J= 8.3, 2H), 3.86 - 3.69 (m, 4H), 3.53 (s, 6H), 2.22
(t, J = 8.5, 1H), 2.18 - 1.81 (m, 10H), 1.79 - 1.72 (m, 1H), 1.65 (s, 3H), 0.92 - 0.77 (m, 12H). MS
(ESI; M+H) m/z = 1003.
Example 153
methyl [(2S)-l-{(2S)-2-[4-(4-{l-[4-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-5-(4-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] - lH-imidazol-4-
yl }phenyl)- lH-pyrrol-2-yl }phenyl)-lH-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-l -oxobutan-2-
yl] carbamate
Example 138B and 2-(4-aminophenyl)-l,l,l,3,3,3-hexafluoropropan-2-ol were processed
using the methods of Examples 139A and 138D to provide the title compound (45 mg). :H NMR
(400 MHz, DMSO-D6) δ 12.08 - 11.71 (m, 2H), 8.80 (s, 1H), 8.01 - 7.37 (m, 8H), 7.33 - 7.13 (m,
4H), 7.06 - 6.89 (m, 4H), 6.57 - 6.47 (m, 2H), 5.03 (d, J= 6.8, 2H), 4.03 (t, J = 8.4, 2H), 3.77 (d, J =
6.2, 4H), 3.53 (s, 6H), 2.21 - 1.80 (m, 10H), 0.92 - 0.76 (m, 12H). MS (ESI; M+H) m/z = 1047.
Example 154 methyl [(2S)-l-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-iniidazol-4-yl}phenyl)-l-[6-(morpholin-4-yl)pyridin-3-yl]-lH-
pyrrol-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 154A
4-(5-nitropyridin-2-yl)morpholine
The title compound was prepared using the methods from Example 144A substituting
morpholine for piperidine to provide the title compound.
Example 154B
6-morpholinopyridin-3-amine
To a solution of the product from Example 154A (12.5, 59.5 mmol) in THF (150 mL) was
added to Ra-Ni 2800, water slurry (12.5 g, 212 mmol) in a 500 mL SS pressure bottle. The mixture
was pressurizied (H2, 30 psi) and stirred for 2 hours at room temperature. The mixture was filtered
and then concentrated under reduced pressure to provide the title compound.
Example 154C
methyl [(2S)-l-{(2S)-2-[4-(4-{5-(4-{2-t(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-[6-(rnorpholin-4-yl)pyridin-3-yl]-lH-
pyrrol-2-yl}phenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-l -oxobutan-2-yl]carbamate
Example 138B and Example 154B were processed using the methods of Examples 139A and
138D to provide the title compound. 2H NMR (400 MHz, DMSO-D6) δ 12.16 - 11.69 (m, 2H), 7.89
- 7.80 (m, 1H), 7.63 - 7.50 (m, 4H), 7.50 - 7.40 (m, 2H), 7.39 - 7.02 (m, 7H), 6.80 - 6.71 (m, 1H),
6.52 - 6.41 (m, 2H), 5.10 - 5.00 (m, 2H), 4.04 (t, J = 8.7, 2H), 3.85 - 3.72 (m, 4H), 3.69 - 3.59 (m,
4H), 3.53 (s, 6H), 3.45 - 3.37 (m, 4H), 2.20 - 1.82 (m, 10H), 0.94 - 0.77 (m, 12H). MS (ESI; M+H)
m/z = 967.
Example 155
methyl {(2S)-1 -[(2S)-2-(4-{4-[ 1 -{6-tbis(2-methoxyethyl)amino]pyridin-3-yl}-5-(4-{2-[(2S)-1-{(2S)-
2-[(memoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-
pyrrol-2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 155 A
N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine
The title compound was prepared using the methods from Example 144A substituting bis(2-
methoxyethy 1)amine for piperidine to provide the title compound.
Example 155B
N2,N2-bis(2-methoxyethyl)pyridine-2,5 -diamine
Example 155A was processed using the methods of Example 154B to provide the title
compound.
Example 155C
methyl {(2S)-1 -[(2S)-2-(4-{4-[ 1 -{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-5-(4-{2-[(2S)-1 -{(2S)-
2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-
pyrrol-2-yl] phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 138B and Example 155B were processed using the methods of Examples 139A and
138D to provide the title compound.1H NMR (400 MHz, DMSO-D6) δ 12.17 - 11.67 (m, 2H), 7.86
- 7.77 (m, 1H), 7.63 - 7.49 (m, 4H), 7.49 - 7.38 (m, 2H), 7.34 - 7.20 (m, 3H), 7.20 - 7.03 (m, 4H),
6.64 - 6.56 (m, 1H), 6.52 - 6.40 (m, 2H), 5.09 - 5.00 (m, 2H), 4.04 (t, J = 8.2, 2H), 3.84 - 3.69 (m,
4H), 3.65 - 3.57 (m, 4H), 3.53 (s, 6H), 3.47 - 3.40 (m, 4H), 3.21 (s, 6H), 2.20 - 1.84 (m, 10H), 0.84
(m, 12H). MS (ESI; M+H) m/z = 1013.
Example 156
methyl {(2S)-1 -[(2S)-2-(4-{4-[ 1 -(2-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-lH-pyrrol-
2-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
Example 138B and 2-tert-butylaniline were processed using the methods of Examples 139A
and 138D to provide the title compound (10 mg). 1H NMR (400 MHz, DMSO-D6) δ 12.07 - 11.64
(m, 2H), 7.61 - 7.11 (m, 12H), 7.06 - 6.93 (m, 4H), 6.65 - 6.49 (m, 2H), 5.08 - 4.97 (m, 2H), 4.04 (t,
j = 7.2, 2H), 3.82 - 3.69 (m, 4H), 3.53 (s, 6H), 2.17-1.83 (m, 10H), 0.92 - 0.77 (m, 21H). MS (ESI;
M+H) m/z = 937.
Example 157
methyl [(2S)-l-{(2S)-2-[4-(4-{l-[4-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-5-(4-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl]- lH-imidazol-4-yl Jphenyl)-
lH-pyrrol-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 138B and 4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline were processed using the
methods of Examples 139A and 138D to provide the title compound (156 mg).1H NMR (400 MHz,
DMSO-D6) δ 12.06 - 11.65 (m, 2H), 7.59 - 7.46 (m, 4H), 7.44 - 7.36 (m, 2H), 7.30 - 7.13 (m, 2H),
7.09 - 6.96 (m, 4H), 6.90 (p, 4H), 6.53 - 6.39 (m, 2H), 5.08 - 4.98 (m, 2H), 4.04 (t, J = 8.4, 2H), 3.90
(s, 4H), 3.86 - 3.71 (m, 4H), 3.53 (s, 6H), 3.29 - 3.20 (m, 4H), 2.19 - 1.83 (m, 10H), 1.73 - 1.64 (m,
4H), 0.93 - 0.77 (m, 12H). MS (ESI; M+H) m/z = 1022.
Example 158
dimethyl ([ 1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis {benzene-4,1 -
diylmethanediylcarbamoyl(2S)pyrroUdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-
diyl] })biscarbamate
Example 15 8 A
4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile
A solution of Example 42C (2.0 g, 3.9 mmol) and copper(I) cyanide (1.047 g, 11.69 mmol) in
DMF (19 mL) was heated in a microwave for 7 hours at 160 °C. Afterwards the mixture was poured
in water (700 mL) and then concentrated ammonium hydroxide (40 mL) was added and the solution
extracted with EtOAc. The organic extract was dried, filtered, concentrated and the residue purified
by flash chromatography (silica gel, EtOAc/hexanes) to afford 1.23 g (78%) of the title compound.
MS (ESI) m/z 406 (M+H)+.
Example 158B
4,4'-(l-(44ert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene)dimemanamine
To a solution of Example 158A (0.63 g, 1.554 mmol) in THF (21 mL) was added lithium
aluminum hydride (0.236 g, 6.21 mmol) then stirred at room temperature for 20 minutes and at 70 °C
for 1Hour. The mixture was then cooled in an ice bath and a solution of saturated aqueous
ammonium chloride was added followed by extraction with EtOAc and the organic layer extracted
with Rochelle's solution. The organic solution was then dried, filtered and concentrated to give the
title compound. MS (ESI) m/z 414 (M+H)+.
Example 158C
dimethyl ([l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylmethanediylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-
diyl] })biscarbamate
The product from Example 158B (45 mg, 0.109 mmol), the product from Example 37B (62.2
mg, 0.228 mmol) and HATU (91 mg, 0.239 mmol) in DMSO (3 mL) was added Hunig's base (0.095
mL, 0.544 mmol), and the reaction mixture was stirred at room temperature for 1Hr. The reaction
mixture was partitioned between water and dichloromethane, and the organic layer was dried over
MgS04, filtered and concentrated. Purification by flash chromatography (silica gel, 0-10%
methanol/dichloromethane) afforded 55 mg (55%) of the title compound as a mixture of
stereoisomers. 1H NMR (400 MHz, DMSO-D6) 8 ppm 8.11 (m, 2 H), 7.08 (s, 2 H), 6.95 (m, 8 H),
6.74 (d, 7=8.8 Hz, 2 H), 5.97 (d, J=8.7 Hz, 2 H), 5.01 (m, 2H), 4.15 (m, 4H), 4.05 (m, 4 H), 3.80 (m,
2 H), 3.31 (s, 6 H), 2.40 (m, 2 H), 1.90 (m, 2 H), 1.85 (m, 4 H), 1.80 (m, 4 H), 0.95 (s, 9 H), 0.70 (m,
2H), 0.65 (m, 12 H); MS (ESI) m/z 923 (M+H)+.
Example 159
methyl {(2S)-1-[(2S)-2-(4-{4-t(3S,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol4-
yl}phenyl)tMomorpholin-3-yl]phenyl}4H-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl} carbamate
Example 159A
2,2'-thiobis(l-(4-bromophenyl)ethanone)
A solution of 2-bromo-l-(4-bromophenyl)ethanone (27.8 g, 100 mmol) was dissolved in
acetone, the solution was cooled in an ice bath then sodium sulfide nonahydrate (12.01 g, 50 mmol)
dissolved in water (100 mL) was added dropwise over 45 minutes time. The resultant solution was
stirred an additional 2 hours at room temperature, the solid formed in the reaction was collected and
then washed with water then ethanol and dried in a vacuum oven to provide 18.5 g (43%) of the title
compound.
Example 159B
2,2'-thiobis( 1 -(4-bromophenyl)ethanol)
To a solution of Example 159A (5.0 g, 11.68 mmol) in ethanol (78 mL) was added sodium
borohydride (0.972 g, 25.7 mmol) portionwise and the mixture was stirred at room temperature for 20
minutes. Afterwards the solution was concentrated, then a solution of IN aqueous hydrochloric acid
(100 mL) was added and extracted with EtOAc. The organic extract was dried, filtered and
concentrated to 5.05 g (100%) of a colorless solid as the title compound.
Example 159C
N,N'-(2,2'-thiobis(l-(4-bromophenyl)ethane-2,l-diyl))bis(4-tert-butylaniline)
To a solution of Example 159B (5.05 g, 11.68 mmol) in THF (145 mL) and dichloromethane
(145 mL) was added triethylamine (4.86 mL, 35.1 mmol) and the mixture cooled in an ice bath. To
this solution was added methanesulfonyl chloride (2.276 mL, 29.2 mmol) dropwise followed by
stirring at 0 °C for an additional 30 minutes followed by concentration at room temperature to a
residue. The resultant residue was dissolved in DMF (39 mL) followed by the addition of 4-tert-
butylaniline (18.62 mL, 117 mmol) and the mixture heated at 50 °C for 5 hours. Afterwards IN
aqueous hydrochloric acid was added followed by extraction with EtOAc. The organic extract was
dried, filtered and concentrated. Purification by flash chromatography (silica gel, 0-30%
EtOAc/hexanes) afforded 2.67g (42%) of the title compound.
Example 159D
3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)thiomorpholine
To a solution of Example 159C (350 mg, 0.504 mmol) in toluene (5 mL) was added silica gel
(1.0 g) that had been dehydrated by heating at 180°C in a vacuum oven for 3 hours, and
trifluoromethanesulfonic acid (0.045 mL, 0.504 mmol) and heated at 100°C for 3 hours. After
cooling to ambient temperature, dichloromethane was added and the silica gel was removed by
filtration and the solution extracted with half-saturated aqueous sodium bicarbonate solution. The
organic extract was dried, filtered and concentrated to afford 220 mg (80%) of the title compound as a
mixture of isomers. MS (ESI) m/z 546 (M+H)+.
Example 159E
4-(4-tert-butylphenyl)-3,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine
The product of Example 159D (200 mg, 0.367 mmol) was processed using the method
described in Example 42D to provide 105 mg (45%) of the title compound as a mixture of isomers.
MS (ESI) m/z 640 (M+H)+.
Example 159F
(2S,2'S)-tert-butyl2,2'-(4,4'-(4,4,-(4-(4-tert-butylphenyl)thiomorpholine-3,5-diyl)bis(4,l-
phenylene))bis(lH-imidazole-4,2-diyl))dipyrrolidine-l-carboxylate
The product of Example 159E (190 mg, 0.297 mmol) and the product from Example 26D
(282 mg, 0.891 mmol) were processed using the method described in Example 42E to provide 110 mg
(43%) of the title compound as a mixture of isomers. MS (ESI) m/z 859 (M+H)+.
Example 159G
4-(4-tert-butylphenyl)-3,5-bis(4-(2-((S)-pyrrolidm-2-yl)-lH-imidazol-4-yl)phenyl)thiomorpholine
To the product of Example 159F (110 mg, 0.128 mmol) was added dimethoxyethane (5 mL)
and a solution of 4N hydrochloric acid in dioxane (5 mL) and the resultant solution stirred at room
temperature for 1Hr. The solvent was then removed under vacuum and the resultant residue was
diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18),
eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 12 mg (14%) of the tide compound
as a mixture of stereoisomers. MS (ESI) m/z 658 (M+H)+.
Example 159H
methyl {(2S)-1-[(2S)-2-(4-{4-[(3S,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1 -{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl}phenyl)tMomorphoUn-3-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yljcarbamate
The product from Example 159G (10 mg, 0.015 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (5.86 mg, 0.033 mmol) and HATU (12.71 mg, 0.033 mmol) in DMSO (0.5 mL)
was added Hunig's base (0.013 mL, 0.076 mmol), and the reaction mixture was stirred at room
temperature for 1.5 hr. The reaction mixture was partitioned between water and dichloromethane, and
the organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was
redissolved in methanol (5 mL) then added potassium carbonate (50 mg) then stirred at room
temperature for 20 minutes, the solids removed by filtration, the filtrate concentrated and purified by
chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 7 mg (47%) of the title
compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.65 (m, 2 H), 7.47 (m, 2 H), 7.32 (m, 4 H),
7.23 (m, 4H), 6.85 (m, 4 H), 5.02 (m, 2 H), 4.38 (m, 2H), 4.02 (m, 2 H), 3.75 (m, 4 H), 3.52 (s, 6 H),
3.10 (m, 2 H), 2.66 (m, 2 H), 2.08 (m, 4 H), 1.91 (m, 4 H), 0.97 (s, 9 H), 0.82 (m, 12 H); MS (ESI)
m/z 973 (M+H)+.
methyl {(25)-l-[(215)-2-(4-{4-[(35,5lS)4-(4-tert-butylphenyl)-5-(4-{2-[(21S0-l-{(25)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lif-imidazol-4-
yl }phenyl)ttaomorpholin-3-yl]phenyl} -lH-imidazol-2-yl)pyrrolidin-1 -yl]-3-methyl-l -oxobutan-2-
yl}carbamate
and
methyl {(25)-l-[(25)-2-(4-{4-[(3fl,5/?)-4-(4-terf-butylphenyl)-5-(4-{2-[(2S)-1-{(25)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-
yl }phenyl)thiomorpholin-3-yl]phenyl} -lif-imidazol-2-yl)pyrrolidin-1 -yl]-3-methyl-l -oxobutan-2-
yl}carbamate
The product from Example 159E (100 mg, 0.156 mmol), the product from Example 126G
(146 mg, 0.391 mmol), and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane adduct (25.5 mg, 0.031 mmol) in a mixture of toluene (3 mL), ethanol (3 mL) and a
IN aq. sodium bicarbonate solution (0.469 mL, 4.69 mmol) and bubbled nitrogen gas through the
solution for 10 min, then heated at 80 °C for 18 h. Solution was cooled to room temperature and
water (20 mL) added then extracted with dichloromethane (50 mL), then dried, concentrated and the
residue purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water
(0.1% TFA) to afford 8.5 mg (6%) of the tide compound as a mixture of stereoisomers. 1H NMR
(free base) (400 MHz, DMSO-D6) δ ppm 11.70 (bs, 2 H), 7.64 (m, 4 H), 7.45 (m, 2 H), 7.37 (m, 4H),
7.28 (m, 2 H), 7.01 (m, 2 H), 6.46 (d, 7=8.7 Hz, 2 H), 5.38 (m, 2 H), 5.07 (m, 2H), 4.03 (m, 2 H), 3.52
(s, 6 H), 3.10 (m, 2 H), 2.12 (m, 4 H), 1.91 (m, 4 H), 1.12 (s, 9 H), 0.86 (m, 12 H); MS (ESI) m/z 973
(M+H)+.
Example 161
methyl {(2S)-l-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl] - lH-imidazol-4-yl}phenyl)-1,1 -
dioxidothiomorpholin-3-yl]phenyl}- lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-
yljcarbamate
Example 161A
3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)thiomorpholine 1,1-dioxide (ACD vl2)
A solution of Example 159D (850 mg, 1.56 mmol) in mixture of acetone (15 mL), water (5
mL) and THF (5 mL) was added a solution of osmium tetroxide (2.5% in tert-butanol, 0.587 mL,
0.047 mmol) and the mixture was stirred at room temperature for 1.5 hr. The solution was then
diluted with water and extracted with EtOAc, the organic extract dried, filtered and concentrated to
afford 900 mg (100%) of the title compound. MS (ESI) m/z 578 (M+H)+.
Example 16 IB
methyl {(2S)-1 -[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l,l-
dioxidomiomorpholin-3-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yljcarbamate
Example 161A was processed using sequentially the methods of Examples 42D, 42E, 159G,
and 159H to provide the title compound as a mixture of trans stereoisomers. 1H NMR (400 MHz,
DMSO-D6) δ ppm 11.73 (bs, 2 H), 7.64 (m, 4 H), 7.55 (m, 2 H), 7.44 (m, 4H), 7.24 (m, 2 H), 7.04
(m, 2 H), 6.60 (m, 2 H), 5.48 (m, 2 H), 5.06 (m, 2H), 4.04 (m, 2 H), 3.78 (m, 6 H), 3.52 (s, 6 H), 2.11
(m, 4 H), 1.92 (m, 6 H), 1.13 (s, 9 H), 0.92 (m, 12 H); MS (ESI) m/z 1005 (M+H)+.
Example 162
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R)-l-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)aimno]-3-memylbutanoyl}pyrrolidm-2-yl]-lH4midazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
The product from Example 95B was purified by chiral chromatography on a Chiralpak IB
column eluting with a mixture of hexane/THF/methanol (85/10/5). The title compound was the first
of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.33 - 0.43 (m, 2 H) 0.65 -
0.72 (m, 2 H) 0.79 - 0.91 (m, 12 H) 1.56 -1.64 (m, 1H) 1.66 -1.72 (m, 2 H) 1.84 - 2.03 (m, 6 H) 2.06
- 2.19 (m, 4 H) 3.53 (s, 6 H) 3.73 - 3.84 (m, 4 H) 4.04 (t, J=8.35 Hz, 2 H) 5.06 (dd, J=6.89, 3.09 Hz, 2
H) 5.14 - 5.23 (m, 2 H) 6.19 (d, J=8.67 Hz, 2 H) 6.60 - 6.67 (m, 2 H) 7.09 - 7.31 (m, 6 H) 7.34 - 7.68
(m, 6 H) 11.62 -12.11 (m, 2 H); MS (ESI+) m/z 924.6 (M+H).
Example 163
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-cyclopropylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arruno]-3-memylbutanoyl}pyn-olidin-2-yl]4H-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 109C and 4-cyclopropylaniline were processed using sequentially the methods of
Examples 113A (cyclization reaction conducted at room temperature overnight), 113B, 113C, 281
(reaction conducted at 50 °C for 3 hours), 28J, and 66E to provide the tide compound (122 mg) as a
solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.32 - 0.39 (m, 2 H) 0.63-0.69 (m, 2 H) 0.77 - 0.90 (m,
12 H) 1.53 -1.61 (m, 1H) 1.66 - 1.74 (m, 2 H) 1.86 - 2.04 (m, 8 H) 2.14 - 2.23 (m, 4 H) 3.54 (s, 6 H)
3.78 - 3.87 (m, 4 H) 4.00 - 4.07 (m, 2 H) 5.10 - 5.18 (m, 2 H) 5.31 - 5.39 (m, 2 H) 6.22 (d, J=8.67 Hz,
2 H) 6.57 - 6.65 (m, 2 H) 7.00 - 7.07 (m, 2 H) 7.16 - 7.32 (m, 4 H) 7.36 (d, J=8.13 Hz, 1H) 7.44 (d,
J=8.24 Hz, 1H) 11.97 - 12.27 (m, 2 H); MS (ESI+) m/z 872.5 (M+H)+.
Example 164
methyl {(2S)-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -1 - [4-(morpholin-4-yl)phenyl]pyrrolidin-2-
yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 109C and 4-morpholinoaniline were processed using sequentially the
methods of Examples 113A (cyclization reaction conducted at room temperature overnight), 113B,
113C, 281 (reaction conducted at 50 °C for 2 hours), 28J, and 28K to provide the title compound (100
mg) as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.76 - 0.91 (m, 12 H) 1.66 - 1.72 (m, 2 H)
1.87 - 2.03 (m, 8 H) 2.15 - 2.22 (m, 4 H) 2.72 - 2.78 (m, 4 H) 3.53 (s, 6 H) 3.57 - 3.62 (m, 4 H) 3.78 -
3.86 (m, 4 H) 4.00 - 4.12 (m, 2 H) 5.09 - 5.18 (m, 2 H) 5.30 - 5.37 (m, 2 H) 6.25 (d, J=8.78 Hz, 2 H)
6.52 - 6.59 (m, 2 H) 7.05 (t, J=7.54 Hz, 2 H) 7.18 - 7.32 (m, 4 H) 7.36 (d, J=8.13 Hz, 1H) 7.44 (d,
J=8.24 Hz, 1H) 11.91 -12.28 (m, 2 H); MS (ESI+) m/z 917.5 (M+H)+.
Example 165
dimethyl ([(2R,5R)-l-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-2,5-diyl]bis{(2-
aminobenzene-4,1 -diyl)carbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-
diyl] })biscarbamate
Example 165 A
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-iodophenyl)pyrrolidine
Example 109C (3.34 g, 6.0 mmol) and 4-iodoaniline (7.88 g, 36.0 mmol) were processed
using the method of Example 113A with the reaction allowed to proceed for 4 days at room
temperature to provide the title compound (2.01 g, 57%) as a yellow solid.
Example 165B
4-(5-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)phenyl)pyridin-2-yl)morpholine
The product from 165A (1.869 g, 3.2 mmol), 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)pyridin-2-yl)morpholine (0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol),
tris(dibenzylideneacetone)dipalladium(O) (0.029 g, 0.032 mmol) and l,3,5,7-tetramethyl-6-phenyl-
2,4,8-trioxa-6-phosphaadamante (0.028 g, 0.096 mmol) were combined in THF (18 mL)/water (6
mL). The mixture was purged with nitrogen for 15 minutes and stirred at room temperature for 24
hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate.
The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The
residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (20% to 40%)
to give the tide compound (1.01 g, 51%) as a solid.
Example 165C
dimethyl (2S,2'S)-1,1 '-((2S,2,S)-2,2'-(4,4'-((2R,5R)-1 -(4-(6-morpholinopyridin-3-
yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,l-
phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -oxobutane-2,1 -
diyl)dicarbamate
The product from Example 165B (683 mg, 1.10 mmol), the product from Example 116C (895
mg, 3.30 mmol), cesium carbonate (1004 mg, 3.08 mmol), tris(dibenzylideneacetone)dipalladium(O)
(60.4 mg, 0.066 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (115 mg,
0.198 mmol) were combined in dioxane (15 mL). The mixture was purged with nitrogen for 15
minutes and stirred at 100 °C for 3 hours. The mixture was partitioned between ethyl acetate and
saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate,
filtered and evaporated. The residue was purified by chromatography on silica gel eluting with
methanol/dichloromethane (1% to 3%) to give the title compound (631 mg, 53%) as a solid.
Example 165D
dimethyl ([(2R,5R)-1 - {4-[6-(morpholin-4-yl)pyridin-3-yl] phenyl} pyrrolidine-2,5-diyl] bis {(2-
aminobenzene-4,l-diyl)carbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-
diyl] })biscarbamate
The product from Example 165C (628 mg, 0.576 mmol) and Ra-Ni 2800 (628 mg) were
combined in THF (40 mL). The mixture was hydrogenated at 30psi for 4 hours. The mixture was
filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel
eluting with methanol/dichloromethane (2% to 5%) to give the title compound (590 g, 99%) as a
solid. 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.88 (d, J=6.61Hz, 6 H) 0.91 (d, J=6.72 Hz, 6 H) 1.62
-1.69 (m, 2 H) 1.82 - 2.04 (m, 8 H) 2.10 - 2.20 (m, 2 H) 2.52 - 2.56 (m, 2 H) 3.37 - 3.41 (m, 4 H) 3.52
(s, 6 H) 3.56 - 3.62 (m, 2 H) 3.65 - 3.70 (m, 4 H) 3.78 - 3.85 (m, 2 H) 3.98 - 4.07 (m, 2 H) 4.36 - 4.44
(m, 2 H) 4.87 (s, 4 H) 5.06 (d, J=6.32 Hz, 2 H) 6.36 (d, J=8.78 Hz, 2 H) 6.42 (d, J=8.02 Hz, 2 H) 6.57
(d, J=1.19 Hz, 2 H) 6.78 (d, J=8.89 Hz, 1H) 6.96 (d, J=8.02 Hz, 2 H) 7.23 (d, J=8.78 Hz, 2 H) 7.36
(d, J=8.24 Hz, 2 H) 7.68 (dd, J=8.78, 2.49 Hz, 1H) 8.27 (d, J=2.49 Hz, 1H) 9.24 (s, 2 H); MS (ESI+)
m/z 1030.6 (M+H)+.
Example 166
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl]- lH-benzimidazol-5-yl} -1 -{4-[6-(morpholin-4-yl)pyridin-3-
yl]phenyl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yljcarbamate
The product from Example 165D (520 g, 0.505 mmol) and acetic acid (0.087 mL, 1.514
mmol) were combined in toluene (10 mL). The mixture was stirred at 50 °C for 4 hours. The solvent
was evaporated and the residue was purified by chromatography on silica gel eluting with
methanol/dichloromethane (2% to 5%) to give the title compound (309 mg, 62%) as a solid. 1H NMR
(400 MHz, DMSO-D6) 8 ppm 0.73 - 0.90 (m, 12 H) 1.70 - 1.76 (m, 2 H) 1.84 - 2.05 (m, 8 H) 2.14 -
2.21 (m, 2 H) 2.55 - 2.60 (m, 2 H) 3.34 - 3.39 (m, 4 H) 3.53 (s, 6 H) 3.62 - 3.69 (m, 4 H) 3.75 - 3.87
(m, 4 H) 4.02 - 4.08 (m, 2 H) 5.06 - 5.17 (m, 2 H) 5.40 - 5.47 (m, 2 H) 6.40 (d, J=8.67 Hz, 2 H) 6.75
(d, J=8.89 Hz, 1H) 7.02 - 7.20 (m, 4 H) 7.25 (s, 1H) 7.28 (d, J=8.46 Hz, 2 H) 7.34 (s, 1H) 7.39 (d,
J=8.13 Hz, 1H) 7.47 (d, J=8.24 Hz, 1H) 7.60 (d, J=8.60 Hz,l H) 8.21 (s, 1H) 11.96 -12.11 (m, 2 H);
MS (ESI+) m/z 994.5 (M+H)+.
Example 167
me%l[(2S)-l-{(2S)-2-[5-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-5-yl Jphenyl)-1 - [4-(piperidin-l -yl)phenyl] - lH-pyrrol-2-
yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 26E and 4-piperidinoaniline (Maybridge) were processed using sequentially the
methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the title compound (106 mg). :H
NMR (400 MHz, DMSO-D6) δ 0.83 (d, J=6.73 Hz, 6 H) 0.87 (d, J=6.73 Hz, 6 H) 1.50 - 1.62 (m, 6
H) 1.90 - 2.15 (m, 10 H) 3.13 (m, 4 H) 3.53 (s, 6 H) 3.77 (m, 4 H) 4.04 (m, 2 H) 5.04 (m, 2 H) 6.47
(m, 2 H) 6.80-7.35 (m, 10 H) 7.42 (m, 2 H) 7.53 (m, 4 H) 11.73 (s, 2 H).
Example 168
methyl [(2S)-1 -{(2S)-2-[5-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrroUdin-2-yl]-lH-imidazol-5-yl}phenyl)-l-[4-(rricyclo[3.3.1.13,7~]dec-l-
yl)phenyl]- lH-pyrrol-2-yl Jphenyl)- lH-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl- l-oxobutan-2-
yl]carbamate
Example 26E and 4-(l-adamantanyl)aniline hydrochloride (Enamine) were processed using
sequentially the methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the title compound
(320 mg). 1H NMR (400 MHz, methanol-D4) δ 0.91 (m, 12 H) 1.75 - 2.35 (m, 25 H) 3.64 (s, 6 H)
3.84 (m, 2 H) 4.00 (m, 2 H) 4.20 (m, 2 H) 5.12 (m, 2 H) 6.48 (s, 2 H) 7.02 (m, 6 H) 7.31 (m, 4 H) 7.46
(m, 6 H) 7.72 (d, J=8.13 Hz, 1H) 7.82 (d, J=8.24 Hz, 1H).
Example 169
methyl [(2S)-l-{(2S)-2-[5-(4-{5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-[4-(morpholin-4-yl)phenyl]-lH-pyrrol-
2-yl Jphenyl)- lH-irrridazol-2-yl]pyrrolidin-l -yl} -3-methyl-l -oxobutan-2-yl]carbamate
Example 26E and 4-morpholinoaniline (Aldrich) were processed using sequentially
the methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the tide compound (133 mg). :H
NMR (400 MHz, DMSO-D6) 8 0.83 (d, J=6.83 Hz, 6 H) 0.87 (d, J=6.61Hz, 6 H) 1.88 - 2.17 (m, 10
H) 3.11 (m, 4 H) 3.53 (s, 6 H) 3.70 - 3.80 (m, 8 H) 3.97 - 4.08 (m, 2 H) 5.04 (m, 2 H) 6.41 - 6.51 (m,
2 H) 6.84 - 7.35 (m, 10 H) 6.93 - 7.02 (m, 6 H) 11.71 - 12.03 (m, 2 H).
Example 170
methyl {(2S)-l-[(2S)-2-(5-bromo-4-{4-[(2S,5S)-5-(4-{5-bromo-2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl) amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl)-1 -(4-tert-
butylphenyl)pyrrolidm-2-yi]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl {carbamate
To a solution of Example 44 (0.100 g, 0.106 mmol) in CH2C12 (5 mL) at rt was added N-
bromosuccinimide (0.019 mL, 0.223 mmol). After 15 min, the reaction was washed with saturated
NaHC03 and concentrated. Residue purified by chromatography (1% gradient elution from 0% to 4%
MeOH-CH2Cl2; 12 g column) to provide 60 mg (51%) of the tide compound as a light yellow solid.1H NMR (400 MHz, DMSO-D6) δ 0.8 (d, J=6.61Hz, 6 H) 0.87 (d, J=6.56 Hz, 6 H) 1.11 (s, 9 H) 1.72
- 1.75 (m, 2 H) 1.87 -1.98 (m, 7 H) 2.10-2.15 (m, 5 H) 3.53 (s, 6 H) 3.70 -3.75 (m, 4 H) 4.00 = 4.06
(m, 2 H) 4.96 - 5.00 (m, 2 H) 5.27 - 5.35 (m, 2 H) 6.24 (d, J=8.78 Hz, 2 H) 6.97 (d, J=8.78 Hz, 2 H)
7.24 - 7.35 (m, 6 H) 7.60 - 7.65 (m, 4 H) 12.41 (m, 2 H).
Example 171
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl} pyrrolidin-2-yl] -4H-1,2,4-triazol-3-
yl }phenyl)pyrrolidin-2-yl]phenyl} -4H- l,2,4-triazol-3-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-
yl}carbamate
and
methyl {(2S)-l-[(2S)-2-(5-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-l,2,4-triazol-3-
yl }phenyl)pyrrolidin-2-yl]phenyl} -4H- l,2,4-triazol-3-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-
yl}carbamate
Example 171A
Dimethyl 4,4'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzoate
A mixture of Example 42C (0.5 g, 0.974 mmol), Et3N (0.407 mL, 2.92 mmol) and [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (71.3 mg, 0.097 mmol) in methanol (20 mL)
was subjected to an atmosphere of carbon monoxide gas (60 psi) for 24 hours at 100 °C. The mixture
was filtered through celite and concentrated. Purification by chromatography (silica gel, 25% EtOAc
in hexanes) afforded 396 mg (86%) of the title compound. MS (ESI) m/z 472 (M+H)+.
Example 17 IB
4,4'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5 -diyi)dibenzohydrazide
A mixture of Example 171A (350 mg, 0.742 mmol) and Hydrazine (0.140 |iL, 4.45 mmol) in
methanol (10 mL) was refluxed for 72 hours. The mixture was concentrated to afford 350 mg of the
title compound as a mixture of stereoisomers. MS (ESI) m/z 472 (M+H)+.
Example 171C
(2S,2'S)-tert-butyl2,2'-(5,5'-(4,4,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-
phenylene))bis(4H-1,2,4-triazole-5,3-diyl))dipyrrolidine-l -carboxylate
A mixture of Example 171B (105 mg, 0.223 mmol), (S)-l-N-Boc-2-cyano-pyrrolidine (175
mg, 0.891 mmol), and K2C03 (9.23 mg, 0.067 mmol) in n-butanol (0.5 mL) was heated to 150 °C for
90 minutes in a microwave. The mixture was diluted with EtOAc and then washed with H20 and
Brine. The organic was then dried (MgS04), filtered and concentrated. Purification by
chromatography (silica gel, 90% EtOAc in Hexanes) afforded 59 mg (32%) of the title compound as a
mixture of stereoisomers. MS (ESI) m/z 829 (M+H)+.
Example 17 ID
(S)-5,5'-(4,4,-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(3-((S)-pyrrolidin-2-
yl)-4H-1,2,4-triazole) pentahydrochloride
A mixture of Example 171C (59 mg, 0.071 mmol) in 4M HCl/Dioxane (2 mL) was allowed to
stir for one hour. The mixture was concentrated to afford 58 mg (100%) of the title compound as a
mixture of stereoisomers. MS (ESI) m/z 628 (M+H)+.
Example 17 IE
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-l,2,4-triazol-3-
yl }phenyl)pyrrolidin-2-yl]phenyl} -4H- l,2,4-triazol-3-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-
yl}carbamate
and
methyl {(2S)-l-[(2S)-2-(5-{4-t(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -4H- l,2,4-triazol-3-
yl }phenyl)pyrrolidin-2-yl]phenyl} -4H-1,2,4-triazol-3-yl)pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-
yl} carbamate
A mixture of Example 171D (58 mg, 0.071 mmol), (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (25 mg, 0.142 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (30 mg, 0.157 mmol), 1-Hydroxy-benzotriazole hydrate (24 mg, 0.157 mmol) and N-
methylmorpholine (78 μL, 0.712 mmol) in DMF (1 mL) were allowed to stir overnight. Mixture was
diluted with EtOAc. The organic was then washed with H20 and Brine. The organic was then dried
(MgS04), filtered and concentrated. Compound subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to afford both the
title compounds of Example 171 (24 mg, 70%) which eluted first (trans isomers) and title compound
of Example 172 which eluted second (Cis isomer). :H NMR (free base) (400 MHz, DMSO-4) δ ppm
0.27 (d, 7=6.72 Hz, 2 H), 0.71 (dd, J=6.61, 2.49 Hz, 2 H), 0.78 - 0.95 (m, 9 H), 1.03 (d, 7=6.07 Hz, 12
H), 1.09 (s, 9 H), 1.22 (s, 2 H), 1.65 - 1.77 (m, 3 H), 1.82 - 2.30 (m, 10 H), 3.52 (s, 6 H), 3.57 - 3.66
(m, 1H), 3.71 - 3.92 (m, 3 H), 4.00 - 4.16 (m, 2 H), 5.07 - 5.15 (m, 1H), 5.25 - 5.34 (m, 2 H), 5.65 (d,
7=4.88 Hz, 1H), 6.21 (dd, 7=8.73, 3.20 Hz, 2 H), 6.94 (dd, 7=8.78, 2.82 Hz, 2 H), 7.16 - 7.46 (m, 6
H), 7.83 - 7.92 (m, 4 H), 14.01 (s, 1H); MS (ESI) m/z 943 (M+H)+.
Example 172
methyl {(2S)-l-[(2S)-2-(5-{4-[(2R,5S)-l-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-l,2,4-triazol-3-
yl }phenyl)pyrrolidin-2-yl]phenyl} -4H- l,2,4-triazol-3-yl)pyrrolidin-1 -yl] -3-methyl- l-oxobutan-2-
yl}carbamate
The title compound, Example 172, was the second eluting compound described in the
procedures for Example 171E. The procedure afforded 21 mg (61%) of the title compound (Cis
isomer).1H NMR (free base) (400 MHz, DMSO-rf6) 8 ppm 0.27 (d, 7=6.29 Hz, 2 H), 0.71 (d, 7=6.61Hz, 2 H), 0.81 - 0.96 (m, 9 H), 1.03 (d, 7=6.07 Hz, 12 H), 1.12 (s, 9 H), 1.22 (s, 2 H), 1.82 - 2.30 (m,
12 H), 3.52 (s, 6 H), 3.72 - 3.91 (m, 4 H), 4.03 - 4.17 (m, 2 H), 4.33 (d, 7=4.23 Hz, 1H), 4.73 - 4.83
(m, 2 H), 5.09 - 5.18 (m, 2 H), 6.33 (d, 7=8.78 Hz, 2 H), 7.03 (dd, 7=8.78, 3.04 Hz, 2 H), 7.29 (d,
7=7.70 Hz, 1H), 7.57 - 7.69 (m, 4 H), 7.92 - 8.01 (m, 4 H), 13.84 (s, 2 H); MS (ESI) m/z 943
(M+H)+.
Example 173
methyl {(2S)-l-[(2S)-2-(2-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-(4-{4-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arrdno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-2-yl}phenyl)pyrrolidin-
2-yl]phenyl} -1H-imidazol-4-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
and
methyl {(2S)-l-t(2S)-2-(2-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{4-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)aimno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-2-yl}phenyl)pyrrolidm-
2-yl]phenyl} -1H-imidazol-4-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 173A
4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile
A mixture of Example 42C (1.0 g, 1.948 mmol) and CuCN (523 mg, 5.84 mmol) in
Dimethylformamide (9.5 mL) was heated to 160 °C for 4.5 hours in a microwave. Mixture was
poured into a dimethylamine/HaO mixture (1/10) and extracted with EtOAc (3 x 150 mL). The
combined organics were washed with H20 and Brine. The organic was then dried (MgS04), filtered
and concentrated. Purification by chromatography (silica gel, 20% EtOAc in Hexanes) afforded 395
mg (50%) of the title compound. MS (ESI) m/z 406 (M+H)+.
Example 173B
dimethyl 4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzimidate
A mixture of Example 173A (0.5 g, 1.233 mmol) in anhydrous MeOH (12 mL) at 0 °C was
bubbled an excess amount of HC1 (g) for 45 minutes. Mixture was then stirred at ambient
temperature for 24 hours and then concentrated to afford the title compound.
Example 173C
4,4'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5 -diyl)dibenzimidamide
A mixture of Example 173B (0.579 g, 1.233 mmol) in anhydrous MeOH (12 mL) at 0 °C was
bubbled an excess amount of NH3 (g) for 45 minutes. Mixture was then stirred at ambient
temperature for 24 hours and then concentrated and subjected to purification via chromatography
(CI8 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA) to afford the
title compound as a mixture of trans isomers; Cis isomer was discarded.. MS (ESI) m/z 440 (M+H)+.
Example 173D
methyl (S)-l-((S)-2-(2-diazoacetyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate
A mixture of Example 37B (100 mg, 0.367 mmol) and Et3N (154 jiL, 1.102 mmol) in
tetrahydrofuran (4 mL) at 0 °C was added Isobutyl chloroformate (50 ^L, 0.386 mmol). Mixture was
then stirred at 0 °C for 30 minutes followed by addition of excess diazomethane in Et20. Mixture was
allowed to slowly come to ambient temperature over 3 hours. Mixture was then concentrated and
diluted with EtOAc. Organic was then washed with saturated aqueous NaHC03 and brine. Organic
was dried (MgS04), filtered and concentrated. Purification by chromatography (silica gel, 100%
EtOAc) afforded 82 mg (75%) of the title compound. MS (ESI) m/z 297 (M+H)+.
Example 173E
methyl (S)-l-((S)-2-(2-bromoacetyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate
A mixture of Example 173D (70 mg, 0.236 mmol) in HOAc (0.6 mL) at ambient temperature
was added 48%HBr (80 |J.L, 0.709 mmol). Mixture was stirred at ambient temperature for 1Hour.
Mixture was poured into ice/H20 and extracted with CH2C12 (3 x 75 mL). Organic was dried
(Na2S04), filtered and concentrated afford 63 mg (76%) of the title compound. MS (ESI) m/z 350
(M+H)+.
Example 173F
methyl {(2S)-l-[(2S)-2-(2-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-(4-{4-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidm-2-yl]-lH-irnidazol-2-yl}phenyl)pyrrolidin-
2-yl]phenyl}- lH-imidazol-4-yl)pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl Jcarbamate
and
methyl {(2S)-l-[(2S)-2-(2-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{4-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-2-yl}phenyl)pyrrolidin-
2-yl]phenyl}-lH-imidazol-4-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
A mixture of Example 173E (59.6 mg, 0.171 mmol), Example 173C (25 mg, 0.057 mmol)
and K2C03 (65 mg, 0.470 mmol) in tetrahydrofuran (1 mL) was refluxed for 4 hours. Mixture was
diluted with CH2C12 and washed with H20 and Brine. The organic was then dried (MgS04), filtered
and concentrated. Compound subjected to HPLC purification on a semi-prep CI 8 reverse-phased
column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to afford 4.5 mg (6.7%) the title
compound Example 173 (Trans isomers). LH NMR (free base) (400 MHz, DMSO-d6) 8 ppm 0.78 -
0.89 (m, 12 H), 1.09 (s, 9 H), 1.68 -1.74 (m, 4 H), 1.88 - 2.04 (m, 8 H), 3.52 (s, 6 H), 3.70 - 3.78 (m,
4 H), 4.04 (t, 7=8.19 Hz, 2 H), 5.07 (t, 7=4.61Hz, 2 H), 5.26 (s, 2 H), 6.21 (d, 7=8.46 Hz, 2 H), 6.82
(s, 2 H), 6.93 (d, 7=8.67 Hz, 2 H), 7.22 (d, 7=8.89 Hz, 2 H), 7.26 (d, 7=8.13 Hz, 4 H), 7.78 (d, 7=8.13
Hz, 4 H), 7.82 (d, 7=7.70 Hz, 2 H), 12.11 -12.20 (m, 2 H). MS (ESI) m/z 941 (M+H)+.
Example 174
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-6-yl} -1 -(6-methoxypyridin-3-yl)pyrrolidin-2-yl]-
1H-benzirnidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
Example 109C and 6-methoxypyridin-3-amine were processed using sequentially the methods
of Examples 113A (dichloromethane used as solvent and cyclization conducted at room temperature
overnight), 165C, 113C, and 166 to provide the title compound which was purified by HPLC on a
semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to
afford 27 mg of the title compound. JH NMR (free base) (400 MHz, DMSO-4) δ ppm 0.76 - 0.86 (m,
12 H), 1.69 - 1.76 (m, 2 H), 1.84 - 2.04 (m, 4 H), 2.13 - 2.22 (m, 4 H), 2.52 - 2.60 (m, 2 H), 3.52 (s, 6
H), 3.55 (s, 3 H), 3.76 - 3.85 (m, 4 H), 4.05 (t, J=8.40 Hz, 2 H), 5.08 - 5.16 (m, 2 H), 5.31 - 5.41 (m, 2
H), 6.36 - 6.45 (m, 2 H), 6.74 (dd, J=9.00, 3.04 Hz, 2 H), 7.05 (t, J=8.57 Hz, 2 H), 7.15 - 7.24 (m,
J=17.02 Hz, 3 H), 7.28 (d, J=8.46 Hz, 2 H), 7.31 (s, 1H), 7.37 (d, J=8.13 Hz, 1H), 7.45 (d, J=8.13
Hz, 1H), 12.03 (s, 2 H); MS (ESI) m/z 864 (M+H)+.
Example 175
me±yl{(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[6-(dimemylamino)pyridin-3-yl]-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzirnidazol-6-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
Example 175 A
N,N-dimethyl-5-nirropyridin-2-amine
A mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) and 40% solution of Dimethylamine
(10.66 g, 95 mmol) in ethanol (40 mL) was heated to 75 °C for 1Hour. The mixture was cooled to
ambient temperature, diluted with CH2C12 and washed with saturated aqueous NaHC03 (3 x 100 mL)
and brine. The organic was dried (MgS04), filtered and concentrated to afford 5.27 g (100%) of the
tide compound. MS (ESI) m/z 168 (M+H)+.
Example 175B
N2,N2-dimethylpyridine-2,5-diamine
A mixture of Example 175A (5.27 g, 31.5 mmol) and Raney Nickel (5.27 g, 90 mmol) in
tetrahydrofuran (60 mL) was subjected to an atmosphere (30 psi) of hydrogen gas for 2 hours at
ambient temperature. Mixture was filtered and concentrated to afford 4.3 g (100%) of the title
compound. MS (ESI) m/z 138 (M+H)+.
Example 175C
methyl {(2S)-1 -[(2S)-2-{6-[(2R,5R)-l-[6-(dimethylamino)pyridin-3-yl]-5-(2-[(2S)-1 -{(2S)-2-
[(memoxycarbonyl)arruno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzirnidazol-6-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
Example 175B was processed using the methods referred to or described in Example 174 to
provide the tide compound (8.5 mg). 1H NMR (free base) (400 MHz, DMSO-d6) 8 ppm 0.75 - 0.86
(m, 12 H), 1.71 (d, J=4.99 Hz, 2 H), 1.86 - 2.05 (m, 6 H), 2.12 - 2.23 (m, 3 H), 2.55 (s, 2 H), 2.70 (s, 6
H), 3.16 (s, 2 H), 3.52 (s, 6 H), 3.81 (s, 3 H), 4.05 (t, J=8.35 Hz, 2 H), 5.09 - 5.18 (m, 2 H), 5.33 (d,
J=5.53 Hz, 2 H), 6.33 (d, J=9.00 Hz, 1H), 6.63 (dd, J=9.05, 2.98 Hz, 1H), 7.04 (d, J=7.70 Hz, 2 H),
7.19 - 7.31 (m, 4 H), 7.34 - 7.48 (m, 2 H), 12.02 (s, 2 H); MS (ESI) m/z 877 (M+H)+.
Example 176
methyl {(2S)-1 -[(2S)-2-{6-[(2R,5R)-1 -(6-tert-butylpyridin-3-yl)-5-{2-[(2S)-1 -{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
6-tert-Butylpyridin-3-amine was processed using the methods referred to or described in
Example 174 to provide the title compound (62.5 mg) of the title compound. 1H NMR (free base)
(400 MHz, DMSCWe) δ ppm 0.74 - 0.88 (m, 12 H), 1.08 (s, 9 H), 1.68 -1.77 (m, 2 H), 1.83 - 2.04 (m,
7 H), 2.12 - 2.23 (m, 4 H), 2.53 - 2.61 (m, 2 H), 3.16 (d, J=5.20 Hz, 2 H), 3.52 (s, 6 H), 3.76 - 3.85 (m,
4 H), 4.00 - 4.11 (m, 3 H), 5.08 - 5.16 (m, 2 H), 5.37 - 5.46 (m, 2 H), 6.54 - 6.61 (m, 1H), 6.88 - 6.96
(m, 2 H), 7.08 (t, J=9.00 Hz, 2 H), 7.20 (s, 1H), 7.25 - 7.31 (m, 3 H), 7.39 (d, J=8.13 Hz, 1H), 7.47
(d, J=8.24 Hz, 1H), 7.60 (d, J=3.25 Hz, 1H), 12.04 (d, J=27.76 Hz, 2 H); MS (ESI) m/z 890
(M+H)+.
Example 177
me%l{(2S)4-[(2S)-2<6-{(2S,5S)-5-{24(2S)4-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyn:olidm-2-yl]-lH-beii2imidazol-6-yl}-l-[6-(piperidin-l-yl)pyridin-3-yl]pyrroUdin-
2-yl} -lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 177A
5-((2S,5S)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-(piperidin-l-yl)pyridine
(lR,4R)-l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-diol (prepared using (S)-(+)-alpha,alpha-
diphenyl-2-pyrrolidinemethanol and the method of Example 109C) (0.60 g, 1.5 mmol) was processed
using the method described in Example 182A to give the title compound (0.41 g, 50%).
Example 177B
dimethyl (2SJ2,S)-l,l,-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(6-(piperidin-l-yl)pyridin-3-yl)pyrrolidine-2,5-
diyl)bis(2-nitro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
The product from Example 177A (0.20 g, 0.369 mmol) was combined with the product from
Example 116C (0.30 g, 1.11 mmol), cesium carbonate (0.336 g, 1.03 mmol), Xantphos (38 mg, 0.066
mmol) and tris(dibenzylideneacetone)dipalladium (20.3 mg, 0.022 mmol). Anhydrous 1,4-dioxane
(3.7 mL) was added, and the mixture was bubbled with N2 gas for 15 min. The resulting mixture was
stirred in a sealed tube at 100 °C for 2 h. The mixture was cooled to ambient temperature, diluted
with water and extracted with ethyl acetate. The organic extract was washed with brine, dried
(NaS04), filtered and concentrated. Purification by flash chromatography twice (silica gel, 0-10%
MeOH/CH2Cl2) afforded the title compound (235 mg, 60%).
Example 177C
dimethyl (2S,2'S)-l,l,-((2S,2,S)-2,2,-(4,4'-((2S,5S)-l-(6-(piperidin-l-yl)pyridin-3-yl)pyrrolidine-2,5-
diyl)bis(2-amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-
methyl-1 -oxobutane-2,1 -diyl)dicarbamate
To a solution of the product from Example 177B (237mg, 0.234 mmol) in ethanol (1.2 mL)
and tetrahydrofuran (1.2 mL) was added platinum(IV) oxide (13.29 mg, 0.059 mmol). The mixture
was placed under a hydrogen atmosphere for about 1Hour. The mixture was filtered over celite,
washing with methanol and concentrated. Purification by flash chromatography (silica gel, 0-10%
MeOH/CH2Cl2) afforded the tide compound (186 mg, 84%).
Example 177D
irK%l{(2S)44(2S)-2-(6-{(2S,5S)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolito-2-yl]-lH-berizimidazol-6-yl}-l-[6-(piperidin-l-yl)pyridin-3-yl]pyrrolidm-
2-yl} -1H-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
To a solution of the product from Example 177C (113 mg, 0.119 mmol) in toluene (1.2 mL)
was added acetic acid (34 ^L, 0.593 mmol) and 3A molecular sieves. The mixture was heated to 60
°C for 2 hours. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The
organic phase was washed with saturated aqueous NaHC03, dried (Na2S04), filtered and
concentrated. The crude product was purified by reverse-phase HPLC (CI8) using a solvent gradient
of 10-90% CH3CN in water (0.1% TFA). Fractions containing the desired product were pooled and
concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCOs, and CH2C12.
The organic layer was dried (Na2S04), filtered and concentrated to afford the title compound (9 mg,
8%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.78 - 0.85 (m, 7 H), 0.87 (dd, 7=6.7, 3.0 Hz, 6 H),
1.23 (s, 1H), 1.43 (s, 6 H), 1.72 (s, 2 H), 1.97 (s, 5 H), 2.18 (s, 3 H), 3.09 (s, 4 H), 3.30 (s, 2 H), 3.53
(d, 7=1.5 Hz, 6 H), 3.81 (s, 4 H), 4.07 (s, 2 H), 5.13 (s, 2 H), 5.33 (s, 2 H), 6.48 (d, 7=4.4 Hz, 1H),
6.59 - 6.64 (m, 1H), 7.05 (s, 2 H), 7.22 (s, 1H), 7.25 - 7.34 (m, 4 H), 7.37 (s, 1H), 7.44 (s, 1H),
12.06 (s, 2 H); MS (ESI) m/z 916 (M+H)+.
Example 178
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-6-yl} -1 -[6-(trifluoromethyl)pyridin-3-
yl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 109C and 5-amino-2-(frifluoromethyl)pyridine were processed using sequentially
the methods of Examples 182A, 177B, 177C, and 177D to provide the title compound. 1H NMR (400
MHz, DMSO-D6) δ ppm 0.79 - 0.89 (m, 15 H), 1.61 (s, 4 H), 1.97 (s, 6 H), 2.19 (s, 5 H), 3.50 - 3.58
(m, 7 H), 3.82 (s, 4 H), 3.99 - 4.10 (m, 2 H), 5.15 (s, 2 H), 6.89 - 6.98 (m, 2 H), 7.19 (s, 1H), 7.26 -
7.34 (m, 4 H), 7.36 (d, 7=8.2 Hz, 1H), 11.94 (d, 7=12.9 Hz, 2 H). MS m/z 901 (M+H)+.
Example 179
N-(methoxycarbonyl)-L-valyl-N-{4-[(25',55)l-(4-tert-butylphenyl)-5-(2-{(2S)-l-[N-
(methoxycarbonyl)-L-valyl]pyirolidin-2-yl}-lH-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L-
prolinamide
and
AHmethoxycarbonyl)-L-valyl-N {4-[(2i?,5#)-l -(4-te/t-butylphenyl)-5-(2- {(25)-1 -[N-
(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl} - lff-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl} -L-
prolinamide
Example 179A
1 -(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butane-1,4-dione
To a mixture of zinc chloride (39.1 g, 287 mmol) in benzene (215 mL) was added
diethylamine (22.24 mL, 215 mmol) and 2-methylpropan-2-ol (20.57 mL, 215 mmol). The resulting
mixture was stirred at rt for 2h, and 2-bromo-l-(4-nitrophenyl)ethanone (35.0 g, 143 mmol) and l-(4-
chloro-3-nitrophenyl)ethanone (42.9 g, 215 mmol) were added in one portion. The resulting mixture
was stirred at rt overnight. Added 5% aq. H2SO4 (50 mL) and stirred vigorously to induce
precipitation. The resulting solid was collected by filtration and washed successively with benzene,
water, methanol, and CH2C12. The solid was dried in vacuo to give the title compound.
Example 179B
l-(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butane-l,4-diol
To a solution of the product from Example 179 A (10.0 g, 27.6 mmol) in EtOH (220 mL) was
added sodium borohydride (2.190 g, 57.9 mmol) in several portions over 1H. The resulting mixture
was stirred at rt for 1H, filtered through celite, and concentrated in vacuo. The residue was dissolved
in EtOAc and washed by IN aq. HC1. The organic layer was dried over Na2S04, filtered and
concentrated in vacuo to give the title compound (9.29 g, 92%)
Example 179C
l-(4-tert-butylphenyl)-2-(4-chloro-3-nitrophenyl)-5-(4-nitrophenyl)pyrrolidine
To a solution of product from Example 179B (9.29 g, 25.3 mmol) in anhydrous CH2C12 (200
mL) at 0 °C was added triethylamine (10.53 mL, 76 mmol), followed by dropwise addition of
methanesulfonyl chloride (4.93 mL, 63.3 mmol). The resulting mixture was stirred at 0 °C for 2 h,
and then concentrated in vacuo. The resulting solid was dissolved in anhydrous DMF (70 mL), 4-tert-
butylaniline (40.4 mL, 253 mmol) was added, and the resulting mixture was stirred at 50 °C for 1H.
The resulting mixture was cooled to rt and poured into ice cold IN aq. HC1 (500 mL) to give a yellow
precipitate. The precipitate was collected by filtration and dried to give the title compound (13.2 g).
Example 179D
4-(l-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyirolidm-2-yl)-N-(4-methoxybenzyl)-2-nitroaniline
The product from Example 179C (13.2 g, 27.5 mmol) and 4-methoxybenzylamine (18 mL,
139 mmol) were combined and stirred at 145 °C for 1.5 h. The mixture was cooled to rt, and CH2Q2
was added. The resulting precipitate was filtered off, and the filtrate was washed successively with IN
aq. HC1 and saturated aq. NaHC03. The organic layer was dried over Na2S04, filtered and
concentrated in vacuo. The crude product was purified by column chromatography on silica gel using
a solvent gradient of 0-25% EtOAc in hexane to give the title compound (5.0 g, 31%).
Example 179E
4-(5-(4-aminophenyl)-1 -(4-tert-butylphenyl)pyrrolidin-2-yl)-Nl-(4-methoxybenzyl)benzene-1,2-
diamine
To a solution of the product from Example 179D (2.74 g, 4.72 mmol) in EtOH (25 mL) and
THF (25 mL) was added platinum(IV) oxide (0.5 g, 2.2 mmol). The resulting mixture was stirred at rt
under 1 atm H2 overnight. The mixture was filtered through celite, washed with methanol, and the
filtrate was concentrated in vacuo. The crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-45% EtOAc in hexane to give the title compound (1.74 g,
71%).
Example 179F
(2S)-tert-butyl2-(4-(5-(3-((S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-4-(4-
memoxybenzylamino)phenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-l-
carboxylate
To a mixture of the product from Example 179E (1.74 g, 3.33 mmol), (S)-l-(tert-
butoxycarbonyi)pyrrolidine-2-carboxylic acid (1.793 g, 8.33 mmol) and HATU (3.17 g, 8.33 mmol)
in DMSO (33 mL) was added Hunig's base (1.746 mL, 10.00 mmol). The resulting mixture was
stirred at rt for 1H and was partitioned between H20 and CH2C12. The organic layer was dried over
Na2S04, filtered and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title
compound (2.1 g, 69%).
Example 179G
(2S)-tert-butyl2-(4-(5-(4-amino-3-((S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-l-
(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-l-carboxylate
To a solution of the product from Example 179F (1.06 g, 1.16 mmol) in CH2C12 (40 mL) and
H20 (2 mL) was added 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) (0.316 g, 1.393 mmol) in
several portions. The mixture was stirred at rt for 20 min and was washed with saturated.aq. NaHC03.
The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane
to give the title compound (0.53 g, 57%).
Example 179H
(2S)-tert-butyl2-(4-(5-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lH-benzo[d]imidazol-5-yl)-l-
(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-l-carboxylate
A solution of product from Example 179G (0.526 g, 0.662 mmol) in acetic acid (4.73 mL, 83
mmol) was stirred at 65 °C for 1H. The resulting mixture was partitioned between CH2C12 and
saturated aq. NaHC03. The organic layer was dried over Na2S04, filtered and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-
2.5% MeOH in CH2C12 to give the title compound (0.23 g, 45%).
Example 1791
(S)-N-(4-((2S,5S)-l-(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-5-
yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
and
(S)-N-(4-((2R,5R)-l-(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-5-
yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
To a solution of the product from Example 179H (0.302 g, 0.389 mmol) in CH2C12 (3 mL)
was added TFA (2.5 mL), and the resulting mixture was stirred at rt for 1.5 h. The mixture was
concentrated in vacuo, and the crude product was purified by reversed-phase HPLC (CI8) using a
solvent gradient of 10-100% acetonitrile in H20 (0.1% TFA). The trans-pyrrolidine isomer elutec
before the cis-pyrrolidine isomer. Fractions containing the trans-isomer were concentrated in vacuo
and the residue was partitioned between CH2C12 and saturated aq. NaHC03. The organic layer was
dried over Na2S04, filtered and concentrated in vacuo to give the title compound (83 mg, 37%).
Example 179J
N-(methoxycarbonyl)-L-valyl-N-{4-[(25,55)l-(4-tert-butylphenyl)-5-(2-{(2S)-l-[N-
(memoxycarbonyl)-L-valyl]pyrrolidm-2-yl}-lH-benzirnidazol-5-yl)pyrrolidin-2-yl]phenyl}-L-
prolinamide
and
N-(methoxycarbonyl)-L-valyl-Ar-{4-[(2R,5R)-l-(4-terf-butylphenyl)-5-(2-{(25)-l-[^-
(memoxycarbonyl)-L-valyl]pyrrolidm-2-yl}-lH-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L-
prolinamide
To a mixture of the product from Example 1791 (83 mg, 0.144 mmol), (S)-2
(methoxycarbonylamino)-3-methylbutanoic acid (63 mg, 0.361 mmol), and HATU (0.137 g, 0.361
mmol) in DMSO (1.5 mL) was added Hunig's base (0.101 mL, 0.578 mmol), and the resulting
mixture was stirred at rt for 1H. The mixture was partitioned between CH2C12 and H20. The organic
layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified b]
column chromatography on silica gel using a solvent gradient of 0-3.5% MeOH in CH2C12 to give tht
title compounds (80 mg, 60%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.74 - 0.99 (m, 12 H), 1.0S
(s, 9 H), 1.59 - 1.73 (m, 2 H), 1.81 - 2.05 (m, 6 H), 2.07 - 2.24 (m, 2 H), 3.50 - 3.56 (m, 6 H), 3.58
3.67 (m, 1H), 3.76 - 3.85 (m, 2 H), 3.99 - 4.10 (m, 2 H), 4.43 (dd, 7=8.0, 4.9 Hz, 1H), 5.08 - 5.16 (m
1H), 5.16 - 5.25 (m, 1H), 5.26 - 5.37 (m, 1H), 6.21 (d, .7=8.8 Hz, 2 H), 6.88 - 6.97 (m, 2.5 H), 7.00
7.08 (m, 1H), 7.11 - 7.20 (m, 7=5.7 Hz, 2.5 H), 7.21 - 7.34 (m, 2 H), 7.37 (dd, 7=8.2, 2.0 Hz, 0.5 H)
7.45 (d, 7=8.3 Hz, 0.5 H), 7.50 (d, 7=8.3 Hz, 2 H), 9.98 (s, 1H), 12.01 (m, 1H); MS m/z 891.(
(M+H)+.
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-(4-{5-chloro-2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)pyrrolidin-
2-yl]phenyl} -5-chloro-1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
To a solution of the product from Example 43 (114 mg, 0.121 mmol) in CH2C12 (1.2 mL) was
added N-chlorosuccinimide (54 mg, 0.41 mmol), and the resulting mixture was stirred at rt for 9 h.
The mixture was diluted by CH2C12 and washed with saturated aq NaHC03. The organic layer was
dried over Na2S04, filtered, and concentrated in vacuo. The crude product was subjected to reversed-
phase HPLC (C18) using a solvent gradient of 40%-100% acetonitrile in water (0.1% TFA).
Fractions containing the desired product were pooled and concentrated in vacuo. The residue was
purified on a preparative TLC plate, eluting with 3% MeOH in CH2C12 to give the title compound (3.5
mg, 3%). 1H NMR (400 MHz, DMSO-D6) δ ppm0.80 - 0.92 (m, 12 H), 1.11 (s, 9 H), 1.72 (d, 7=5.0
Hz, 2 H), 1.87 - 2.04 (m, 6 H), 2.05 - 2.23 (m, 2 H), 3.53 (s, 6 H), 3.72 - 3.82 (m, 2 H), 4.04 (t, 7=8.4
Hz, 2 H), 4.98 (dd, 7=6.8, 3.5 Hz, 2 H), 5.29 (dd, 7=3.5, 2.5 Hz, 2 H), 6.23 (d, 7=8.8 Hz, 2 H), 6.96 (d,
7=8.8 Hz, 2 H), 7.27 (d, 7=8.6 Hz, 2 H), 7.32 (d, 7=8.2 Hz, 4 H), 7.61 (d, 7=8.1Hz, 4 H), 12.41 (s, 2
H); MS m/z 1009.1 (M+H)+.
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R)-l-(4-tert-butyl-2-chlorophenyl)-5-(4-{5-chloro-2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl] - lH-imidazol-4-
yl}phenyl)pyn:oliaUn-2-yl]phenyl}-5-cMoro-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-
2-yl Jcarbamate
The product from Example 43 (114 mg, 0.121 mmol) was subjected to the procedure
described in Example 180 to give the title compound (4.7 mg, 4%). 1H NMR (TFA salt) (400 MHz,
DMSO-D6) δ ppm 0.78 - 0.89 (m, 12 H), 1.05 (s, 9 H), 1.85 - 1.97 (m, 10 H), 2.04 - 2.18 (m, 4 H),
3.52 (s, 6 H), 3.69 - 3.81 (m, 4 H), 4.03 (t, 7=8.3 Hz, 2 H), 4.95 (dd, 7=7.0, 4.0 Hz, 2 H), 5.53 (d,
7=7.5 Hz, 2 H), 6.91 - 6.95 (m, 1H), 6.96 - 7.02 (m, 2 H), 7.26 (d, 7=8.5 Hz, 2 H), 7.30 - 7.41 (m, 4
H), 7.49 (d, 7=7.6 Hz, 4 H), 12.34 (s, 2 H); MS m/z 1045.1 (M+H)+.
Example 182 methyl [(2S)-l-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -lH-imidazol-4-yl }phenyl)-l -[6-
(piperidin- l-yl)pyridin-3-yl]pyrrolidin-2-yl }phenyl)-1H-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1 -
oxobutan-2-yl]carbamate
Example 182A
5-((2S,5S)-2,5-bis(4-bromophenyl)pyrrolidin-l-yl)-2-(piperidin-l-yl)pyridine
To a suspension of the product of Example 69 A (0.50 g, 1.25 mmol) in anhydrous CH2C12 (12
mL) at 0 °C was added EtsN (0.52 mL, 3.75 mmol), followed by methanesulfonyl chloride (0.243 mL,
3.12 mmol). The resulting mixture was stirred and 0 °C for 90 min and then evaporated to dryness.
The solid was dissolved in anhydrous DMF (10 mL), and Example 144C (1108 mg, 6.25 mmol) was
added. The resulting mixture was stirred at 40 °C overnight, and was partitioned between 0.2 N aq
HC1 and EtOAc. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel using a solvent gradient of EtOAc
and hexane to give the title compound (107 mg, 16%).
Example 182B
methyl [(2S)-l-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-imidazol-4-yl } phenyl)-1 - [6-(piperidin-1 -yl)pyridin-3-
yl]pyrrolidin-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
The product from Example 182A was subjected to the procedures described in Examples
42D, 42E, 42F, and 42G to give the title compound. 1H NMR (free base) (400 MHz, DMSO-D6) 5
ppm 0.80 - 0.94 (m, 12 H), 1.24 (s, 4 H), 1.44 (s, 6 H), 1.89 - 2.04 (m, 6 H), 2.07 - 2.20 (m, 4 H), 3.12
(s, 4 H), 3.53 (s, 6 H), 3.77 (d, 7=6.7 Hz, 2 H), 4.05 (t, 7=8.4 Hz, 2 H), 5.06 (dd, 7=6.7, 3.0 Hz, 2 H),
5.19 (d, 7=6.4 Hz, 2 H), 6.45 - 6.53 (m, 1H), 6.56 - 6.63 (m, 1H), 7.15 (d, 7=8.2 Hz, 4 H), 7.21 - 7.32
(m, 4 H), 7.38 (d, 7=1.8 Hz, 2 H), 7.62 (d, 7=8.0 Hz, 4 H), 11.69 (s, 2 H); MS m/z = 968.8 (M+H)+.
Example 183
methyl [(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)-l-t6-(trifluoromethyl)pyridm-3-
yl]pyrrolidin-2-yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
Example 183A
5-((2S,5S)-2,5-bis(4-bromophenyl)pyrrolidin-l-yl)-2-(trifluoromethyl)pyridme
The product from Example 69A (1.0 g, 2.5 mmol) was subjected to the procedure described in
Example 182A, substituting 6-(trifluoromethyl)pyridin-3-amine for Example 144C, to give the title
compound (0.13 g, 10%).
Example 183B
methyl [(2S)-l-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]4H-imidazol-4-yl}phenyl)-l-[6-(trifluoromethyl)pyridin-3-
yl]pvrrolidm-2-yl}phenyl)-lH4midazol-2-yl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-yl]carbamate
The product from Example 183A was subjected to the procedures described in Examples
42D, 42E, 42F, and 42G to give the title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) 5
ppm 0.75 - 0.91 (m, 12 H), 1.84 (d, 7=5.6 Hz, 2 H), 1.96 - 2.10 (m, 6 H), 2.11 - 2.20 (m, 7=10.8, 5.5
Hz, 2 H), 3.54 (s, 6 H), 3.76 - 3.91 (m, 4 H), 4.10 (t, 7=7.9 Hz, 2 H), 5.11 (t, 7=6.8 Hz, 2 H), 5.56 (d,
7=5.1Hz, 2 H), 6.74 (dd, 7=8.8, 2.5 Hz, 1H), 7.32 (d, 7=8.5 Hz, 2 H), 7.41 (d, 7=7.8 Hz, 4 H), 7.44 -
7.48 (m, 7=8.8 Hz, 1H), 7.71 (d, 7=8.2 Hz, 4 H), 7.76 (d, 7=2.5 Hz, 1H), 7.97 (s, 2 H), 14.50 (s, 2
H); MS m/z 953.6 (M+H)+.
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-6-yl} -1 - [2-(piperidin-1 -yl)pyrimidin-5-
yl]pyrrolidin-2-yl} -1H-benzimdazol-2-yi)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 184A
2-(piperidin-l-yl)pyrimidin-5-amine
To a suspension of 2-chloro-5-nitropyrimidine (1.5 g, 9.40 mmol) in EtOH (15 mL) was
added piperidine (2.79 mL, 28.2 mmol), and the resulting mixture was refluxed for 2 h. The cooled
mixture was concentrated in vacuo, and the residue was partitioned between CH2C12 and saturated aq.
NaHC03. The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give a solid
(1.65 g, 84%). The solid was placed in a 250 mL stainless steel pressure botde and dissolved in THF
(20 mL). Raney-Ni 2800 in water slurry (1.650 g, 28.1 mmol) was added, and the mixture was stirred
at rt for 2 h under H2 gas at a pressure of 30 psi. The mixture was filtered through a nylon membrane
and concentrated in vacuo to give the title compound (1.4 g, 99%).
Example 184B
5-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-(piperidin-l-yl)pyrimidine
The product from Example 109C (1.09 g, 2.72 mmol) was subjected to the conditions
described in Example 182A, substituting Example 184A for Example 144C, to give the title
compound (0.59 g, 40%).
Example 184C
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl]-lH-benzimidazol-6-yl}-1 -[2-(piperidin-1 -yl)pyrimidin-5-
yl]pyrrolidin-2-yl} -1H-benzimdazol-2-yl)pyrroUdin-l -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
The product from Example 184B was subjected to the procedures described in Examples
177B, 177C, and 177D to give the title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) 5
ppm0.71 - 0.91 (m, 12 H), 1.24 (s, 2 H), 1.32 - 1.41 (m, 4 H), 1.44 -1.52 (m, 2 H), 1.82 (d, 7=5.1Hz,
2 H), 1.92 - 2.26 (m, 12 H), 3.86 (s, 6 H), 4.12 (t, 7=8.0 Hz, 2 H), 5.20 (dd, 7=8.0, 5.2 Hz, 2 H), 5.54
(d, 7=6.2 Hz, 2 H), 7.33 (d, 7=8.3 Hz, 2 H), 7.40 (d, 7=7.8 Hz, 2 H), 7.51 (s, 2 H), 7.57 - 7.61 (m, 2
H), 7.72 (d, 7=8.3 Hz, 2 H); MS m/z 917.5 (M+H)+.
methyl {(25,)-l-[(21S)-2-(5-{4-[(25,55)-5-(4-{2-[(25)-l-{(2lSl-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-5-yl}phenyl)-l-{4-[6-(morpholin-4-yl)pyridin-3-
yl]phenyl}pyrrolidin-2-yl]phenyl}-l//-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl} carbamate
and
methyl {(25')-l-[(25)-2-(5-{4-[(2R,5R)-5-(4-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl}phenyl)-l-{4-[6-(morpholin-4-yl)pyridin-3-
yl]phenyl}pyrrolidin-2-yl]phenyl}-l//-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl}carbamate
Example 185A
2,5-bis(4-bromophenyl)-l-(4-iodophenyl)pyrrolidine
The product from Example 42B (1.39 g, 2.499 mmol) in DMF (6.25 mL) was treated with 4-
iodoaniline (Aldrich, 4.38 g, 19.99 mmol), heated at 40-50 °C for two hours, cooled and diluted into
EtOAc. The EtOAc layer was washed 3 X 50 mL with 1 M HC1, with water, brine, dried (Na2S04),
Filtered and concentrated. Purification by flash chromatography on an ISCO 40 g silica cartridge
eluting with 0-20% EtOAc in hexane afforded the title compound as a tan foam as a mixture of
stereoisomers (0.96 g, 66 %). MS (ESI) m/z 584 (M+H)+.
Example 185B
4-(5-(4-(2,5-bis(4-bromophenyl)pyrrolidin-l-yl)phenyl)pyridin-2-yl)morpholine
The product from Example 185A (0.1 g, 0.171 mmol), 4-(5-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.050 g, 0.171 mmol), potassium phosphate (0.028 mL,
0.343 mmol), tris(dibenzylideneacetone)dipalladium(O) (1.570 mg, 1.715 \imo\) and 1,3,5,7-
tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (1.504 mg, 5.14 \imol) were combined in THF
(1.2 mL) Jwater (0.4 mL). The mixture was sparged with nitrogen for 15 minutes diluted into EtOAc,
washed with 1M sodium bicarbonate, brine, dried (Na2S04), filtered and concentrated. Purification
by flash chromatography on an Isco 12 g silica cartridge eluting with 20-70 % EtOAc in hexane gave
the title compound as a cream colored powder (91 mg, 86%). %). MS (ESI) m/z 620 (M+H)+.
Example 185C
memyl{(2^44(25)-2K5-{44(25,55)-5<4-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyn-olidin-2-yl]-1H-imidazol-5-yl}phenyl)-l-{4-[6-(morpholin-4-yl)pyridin-3-
yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl}carbamate
and
methyl {(25')-l-[(25)-2-(5-{4-[(2i?,5R)-5-(4-{2-[(25)-l-{(25,)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-l-{4-[6-(morpholin-4-yl)pyridin-3-
yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl}carbamate
The product from Example 185B was processed as described in Example 42D, 42E, 42F, and
42G to afford the tide compounds. :H NMR (free base) (400 MHz, DMSO-i6) δ 0.77 - 0.94 (m, 12 H)
1.71 - 2.47 (m, 16 H) 3.36 - 3.42 (m, 4 H) 3.53 (s, 6 H) 3.63 - 3.71 (m, 4 H) 3.74 - 3.84 (m, 3 H) 4.00
- 4.08 (m, 1H) 4.79 (d, J=4.23 Hz, 1H) 5.02 - 5.11 (m, 2 H) 5.24 - 5.32 (m, 1H) 6.37 (d, J=8.89 Hz,
1H) 6.49 (d, J=8.78 Hz, 1H) 6.79 (dd, J=14.91, 8.95 Hz, 1H) 7.12 - 7.78 (m, 15 H) 8.23 - 8.31 (m, 1H) 11.64 -12.11 (m, 2 H). MS (ESI) m/z 1046 (M+H)+.
Example 186
methyl {(2S)-l-[(2S)-2-(4-{4-[(2S,5S)-l-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arnmo]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-yl}phenyl)pyrroUdin-
2-yl]phenyl} -1H-imidazol-2-yl)pyrrolidm-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
The product from Example 95B was purified by chiral chromatography on a Chiralpak IB
column eluting with a mixture of hexane/THF/methanol (85/10/5). The title compound was the
second of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.35 - 0.42 (m, 2 H)
0.65 - 0.73 (m, 2 H) 0.80 - 0.92 (m, 12 H) 1.58 - 1.65 (m, 1H) 1.67 - 1.71 (m, 2 H) 1.87 - 2.02 (m, 6
H) 2.07 - 2.17 (m, 4 H) 3.53 (s, 6 H) 3.70 - 3.85 (m, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.06 (dd, J=6.72,
2.82 Hz, 2 H) 5.16 - 5.25 (m, 2 H) 6.19 (d, J=8.67 Hz„ 2 H) 6.64 (d, J=8.57 Hz, 2 H) 7.09 - 7.32 (m, 6
H) 7.36 - 7.69 (m, 6 H) 11.60 -12.09 (m, 2 H); MS (ESI+) m/z 924.6 (M+H).
dimethyl ([(2R,5R)-1- {3-[6-(morpholin-4-yl)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis {(2-
aminobenzene-4,1 -diyl)carbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-
diyl] })biscarbamate
Example 187 A
(2R,5R)-2,5 -bis(4-chloro-3-nitrophenyl)-1 -(3-iodophenyl)pyrrolidine
The mesylate of Example 109C (4.17 g, 7.48 mmol) in DMF (15 ml) was treated with 3-
iodoaniline (Aldrich, 7.2 mL, 59.8 mmol), stirred at ambient temperature for 48 hours and diluted into
EtOAc. The EtOAc layer was washed 3 X 50 mL with 1 M HC1, with water, brine, dried (Na2S04),
filtered and concentrated. Purification by flash chromatography on an Isco 300 g silica cartridge
eluting with 10-30% EtOAc in hexane afforded the title compound as a bright yellow foam (2.6 g, 60
%). MS (ESI) m/z 584 (M+H)+.
Example 187B
4-(5-(3-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)phenyl)pyridin-2-
yl)morpholine
The product from Example 187A (1.4 g, 2.396 mmol), 4-(5-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.695 g, 2.396 mmol), potassium phosphate (1.017 g,
4.79 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.022 g, 0.024 mmol) and 1,3,5,7-tetramethyl-
6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.021 g, 0.072 mmol) were combined in THF (18 mL) Jwater (6 mL). The mixture was sparged with nitrogen for 15 minutes, stirred for 6 hours diluted into
EtOAc, washed with 1M sodium bicarbonate, brine, dried (Na2S04), filtered and concentrated.
Purification by flash chromatography on an Isco 120 g silica cartridge eluting with 20-60 % EtOAc in
hexane gave the title compound as a yellow glass (1.1 g, 74%). MS (ESI) m/z 620 (M+H)+.
Example 187C
dimethyl ([(2R,5R)-1 - {3-[6-(morpholin-4-yl)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis {(2-
aminobenzene-4,l-diyl)carbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-
diyl] })biscarbamate
The product from Example 187B (0.5 g, 0.806 mmol), was processed using the methods in
Examples 165C and 165D to afford the title compound (400 mg, 45% two steps). 1H NMR (400 MHz,
DMSO-is) δ 0.89 (dd, 7=11.82, 6.61Hz, 12 H) 1.35 - 2.22 (m, 14 H) 3.36 - 3.46 (m, 8 H) 3.52 (s, 6
H) 3.56 - 3.86 (m, 4 H) 3.97 - 4.43 (m, 4 H) 4.85 (s, 4 H) 5.09 (s, 2 H) 6.25 (d, 7=7.26 Hz, 1H) 6.42 -
6.51 (m, 3 H) 6.58 (s, 2 H) 6.66 (d, 7=7.59 Hz, 1H) 6.81 (d, 7=8.78 Hz, 1H) 6.95 - 7.02 (m, 3 H)
7.36 (d, 7=8.35 Hz, 2 H) 7.51 (dd, 7=8.73, 2.33 Hz, 1H) 8.12 (d, 7=2.06 Hz, 1H) 9.23 (s, 2 H). MS
(ESI) m/z 1031 (M+H)+.
methyl {(2S)-1-[(2S)-2-{5-[(2R,5R)-5-{2-t(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -1-{ 3-[6-(morpholin-4-yi)pyridin-3-
yljphenyl }pyrrolidin-2-yl]- lH-benzimidazol-2-yl }pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-
yl} carbamate
The product from Example 187C (0.4 g, 0.388 mmol) was treated with acetic acid (0.089 ml,
1.553 mmol) in toluene (7.77 ml) at 50 °C for 4 hours, cooled and concentrated. The residue was
dissolved in EtOAc, washed with 10% sodium bicarbonate, brine, dried (Na2S04), filtered and
concentrated. Purification by flash chromatography on an Isco Gold 12 g silica cartridge eluting with
1-6% MeOH in dichloromethane afforded the title compound (183 mg, 45%).1H NMR (400 MHz,
DMSO-rfe) 8 0.71 - 0.90 (m, 12 H) 1.62 - 2.28 (m, 14 H) 3.37 - 3.43 (m, 4 H) 3.53 (s, 6 H) 3.64 - 3.68
(m, 4 H) 3.80 (s, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.08 - 5.19 (m, 2 H) 5.48 (s, 2 H) 6.29 (d, J=8.02 Hz, 1H) 6.54 - 6.64 (m, 2 H) 6.76 (d, J=8.89 Hz, 1H) 6.93 (d, J=4.66 Hz, 1H) 7.11 (d, J=8.13 Hz, 2 H)
7.23 - 7.30 (m, 3 H) 7.34 - 7.40 (m, 2 H) 7.46 (s, 2 H) 8.05 (s, 1H) 12.01 (s, 2 H). MS (ESI) m/z 995
(M+H)+.
methyl t(2S,3R)-l-{(2S)-2-[(4-{(2S,5S)-l-(4-tert-butylphenyl)-5-[4-({[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]carbonyl}amino)phenyl]pyrrolidin-2-
yl }phenyl)carbamoyl]pyrrolidin-1 -yl} -3-methoxy-1 -oxobutan-2-yl] carbamate
Example 189A
(S)4ert-butyl2<4<(2S,5S)4<44ert-butylphenyl)-5<4-((S)-l-((S)-2-(methoxycarbonylamino)-3-
memylbutanoyl)pyrroUdine-2-carboxaimdo)phenyl)pyrrolidiri-2-yl)phenylcarbamoyl)pyrrolidine-l-
carboxylate
To a solution of the product from Example 213 (33 mg, 0.052 mmol) in anhydrous DMSO
(0.5 mL) was added (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (13.3 mg, 0.062 mmol),
HATU (23.5 mg, 0.062 mmol) and Hunig's base (18 |iL, 0.10 mmol). The resulting mixture was
stirred at rt for 90 min and then partitioned between H20 and EtOAc. The organic layer was dried
over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-10% MeOH in CH2C12 to give the title
compound (33 mg, 76%).
Example 189B
methyl [(2S,3R)-l-{(2S)-2-t(4-{(2S,5S)-l-(4-tert-butylphenyl)-5-[4-({[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]carbonyl}amino)phenyl]pyrrolidin-2-
yl }phenyl)carbamoyl]pyrrolidin-l -yl} -3-methoxy-1 -oxobutan-2-yl]carbamate
A solution of the product from Example 189A (30 mg, 0.036 mmol) in a 1:1 mixture of
CH2C12:TFA (0.4 mL) was stirred at rt for 45 min. The mixture was concentrated in vacuo, and the
residue was partitioned between saturated aq. NaHC03 and EtOAc (2x). The combined organic layers
were dried over Na2S04, filtered and concentrated in vacuo to give a solid. The solid was subjected to
the procedure described in Example 189A (27 mg), substituting (2S,3R)-3-methoxy-2-
(methoxycarbonylamino)butanoic acid for (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid,
to give the title compound (17 mg, 52%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.85 - 0.97 (m, 6
H), 1.08 - 1.19 (m, 12 H), 1.60 - 1.66 (m, 2 H), 1.80 - 2.05 (m, 8 H), 2.08 - 2.20 (m, 2 H), 3.25 (s, 3
H), 3.42 - 3.50 (m, 2 H), 3.52 (s, 3 H), 3.53 (s, 3 H), 3.58 - 3.72 (m, 2 H), 3.76 - 3.87 (m, 2 H), 3.98 -
4.06 (m, 1H), 4.26 (t, 7=7.81Hz, 1H), 4.38 - 4.46 (m, 2 H), 5.15 (d, 7=6.40 Hz, 2 H), 6.17 (d, 7=8.78
Hz, 2 H), 6.94 (d, 7=8.89 Hz, 2 H), 7.13 (d, 7=8.24 Hz, 4 H), 7.32 (t, 7=8.84 Hz, 2 H), 7.49 (dd,
7=8.57, 2.06 Hz, 4 H), 9.96 (d, 7=15.51Hz, 2 H). MS (ESI) m/z 910.6 (M+H)+.
dimethyl ([l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbonylliydrazine-2,l-
diylcarbonyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate)
To a solution of the product from Example 171B (50 mg, 0.106 mmol) and the product from
Example 37B (72 mg, 0.27 mmol) in anhydrous DMSO (1 mL) was added HATU (100 mg, 0.27
mmol) and Hunig's base (56 (i.L, 0.32 mmol). The resulting mixture was stirred at rt for 90 min, and
then partitioned between H20 and EtOAc (2x). The combined organic layers were dried over Na2S04,
filtered, and concentrated in vacuo. The crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-10% MeOH in CH2C12 to give the title compound (68 mg,
65%) as a mixture of cis and trans stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.81 - 0.98
(m, 12 H), 1.08 -1.17 (m, 9 H), 1.64 -1.77 (m, 2 H), 1.78 - 2.06 (m, 8 H), 2.07 - 2.22 (m, 2 H), 3.50 -
3.55 (m, 6 H), 3.58 - 3.69 (m, 2 H), 3.70 - 3.83 (m, 2 H), 3.96 - 4.08 (m, 2 H), 4.38 - 4.49 (m, 7=8.13
Hz, 2 H), 4.76 - 4.87 (m, 0.7 H), 5.28 - 5.40 (m, 1.3 H), 6.14 - 6.33 (m, 2 H), 6.92 - 7.08 (m, 2 H),
7.27 - 7.38 (m, 7=8.02 Hz, 5 H), 7.62 (d, 7=8.35 Hz, 1H), 7.79 - 7.96 (m, 4 H), 9.87 - 9.98 (m, 2 H),
10.31 - 10.44 (m, 2 H); MS (ESI) m/z 981.1 (M+H)+.
Example 191
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)arruno]-3-memylbutanoyl}pyrrolidm-2-yI]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl]phenyl} - lH-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
methyl {(2S)-l-[(2S)-2-(5-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
t(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 191A
l-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-l,4-dione
Zinc chloride ( 2.73 g, 20 mmole)was treated with anhydrous benzene (10 mL) followed by
diethylamine (1.55 mL, 15 mmole) and tert-butanol (1.4 mL, 15 mmole) and the resulting slurry was
stirred at room temperature for 1.75 hr until all solids had dissolved. To the cloudy suspension was
added 4'-chloro-3'-nitroacetophenone followed by 2,4'-dibromoacetophenone and the resulting light
yellow slurry was stirred at room temperature for 68 hours. The resulting thick white slurry was
treated with 25 mL 5% aqueous sulfuric acid with stirring and the resulting slurry was filtered. The
solid was washed with water (50 mL), MeOH (50 mL)and CH2C12 (50 mL), then dried in vacuo at
room temperature for 1Hr and at 55°C for 5 hr. giving the title compound as a white solid, 3.4 g, 86%.
Example 19 IB
l-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-l,4-diol
The product from Example 191A (4.62 g, 11.65 mmole) was mixed with EtOH (100 mL) and
the resulting slurry was treated in portions over a five minute period with solid NaBEL, (0.97 g, 25.6
mmole). The resulting foaming slurry was stirred and heated at reflux for 1Hr. The reaction was
deemed complete by LC-MS. The reaction mixture was cooled to room temperature and concentrated
in vacuo to an oily residue. The residue was dissolved in CH2Q2 and applied to an 80 g silica gel
column. The column was eluted with a gradient of hexane/acetone, 90/10 to 20/80 over 32 minutes.
The fractions containing product were pooled and concentrated in vacuo giving the tide compound as
a white solid, 3.14 g, 67%.
Example 191C
l-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-l,4-diyldimethanesulfonate
The product from Example 191B (3.14 g, 7.84 mmole) was dissolved in 70 mL CH2C12 and
cooled in an ice-acetone bath to -10 °C. Triethylamine (3.82 mL, 27.4 mmole) was added dropwise to
the cold solution, followed by dropwise addition of methanesulfonyl chloride (1.53 mL, 19.59 mmole)
in 20 mL CH2C12 over 10 minutes. The resulting clear solution was stirred in the cold for 90 min. The
reaction was deemed complete by LC-MS analysis and the solvent was removed in vacuo leaving a
light yellow solid as the title compound, (4.36 g, 100%), that was used directly in the next reaction.
Example 191D
2-(4-bromophenyl)-l-(4-tert-butylphenyl)-5-(4-chloro-3-nitrophenyl)pyrrolidine
The light yellow solid, obtained in Example 191C (4.36 g, 7.84 mmole) was treated with
DMF (15 mL) followed by dropwise addition of 4-tert-butylaniline (12.47 mL, 78 mmole), then
placed in an oil bath at 52 °C and stirred for a total of 12 hr. The reaction mixture was concentrated in
vacuo to an oily residue. The mixture was diluted with 100 mL EtOAc and washed with 50 mL 0.5 M
HC1. The aqueous layer was back extracted with 100 mL EtOAc. The combined organic extracts
were washed with 10% NaHC03, 10% NaCl, dried over anhydrous Na2S04(s), filtered and solvent
removed in vacuo leaving a reddish oil. The oil was dissolved in CH2C12 (10 mL) and applied to an
80 g silica gel column. The column was eluted with a gradient of hexane/Acetone, 90/10 to 30/70
over 32 minutes. The title compound was isolated as a 1:1 mixture of cis and trans-pyrrolidine
isomers, 3.13 g, 75%.
Example 191E
4-(5-(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-yl)-N-(2,4-dimethoxybenzyl)-2-nitroaniline
The product from Example 191D (1.1 g, 2.14 mmole) was treated with 2,4-
dimethoxybenzylamine (3.22 mL, 21.41 mmole) and the resulting slurry was heated at 140 °C (oil
bath) for 1Hr. The resulting homogeneous red reaction mixture was concentrated in vacuo leaving a
red oil. The oil was diluted with 30 mL CH2C12, filtered solid and applied the filtrate to a 120 g silica
gel column. The column was eluted with CH2C12 over a 25 min period. The fractions were pooled
and concentrated in vacuo giving the tide compound as an orange foamy solid as a mixture of
stereoisomers (1.18 g).
Example 191F
4-(5-(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-yl)-Nl-(2,4-dimethoxybenzyl)benzene-l,2-
diamine
The product from example 191E (1.18 g, 1.831 mmole) was dissolved in a mixture of THF( 10
mL):EtOH(10 mL):EtOAc (10 mL), treated with Pt02 (42 mg)and evacuated 10 minutes, followed by
introduction of H2 (g) via balloon. The reaction mixture was stirred overnight at room temperature.
The next day, the reaction mixture was filtered and the solvent removed in vacuo leaving a dark green
foamy solid. The solid was dissolved in 10 mL CH2C12 applied to a 40 g silica gel column and eluted
with a gradient of hexane/EtOAc; 90/10 to 30/70 over 20 minutes. The tide compound was isolated
as a white foamy solid as a mixture of isomers 0.54 g, 48%.
Example 191G
methyl (2S)-1 -((2S)-2-(5-(5-(4-bromophenyl)-1 -(4-tert-butylphenyl)pyrrolidin-2-yl)-2-(2,4-
dimethoxybenzylamino)phenylcarbamoyl)pyrrolidin-l-yl)-3-metbyl-l-oxobutan-2-ylcarbamate
(S)-l-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrroIidine-2-carboxylic acid
(0.339g, 1.245 mmole) and HOBt (0.191 g, 1.245 mmole) were dissolved in DMF (4 mL) cooled in
an ice bath and treated with ED AC (0.245 g, 1.245 mmole) and N-Methylmorpholine (NMM) (0.55
mL, 4.98 mmole). The resulting solution was stirred 5 minutes in the ice bath, treated dropwise with
the product from Example 19 IF in DMF (4 mL) and the resulting dark mixture was stirred in the ice
bath for 1Hr then at room temperature for 18 hr. The next day, the reaction mixture was diluted with
EtOAc (50 mL) and the organic layer was washed with 10% NaHC03 and 10% NaCl, dried over
anhydrous Na2S04(s), filtered and the solvent was removed in vacuo leaving an oily residue as the
title compound as a mixture of isomers (0.65 g). ESI+ (m/z): 868.2.
Example 191H
methyl (2S)-l-((2S)-2-(2-amino-5-(5-(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-
yl)phenylcarbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate
The product from example 191G (0.65 g, 0.748 mmole) was dissolved in CH2C12 (10 mL)
then added concentrated trifluoroacetic acid (2 mL, 26 mmole)) and the reaction mixture was stirred
10 minutes. The solvent was removed in vacuo and the residue was re-evaporated twice from CH2C12
and once from toluene. The residue was dissolved in EtOAc (100 mL) washed with 10% NaHC03,
dried over anhydrous Na2S04(s), filtered and solvent removed in vacuo leaving a brown foamy
material as the title compound as a mixture of isomers (0.5 g).
Example 1911
methyl (2S)-l-((2S)-2-(6-(5-(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-yl)-lH-
benzo[d]imidazol-2-yl)pyrrolidin-1 -yl) -3 -methyl-1 -oxobutan-2-ylcarbamate
The product from Example 191H (0.5 g, 0.696 mmole) was treated with acetic acid (5 mL, 87
mmole) and heated in an oil bath at 75 °C for 70 min. The reaction mixture was cooled to room
temperature and concentrated in vacuo leaving an oily residue. The residue was dissolved in EtOAc
(100 mL) washed with 10% NaHC03 (20 mL ) and 10% NaCl (20 mL), dried over anhydrous
Na2S04(s), filtered and solvent removed in vacuo leaving a brown foamy solid. The residue was
dissolved in 10 mL CH2C12 and applied to a 12 g silica gel column. The column was eluted with a
gradient of CH2C12/MeOH, 99/1 to 95/5 over 15 minutes and the product was isolated as a tan solid
as a mixture of isomers (0.31g). ESI(m/z)+: 702.3.
Example 191J
methyl (2S)-l-((2S)-2-(6-(l-(4-tert-butylphenyl)-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)phenyl)pyn-olidin-2-yl)-lH-benzo[d]imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-
ylcarbamate
The product from Example 1911 (0.31g, 0.442 mmole), bis(pinacolato)diboron (0.34 g, 1.327
mmole) and potassium acetate (0.17 g, 1.77 mmole) were combined and dissolved in toluene (5 mL),
added l,l'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (32 mg,
0.044 mmole) and the reaction mixture was bubbled with N2 for 5 minutes, sealed and placed in an oil
bath at 95°C for 2 hr. The mixture was cooled to room temperature and diluted with EtOAc (100 mL)
washed with water (20 mL) and 10% NaCl (20 mL), dried over anhydrous Na2S04(s), filtered and
solvent removed in vacuo leaving a brown oil. The oil was dissolved in CH2C12 (10 mL), applied to a
12 g silica gel column and the column was eluted with a gradient of hexane:EtOAc, 50:50 to 0:100
over 18 minutes. The title compound was isolated as a white solid as a mixture of isomers (0.23 g).
Example 191K
(2S)-tert-butyl2-(5-(4-(l-(4-tert-butylphenyl)-5-(2-((S)-l-((S)-2-(methoxycarbonylamino)-3-
memylbutanoyl)pyrrolidin-2-yl)-lH-benzo[d]irrudazol-6-yl)pyrrohN-2-yl)phenyl)-lH4midazol-2-
yl)pyrrolidine-1 -carboxylate.
The product from example 191J (0.23g, 0.308 mmole) and the product from Example 26D
(0.195g, 0.615 mmole) were combined in a 20 mL microwave tube and dissolved in toluene (1.5
mL)/ethanol(1.5 mL). To this solution was added 1M aqueous sodium carbonate 0.92 mL, 0.92
mmole) followed by l,l'-bis(diphenylphosphino)ferrocenedichloro palladium(n) dichloromethane
complex (23 mg, 0.036 mmole) and the resulting mixture was bubbled with N2 for 10 minutes, sealed
and heated at 100°C for 2 hr. The reaction mixture was cooled to room temperature and diluted with
EtOAc (50 mL). The aqueous carbonate layer was separated and the organic layer was washed with
water (20 mL) and 10% NaCl (20 mL), dried over anhydrous Na2S04(s), filtered and solvent removed
in vacuo leaving a foamy solid. The solid was dissolved in 10 mL CH2C12 and applied to a 12 g silica
gel column. The column was eluted with a gradient of CH2C12/MeOH, 99/1 to 95/5 over 20 minutes.
The title compound was obtained as a tan solid as a mixture of isomers (0.1 lg).
Example 191L
(2S)-2-(5-(4-(l-(4-tert-butylphenyl)-5-(2-((S)-l-((S)-2-(methoxycarbonylamino)-3-
memylbutanoyl)pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrroliNn-2-yl)phenyl)4H-imidazol-2-
yl)pyrrolidinium chloride
The product from example 191K (0.11 g, 0.28 mmole) was dissolved in dioxane (2 mL), then
added 4N HCl/dioxane (1 mL). The resulting solid mass is stirred 30 minutes at room temperature.
The solvent is removed in vacuo leaving a tan solid as the title compound as a mixture of isomers
(0.092g) which stored under vacuum overnight.
Example 191M
methyl {(2S)-l-[(2S)-2-(5-{4-[(2S,5S)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyirolidin-2-yl]-lH-benziiiiidazol-6-yl}pyrrolidin-2-
yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
and
methyl {(2S)-l-[(2S)-2-(5-{4-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] phenyl} -1H-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
The product from example 191L (0.092g, 0.116 mmole) , (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid (0.020 g, 0.116 mmole)and HOBt (000.018g, 0.116 mmole) were combined in a
25 mL RB flask and dissolved in DMF (1 mL). The reaction mixture was placed in an ice bath and
treated with EDAC (0.022g, 0.116 mmole) and N-methylmorpholine (0.12 mL, 1.091 mmole. The
light yellow reaction mixture was stirred in the ice bath for 1Hr, then stirred at room temperature for 9
hr. The reaction mixture was diluted with EtOAc (100 mL) washed with water (20 mL) and 10%
NaCl (20 mL), dried over anhydrous Na2S04(s), filtered and solvent removed in vacuo leaving an oily
residue. The residue was dissolved in 5 mL CH2C12 and applied to a 12 g silica gel column. The
column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over 22 minutes. The title
compound was isolated from the first fraction eluted from the column as a white solid consisting of a
mixture of trans-pyrrolidine isomers, 21 mg, 19%. !H NMR (400 MHz, DMSO-d6) S ppm 0.71 - 0.95
(m, 12 H) 1.11 (s, 9 H) 1.99 (m, 6 H) 2.13 (m, 4 H) 3.53 (s, 6 H) 3.81 (m, 4 H) 4.04 (m, 4 H) 5.06 (m,
2 H) 5.11 - 5.15 (m, 1H) 5.18 - 5.26 (m, 1H) 5.32 (m, 1H) 6.25 (m, 2 H) 6.86 - 6.96 (m, 1H) 7.05
(m, 2 H) 7.33 (m, 6 H) 7.61 (m, 2 H) 11.53 (s, 1H) 11.68 (s, 1H) 12.00 (m, 2 H); ESI+: 914.5.
Example 192
methyl {(25)-l-[(25')-2-(5-{4-[(2i?,55)-l-(4-tert-butylphenyl)-5-{2-[(25,)-l-{(2>S,)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidm-2-yl]-l//-benzimidazol-6-yl}pyrrolidin-2-
yl]phenyl}- l#-imidazol-2-yl)pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
and
methyl {(25)-l-[(21S)-2-(5-{4-[(25,5R)-l-(4-tert-butylphenyl)-5-{2-[(25)-l-{(2lS)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrroUdm-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yljphenyl} - l//-imidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
The title compound was isolated from the late fraction eluted from the column described in
Example 191M as a white solid as a mixture of cis pyrrolidine isomers, 18 mg, 17%.1H NMR (free
base) (400 MHz, DMSO-d6) £ppm 0.71 - 0.95 (m, 12 H) 1.11 (s, 9 H) 1.99 (m, 6 H) 2.13 (m, 4 H)
3.53 (s, 6 H) 3.81 (m, 4 H) 4.04 (m, 4 H) 4.72 (m, 1H), 4.83 (m, 1H) 5.11 - 5.15 (m, 1H) 5.18 - 5.26
(m, 1H) 5.32 (m, 1H) 6.25 (m, 2 H) 6.86 - 6.96 (m, 1H) 7.05 (m, 2 H) 7.33 (m, 6 H) 7.61 (m, 2 H)
11.53 (s, 1H) 11.68 (s, 1H) 12.00 (m, 2 H); ESI+: 914.5.
dimethyl ([(2S,5S)-1 - {4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis {benzene-
4, l-diylimino[(25)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
and
dimethyl ([(2i?,5R)-l-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl)pyrrolidine-2,5-diyl]bis{benzene-
4,l-diylimino[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
Example 86A and 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
were processed using sequentially the methods of Examples 99A, 99B, and IF (substituting (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid ( 38.2mg, 0.218mmole) for (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid). Reverse phase (Cis) HPLC provided the title
compound, a white solid, as a 1:1 mixture of trans diastereomers (40.4mg, 50.6% yield). 1H NMR
(free base) (400 MHz, DMSO-D6) δ ppm 0.89 (d, 7=6.72 Hz, 12 H) 1.67 (d, J=5.64 Hz, 2 H) 1.92 -
2.04 (m, 2 H) 3.37 - 3.41 (m, 4 H) 3.53 (d, 7=2.06 Hz, 6 H) 3.67 (d, 7=5.10 Hz, 4 H) 3.94 (t, 7=8.08
Hz, 2 H) 5.25 (s, 2 H) 6.33 (d, 7=8.67 Hz, 2 H) 6.78 (d, 7=8.89 Hz, 1H) 7.14 - 7.23 (m, 6 H) 7.32 (d,
7=8.67 Hz, 2 H) 7.54 (d, 7=7.92 Hz, 4 H) 7.66 (dd, 7=8.84, 2.55 Hz, 1H) 8.26 (d, 7=2.49 Hz, 1H)
10.01 (s, 2 H). MS ESI(+) m/z @ 806.5 (M+H)+.
Example 194
dimethyl ({(2S,5S)-1 -[4-( 1 -hydroxy-2-meihylpropan-2-yl)phenyl]pyrrolidine-2,5-diyl }bis {benzene-
4,1 -diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate)
Example 194A
ethyl 2-methyl-2-(4-nitrophenyl)propanoate
Into a 500mL Morton flask equipped for mechanical stirring was added at room temperature
under nitrogen ethyl 2-(4-nitrophenyl)acetate (lO.Og, 55.2mmole), anhydrous dimethylformamide
(200mL) 18-crown-6 (2.189g, 8.28mmole) and methyl iodide (23.13mL, 370mmole). The flask was
cooled in an ice bam and sodium hydride as a 60% mineral oil dispersion (7.73g, 193mmole) was
added in portions so as to maintain the internal temperature at or below +10°C. The addition required
fifty three minutes. On completion of the addition the reaction mixture was allowed to slowly warm to
room temperature and stirred overnight. Subsequent cooling in an ice bath was followed by the drop
wise addition of water (200mL) with vigorous stirring. The mixture was partitioned between water
(1200mL) and ethyl ether (200mL). The aqueous phase was extracted with ethyl ether (3x200mL
each) and the combined organics water washed (3xl50mL), dried over MgS04, filtered and
concentrated to provide the title compound in nearly quantitative yield sufficiently pure for use as
isolated.
Example 194B
2-methyl-2-(4-nitrophenyl)propan-1 -ol
To a solution of the product from Example 194A (12.32g, 55.2mmole) in anhydrous THF
(300mL) at room temperature under nitrogen was added dropwise via cannulae 1M BH3 in THF
(200mL) over ten and one half minutes. On completion of the addition the flask was equipped with a
condenser and the mixture heated under nitrogen to reflux in an oil bath for ten hours before cooling
to room temperature. The reaction was quenched by the cautious drop wise addition of methanol
(60mL).The resulting mixture was concentrated to an oil which was then dissolved in ethyl acetate
(150mL) and treated with IN HC1 and allowed to stir at room temperature for one hour. The
resulting organic phase was washed with brine (4x50mL), dried over MgS04, filtered and
concentrated. The residue was taken up in toluene (25mL) and re-concentrated. The oily solid was
suspended in hexane (50mL) and collected by vacuum filtration. The cake was washed with hexane
(50mL) then dried under vacuum to provide the title compound (9.55g, 89% yield) as a light orange
solid. MS (DCI+) m/z @ 213.1 (M+NH4)+-
Example 194C
2-(4-aminophenyl)-2-methylpropan-1 -ol
The product from Example 194B (0.321g, 1.644mmole) was dissolved in a mixture of THF
(lOmL) and ethanol (2mL). To this was added platinum(IV)oxide (0.030g, 0.131mmole). The flask
was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced
via a balloon and the mixture stirred at room temperature. An additional 38.2mg ( 0.167mmole) of
catalyst was added in two aliquots before chromatographic analysis indicated that the starting
material was consumed. After stirring overnight under hydrogen the mixture was filtered through a
sand Jcelite plug followed by an ethyl acetate rinse. The filtrate was concentrated to dryness and the
residue purified by chromatography on amine modified silica gel eluting with ethyl acetate - hexane
beginning at 8% and advancing to 66% ethyl acetate to provide the title compound (0.3645g, 68%
yield) as a clear oil. MS (DCI+) m/z @ 183.1 (M+NH4)+.
Example 194D
2-(4-((2S,5S)-2,5-bis(4-nitrophenyl)pyrrolidin-l-yl)phenyl)-2-methylpropan-l-ol
The product from Example 194C (0.595g, 3.60mmole) was combined in DMF (3mL) with
(lR,4R)-l,4-bis(4-nitrophenyl)butane-l,4-diyl dimethanesulfonate (0.259g, O.530mmole), prepared as
described in Example 37C, then heated overnight under nitrogen in an oil bath at 50°C. The reaction
mixture was partitioned between ethyl acetate (50mL) and water (50mL). The organic phase was
water washed (3x25mL), dried over MgS04, filtered and concentrated to an oil. Chromatography on
silica gel eluting with ethyl acetate - hexane provided the title compound (0.0835g, 34.1% yield) as
an orange semi-solid.
Example 194E
2-(4-((2S,5S)-2,5-bis(4-aminophenyl)pyrrolidin-1 -yl)phenyl)-2-methylpropan-1 -ol
The product from Example 194D ( 83.5mg, 0.181mmole) was reacted as described in
Example 99B to provide the title compound in quantitative yield as a light yellow solid. MS (DCI+)
m/z @ 402.3 (M+H)+.
Example 194F
dimethyl ({(2S,5S)-l-[4-(l-hydroxy-2-methylpropan-2-yl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-
4,1 -diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate)
The product from Example 194E (73.0mg, 0.181mmole) was reacted with the product from
Example 37B (104.0mg, 0.380mmole) as described in Example 37F. The title compound was isolated
after purification by reverse phase (C18) HPLC as an off white solid (97.4mg, 59% yield). 1H NMR
(free base) (400 MHz, DMSO-D6) 8 ppm 0.79 - 0.96 (m, 12 H) 1.03 (s, 6 H) 1.61 (s, 2 H) 1.76 - 2.04
(m, 8 H) 2.04 - 2.17 (m, 2 H) 3.20 (dd, 7=5.42, 1.84 Hz, 2 H) 3.51 (s, 6 H) 3.60 (dd, 2 H) 3.78 (s, 2 H)
4.01 (t, 7=8.46 Hz, 2 H) 4.35 - 4.49 (m, 3 H) 5.14 (s, 2 H) 6.16 (d, 7=8.78 Hz, 2 H) 6.89 (d, 7=8.78
Hz, 2 H) 7.12 (d, 7=8.57 Hz, 4 H) 7.29 (d, 7=8.35 Hz, 2 H) 7.48 (d, 7=8.46 Hz, 4 H) 9.97 (s, 2 H). MS
ESI(+), m/z @ 910.7 (M+H)+.
Example 195
me%l[(15',2^)-2-memoxy4K{(2^-244K4-{5-[4-(2-{(25)4-[N-(methoxycarbonyl)-O-methyl-L-
tlu-eonyl]pyrroUdm-2-yl}-lH-irmdazol-4-yl)phenyl]-l-(6-piperidm-l-ylpyridin-3-yl)-17!r-pyrrol-2-
yl}phenyl)-lH-imidazol-2-yl]pyrrolidin-l-yl}carbonyl)propyl]carbamate
The title compound was prepared using the methods from Example 144E substituting
(2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-
methylbutanoic acid to provide the title compound (280 mg, 37% yield). 1H NMR (400 MHz,
DMSO-D6) δ 12.12 - 11.70 (m, 2H), 7.85 - 7.76 (m, 1H), 7.63 - 7.49 (m, 4H), 7.49 - 7.39 (m, 2H),
7.34 - 7.03 (m, 7H), 6.77 - 6.69 (m, 1H), 6.54 - 6.41 (m, 2H), 5.08 - 4.99 (m, 2H), 4.27 (t, 7 = 7.6,
2H), 3.86 - 3.75 (m, 4H), 3.54 (s, 6H), 3.50 - 3.43 (m, 4H), 3.17 (s, 6H), 2.19 - 1.88 (m, 10H), 1.61 -
1.44 (m, 6H), 1.12 - 0.99 (m, 6H). MS (ESI; M+H) m/z = 997.
iV-(methoxycarbonyi)-L-valyl-iV- {4- [(2S,5S>5 -(4- {[iV-(methoxycarbonyl)-L-valyl] amino} phenyl)-1 -
{4-[6-(morpholm-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
and
Ar-(methoxycarbonyl)-L-valyl-Af-{4-[(2R,5/?)-5-(4-{[N-(methoxycarbonyl)-L-valyl]amino}phenyl)-l-
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
Example 196 A
methyl (2S)-l-(4-(5-(4-aminophenyl)-l-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidin-2-
yl)phenylamino)-3-methyl-1 -oxobutan-2-ylcarbamate
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved 4,4'-(l-(4-(6-
morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline (30 mg, 0.061 mmol; prepared from
Example 86A and 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine using
the methods of Examples 99A and 99B), and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(11.22 mg, 0.064 mmol) in anhydrous DMSO (1 mL), added HATU (26.3 mg, 0.067 mmol) and
diisopropylethylamine (0.021 mL, 0.122 mmol), and stirred yellow solution at 25 °C for 30 min.
Diluted the reaction with MeOH (1 mL) and purified by RP-Ci8 HPLC (Waters Prep LC, 40mm
Module with Nova Pak HR Ci8 6um 40x100mm Prep Pak cartridge) eluting with a 30 min gradient of
95:5 0.1% TFA in H20/AcCN to 25:75 0.1% TFA in H20/AcCN, then 10 min to 100% AcCN at 20
mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume,
partitioned between 20% iPrOH/CHCl3 (50 mL) and sat'd aq NaHC03 (15 mL), separated layers,
dried the organic extract over anhydrous MgSC>4, filtered, and concentrated by rotary evaporation to
afford the title compound as an off-white solid (14.6 mg, 37%) as a mixture of stereoisomers. MS
(ESI+) m/z 649 (M+H)+, 707 (M+AcCN+NRt)*, 1297 (2M+H)+.
Example 196B
N-(methoxycarbonyl)-L-valyl-N- {4- [(2S,5S)-5 -(4- {[N(methoxycarbonyl)-L-valyl] amino }phenyl)-1 -
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
and
Af-(methoxycarbonyl)-L-valyl-N- {4-[(2R,5R)-5-(4- {[N-(methoxycarbonyl)-L-valyl]amino } phenyl)-1 -
{4-[6-(morphoUn-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide
In a nitrogen-purged 5-mL round bottom flask, dissolved the product of Example 196A (14
mg, 0.022 mmol) in anhydrous DMSO (1 mL), added the product of Example 37B (6.46 mg, 0.024
mmol), HATU (9.30 mg, 0.024 mmol), and diisopropylethylamine (7.54 ^L, 0.043 mmol). Stirred at
25 °C for 1Hr, diluted the reaction with MeOH (1 mL) and purified by RP-Ci8 HPLC (Waters Prep
LC, 40mm Module with Nova Pak HR Ci8 6^m 40x100mm Prep Pak cartridge) eluting with a 30 min
gradient of 95:5 0.1% TFA in H20/AcCN to 25:75 0.1% TFA in H20/AcCN, then 10 min to 100%
AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°C) to
near-dryness, the residue taken up in 1:5 v/v CH2Cl2/hexanes and evaporated (3 times), and the
residue dried in vacuo to give a yellow solid (llmg). The TFA salt was dissolved in 20%
iPrOH/CHCl3 (30 mL), washed thoroughly with sat'd aq NaHC03 (5 mL), extracted the aqueous
phase with 20% iPrOH/CHCl3 (20 mL), dried the combined organic extracts over anhydrous MgS04,
filtered, and concentrated by rotary evaporation to afford the title compounds as a white solid (7 mg,
35%).1H NMR (400 MHz, DMSO-D6) δ ppm 0.83 - 0.96 (m, 12 H), 1.60 -1.71 (m, 2 H), 1.81 - 2.21
(m, 7 H), 3.36 - 3.43 (m, 4 H), 3.49 - 3.56 (m, 6 H), 3.58 - 3.65 (m, 1H), 3.65 - 3.70 (m, 4 H), 3.75 -
3.85 (m, 1H), 3.94 (t, 7=8.08 Hz, 1H), 4.02 (t, 7=8.19 Hz, 1H), 4.42 (dd, 7=7.86, 4.93 Hz, 1H), 5.24
(d, 7=5.31Hz, 2 H), 6.32 (d, 7=8.35 Hz, 2 H), 6.78 (d, 7=9.00 Hz, 1H), 7.13 - 7.19 (m, 4 H), 7.21 (d,
7=8.78 Hz, 2 H), 7.26 - 7.35 (m, 2 H), 7.48 - 7.56 (m, 4 H), 7.66 (dd, 7=7.86, 1.14 Hz, 1H), 8.25 (d,
7=2.17 Hz, 1H), 10.00 (d, 7=3.47 Hz, 2 H); MS (ESI+) m/z 903 (M+H)+.
Example 197
methyl {(2iS)-l-[(2S)-2-(4-{4-[(25,55)-l-(4-tert-butylphenyl)-5-(4-{2-[(25)-l-{(25)-2-
[(methoxycarbonyl)amino] -3,3-dimethylbutanoyl }pyrrolidin-2-yl]- lH-imidazol-4-
yl }phenyl)pyrrolidin-2-yl]phenyl} -lH-imidazol-2-yi)pyrrolidin-1 -yl]-3,3-dimethyl-l -oxobutan-2-
yl {carbamate
and
methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R> 1 -(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(25)-2-
[(memoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-4-
yl} phenyl)pyrrolidin-2-yl]phenyl} - l/7-imidazol-2-yl)pyrrolidin-1 -yl] -3,3 -dimethyl-1 -oxobutan-2-
yl {carbamate
The product from Example 42F (0.228 g, 0.364 mmol) was processed as in Example 1H to
give 0.035 g (10%) of the title compound as a solid as a mixture of trans isomers. 1H NMR (free
base) (400 MHz, DMSO-D6) δ ppm 0.91 (d, J=7.59 Hz, 18 H) 1.08 (s, 9 H) 1.63 - 1.73 (m, 2 H) 1.83
- 2.24 (m, 12 H) 3.54 (s, 6 H) 3.70 - 3.80 (m, 2 H) 4.21 (d, J=7.92 Hz, 2 H) 5.06 (dd, J=6.99, 3.52 Hz,
2 H) 5.15 - 5.25 (m, 2 H) 6.21 (d, J=8.67 Hz, 2 H) 6.92 (dd, J=8.73, 2.44 Hz, 2 H) 7.05 (d, J=8.78 Hz,
2 H) 7.14 (dd, J=8.24, 3.47 Hz, 4 H) 7.37 (s, 2 H) 7.61 (d, J=8.02 Hz, 4 H) 11.69 (s, 2 H); MS ESI+
m/z 968.8 (M+H)+.
Example 198
methyl [(2^-l-{(25)-2-[(4-{(2J?,5/?)-5-{4-[({l-[(25)-2-[(methoxycarbonyl)amino]-4-
(methylsulfanyl)butanoyl]pyrrolidin-2-yl} carbonyl)amino]phenyl} -1 -[4-
(trifluoromethyl)phenyl]pyrrolidm-2-yl}phenyl)carbamoyl]pyrrolidin-l-yl}-4-(methylsulfanyl)-l-
oxobutan-2-yl] carbamate
Example 198A
(S)-2-(methoxycarbonylamino)-4-(methylthio)butanoicacid
To a solution of (S)-2-ammo-4-(methylthio)butanoic acid (1.0 g, 6.7 mmol) in dioxane at 0 °C
was added NaOH (11.06 g, 22.12 mmol) followed by dropwise addition of methyl chloroformate
(1.04 mL, 13.4 mmol) and the solution was warmed to room temperature with stirring over 2 h. The
solution was diluted with EtOAc, washed with 1 N HC1, brine, dried (Na2S04), filtered and solvent
removed in vacuo to give the tide compound (1.3 g, 6.27 mmol, 94%). JH NMR (400 MHz, CDC13) 8
ppm 1.95-2.07 (m, 1H) 2.07-2.13 (m, 3H) 2.14-2.28 (m, 1H) 2.59 (t, J=7.4 Hz, 2H) 3.71 (s, 3H) 4.52
(brs, lH)5.33(brs, 1H).
Example 198B
(2S,2' S)-N,N' -(4,4' -((2R,5R)-1 -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1 -
phenylene)dipyrrolidine-2-carboxamide
Example 38A and 4-trifluoromethylaniline were processed using the methods of Examples
34A, 34B, 34C, and 34D to provide the title compound.
Example 198C
methyl [(2,S,)-l-{(25)-2-[(4-{(2i?,57?)-5-{4-[({l-[(25)-2-[(methoxycarbonyl)amino]-4-
(methylsulfanyl)butanoyl]pyrrolidin-2-yl}carbonyl)amino]phenyl}-l-[4-
(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-l-yl}-4-(methylsulfanyl)-l-
oxobutan-2-yl]carbamate
Example 198B and Example 198A were processed using the method of Example 1H to
provide the title compound which was purified by flash chromatography on silica gel eluting with 10-
80% EtOAc/CH2Cl2 (29 mg).1H NMR (400 MHz, CDC13) δ ppm 1.78 (d, J=6.1Hz, 2H) 1.83-2.00
(m, 6H) 2.02 (s, 6H) 2.04-2.26 (m, 4H) 2.43-2.61 (m, 8H) 3.47-3.83 (m, 4H) 3.69 (s, 6H) 4.75 (dd,
J=8.0, 2.0 Hz, 4H) 5.15 (d, J=6.7 Hz, 2H) 5.43 (d, 2H) 6.32 (d, J=8.7 Hz, 2H) 7.09 (d, J=8.5 Hz, 4H)
7.18 (d, J=8.8 Hz, 2H) 7.42 (d, J=8.6 Hz, 4H) 9.05 (s, 2H). MS (ESI) m/z 971 (M+H)+.
Example 199
methyl [(25,3iS,)-l-{(25)-2-[(4-{(2i?,5/?)-5-(4-{[(l-{(25,,35)-2-[(methoxycarbonyl)amino]-3-
methylpentanoyl} pyrrolidin-2-yl)carbonyl] amino }phenyl)-1 -[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl }phenyl)carbamoyl]pyrrolidin-1 -yl} -3-methyl-1 -oxopentan-2-yl] carbamate
Example 199 A
(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoicacid
To a solution of (2S,3S)-2-amino-3-methylpentanoic acid (1.0 g, 7.62 mmol) in dioxane (10
mL) at 0 °C was added NaOH (12.58 g, 25.2 mmol) followed by dropwise addition of methyl
chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to room temperature with stirring
over 2 h, diluted with EtOAc, washed with 1 N HC1, brine, dried (Na2S04), filtered and solvent
removed in vacuo to give the title compound (1.4 g, 7.4 mmol, 97%).1H NMR (400 MHz, CDC13) δ ppm 1.27-1.39 (m, 1H) 1.38-1.53 (m, 2H) 1.58-1.72 (m, 3H) 1.82-1.94 (m, 2H) 2.04 (d, J=3.8 Hz, 2H)
3.70 (s, 3H) 4.94 (br s, 1H).
Example 199B
memyl[(25,35)-l-{(2^-2-[(4-{(2i?,5/?)-5-(4-{[(l-{(25,36)-2-[(methoxycarbonyl)amino]-3-
methylpentanoyl }pyrrolidin-2-yl)carbonyl] amino } phenyl)-1 -[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl}phenyl)carbamoyl]pyrrolidin-l-yl}-3-methyl-l-oxopentan-2-yl]carbamate
To a solution of Example 198B (60 mg, 0.101 mmol) in DMSO (0.5 mL) was added Example
199A (48 mg, 0.254 mmol), followed by HATU (96 mg, 0.254 mmol) and N,N-
diisopropylethylamine (0.089 mL, 0.507 mmol) and the solution was stirred at room temperature for 1H. Diluted with EtOAc, washed with H20, brine, dried (Na2S04), filtered and removed solvent in
vacuo to give crude product which was purified by flash chromatography on silica gel eluting with
10-80% EtOAc/CH2Cl2 to give the tide compound (11 mg, 0.012 mmol, 12%).1H NMR (400 Hz,
CDC13) δ ppm 0.78-1.00 (m, 12H) 1.69-1.81 (m, 4H) 1.81-1.94 (m, 2H) 1.99-2.10 (m, 2H) 2.09-2.24
(m, 2H) 2.50 (br s, 2H) 2.53-2.61 (m, 2H) 3.63 (br s, 2H) 3.68 (s, 6H) 3.75-3.87 (m, 2H) 4.34 (t, J=8.5
Hz, 2H) 4.79 (d, J=6.3 Hz, 2H) 5.14 (d, J=6.6 Hz, 2H) 5.28 (d, J=9.3 Hz, 2H) 6.32 (d, J=8.7 Hz, 2H)
7.08 (d, J=8.4 Hz, 4H) 7.18 (d, J=8.8 Hz, 2H) 7.41 (d, J=8.5 Hz, 4H) 9.23 (s, 2H). MS (ESI) m/z 935
(M+H)+.
Example 200
methyl [(25',3i?)-3-methoxy-1 - {(2S)-2-[(4- {(2tf,5/?)-5-(4- {[(1 - {(2S,3i?)-3-methoxy-2-
[(methoxycarbonyl)ainino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-[4-
(trifluoromethyl)phenyl]pyrrolidin-2-yl }phenyl)carbamoyl]pyrrolidin-l -yl} -1 -oxobutan-2-
yl]carbamate
Example 200A
(2S,5R)-3-Methoxy-2-(memoxycarbonylamino)butanoic acid
A solution of O-methyl-L-threonine (1.01 g, 7.59 mmol) in saturated bicarbonate solution (93
mL) was treated dropwise with methyl chloroformate (900 (J.L, 1.10 g, 11.61 mmol), followed by
stirring at RT for 24 h. The mixture was extracted methyl t-butyl ether and cooled to 0 °C. The
mixture was adjusted to pH 1-2 by addition of concentrated hydrochloric acid solution. The mixture
was extracted with ethyl acetate (3 x) and the combined extracts were extracted with saturated sodium
chloride solution and dried (Na2S04). The solution was concentrated in vacuo to afford the title
compound (1.31 g, 90%) as a white solid. lR NMR (400 MHz, CDC13) δ 5.44 (d, J = 8.7 Hz, 1H),
4.39 (dd, J = 8.7, 2.3 Hz, 1H), 4.00 (dd, J= 6.2, 2.4 Hz, 1H), 3.71 (s, 3 H), 3.36 (s, 3 H), 1.21 (t, J =
7.2 Hz, 3 H). MS (+ESI) m/z (rel abundance) 192 (60, M+H), 209 (100, M+NH4).
Example 200B
methyl [(2,S',3i?)-3-methoxy-l-{(21S)-2-[(4-{(2i?,5/?)-5-(4-{[(l-{(25,3/?)-3-methoxy-2-
[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-[4-
(trifluoromethyl)phenyl]pyrrolidin-2-yl }phenyl)carbamoyl]pyrrolidin-1 -yl} -1 -oxobutan-2-
yl]carbamate
Example 198B (60 mg, 0.101 mmol) and Example 200A (48.5 mg, 0.254 mmol) were
processed in the same manner as Example 199B to give the title compound (10.5 mg, 0.011 mmol,
11%). 1H,NMR (400 MHz, CDC13) δ ppm 1.19 (s, 3H) 1.21 (s, 3H) 1.78 (d, J=6.1Hz, 2H) 1.94-2.16
(m, 6H) 2.40-2.57 (m, 4H) 3.36 (s, 6H) 3.66-3.84 (m, 6H) 3.69 (s, 6H) 4.64-4.72 (m, 2H) 4.81 (d,
J=8.1Hz, 2H) 5.14 (d, J=6.7 Hz, 2H) 5.64 (d, J=7.9 Hz, 2H) 6.31 (d, J=8.8 Hz, 2H) 7.08 (d, J=8.6 Hz,
4H) 7.18 (d, J=8.8 Hz, 2H) 7.43(d, J=8.6 Hz, 4H) 8.85 (s, 2H). MS (ESI) m/z 939 (M+H)+.
Example 201
methyl [(25,3^-3-methoxy-l-{(25)-2-[(4-{(2i?,5^)-5-(4-{[(l-{(21S',35)-3-methoxy-2-
[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-[4-
(trifluoromethyl)phenyl]pyrrolidin-2-yl }phenyl)carbamoyl]pyrrolidm-1 -yl} -1 -oxobutan-2-
yljcarbamate
Example 201A
f25,55'J-3-Methoxy-2-(methoxycarbonylarrjino)butanoic acid
A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mmol) in saturated sodium
bicarbonate solution (47.6 mL) was treated dropwise with methyl chloroformate (453 (iL, 553 mg,
5.85 mmol) followed by stirring at RT for 18 h. The mixture was extracted with ether and the
aqueous phase was cooled to 0 °C and acidified to pH 2-3 by addition of concentrated hydrochloric
acid solution. The mixture was extracted with ethyl acetate (3 x). The combined organic layers were
extracted with saturated sodium chloride solution and dried (Na2S04). Concentration in vacuo
afforded the title compound (640 mg, 86%) as a colorless oil.1H NMR (400 MHz, CDC13) δ 5.48 (d, J= 7.8 Hz, 1H), 4.52 (d, 7= 4.7 Hz, 1H), 3.71 (s, 3 H), 3.39 (s, 3 H), 1.25 (t, .7 = 7.6 Hz, 3 H).
Example 201B
methyl [(2S,3S)-3-methoxy-1 - {(25)-2-[(4- {(2R,5R)-5-(4-{[(1 - {(l.S'.S^-S-methoxy^-
[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-[4-
(trifluoromemyl)phenyl]pyrrolidin-2-yl }phenyl)carbamoyl]pyrrolidin-l -yl} -1 -oxobutan-2-
yl]carbamate
Example 198B (40 mg, 0.068 mmol) and Example 201A (32.3 mg, 0.169 mmol) were
processed in the same manner as Example 199B to give the title compound (22 mg, 0.023 mmol,
35%).1H NMR (400 MHz, CDC13) 8 ppm 1.24 (s, 3H) 1.25 (s, 3H) 1.78 (d, J=6.2 Hz, 2H) 1.87-1.99
(m, 2H) 1.99-2.16 (m, 4H) 2.45-2.58 (m, 4H) 3.20 (s, 6H) 3.46-3.56 (m, 2H) 3.65-3.83 (m, 6H) 3.69
(s, 6H) 4.51-4.59 (m, 2H) 4.78 (d, J=6.7 Hz, 2H) 5.14 (d, J=6.7 Hz, 2H) 5.39 (d, J=9.3 Hz, 2H) 6.30
(d, J=8.7 Hz, 2H) 7.08 (d, J=8.5 Hz, 4H) 7.16 (d, J=8.8 Hz, 2H) 7.40 (d, J=8.5 Hz, 4H) 8.94 (s, 2H).
MS (ESI) m/z 939 (M+H)+.
Example 202
methyl [(15')-2-{(25)-2-[(4-{(2i?,5/?)-5-(4-{[(l-{(25,)-2-[(methoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl }phenyl)carbamoyl]pyrrolidin-1 -yl} -2-oxo-1 -phenylethyl] carbamate
Example 202A
(S)-2-(methoxycarbonylamino)-2-phenylaceticacid
To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g, 3.31 mmol) in dioxane at 0 °C was
added NaOH (5.46 g, 10.92 mmol) followed by dropwise addition of methyl chloroformate (0.51 mL,
6.62 mmol) and the solution was warmed to room temperature with stirring over 1H. Diluted with
EtOAc, washed with 1 N HC1, brine, dried (Na2S04), filtered and removed solvent in vacuo to give
the title compound (0.35 g, 1.673 mmol, 51%).
Example 202B
methyl [(l^-2-{(2^-2-[(4-{(2^,5R)-5-(4-{[(l-{(25)-2-[(methoxycarbonyl)amino]-2-
phenylacetyl }pyrrolidin-2-yl)carbonyl] amino }phenyl)-l -[4-(trifluoromethyl)phenyl]pyrrolidin-2-
yl }phenyl)carbamoyl]pyrrolidin- 1-yl} -2-oxo-1 -phenylethyl] carbamate
Example 198B (40 mg, 0.068 mmol) and Example 202A (35 mg, 0.169 mmol) were
processed in the same manner as Example 199B to give the title compound (7.5 mg, 7.7 (xmol, 11%).
2H NMR (400 MHz, CDC13) δ ppm 1.76-2.05 (m, 8H) 2.43-2.58 (m, 4H) 3.18-3.29 (m, 2H) 3.57-3.65
(m, 2H) 3.67 (s, 6H) 4.82-4.86 (m, 2H) 5.18 (d, J=6.9 Hz, 2H) 5.48 (d, J=7.7 Hz, 2H) 5.99 (d, J=7.7
Hz, 2H) 6.35 (d, J=8.8 Hz, 2H) 7.11 (d, J=8.5 Hz, 4H) 7.21 (d, J=8.7 Hz, 2H) 7.27-7.32 (m, 4H) 7.32-
7.43 (m, 10H) 8.92 (s, 2H). MS (ESI) m/z 975 (M+H)+.
Example 203
methyl [(2,S')-3-methoxy-l-{(21S)-2-[(4-{(2i?,5R)-5-(4-{[(l-{(2lS)-3-methoxy-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyiTolidin-2-yl)carbonyl]amino}phenyl)-l-[4-
(trifluoromethyl)phenyl]pyrrolidm-2-yl}phenyl)carbamoyl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-
yljcarbamate
Example 203A
f5'J-(ferf-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid
A solution of die f5J-2-amino-3-hydroxy-3-methylbutanoic acid (252 mg, 1.89 mmol) in
saturated sodium bicarbonate solution (6.3 mL) and tetrahydrofuran (6.3 mL) was treated with di-tert-
butyl-dicarbonate (764 mg, 3.50 mmol) followed by stirring at RT for 24 h. The mixture was
concentrated in vacuo to remove tetrahydrofuran and the mixture was extracted with hexanes. The
aqueous phase was cooled to 0 °C and was acidifed to pH 3 by addition of 1 M citric acid solution.
The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na2S04).
Concentration in vacuo afforded a gummy solid, containing other impurities in addition to the desired
product. This material was dissolved in ethyl acetate and the mixture filtered through a millipore
filter to remove undissolved material. The filtrate was concentrated in vacuo and after setting at RT
for a week, eventually solidified to give the title compound as a white solid. 1H NMR (400 MHz,
Methanol-^) δ 4.08 (s, 1H), 1.45 (s, 9 H), 1.29 (s, 3 H), 1.25 (s, 3 H). MS (-ESI) m/z (rel abundance)
232 (100, M-H).
Example 203B
(S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methylbutanoic acid
To a solution of Example 203 A (363 mg, 1.56 mmol) in THF (7 mL) at 0 °C was added NaH
(373 mg, 9.34 mmol) and stirring was continued for 15 min. Iodometihane (0.78 mL, 12.45 mmol)
was added and the solution was allowed to warm to room temperature and stirred for 18 h. Solution
was quenched with H20, diluted with EtOAc, washed with H20, brine, dried (Na2S04), filtered and
solvent removed to give the title compound (165 mg, 0.67 mmol, 43%). MS (ESI) m/z 248 (M+H)+.
Example 203C
(S)-3-methoxy-2-(methoxycarbonylamino)-3-methylbutanoic acid
To a solution of Example 203B (163 mg, 0.66 mmol) in CH2C12 (2 mL) was added
trifluoroacetic acid (2 mL) and the solution was stirred at room temperature for 1H. Solvent was
removed in vacuo and the residue was suspended in saturated NaHC03, extracted with EtOAc, the
organic extracts combined, washed with brine, dried (Na2S04), filtered and solvent removed in vacuo.
The residue was dissolved in dioxane (1 mL) and 1 M NaOH (1.1 mL, 2.175 mmol) was added
followed by the dropwise addition of methyl chloroformate (0.102 mL, 1.3 mmol). The solution was
stirred at room temperature for 16 h, diluted with EtOAc, washed with 1 N HC1, brine, dried
(Na2S04), filtered and solvent removed in vacuo to give the tide compound (96 mg, 0.468 mmol,
71%).
Example 203D
methyl [(25)-3-methoxy-l-{(25)-2-[(4-{(2J?,5R)-5-(4-{[(l-{(25)-3-methoxy-2-
[(memoxycarbonyl)airdno]-3-methylbutanoyl}pyrrolidin-2-yl)carbonyl]arnino}phenyl)-l-[4-
(trifluoromemyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-l-yl}-3-methyl-l-oxobutan-2-
yl]carbamate
Example 198B (80.7 mg, 0.136 mmol) and Example 203C (70 mg, 0.341 mmol) were
processed in the same manner as Example 199B to give the title compound (62 mg, 0.064 mmol,
47%). :H NMR (400 MHz, CDC13) δ ppm 1.25 (s, 3H) 1.33 (s, 3H) 1.39 (s, 2H) 1.74-1.82 (m,2H)
1.89 (s, 2H) 1.93-2.16 (m, 5H) 2.38-2.59 (m, 4H) 3.16-3.27 (m, 2H) 3.24 (s, 3H) 3.43-3.56 (m, 2H)
3.69 (s, 3H) 3.71-3.78 (m, 2H) 3.80 (s, 3H) 3.84-3.94 (m, 1H) 4.61 (s, 1H) 4.70-4.81 (m, 2H) 5.15 (d,
J=6.3 Hz, 2H) 5.58 (s, 1H) 6.32 (d, J=8.7 Hz, 2H) 7.05-7.13 (m, 4H) 7.19 (d, J=8.7 Hz, 2H) 7.33-7.50
(m, 4H) 8.71 (s, 1H) 8.92 (s, 1H). MS (ESI) m/z 967 (M+H)+.
Example 204
dimethyl ([(25,55)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2i?,5/?)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(25)pyrrolidine-2,1 -diyl[(25)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
Example 204A
(2S,2'S)-tert-butyl 2,2'-(3,3'-((2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
and
(2S,2'S)-tert-butyl2,2'-(3,3,-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate
The ether fraction from the work up of Example 55F was concentrated and purified by flash
chromatography (silica gel, dichloromethane/EtOAc) to afford the title compound as a mixture of
trans diastereomers (0.20 g, 10%). MS (ESI) m/z 742 (M+H)+.
Example 204B
dimethyl ([(25,55)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl]bis {benzene-3,1 -
diylcarbamoyl(25)pyrrolidine-2,1 -diyl[(25)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
and
dimethyl ([(2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,l-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(25)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 204A was processed using the method described in Examples 19D
and 19E (used (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid) to afford the title compounds
(60.5 mg, 22%). lR NMR (free base) (400 MHz, DMSO-D6) δ 0.99 - 0.81 (m, 12H), 1.67 (dd, J =
3.4, 5.0, 3H), 2.06 -1.79 (m, 8H), 2.20 - 2.06 (m, 5H), 3.52 (d, J = 2.3, 6H), 3.63 (q, J = 7.1, 1H), 3.88
- 3.75 (m, 1H), 4.08 - 3.96 (m, 2H), 4.41 (dt, J = 12.8, 25.2, 2H), 5.11 (d, J = 28.1, 2H), 6.24 (dd, J =
6.0, 10.9, 2H), 6.80 (td, J = 4.2, 8.9, 2H), 6.88 (dd, J = 5.5, 6.4, 2H), 7.22 (ddd, J = 5.3, 10.4, 20.8,
2H), 7.32 (d, J = 8.3, 2H), 7.43 - 7.34 (m, 2H), 7.57 (d, J = 7.8, 2H), 10.00 (d, J = 7.8, 2H). MS (ESI)
m/z 856 (M+H)+.
Example 205
dimethyl ({(2R,5R)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-3,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl] })biscarbamate
Example 205A
(lS,4S)-l,4-bis(3-nitrophenyl)butane-l,4-diol
The product from Example 55A was processed using the method described in Example 33 to
afford the title compound (1.74 g, 84%). MS (DCI) m/z 350 (M+NH4)+.
Example 205B
(2R,5R)-2,5-bis(3-nitrophenyl)-l-(4-(trifluoromethyl)phenyl)pyrrolidine
The product from Example 205A and 4-aminobenzotrifluoride were processed using the
method described in Examples 55C and 55D to afford the title compound (0.27 g, 19%). MS (ESI)
m/z 858 (M+H)+.
Example 205C
3,3'<(2R,5R)4<4Ktrifluoromemyl)phenyl)pyrrolidine-2,5-diyl)dianiline
The product from Example 205B was processed using the method described in Example 55E.
The title compound was isolated by flash chromatography (silica gel, methanol/dichloromethane). MS
(ESD m/z 398 (M+H)+, 396 (M-H)+.
Example 205D
(2S,2'S)-tert-butyl2,2'-(3,3'-((2R,5R)-l-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(3,l-
phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate
The product from Example 205C was processed using the method described in Example 19C
replacing DMF with dichloromethane to afford the tide compound (0.36 g, 77%). MS (ESI) m/z 792
(M+H+).
Example 205E
dimethyl ({(2R,5R)-l-[4-(trifluoromethyl)phenyl]pyrroUdine-2,5-diyl}bis{benzene-3,1 -
diylcarbamoyl(2S)pyrrohdine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 205D was processed using the method described in Examples 19D
and 19E (used (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and replacing HATU with
HOBt and EDC) to afford the title compound (13.5 mg, 3%). 1H,NMR (TFA salt) (400 MHz,
METHANOL-D4) δ 1.08 - 0.89 (m, 12H), 1.88 - 1.73 (m, 2H), 2.32- 1.93 (m, 10H), 2.62 (t, J= 6.9,
2H), 3.64 (s, 6H), 3.77 - 3.67 (m, 2H), 4.00 - 3.90 (m, 2H), 4.20 (d, J= 8.0, 2H), 4.56 - 4.45 (m, 2H),
5.26 (d, 7= 6.5, 2H), 6.42 (d, 7 = 8.8, 2H), 6.98 (d, 7 = 7.6,2H), 7.17 (d, J = 7.4, 2H), 7.27 (t, 7 = 7.8,
2H), 7.52 - 7.37 (m, 4H). MS (ESI) m/z 906 (M+H)+, 904 (M-H)+.
Example 206
dimethyl ({(2R,5S)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-3,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The product for Example 206 was isolated from the purification of Example 205E (12.5 mg,
3%). JH NMR (TFA salt) (400 MHz, DMSO-D6) 8 0.90 (dt, 7 = 6.2,10.3,12H), 2.23 - 1.73 (m,
12H), 2.47 - 2.39 (m, 6H), 3.52 (d, 7 = 3.3,4H), 3.89 - 3.73 (m, 2H), 4.03 (t, 7 = 8.4,2H), 4.44 (dd, 7
= 4.9, 7.8,2H), 4.83 (t, 7 = 5.5, 2H), 6.50 (d, 7 = 8.7, 2H), 7.36 - 7.15 (m, 6H), 7.39 (d, 7 - 8.7, 2H),
7.73 - 7.57 (m, 4H), 10.04 (d, 7= 10.0, 2H). MS (ESI) m/z 906 (M+H)+, 904 (M-H)+.
Example 207
dimethyl ([(25,55)-l -(4-ter?-butylphenyl)pyrrolidine-2,5-diyl]bis {pyridine-5,2-
diylcarbamoyl(25)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
and
dimethyl ([(2R,5/?)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-5,2-
diylcarbamoyl(25r)pyrrolidine-2,1 -diyl[(25>3-methyl-1 -oxobutane-1,2-diyl] })biscarbamate
Example 207A
l,4-bis(6-chloropyridin-3-yl)butane-l,4-dione
The zinc chloride (3.04 g, 22.82 mmol), tert-butyl alcohol (1.576 mL, 16.71 mmol) and
diethylamine (1.731 mL, 16.71 mmol) were combined in benzene (12 mL). The resulting slurry was
stirred at room temperature for 2 hours until all solid dissolved. To this slurry was added l-(6-
chloropyridin-3-yl)ethanone (2.60 g, 16.71 mmol; reference: Bioorganic & Medicinal Chemistry
Letters, 1998, 8, 3087-3092), followed by 2-bromo-l-(6-chloropyridin-3-yl)ethanone (2.61 g, 11.14
mmol; reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-3092). The resulting
clear yellow solution was stirred at room temperature for 88 hours. The thick reaction mixture was
treated with 5% H2SO4 (10 mL), stirred for 30 minutes, filtered and dried to give the tide compound
(2.9 lg, 85%) as a solid.
Example 207B
l,4-bis(6-chloropyridin-3-yl)butane-l,4-diol
The product from Example 207A (2.90 g, 9.38 mmol) and sodium borohydride (0.745g, 19.70
mmol) were combined in ethanol (94 mL) at 0 °C. The mixture was warmed to room temperature and
stirred for 6 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate
and 1M HC1. The organic layer was washed with water, brine, dried with sodium sulfate, filtered and
evaporated to give the tide compound (2.62 g, 89%).
Example 207C
l,4-bis(6-chloropyridin-3-yl)butane-l,4-diyldimethanesulfonate
The product from Example 207B (2.23 g, 7.12 mmol) and triethylamine (2.98 mL, 21.36
mmol) were combined in dichloromethane (50 mL). The mixture was cooled to -20 °C and
methanesulfonyl chloride (1.383 mL, 17.80 mmol) was added. The mixture was stirred at room
temperature for 1Hour. The solvent was evaporated to give the title product (approx 3.34 g) which
was directly used for the next reaction.
Example 207D
5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-chloropyridine)
The product from Example 207C (3.34 g, 7.12 mmol) and 4-tert-butylaniline (6.38 g, 42.7
mmol) were combined in DMF (20 mL). The mixture was stirred at room temperature for 24 hours.
The reaction mixture was partitioned between ethyl acetate and 1M HC1. The organic layer was
washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified
by chromatography on silica gel eluting with ethyl acetate/hexane (5% to 30%) to give the title
compound (2.95 g, 97%) as a yellow solid as a mixture of stereoisomers.
Example 207E
dimethyl ([(2S',55)-l-(4-ferf-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-5,2-
diylcarbamoyl(25)pyrrolidine-2,1 -diyl[(25)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
and
dimethyl ([(2R,5/?)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-5,2-
diylcarbamoyl(25r)pyrrolidine-2,1 -diyl[(25>3-methyl-1 -oxobutane-1,2-diyl] })biscarbamate
The product from Example 207D (0.171 g, 0.40 mmol), the product from Example 116C
(0.326 g, 1.200 mmol), cesium carbonate (0.365 g, 1.120 mmol),
tris(dibenzylideneacetone)dipalladium(O) (0.022 g, 0.024 mmol) and (9,9-dimethyl-9H-xanthene-4,5-
diyl)bis(diphenylphosphine) (0.042 g, 0.072 mmol) were combined in dioxane (4 mL). The mixture
was purged with nitrogen for 15 minutes and stirred at 100 °C for 3 hours. The reaction mixture was
partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed
with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane (1% to 4%) to give the title
compound (5 mg, 1%) as a mixture of trans diastereomers. 1H NMR (500 MHz, DMSO-D6) δ ppm
0.88 (t, J=6.41Hz, 6 H) 0.92 (t, J=7.32 Hz, 6 H) 1.12 (s, 9 H) 1.68 - 1.75 (m, 2 H) 1.81 - 1.99 (m, 8
H) 2.07 - 2.18 (m, 2 H) 2.50 - 2.53 (m, 2 H) 3.52 (s, 6 H) 3.57 - 3.64 (m, 2 H) 3.78 - 3.86 (m, 2 H)
3.98 - 4.03 (m, 2 H) 4.55 - 4.63 (m, 2 H) 5.27 (d, J=6.26 Hz, 2 H) 6.18 - 6.27 (m, 2 H) 6.99 (dd,
J=8.77, 1.60 Hz, 2 H) 7.28 - 7.37 (m, 2 H) 7.59 (dd, J=8.62, 2.06 Hz, 2 H) 7.96 (d, J=8.39 Hz, 2 H)
8.12 - 8.20 (m, 2 H) 10.53 (s, 2 H); MS (ESI+) m/z 896.6 (M+H)+.
Example 208
dimethyl ([(2S,5S)-1 -phenylpyrrolidine-2,5-diyl]bis {benzene-4,1 -diylcarbamoyl(2S)pyrrolidine-2,1 -
diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
and
dimethyl ([(2R,5R)-l-phenylpyrrolidine-2,5-diyl]bis{benzene-4,l-diylcarbamoyl(2S)pyrrolidine-2,l-
diyl[(2S)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
The title compound was isolated from Example 85C as an additional product. 1H NMR (TFA
salt) (400 MHz, DMSO-D6) δ ppm 0.83 - 0.88 (m, 6 H), 0.88 - 0.94 (m, 6 H), 1.60 - 1.65 (m, 2 H),
1.79 - 2.02 (m, 8 H), 2.06 - 2.18 (m, 2 H), 3.51 (s, 6 H), 3.55 - 3.64 (m, 2 H), 3.75 - 3.83 (m, 2 H),
4.01 (t, 7=8.3 Hz, 2 H), 4.38 - 4.43 (m, 2 H), 5.16 (d, 7=6.4 Hz, 2 H), 6.23 (d, 7=8.3 Hz, 2 H), 6.39 (t,
7=7.3 Hz, 1H), 6.90 (t, 7=7.9 Hz, 2 H), 7.09 - 7.14 (m, 4 H), 7.25 - 7.31 (m, 2 H), 7.45 - 7.50 (m, 4
H), 9.97 (s, 2 H); MS m/z 838.4 (M+H)+.
Example 209
dimethyl ({(2S,5S)-1 -[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis {benzene-4,1-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl [(2S)-3,3-dimethyl-1 -oxobutane-1,2-diyl]} )biscarbamate
The product from Example 23C was separated by chiral chromatography on a Chiralpak AD-
H semi-prep column eluting with 40% 2-PrOH:EtOH (1:1) J60% hexanes. The title compound was
the first of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.97 (s, 18 H), 1.61 - 1.73
(m, 2 H), 1.75 -1.93 (m, 4 H), 1.94 - 2.06 (m, 2 H), 2.08 - 2.21 (m, 2 H), 3.54 (s, 6 H), 3.57 - 3.70 (m,
2 H), 3.70 - 3.83 (m, 2 H), 4.21 (d, 7=8.89 Hz, 2 H), 4.38 - 4.48 (m, 2 H), 5.27 (d, 7=6.51Hz, 2 H),
6.37 (d, 7=8.78 Hz, 2 H), 7.08 (d, 7=8.89 Hz, 2 H), 7.15 (d, 7=8.57 Hz, 4 H), 7.25 (d, 7=8.89 Hz, 2 H),
7.52 (d, 7=8.57 Hz, 4 H), 10.02 (s, 2 H); MS (ESI) m/z 951.6 (M+H)+.
Example 210
dimethyl ({(2R,5R)-l-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3,3-dimethyl-l-oxobutane-l,2-diyl]})biscarbamate
The product from Example 23C was separated by chiral chromatography on a Chiralpak AD-
H semi-prep column eluting with 40% 2-PrOH:EtOH (1:1) J60% hexanes. The tide compound was
the second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.96 (s, 18 H), 1.64 -
1.75 (m, 2 H), 1.76 - 1.93 (m, 4 H), 1.94 - 2.06 (m, 2 H), 2.07 - 2.21 (m, 2 H), 3.54 (s, 6 H), 3.58 -
3.70 (m, 2 H), 3.70 - 3.86 (m, 2 H), 4.20 (d, 7=8.89 Hz, 2 H), 4.38 - 4.47 (m, 2 H), 5.28 (d, 7=6.18 Hz,
2 H), 6.36 (d, 7=8.89 Hz, 2 H), 7.07 (d, 7=8.89 Hz, 2 H), 7.14 (d, 7=8.57 Hz, 4 H), 7.25 (d, 7=8.78 Hz,
2 H), 7.52 (d, 7=8.57 Hz, 4 H), 10.03 (s, 2 H); MS (ESI) m/z 951.4 (M+H)+.
Example 211
dimethyl ([(2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S,3R)-3-methyl-l-oxopentane-l,2-diyl]})biscarbamate
The product from Example 25 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with 50% 2-PrOH:EtOH (1:1)/ 50% hexanes. The tide compound was the
second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.76 - 0.92 (m, 12 H), 1.05
- 1.19 (m, 2 H), 1.37 -1.54 (m, 2 H), 1.57 - 1.70 (m, 2 H), 1.69 - 1.96 (m, 6 H), 1.94 - 2.07 (m, 2 H),
2.07 - 2.22 (m, 2 H), 3.53 (s, 6 H), 3.55 - 3.64 (m, 2 H), 3.69 - 3.83 (m, 2 H), 4.17 - 4.28 (m, 2 H),
4.42 (dd, 7=7.81, 5.20 Hz, 2 H), 5.16 (d, 7=6.29 Hz, 2 H), 6.20 (dd, 7=9.22, 4.45 Hz, 2 H), 6.77 (t,
7=8.95 Hz, 2 H), 7.13 (d, 7=8.46 Hz, 4 H), 7.49 (d, 7=8.46 Hz, 2 H), 9.97 (s, 2 H); MS (ESI) m/z
884.4 (M+H)+.
Example 212
dimethyl ([(2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S,3S)-3-methyl-l-oxopentane-l,2-diyl]})biscarbamate
The product from Example 24 was separated by chiral chromatography on a Chiralpak AD-H
semi-prep column eluting with 50% 2-PrOH:EtOH (1:1) J50% hexanes. The title compound was the
second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (t, 7=7.37 Hz, 6 H),
0.88 (d, 7=6.72 Hz, 6 H), 1.02 - 1.18 (m, 2 H), 1.41 - 1.59 (m, 2 H), 1.59 - 1.75 (m, 4 H), 1.80 - 1.95
(m, 4 H), 1.95 - 2.06 (m, 2 H), 2.08 - 2.23 (m, 2 H), 3.52 (s, 6 H), 3.56 - 3.67 (m, 2 H), 3.74 - 3.89 (m,
2 H), 4.07 (t, 7=8.95 Hz, 2 H), 4.39 - 4.47 (m, 2 H), 5.16 (d, 7=6.18 Hz, 2 H), 6.20 (dd, 7=9.22, 4.45
Hz, 2 H), 6.78 (t, 7=8.95 Hz, 2 H), 7.13 (d, 7=8.46 Hz, 4 H), 7.35 (d, 7=8.46 Hz, 2 H), 7.50 (d, 7=8.57
Hz, 4 H), 9.99 (s, 2 H); MS (ESI) m/z 884.4 (M+H)+.
Example 213
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)-5-(4-aminophenyl)-l-(4-tert-butylphenyl)pyrrolidin-2-
yljphenyl} -L-prolinamide
To a solution of the product from Example 37B (17.7 mg, 0.065 mmol) and the product from
Example 37E (50 mg, 0.130 mmol) in anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071
mmol) and Hunig'sBase (0.015 mL, 0.084 mmol). The resulting mixture was stirred at rt for 30 min,
and was then partitioned between H20 (5 mL) and EtOAc (3x5 mL). The combined organic layers
were dried over Na2S04. The drying agent was filtered off, and solvent was removed in vacuo. The
crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5%
MeOH in CH2C12 to give the title compound (20 mg, 24%). 1H NMR (400 MHz, DMSO-D6) δ ppm
0.88 (d, 7=6.72 Hz, 3 H), 0.93 (d, 7=6.72 Hz, 3 H), 1.11 (s, 9 H), 1.52 - 1.66 (m, 2 H), 1.79 - 2.06 (m,
4 H), 2.06 - 2.20 (m, 1H), 2.34 - 2.47 (m, 2 H), 3.52 (s, 3 H), 3.56 - 3.67 (m, 1H), 3.74 - 3.87 (m, 1H), 4.02 (t, 7=8.51Hz, 1H), 4.42 (dd, 7=8.08, 4.83 Hz, 1H), 4.83 - 4.94 (m, 2 H), 5.02 (d, 7=7.16 Hz,
0.5 H), 5.08 (d, 7=7.59 Hz, 0.5 H), 6.18 (d, 7=8.78 Hz, 2 H), 6.48 (d, 7=8.35 Hz, 2 H), 6.84 (d, 7=8.35
Hz, 2 H), 6.93 (d, 7=8.89 Hz, 2 H), 7.11 (d, 7=8.57 Hz, 2 H), 7.31 (d, 7=8.35 Hz, 1H), 7.48 (d, 7=8.57
Hz, 2 H), 9.97 (s, 1H); MS (ESI) m/z 640.3 (M+H)+.
Example 214
dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4,-((2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-
diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4'-((2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-
diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
oxobutane-2,1 -diyl)dicarbamate
Example 214A
diethyl l-(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylate
A solution of diethyl meso-2,5-dibromoadipate (2.0 g, 5.55 mmol) and 4-tert-butylaniline
(3.32 g, 22.22 mmol) in dimethoxyethane (12 mL) was stirred at reflux for 10 h. The cooled mixture
was partitioned between EtOAc (100 mL) and IN aq HC1 (2x100 mL), and the organic layer was
dried over Na2S04. The drying agent was filtered off, and the solvent was removed in vacuo. The
crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20%
EtOAc in hexanes to give the title compound as an oil (1.95 g, quant.). 1H NMR indicated a 3:2
mixture of cis:trans pyrrolidine isomers.
Example 214B
1 -(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid
To a solution of the product from Example 214A (1.95 g, 5.61 mmol) in MeOH (50 mL) was
added a solution of NaOH (0.95 g, 23.8 mmol) in H20 (10 mL). The resulting mixture was stirred at
rt overnight. The mixture was concentrated in vacuo to ca. 10 mL and was poured into IN HC1 (50
mL). The mixture was extracted with CH2C12 (3 x 50 mL), and the combined organic layers were
dried over Na2S04. The drying agent was filtered off, and the solvent was removed in vacuo to give
the title compound as a light orange solid (1.42 g, 87%) as a mixture of stereoisomers.
Example 214C
trans-1 -(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid
The product from Example 214B was subjected to column chromatography on CI8 silica gel
using a solvent gradient of 10-60% acetonitrile in H20 (0.1% TFA). The title compound was the first
of 2 major components to elute.
Example 214D
1,1 '-(trans-1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-diazoethanone)
To a solution of the product from Example 214C (0.963 g, 3.31 mmol) in dry CH2C12 (20 mL)
at 0 °C was added oxalyl chloride (1.157 mL, 13.22 mmol), followed by 2-3 drops of DMF, and the
resulting mixture was stirred at rt for 30 min until no further bubbling was observed. The cooled
mixture was cone by evaporation with dry N2, and the residue was dissolved in dry CH2C12 (10 mL).
To the 0 °C solution was added a solution of diazomethane in Et20 (-0.6 M, 20 mL) and the resulting
mixture was stirred at 0 °C for lh. The mixture was concentrated in vacuo, and the crude product was
purified by column chromatography on silica gel using a solvent gradient of 0-100% EtOAc in
hexanes to give the tide compound (0.54 g, 48%).
Example 214E
4,4'-(trans-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dithiazol-2-amine
A solution of the product from Example 214D (0.50 g, 1.47 mmol) in Et20 (10 mL) was
treated dropwise with 48% aq. hydrogen bromide (0.500 mL, 4.42 mmol). The resulting mixture was
stirred at rt for 30 min. Water (1 mL) was added, and the mixture was extracted with Et20 (3 x 10
mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The
residue was dissolved in EtOH (15 mL). To the resulting solution was added thiourea (0.45 g, 5.89
mmol), and the resulting mixture was stirred at rt for 1H and then concentrated to ca. 1 mL. Water
(10 mL) was added, and the pH was neutralized using saturated aq. NaHCC>3. The resulting solid was
collected by filtration and dried in vacuo to give the title compound (0.455 g, 77%).
Example 214F
(2S,2'S)-tert-butyl2,2'-(4,4^(trans-l-(4-tert-butylphenyl)pyrroUdme-2,5-diyl)bis(thiazole-4,2-
diyl)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1 -carboxylate
A mixture of the product from Example 214E (0.2 g, 0.501 mmol), (S)-l-(tert-
butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.431 g, 2.002 mmol), and Nl-
((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (1.151 g, 6.01 mmol) in
DMF (4 mL) and pyridine (4 mL) was stirred at rt overnight. The mixture was partitioned between
IN aq. HC1 and EtOAc (3x), and the combined organic layers were dried over Na2S04. The drying
agent was filtered off, and the solvent was removed in vacuo. The crude product was purified by
column chromatography on silica gel using a solvent gradient of 0-100% EtOAc in hexanes to give
the title compound (0.28 g, 71%) as a mixture of trans diastereomers.
Example 214G
dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2,-(4,4,-((2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-
diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene))bis(pyrrohdine-2,1 -diyl))bis(3-methyl-1 -
oxobutane-2,1 -diyl)dicarbamate
and
dimethyl (2S,2'S)-l,l,-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l-(4-tert-butylphenyl)pvrrolidine-2,5-
diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2,l-diyl))bis(3-methyl-l-
oxobutane-2,1 -diyl)dicarbamate
A solution of the product from Example 214F was stirred in 2N HC1 in dioxane (0.4 mL) for
1H and then concentrated in vacuo. The residue was subjected to the procedure described in Example
10 to give the tide compound as mixture of trans diastereomers. 1H NMR (free base) (400 MHz,
DMSO-D6) δ ppm0.80 - 0.97 (m, 14 H), 1.12 - 1.16 (m, 9 H), 1.69 - 2.06 (m, 8 H), 2.08 - 2.22 (m, 2
H), 3.51 - 3.57 (m, 6 H), 3.57 - 3.68 (m, 2 H), 3.77 - 3.91 (m, 2 H), 3.95 - 4.06 (m, 2 H), 4.47 - 4.59
(m, 7=7.16 Hz, 1H), 5.08 - 5.17 (m, 2 H), 6.31 (t, 7=8.24 Hz, 2 H), 6.70 (d, 7=21.04 Hz, 2 H), 7.02
(dd, 7=8.67, 6.40 Hz, 2 H), 7.35 (d, 7=8.35 Hz, 2 H), 12.24 (s, 2 H).
Example 215
dimethyl ([3-bromo-l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(25)pyrrolidine-2,l-diyl[(2lS)-3-methyl-l-oxobutane-l,2-diyl]})biscarbamate
To a suspension of the product from Example 51 (455 mg, 0.534 mmol) in CH2C12 (2.7 mL)
was added a mixture of l-bromopyrrolidine-2,5-dione (95 mg, 0.534 mmol) in CH2C12 (2.7 mL). The
mixture was stirred overnight at room temperature then concentrated under reduced pressure and
triturated with diethyl ether to provide a mixture of compounds that was subjected to reverse phase
HPLC purification eluted with a gradient of 60-100% MeOH in lOmM ammonium acetate to afford
the tide compound (84 mg, 17% yield).1H NMR (free base) (400 MHz, DMSO-D6) δ 10.06 (s, 1H),
10.02 (s, 1H), 7.46 (d, 7 = 8.7, 2H), 7.41 (d, 7 = 8.7, 2H), 7.30 (d, 7 = 7.7, 2H), 7.15 - 7.03 (m, 6H),
6.98 (d, 7 = 8.7, 2H), 6.53 (s, 1H), 4.45 - 4.33 (m, 2H), 4.01 (t, 7 = 7.7, 2H), 3.85 - 3.73 (m, 2H), 3.66
- 3.54 (m, 2H), 3.51 (s, 6H), 2.20 - 2.05 (m, 2H), 2.03 - 1.77 (m, 8H), 0.97 - 0.79 (m, 12H). MS
(ESI; M+H) m/z = 933.
Example 216
dimethyl ([3,4-dibromo-l-(4-fluorophenyl)-lH-pyrrole-2,5-diyl]bis{benzene-4,l-
diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl-1 -oxobutane-1,2-diyl]} )biscarbamate
The title compound was formed as an additional product in Example 215. The mixture of
products was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH
in lOmM ammonium acetate to afford the title compound (125 mg, 23% yield). 1H NMR (free base)
(400 MHz, DMSO-D6) δ 10.08 (bs, 2H), 7.47 (d, 7 = 8.7, 4H), 7.33 - 7.27 (m, 2H), 7.13 - 7.01 (m,
8H), 4.43 - 4.35 (m, 2H), 4.01 (t, 7 = 8.4, 2H), 3.84 - 3.74 (m, 2H), 3.65 - 3.55 (m, 2H), 3.51 (s, 6H),
2.21 -2.05 (m, 2H), 2.05 - 1.78 (m, 8H), 0.91 (d, 7 = 6.7, 6H), 0.86 (d, 7 = 6.6, 6H). MS (ESI; M+H)
m/z =1011.
Example 217
The title compound was formed as a by-product in Example 215. The mixture of products
was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH in lOmM
ammonium acetate to afford the title compound (61 mg, 12% yield). :H NMR (free base) (400 MHz,
DMSO-D6) δ 10.00 (s, 2H), 7.41 (d, 7= 8.7, 2H), 7.38 (d, 7= 8.9, 2H), 7.29 (d, 7= 6.6, 2H), 7.14 (d,
7 = 7.3, 1H), 7.11 - 7.05 (m, 3H), 7.01 - 6.93 (m, 2H), 6.89 (t, 7 = 8.7, 2H), 4.37 (dd, 7 = 4.9, 7.4,
2H), 4.00 (t, 7 = 8.4, 2H), 3.84 - 3.74 (m, 2H), 3.64 - 3.55 (m, 2H), 3.51 (s, 6H), 2.19 - 2.05 (m, 2H),
2.03 - 1.78 (m, 8H), 1.23 (s, 9H), 0.91 (dd, 7= 2.1, 6.6, 6H), 0.86 (d, 7 = 6.4, 6H). MS (ESI; M+H)
m/z = 989.
Example 218
methyl {(25')-l-[(25)-2-(4-{4-[4-(4-terf-butylphenyl)-5-(4-{2-[(25)-l-{(ZS,)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] - l/f-imidazol-4-yl} phenyl)-4#-1,2,4-
triazol-3-yl]phenyl} - lH-imidazol-2-yi)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
Example 218A
4-bromo-N'-(4-bromobenzoyl)benzoylhydrazide
Dissolved equimolar amounts of 4-bromobenzohydrazide (1.097 g, 5 mmol) and 4-
bromobenzoyl chloride (1.120 g, 5 mmol) in anhydrous pyridine (25 mL) under nitrogen and heated at
reflux (oil bath 135 °C) for 6 hr. Cooled reaction to room temperature, poured the mixture into
absolute EtOH (100 mL), and cooled in a freezer overnight to give white crystals. Collected solids by
vacuum filtration, washed solids with absolute EtOH (2x5 mL), and dried in vacuo to afford the title
compound as a white solid (953 mg, 48%). LH NMR (400 MHz, DMSO-D6) δ ppm 7.75 (d, 7=8.57
Hz, 4 H), 7.86 (d, 7=8.46 Hz, 4 H), 10.63 (s, 2 H); MS (ESI-) m/z 395/397/399 (M-H)" with two
bromines.
Example 218B
3,5-bis(4-bromophenyl)-4-(4-fert-butylphenyl)-4H-l,2,4-triazole
In an oven-dried 10-mL round bottom flask, equipped with a septum and purged with
nitrogen, 4-tert-butylaniline (450 mg, 3.01 mmol) was dissolved in anhydrous 1,2-dichlorobenzene
(1.5 mL) and the solution cooled to 0 °C. A solution of phosphorus oxychloride (0.047 mL, 0.502
mmol) in anhydrous 1,2-dichlorobenzene (0.5 mL) was added slowly in dropwise manner from a gas-
tight syringe. Upon completion of addition, removed the cooling bath and stirred at room temperature
for 1Hr to form the phosphoryl triamide in situ (reaction became progressively cloudy). Then added
the product of Example 218A (200 mg, 0.502 mmol), replaced septum with a reflux condenser, and
heated reaction in an oil bath at 200 °C for 4 hr. Cooled light brown colored solution to room
temperature, then placed in a freezer for 3 days and collected an off-white solid (20 mg, 4-bromo-N-
(4-tert-butylphenyl)benzamide by-product) by vacuum filtration. The filtrate was treated with
hexanes (-50 mL) and the cloudy solution cooled in a freezer for 30 min. Collected an off-white solid
(73 mg) by vacuum filtration and concentrated the filtrate by rotary evaporation to a solution of
product in 1,2-dichlorobenzene. The latter was purified by flash chromatography (silica gel, 3.8 cm x
15 cm bed, gradient of CH2C12 , 20% EtOAc/CH2Cl2, and 30% EtOAc/CH2Cl2) to afford the title
compound as a fluffy white solid (154 mg, 60%). :H NMR (400 MHz, CDC13) δ ppm 1.36 (s, 9 H),
7.06 (d, 7=8.46 Hz, 2 H), 7.29 (d, 7=8.57 Hz, 4 H), 7.43 (d, 7=8.57 Hz, 4 H), 7.46 (d, 7=8.57 Hz, 2 H);
MS (ESI+) m/z 510/512/514 (M+H)+ with two bromines.
Example 218C
4-(4-tert-butylphenyl)-3,5-bis((4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4H-l,2,4-
triazole
Charged an oven-dried 25-mL round bottom flask, purged with nitrogen, with the product of
Example 218B (144.2 mg, 0.282 mmol), bis(pinacalato)diboron (215 mg, 0.846 mmol), potassium
acetate (90 mg, 0.917 mmol), and anhydrous dioxane (1.5 mL). Sparged the mixture with nitrogen for
30 min, added l,l'-bis(diphenylphosphino)ferrocene-palladium(n)dichloride dichloromethane
complex (23.03 mg, 0.028 mmol), re-sparged with nitrogen for 5 min, replaced rubber septum with a
glass stopper, and heated in an oil bath (85 °C) for 2 hr. Cooled reaction to room temperature,
vacuum filtered through a small bed of Celite 545, washed catalyst thoroughly with CH2C12, and
concentrated the filtrate by rotary evaporation to a dark brown oil. Purified by flash chromatography
(silica gel, Alltech Extract-Clean lOg column, 1:1 EtOAc/CH2Cl2) to afford a dark beige solid (230
mg). Repurified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 3%
MeOH/CH2Cl2) eluting with to afford the title compound as a beige solid (171 mg, 100%). 1H NMR
(400 MHz, CDCI3) 8 ppm 1.27 (s, 9 H), 1.33 (s, 24 H), 7.06 (d, 7=8.46 Hz, 2 H), 7.38 - 7.47 (m, 6 H),
7.71 (d, 7=7.92 Hz, 4 H); MS (ESI+) m/z 606 (M+H)+, 1211 (2M+H)+.
Example 218D
(2S,2'S)-fen-butyl2,2'-(4,4'-(4,4'-(4-(4-te?t-butylphenyl)-4H-l,2,4-triazole-3,5-diyl)bis(4,l-
phenylene))bis( l/f-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate
Charged a nitrogen-purged microwave tube (size M, 5 mL) with the product of Example
218C (171 mg, 0.282 mmol), the product of Example 26D (223 mg, 0.706 mmol), and a mixture of
absolute EtOH (1.5 mL) and toluene (1.5 mL), then added 1M aq sodium carbonate (0.706 mL, 0.706
mmol) and sparged the mixture with nitrogen for 20 min. Added 1,1'-
bis(diphenylphosphino)ferrocene-palladium(I[)dichloride dichloromethane complex (23.07 mg, 0.028
mmol), sparged again with nitrogen for 5 min, sealed the tube with an aluminum crimp cap, and
heated in a microwave reactor (Personal Chemistry Emrys Creator) with stirring at 100 °C for 1Hr.
Cooled the reaction to room temperature, diluted reaction in EtOAc (75 mL), washed with H20 (2 x
25 mL) and brine (25 mL), dried organic phase over anhydrous MgSQ*, filtered, and concentrated by
rotary evaporation to a yellow solid (330 mg). Purified by flash chromatography (silica gel, 3.8 cm x
15 cm, gradient of 4%, 6%, 8%, and 10% MeOH/CH2Cl2) to afford the title compound as a light
yellow solid (135 mg, 58%). MS (ESI+) m/z 824 (M+H)+.
Example 218E
4-(4-tert-butylphenyl)-3,5-bis(4<2<(S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)-4/f-l,2,4-triazole
Dissolved the product of Example 218D (131.5 mg, 0.160 mmol) in anhydrous CH2C12 (2
mL) under nitrogen, added trifluoroacetic acid (1 mL, 12.85 mmol), and stirred at 25 °C for 30 min.
Removed the solvent by rotary evaporation, took up the residue in 20% iPrOH/CHCl3 (50 mL),
washed with sat'd aq NaHC03 (10 mL), extracted the aqueous phase with 20% iPrOH/CHCl3 (2 x 25
mL), dried the combined organic extracts over anhydrous MgSQt, filtered, and concentrated by rotary
evaporation. Took up residue in 1:5 v/v CH2C12/hexanes and concentrated in vacuo to afford the title
compound as a light tan solid (114 mg). 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.30 (s, 9 H), 1.66 -
1.94 (m, 6 H), 1.98 - 2.12 (m, 2 H), 2.80 - 3.07 (m, 4 H), 3.70 - 3.86 (m, 1H), 4.12 - 4.22 (m, 2 H),
4.34 (d, 7=4.01Hz, 1H), 7.34 (t, 7=8.08 Hz, 6 H), 7.47 - 7.57 (m, 4 H), 7.68 (d, 7=8.35 Hz, 4 H),
11.90 (s, 2 H); MS (ESI+) 624 (M+H)+; (ESI-) m/z 622 (M-H)Example 218F
(methyl {(25')-l-[(25)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2^-l-{(2^-2-
[(memoxycarbonyl)armno]-3-memylbutanoyl}pyiTohdin-2-yl]-lH-imidazol-4-yl}phenyl)-4/f-l,2,4-
triazol-3-yl]phenyl} - lZf-imidazol-2-yi)pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of
Example 218E (50 mg, 0.080 mmol) in anhydrous DMF (1 mL), and cooled to 0 °C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29.5 mg, 0.168 mmol), HOBt
hydrate (27.6 mg, 0.180 mmol), EDAC (35.3 mg, 0.180 mmol), and N-methylmorpholine (0.035 mL,
0.321 mmol). Stirred the solution at 25 °C for 15 hr. Diluted the reaction in EtOAc (50 mL), washed
with sat'd aq NaHC03 (25 mL), H20 (3 x 25 mL), and brine (25 mL), dried the organic phase over
anhydrous MgS04, filtered, and concentrated by rotary evaporation to an off-white solid (72 mg).
Purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, gradient of 6% to 8%
MeOH/CH2Cl2) to afford the title compound as an off-white solid (49 mg, 65%).1H NMR (400 MHz,
DMSO-D6) δ ppm 0.82 (d, 7=6.72 Hz, 6 H), 0.86 (d, 7=6.72 Hz, 6 H), 1.29 (s, 9 H), 1.79 - 2.01 (m, 5
H), 2.03 - 2.22 (m, 4 H), 3.53 (s, 6 H), 3.70 - 3.86 (m, 4 H), 4.04 (t, 7=8.35 Hz, 2 H), 5.04 (dd, 7=6.67,
3.20 Hz, 2 H), 7.23 - 7.43 (m, 8 H), 7.48 - 7.60 (m, 4 H), 7.61 - 7.73 (m, 4 H), 11.77 -12.21 (m, 2 H);
MS (ESI+) m/z 939 (M+H)+.
Example 219
methyl {(l^-l-^^^^-l^^^-cyclohexylphenyD-S^-lZ-tCZ^-l-Kl^)^-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-l//-imidazol-4-yl}phenyl)-4/f-l,2,4-
triazol-3-yl]phenyl}-lH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
Example 219A
3,5-bis(4-bromophenyl)-4-(4-cyclohexylphenyl)-4#-l,2,4-triazole
In an oven-dried 10-mL round bottom flask, equipped with a septum and purged with
nitrogen, 4-cyclohexylaniline (545 mg, 3.01 mmol) was dissolved in anhydrous 1,2-dichlorobenzene
(1.5 mL) and the solution cooled to 0 °C. A solution of phosphorus oxychloride (78 mg, 0.502 mmol)
in anhydrous 1,2-dichlorobenzene (0.5 mL) was added slowly in a dropwise manner from a gas-tight
syringe. The reaction became an unstirrable solid gel; removed the cooling bath, added additional
1,2-dichlorobenzene (0.5 mL), sonicated the mixture, and stirred the thick suspension at room
temperature for 1Hr to form the phosphoryl triamide in situ. Added the product of Example 218A
(200 mg, 0.502 mmol), replaced the septum with a reflux condenser, and heated the reaction in an oil
bath at 200 °C for 4 hr under nitrogen. The reaction quickly became a homogeneous gold colored
solution upon refluxing. Cooled the solution to room temperature and purified by flash
chromatography (silica gel, 3.8 cm x 15 cm, gradient of CH2C12 to 20% EtOAc/CH2Cl2 to 40%
EtOAc/CH2Cl2) to afford the title compound as a fluffy white solid (201 mg, 74%). !H NMR (400
MHz, CDC13) δ ppm 1.19 - 1.33 (m, 1H) 1.35 - 1.50 (m, 4 H) 1.78 (d, 7=14.42 Hz, 1H) 1.84 - 1.98
(m, 4 H) 2.51 - 2.65 (m, 1H) 7.04 (d, 7=8.35 Hz, 2 H) 7.28 (d, 7=8.57 Hz, 6 H) 7.43 (d, 7=8.57 Hz, 4
H); MS (ESI+) m/z 536/538540 (M+H)+, 1072/1074/1076 (2M+H)+ with two bromines.
Example 219B
4-(4-cyclohexylphenyl)-3,5-bis(4(4,4,5,5-tetramethyl-l,3,2-dioxaboralan-2-yl)phenyl)-4H-l,2,4-
triazole
Charged an oven-dried 10-mL round bottom flask, purged with nitrogen, with the product of
Example 219A (100 mg, 0.186 mmol), bis(pinacalato)diboron (142 mg, 0.558 mmol), potassium
acetate (59.4 mg, 0.605 mmol), and anhydrous dioxane (3 mL). Sparged the thick white mixture with
nitrogen for 30 min, added l,r-bis(diphenylphosphino)ferrocene-palladium(H)dichloride
dichloromethane complex (15.20 mg, 0.019 mmol), re-sparged with nitrogen for 5 min, replaced
rubber septum with a glass stopper, and heated in an oil bath (85 °C). Reaction became homogeneous
upon heating and darkened with time to a reddish-brown color. TLC (Si02, 50% EtOAc/CH2Cl2).
After 2 hr, cooled reaction to room temperature, added additional bis(pinacalato)diboron (71 mg, -1.5
equiv) and potassium acetate (30 mg, -1.75 equiv), and heated for 1Hr at 85 °C. Cooled the brown
colored reaction to room temperature, vacuum filtered through a small bed of Celite 545, washed the
collected solids thoroughly with CH2C12, and concentrated the filtrate by rotary evaporation to a
brown foam. Purified by silica gel flash chromatography (Alltech Extract-Clean column, lOg bed)
eluting with 30% EtOAc/CH2Cl2 to afford the product as a light brown oil (190 mg). Repurified by
silica gel flash chromatography (Alltech Extract-Clean column, lOg bed) eluting with 3%
MeOH/CH2Cl2 to afford the title compound as a light beige foam (122 mg, 100%). MS (ESI+) m/z
632 (M+H)+, 1263 (2M+H)+.
Example 219C
methyl {(25')-l-[(25,)-2-(4-{4-[4-(4-cyclohexylphenyl)-5-(4-{2-[(25,)-l-{(25,)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrroho^n-2-yl]-lH-imidazol-4-yl}phenyl)-4//-l,2,4-
triazol-3-yl]phenyl}- lif-imidazol-2-yl)pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
Charged a nitrogen-purged microwave tube (size M, 5 mL) with the product of Example
219B (118 mg, 0.187 mmol), the product of Example 126G (174 mg, 0.467 mmol), and a mixture of
absolute EtOH (1 mL) and toluene (1 mL), then added 1M aq sodium carbonate (0.467 mL, 0.467
mmol) and sparged the mixture with nitrogen for 20 min. Added 1,1'-
bis(diphenylphosphino)ferrocene-palladium(n)dichloride dichloromethane complex (15.26 mg, 0.019
mmol), sparged again with nitrogen for 5 min, sealed the tube with an aluminum crimp cap, and
heated in a microwave reactor (Personal Chemistry Emrys Creator) with stirring at 100 °C for 1Hr.
Cooled reaction to room temperature, diluted reaction in EtOAc (50 mL), washed with H20 (2 x 25
mL) and brine (25 mL), dried the organic phase over anhydrous MgS04, filtered, and concentrated by
rotary evaporation to a solid. Purified by flash chromatography (silica gel, step gradient 5% to 8% to
10% MeOH/CH2Cl2) to afford the product as a tan solid (72 mg) which was -85% pure (2 main
impurities). Dissolved impure product in 1.5 mL 1:1 v/v MeOH/DMSO and purified by RP-C18
HPLC (Waters Prep LC, 40mm Module with Nova Pak HR C)8 6|im 40x100mm Prep Pak cartridge)
eluting with a 30 min gradient of 95:5 0.1% TFA in H20/AcCN to 25:75 0.1% TFA in H20/AcCN,
then 10 min to 100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation
(water bath 35°C) to a small volume, partitioned between 20% iPrOH/CHCl3 (50 mL) and sat'd aq
NaHC03 (15 mL), separated layers, dried the organic extract over anhydrous MgS04, filtered, and
concentrated by rotary evaporation to afford the title compound as a white solid (34.5 mg, 19%). :H
NMR (400 MHz, DMSO-D6) δ ppmO.83 (d, 7=6.72 Hz, 6 H) 0.86 (d, 7=6.72 Hz, 6 H) 1.29 -1.47 (m,
5 H) 1.65 - 2.01 (m, 12 H) 2.04 - 2.21 (m, 4 H) 3.53 (s, 6 H) 3.72 - 3.84 (m, 4 H) 4.04 (t, 7=8.40 Hz, 2
H) 5.04 (dd, 7=6.89, 3.20 Hz, 2 H) 7.23 - 7.40 (m, 10 H) 7.51 - 7.72 (m, 6 H) 11.84 (s, 2 H); MS
(ESI+) m/z 965 (M+H)+.
Examples 220-308 were prepared in analogous fashion according to the methods and
conditions illustrated in the foregoing schemes and examples.
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)aniino]-3,3-dimethylbutanoyl}pvrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-
2-yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3,3-dimethyl-1 -oxobutan-2-yl} carbamate
lU NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, 7=13.55 Hz, 18 H), 1.07 (s, 9 H), 1.62 - 1.78 (m, 2
H), 1.91 - 2.09 (m, 4 H), 2.10 - 2.26 (m, 4 H), 2.54 - 2.62 (m, 2 H), 3.55 (s, 6 H), 3.74 - 3.90 (m, 4 H),
4.23 (dd, 7=8.78, 4.55 Hz, 2 H), 5.09 - 5.23 (m, 2 H), 5.31 - 5.43 (m, 2 H), 6.26 (d, 7=8.89 Hz, 2 H),
6.84 - 6.97 (m, 2 H), 7.06 (dd, 7=8.29,2.55 Hz, 2 H), 7.12 (t, 7=9.43 Hz, 2 H), 7.20 (s, 1H), 7.30 (s, 1H), 7.38 (d, 7=8.24 Hz, 1H) 7.45 (d, 7=8.24 Hz, 1H), 12.02 (s, 2 H); MS (ESI+) m/z 916 (M+H)+.
dimethyl ([(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{lH-benzimidazole-5,2-
diyl(2S)pyrrolidine-2,1-diyl[(2R)-l-oxo-2-phenylpropane-l ,2-diyl] ))biscarbamate
1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 - 1.10 (m, 9 H), 1.49 - 1.58 (m, 2 H), 1.67 (d, 7=16.70
Hz, 6 H), 1.70 -1.95 (m, 4 H), 2.04 (s, 3 H), 2.35 - 2.43 (m, 1H), 2.97 - 3.11 (m, 2 H), 3.22 - 3.29 (m,
1H), 3.50 (s, 6 H), 3.61 - 3.91 (m, 1H), 5.08 - 5.22 (m, 2 H), 5.29 - 5.49 (m, 2 H), 6.21 - 6.39 (m, 2
H), 6.84 - 6.99 (m, 2 H), 7.07 - 7.50 (m, 17 H), 7.53 (d, J=8.24 Hz, 1H), 7.61 (s, 2 H), 12.10 (two s, 2
H); MS (ESI+) m/z 984 (M+H)+.
(2R,2R)-l,l'-{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimida2ole-5,2-
diyl(2S)pyrrolidine-2,1 -diyl] }bis(2-amino-2-phenylpropan-1 -one)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 9 H), 1.55 -1.66 (m, 3 H), 1.68 -1.82 (m, 4 H), 1.83 -
2.02 (m, 5 H), 1.93 (s, 6 H), 2.12 - 2.31 (m, 3 H), 2.57 (d, 7=3.90 Hz, 2 H), 5.26 - 5.36 (m, 2 H), 5.41
- 5.57 (m, 2 H), 6.30 (d, 7=8.78 Hz, 2 H), 6.93 (d, 7=8.78 Hz, 2 H), 7.17 - 7.31 (m, 2 H), 7.38 (s, 2 H),
7.47 - 7.66 (m, 13 H), 8.43 (s, 6 H); MS (ESI+) m/z 868 (M+H)+.
methyl{(2S,3R)-l-[(2S,4S)-2-{5-[(2R,5R)-l-(4-tert-butylphenyl)-5-(2-{(2S,4S)-4-hydroxy-l-[N-
(methoxycarbonyl)-O-memyl-L-threonyl]pyrrolidin-2-yl}-lH-benzimidazol-5-yl)pyrrolidin-2-yl]-lH-
benzimidazol-2-yl} -4-hydroxypyrrolidin-1 -yl] -3-methoxy-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-d6) 8 ppm 0.96 (d, 7=5.96 Hz, 6 H), 1.09 (s, 9 H), 1.74 (d, 7=5.64 Hz, 2
H), 2.06 - 2.15 (m, 3 H), 2.96 - 3.03 (m, 1H), 3.10 (s, 6 H), 3.55 (s, 6 H), 3.72 (dd, 7=9.65, 2.39 Hz, 3
H), 3.94 (dd, 7=10.25, 4.72 Hz, 2 H), 4.23 - 4.33 (m, 2 H), 4.38 (t, 7=7.10 Hz, 1H), 4.44 - 4.53 (m, 2
H), 5.26 (dd, 7=8.46, 4.23 Hz, 2 H), 5.49 (d, 7=5.53 Hz, 2 H), 6.25 (d, 7=8.78 Hz, 2 H), 6.94 (d,
7=8.78 Hz, 2 H), 7.22 (d, 7=8.46 Hz, 2 H), 7.37 (d, 7=7.59 Hz, 2 H), 7.46 (s, 2 H), 7.69 (d, 7=7.92 Hz,
2 H); MS (ESI+) m/z 952 (M+H)+.
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -1 -[4-( 1 -methoxy-2-methylpropan-2-
yl)phenyl]pyrrolidin-2-yl} - lH-benzimidazol-2-yl)pyrrolidin- 1-yl] -3-methyl-l -oxobutan-2-
yl} carbamate
1H NMR (400 MHz, DMSO-D6) 8 ppm 0.74 - 0.93 (m, 12 H) 1.04 (s, 6 H) 1.69 (d, J=4.34 Hz, 2 H)
1.85 - 1.94 (m, 2 H) 1.95 - 2.03 (m, 6 H) 2.13 - 2.25 (m, 2 H) 2.53 - 2.63 (m, 4 H) 3.11 (s, 3 H) 3.53
(s, 6 H) 3.81 (s, 4 H) 4.05 - 4.15 (m, 2 H) 5.09 - 5.19 (m, 2 H) 5.32 - 5.41 (m, 2 H) 6.25 (d, J=8.78 Hz,
2 H) 6.87 (ddd, J=8.89, 4.77, 4.55 Hz, 2 H) 7.07 (t, J=7.37 Hz, 2 H) 7.20 (s, 1H) 7.25 - 7.33 (m, 3 H)
7.38 (d, J=8.24 Hz, 1H) 7.46 (d, J=8.46 Hz, 1H) 12.00 -12.09 (m, 2 H); MS ESI+ 918.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[4-(l-hydroxy-2-methylpropan-2-yl)phenyl]-5-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-
yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrroUdin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.76 - 0.91 (m, 12 H) 1.01 (d, J=2.60 Hz, 6 H) 1.64 - 1.72
(m, 2 H) 1.91 (dd, J=14.42, 6.83 Hz, 2 H) 1.95 - 2.05 (m, 4 H) 2.14 - 2.23 (m, 4 H) 2.54 - 2.60 (m, 2
H) 3.53 (s, 6 H) 3.76 - 3.87 (m, 4 H) 4.11 (q, J=4.77 Hz, 4 H) 4.42 (s, 1H) 5.09 - 5.17 (m, 2 H) 5.31 -
5.40 (m, 2 H) 6.25 (d, J=8.78 Hz, 2 H) 6.83 - 6.92 (m, 2 H) 7.07 (t, J=7.21Hz, 2 H) 7.20 (s, 1H) 7.26
- 7.32 (m, 3 H) 7.38 (d, J=8.13 Hz, 1H) 7.46 (d, J=8.35 Hz, 1H) 11.99 - 12.06 (m, 2 H); MS ESI+
m/z 904.5 (M+H)+.
methyl {(2S)-1 -[(2S)-2- {6-[(2R,5R)-5- {2-[(2S)-1 -{(2S)-2-[(methoxycarbonyl)amino] -3-
methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-5-yl} -1 - {2- [4-(trifluoromethyl)phenyl] -1,3-
thiazol-5-yl}pyrrolidm-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-
yl}carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.73 - 0.91 (m, 12 H) 1.79 - 1.95 (m, 4 H) 1.96 - 2.06 (m, 4
H) 2.15 - 2.27 (m, 2 H) 2.69 - 2.76 (m, 2 H) 3.43 - 3.50 (m, 2 H) 3.53 (s, 6 H) 3.78 - 3.88 (m, 4 H)
4.01 - 4.10 (m, 2 H) 5.11 - 5.18 (m, 2 H) 5.32 - 5.41 (m, 2 H) 6.43 (s, 1H) 7.09 - 7.18 (m, 2 H) 7.27
(dd, J=8.24, 2.39 Hz, 2 H) 7.35 (s, 1H) 7.41 - 7.46 (m, 2 H) 7.51 (d, J=8.35 Hz, 1H) 7.57 - 7.62 (m, 2
H) 7.64 - 7.70 (m, 2 H) 12.12 (s, 2 H); MS ESI+ m/z 983.4 (M+H)+.
methyl{(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(4-tert-butyl-2,6-dimethylphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]4H-ben2imidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl}pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.77 - 0.89 (m, 12 H) 1.02 (s, 9 H) 1.84 - 2.05 (m, 10 H) 2.13
- 2.19 (m, 4 H) 2.24 - 2.30 (m, 6 H) 3.53 (s, 6 H) 3.80 (s, 4 H) 4.04 (t, J=8.08 Hz, 2 H) 5.07 - 5.14 (m,
2 H) 5.25 (s, 2 H) 6.61 (dd, J=5.10, 2.71Hz, 2 H) 7.06 (dd, J=11.87, 8.51Hz, 2 H) 7.20 - 7.37 (m, 6
H) 11.89 (s, 1H) 11.99 (s, 1H); MS ESI+ m/z 916.6 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-benziiriidazol-5-yl}-l-(4-phenylcyclohexyl)pyrrolidin-2-yl]-lH-
benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.78 - 0.93 (m, 12 H) 1.15 - 1.44 (m, 4 H) 1.46 - 1.59 (m, 2
H) 1.67 -1.78 (m, 2 H) 1.84 -1.96 (m, 4 H) 1.98 - 2.10 (m, 4 H) 2.14 - 2.27 (m, 4 H) 2.67 - 2.75 (m, 2
H) 3.07 - 3.21 (m, 1H) 3.45 - 3.52 (m, 1H) 3.54 (s, 6 H) 3.78 - 3.91 (m, 4 H) 4.03 - 4.13 (m, 2 H)
4.64 - 4.73 (m, 2 H) 5.17 (d, J=4.88 Hz, 2 H) 7.00 - 7.06 (m, 2 H) 7.09 (t, J=7.32 Hz, 2 H) 7.14 - 7.24
(m, 3 H) 7.30 (d, J=8.46 Hz, 2 H) 7.38 (d, J=8.02 Hz, 1H) 7.43 - 7.50 (m, 3 H) 12.00 (s, 2 H); MS
ESLD+ m/z 914.
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrohdin-2-yl]-lH-benzimidazol-5-yl}-l-[4-(tetrahydro-2H-pyran-4-
yl)phenyl]pyrrolidin-2-yl}-lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl}carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.73 - 0.94 (m, 12 H) 1.41 - 1.60 (m, 6 H) 1.65 - 1.75 (m, 2
H) 1.86 - 1.94 (m, 2 H) 1.95 - 2.05 (m, 4 H) 2.14 - 2.24 (m, 4 H) 2.37 - 2.46 (m, 2 H) 3.53 (s, 6 H)
3.77 - 3.86 (m, 7 H) 4.02 - 4.10 (m, 2 H) 5.09 - 5.17 (m, 2 H) 5.32 - 5.39 (m, 2 H) 6.26 (d, J=8.67 Hz,
2 H) 6.72 - 6.81 (m, 2 H) 7.06 (t, J=7.64 Hz, 2 H) 7.20 (s, 1H) 7.26 - 7.31 (m, 3 H) 7.37 (d, J=8.13
Hz, 1H) 7.45 (d, J=8.13 Hz, 1H) 12.00 -12.05 (m, 2 H); MS ESLD+ m/z 917 (M+H)+.
methyl {(2S)-l-[(2S,4S)-2-{6-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S,4S)-4-hydroxy-1 -{(2S)-2-
t(methoxycarbonyl)ammo]-3-methylbutanoyl}pyirolidin-2-yl]4H-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} -4-hydroxypyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (500 MHz, DMSO-D6) d ppm 0.67 - 0.91 (m, 12 H) 1.07 (s, 9 H) 1.69 (d, J=3.97 Hz, 2 H)
1.78 -1.89 (m, 2 H) 2.01 (d, J=13.12 Hz, 2 H) 2.37 - 2.44 (m, 2 H) 3.53 (s, 6 H) 3.67 (d, J=10.07 Hz,
2 H) 3.95 - 4.07 (m, 4 H) 4.38 (s, 2 H) 5.12 (s, 2 H) 5.37 (s, 2 H) 6.25 (d, J=8.54 Hz, 2 H) 6.34 (s, 2
H) 6.86 - 6.94 (m, 2 H) 7.09 (d, J=7.93 Hz, 2 H) 7.22 - 7.33 (m, 4 H) 7.39 - 7.51 (m, 2 H) 12.27 (d,
J=21.05 Hz, 2 H); MS ESLD+ m/z 920.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(l,3-benzodioxol-5-yl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]4H-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.78 - 0.91 (m, 12 H) 1.64 - 1.72 (m, 2 H) 1.86 - 2.04 (m, 6
H) 2.14 - 2.24 (m, 4 H) 3.29 (s, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.05 - 4.11 (m, 2 H) 5.10 - 5.18 (m, 2
H) 5.29 - 5.36 (m, 2 H) 5.66 (d, J=2.93 Hz, 1H) 5.70 - 5.75 (m, 2 H) 5.99 (d, J=2.28 Hz, 1H) 6.45 -
6.51 (m, 1H) 7.02 - 7.09 (m, 2 H) 7.21 (s, 1H) 7.28 (s, 1H) 7.31 (d, J=6.40 Hz, 2 H) 7.37 (d, J=8.13
Hz, 1H) 7.45 (d, J=8.24 Hz, 1H) 12.03 (s, 2 H); MS TFA+ m/z 876.8 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] - lH-benzimidazol-5 -yl} -1 -(4- {[(4S)-2-oxo-1,3-oxazolidin-4-
yl]methyl }phenyl)pyrrolidin-2-yl] -lH-benzimidazol-2-yl }pyrrolidin- 1-yl] -3-methyl-l -oxobutan-2-
yljcarbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.77 - 0.92 (m, 12 H) 1.63 - 1.74 (m, 2 H) 1.86 - 2.04 (m, 6
H) 2.13 - 2.26 (m, 4 H) 2.55 - 2.65 (m, 2 H) 3.25 - 3.33 (m, 2 H) 3.54 (s, 6 H) 3.75 - 3.87 (m, 6 H)
4.05 - 4.17 (m, 3 H) 5.09 - 5.19 (m, 2 H) 5.36 (d, J=5.10 Hz, 2 H) 6.27 (d, J=8.57 Hz, 2 H) 6.71 - 6.79
(m, 2 H) 7.05 (t, J=9.60 Hz, 2 H) 7.20 (s, 1H) 7.27 - 7.33 (m, 3 H) 7.37 (d, J=8.24 Hz, 1H) 7.45 (d,
J=8.13 Hz, 1H) 7.63 (s, 1H) 12.03 (s, 2 H); MS ESI+ m/z 931.5 (M+H)+.
methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl} pyrrolidin-2-yl] - lH-benzimidazol-5 -yl} -1 - [4-(propan-2-yloxy)phenyl]pyrrolidin-2-
yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.76 - 0.89 (m, 12 H) 1.07 (t, J=5.42 Hz, 6 H) 1.68 (d, J=3.47
Hz, 2 H) 1.85 - 2.05 (m, 6 H) 2.14 - 2.25 (m, 4 H) 2.58 (d, J=4.77 Hz, 2 H) 3.53 (s, 6 H) 3.81 (s, 4 H)
4.05 (t, J=8.40 Hz, 2 H) 4.13 - 4.25 (m, 1H) 5.08 - 5.20 (m, 2 H) 5.32 (d, J=5.31Hz, 2 H) 6.23 (d,
J=9.00 Hz, 2 H) 6.45 - 6.55 (m, 2 H) 7.05 (t, J=8.19 Hz, 2 H) 7.20 (s, 1H) 7.26 - 7.33 (m, 3 H) 7.37
(d, J=8.24 Hz, 1H) 7.44 (d, J=8.35 Hz, 1H) 12.02 (d, J=4.55 Hz, 2 H); MS ESI+ m/z 890.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[2-(4-fluorophenyl)-l,3-thiazol-5-yl]-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)ainino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.85 (m, 12 H) 1.77 - 1.83 (m, 2 H) 1.87 - 1.93 (m, 2
H) 1.95 - 2.06 (m, 4 H) 2.14 - 2.25 (m, 6 H) 3.53 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.03 - 4.10 (m, 2 H)
5.12 - 5.18 (m, 2 H) 5.28 - 5.35 (m, 2 H) 7.06 - 7.16 (m, 5 H) 7.28 (dd, J=8.29, 2.01Hz, 2 H) 7.33 (s,
1H) 7.40 - 7.45 (m, 2 H) 7.47 - 7.55 (m, 3 H) 12.10 (s, 2 H); MS ESI+ m/z 933.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}-l-[4-(trifluoromedioxy)phenyl]pyiroUdin-2-
yl} - lH-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMS0-D6) d ppm 0.74 - 0.87 (m, 12 H) 1.67 - 1.76 (m, 2 H) 1.86 - 1.92 (m, 2
H) 1.96 - 2.06 (m, 4 H) 2.15 - 2.23 (m, 6 H) 3.53 (s, 6 H) 3.77 - 3.88 (m, 4 H) 4.05 (t, J=8.84 Hz, 2 H)
5.12 (t, J=7.05 Hz, 2 H) 5.37 - 5.46 (m, 2 H) 6.34 (d, J=9.11Hz, 2 H) 6.89 (q, J=7.30 Hz, 2 H) 7.02 -
7.11 (m, 2 H) 7.21 (s, 1H) 7.26 - 7.33 (m, 3 H) 7.39 (d, J=8.35 Hz, 1H) 7.47 (d, J=8.13 Hz, 1H)
12.06 (d, J=17.02 Hz, 2 H); MS ESI+ m/z 916.4 (M+H)+.
methyl {(2S)-l-[(2S,4S)-2-{5-[(2R,5R)-l-(4-tert-butylphenyl)-5-{2-[(2S,4S)-4-methoxy-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} -4-methoxypyrrolidin-1 -yl]-3-methyl-l -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.88 (m, 12 H) 1.07 (s, 9 H) 1.67 - 1.76 (m, 2 H) 1.88
- 2.00 (m, 4 H) 2.06 - 2.16 (m, 2 H) 3.12 - 3.21 (m, 2 H) 3.25 (d, J=4.23 Hz, 6 H) 3.54 (s, 6 H) 3.59 -
3.69 (m, 2 H) 4.02 - 4.13 (m, 4 H) 4.16 - 4.28 (m, 2 H) 5.11 (td, J=9.38, 6.51Hz, 2 H) 5.35 (t, J=5.37
Hz, 2 H) 6.23 - 6.28 (m, 2 H) 6.90 (d, J=8.89 Hz, 2 H) 7.06 (d, J= 10.19 Hz, 2 H) 7.22 (d, J=3.25 Hz, 1H) 7.25 - 7.32 (m, 3 H) 7.38 (d, J=8.35 Hz, 1H) 7.45 (d, J=8.24 Hz, 1H) 11.79 (d, J=18.32 Hz, 2 H);
MS ESI+ m/z 948.5 (M+H)+.
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[2,5-difluoro-4-(trifluoromethyl)phenyl]-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.74 - 0.90 (m, 12 H) 1.74 - 1.83 (m, 2 H) 1.86 - 1.93 (m, 2
H) 1.94 - 2.05 (m, 4 H) 2.13 - 2.25 (m, 4 H) 3.44 - 3.48 (m, 2 H) 3.53 (s, 6 H) 3.77 - 3.88 (m, 4 H)
4.06 (t, J=4.23 Hz, 2 H) 5.10 - 5.16 (m, 2 H) 5.63 - 5.74 (m, 2 H) 6.60 - 6.73 (m, 1H) 7.04 - 7.20 (m,
4 H) 7.24 - 7.31 (m, 3 H) 7.38 (d, J=8.46 Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 12.08 (d, J=27.11Hz, 2
H); MS ESI+ m/z 936.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[3-fluoro-4-(trifluoromethyl)phenyl]-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrroUdm-2-yl]-lH-benzimidazpl-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.90 (m, 12 H) 1.71 - 1.79 (m, 2 H) 1.87 - 1.95 (m, 2
H) 1.97 - 2.04 (m, 4 H) 2.13 - 2.25 (m, 6 H) 3.53 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.04 - 4.11 (m, 2 H)
5.11 - 5.18 (m, 2 H) 5.46 - 5.56 (m, 2 H) 6.24 (dd, J=8.24, 2.39 Hz, 2 H) 7.04 - 7.11 (m, 2 H) 7.19 -
7.25 (m, 2 H) 7.28 (dd, J=8.46, 3.69 Hz, 2 H) 7.32 (s, 1H) 7.41 (d, J=8.13 Hz, 1H) 7.49 (d, J=8.24
Hz, 1H) 12.09 (dd, J=15.72,2.17 Hz, 2 H); MS ESI+ m/z 918.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(4-cyanophenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMS0-D6) d ppm 0.76 - 0.90 (m, 12 H) 1.70 - 1.79 (m, 2 H) 1.90 (dd, J=12.25,
6.40 Hz, 2 H) 1.95 - 2.02 (m, 4 H) 2.15 - 2.24 (m, 6 H) 3.54 (s, 6 H) 3.78 - 3.85 (m, 4 H) 4.06 (t,
J=8.29 Hz, 2 H) 5.10 - 5.16 (m, 2 H) 5.46 - 5.55 (m, 2 H) 6.42 (d, J=8.67 Hz, 2 H) 7.05 (dd, J=12.90,
8.57 Hz, 2 H) 7.22 (s, 1H) 7.25 - 7.34 (m, 5 H) 7.40 (d, J=8.24 Hz, 1H) 7.47 (d, J=8.24 Hz, 1H)
12.09 (s, 2 H); MS ESI+ m/z 857.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-t(2R,5R)-l-[4-(2-cyanopropan-2-yl)phenyl]-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)anuno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.91 (m, 12 H) 1.47 (s, 6 H) 1.67 - 1.76 (m, 2 H) 1.85
- 1.95 (m, 2 H) 1.96 - 2.03 (m, 4 H) 2.15 - 2.24 (m, 6 H) 3.53 (s, 6 H) 3.77 - 3.85 (m, 4 H) 4.05 (t,
J=8.46 Hz, 2 H) 5.10 - 5.17 (m, 2 H) 5.37 - 5.45 (m, 2 H) 6.34 (d, J=8.89 Hz, 2 H) 6.97 - 7.04 (m, 2
H) 7.07 (t, J=8.35 Hz, 2 H) 7.21 (s, 1H) 7.28 (d, J=10.52 Hz, 3 H) 7.39 (d, J=8.13 Hz, 1H) 7.47 (d,
J=8.24 Hz, 1H) 12.05 (d, J=13.01Hz, 2 H); MS ESI+ m/z 899.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(4-cyano-3-fluorophenyl)-5-{2-t(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.74 - 0.92 (m, 12 H) 1.74 (t, J=9.00 Hz, 2 H) 1.87 -1.94 (m,
2 H) 1.96 - 2.06 (m, 4 H) 2.15 - 2.25 (m, 4 H) 2.55 - 2.63 (m, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.06 (t,
J=8.40 Hz, 2 H) 5.14 (d, J=2.28 Hz, 2 H) 5.55 (dd, J=16.26, 6.07 Hz, 2 H) 6.18 - 6.33 (m, 2 H) 7.01 -
7.15 (m, 2 H) 7.23 (s, 1H) 7.25 - 7.35 (m, 4 H) 7.42 (d, J=7.70 Hz, 1H) 7.49 (d, J=8.46 Hz, 1H)
12.10 (s, 2 H); MS ESI+ m/z 875.4 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(2,2-difluoro-l,3-benzodioxol-5-yl)-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)a]rdno]-3-methylbutanoyl}pyrrolidin-2-yl]4H-benzimida2X>l-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.91 (m, 12 H) 1.69 - 1.77 (m, 2 H) 1.91 (dd, J=14.26,
6.67 Hz, 2 H) 1.96 - 2.07 (m, 4 H) 2.14 - 2.24 (m, 4 H) 2.54 - 2.60 (m, 2 H) 3.53 (s, 6 H) 3.78 - 3.86
(m, 4 H) 4.06 (t, J=8.40 Hz, 2 H) 5.10 - 5.17 (m, 2 H) 5.36 - 5.44 (m, 2 H) 6.05 (dd, J=9.11, 2.17 Hz,
1H) 6.29 (d, J=2.60 Hz, 1H) 6.89 - 6.95 (m, 1H) 7.06 (t, J=8.51Hz, 2 H) 7.22 (s, 1H) 7.26 - 7.33
(m, 3 H) 7.39 (d, J=8.35 Hz, 1H) 7.47 (d, J=7.59 Hz, 1H) 12.03 - 12.09 (m, 2 H); MS ESI+ m/z
912.8 (M+H)+.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[4-(l-amino-2-methylpropan-2-yl)phenyl]-5-{2-[(2S)-l-{(2S)-
2-[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.74 - 0.92 (m, 12 H) 1.01 (d, J=5.20 Hz, 6 H) 1.65 - 1.76
(m, 2 H) 1.86 - 1.93 (m, 2 H) 1.98 (d, J=4.01Hz, 4 H) 2.13 - 2.25 (m, 4 H) 2.41 (s, 2 H) 2.53 - 2.61
(m, 2 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.08 - 5.17 (m, 2 H) 5.32 - 5.41 (m, 2 H)
6.27 (d, J=8.89 Hz, 2 H) 6.81 - 6.92 (m, 2 H) 7.07 (t, J=7.97 Hz, 2 H) 7.20 (s, 1H) 7.25 - 7.32 (m, 3
H) 7.38 (d, J=8.13 Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 12.02 (d, J=19.63 Hz, 2 H); MS ESI+ m/z 903.4
(M+H)+.
methyl (2-{4-[(2R,5R)-2-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl} pyrrolidin-2-yl] - lH-benzimidazol-5-yl} -5- {2-[(2S)-1 - {(2S)-2-
[(methoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-l-
yl]phenyl}-2-methylpropyl)carbamate
1H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.91 (m, 12 H) 1.00 (d, J=6.07 Hz, 6 H) 1.64 - 1.75
(m, 2 H) 1.83 - 1.94 (m, 2 H) 1.96 - 2.05 (m, 4 H) 2.14 - 2.23 (m, 4 H) 2.89 - 3.00 (m, 2 H) 3.17 (d,
J=5.20 Hz, 2 H) 3.42 (s, 3 H) 3.53 (s, 6 H) 3.77 - 3.87 (m, 4 H) 3.99 - 4.07 (m, 2 H) 5.08 - 5.20 (m, 2
H) 5.32 - 5.42 (m, 2 H) 6.27 (d, J=8.46 Hz, 2 H) 6.72 - 6.80 (m, 1H) 6.83 - 6.93 (m, 2 H) 7.07 (t,
J=8.62 Hz, 2 H) 7.20 (s, 1H) 7.26 - 7.33 (m, 3 H) 7.38 (d, J=8.13 Hz, 1H) 7.45 (d, J=8.57 Hz, 1H)
12.03 (d, J=12.36 Hz, 2 H)
MS ESI+ m/z 961.4 (M+H)+
methyl {(2S)-1-[(2S)-2-{5-t(2R,5R)-1-[3-fluoro-4-(piperidin-l-yl)phenyl]-5-(2-[(2S)-1-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
MS(ESI)m/z934(M+H)+
methyl {(2S)-1 -[(2S)-2-{5-[(2R,5R)-l-[4-(l, 1 -dioxidothiomorphoUn-4-yl)-3-fluorophenyl]-5-{2-
[(2S)-l-{(2S)-2-[(meflioxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-
yl }pyrrolidin-2-yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
MS (ESI) m/z 984 (M+H)+
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[3-fluoro-4-(4-methylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l-
{(2S)-2-[(memoxycarbonyl)aniino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-
yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
MS (ESI) m/z 948 (M+H)+
methyl {(2S)-1 -[(2S)-2-(6-{(5R)-5-{2-[(2S)-1 -{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}-l-[4-(tricyclo[3.3.1.13,7~]dec-l-
yl)phenyl]pyrrolidin-2-yl} -1H-benzimidazol-2-yl)pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-
yl} carbamate
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[4-(azepan-l-yl)-3-fluorophenyl]-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
+ESI m/z (rel abundance) 948 (100, M+H)
methyl {(2S,3K)-l-[(2S)-2-{6-[(2K,5/?)-l-(4-tert-butylphenyl)-5-(2-{(25)-l-[^-(methoxycarbonyl)-O-
memyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-6-yl)pyrrolidin-2-yl]-lH-benzimidazol-2-
yl} pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2-yl} carbamate
MS (ESI) m/z 920 (M+H)+.
methyl {(2S)-l-t(2S)-2-{6-[(2R,5R)-l-(4-cyclopropyl-2-fluorophenyl)-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-6-yl} pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
MS (ESI) m/z 890 (M+H)+.
methyl [(2S)-l-{(2S)-2-[4-(3-{5-(3-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl }pyrrolidin-2-yl] -lH-imidazol-4-yl }phenyl)-l -[6-(piperidin-1 -yl)pyridin-3-yl] -1H-
pyrrol-2-yl Jphenyl)- lH-imidazol-2-yl]pyrrolidin-l -yl} -3-methyl-1 -oxobutan-2-yl]carbamate
MS (ESI; M+H) m/z = 964.5.
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methyltratanoyl }pyrrolidin-2-yl] -1H-benzimidazol-6-yl} -1 - {6-
[methyl(memylsulfonyl)ainmo]pyridin-3-yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidiii-l-yl]-
3-methyl-l-oxobutan-2-yl}carbamate
ESI+m/z 940 (M+H)+
2-methylpropyl {5-[(2R,5R)-2,5-bis(2-{(2S)-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidiii-2-yl}-lH-
benzimidazol-6-yl)pyrrolidin-1 -yl]pyridin-2-yl} methylcarbamate
ESI+m/z 963 (M+H)+
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[4-(3,5-dimethylpiperidin-l-yl)-3-fluorophenyl]-5-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-
yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl Jcarbamate
ESI+m/z 962 (M+H)+
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[4-(diethylamino)-3-fluorophenyl]-5-{2-t(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrohdin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
ESI+m/z 922 (M+H)+
methyl{(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(6-cyclohexylpyridin-3-yl)-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl) amino] -3-methylbutanoyl }pyrrolidin-2-yl] -1H-benzimidazol-6-yl} pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
LC/MS : m/z 916.4 TFA method
(ESI; M+H) m/z = 908.5
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(3-fluoro-4-hydroxyphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(methoxycarbonyl)annno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] - lH-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
(ESI; M+H) m/z = 866.3
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-(3-fluoro-4-methoxyphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-ben2irmdazol-6-yl}pyrrolidiri-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
(ESI; M+H) m/z =880
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-t(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate
1H NMR (400 MHz, DMS0-D6) δ ppm0.73 - 0.90 (m, 12 H) 1.32 - 2.28 (m, 20 H) 2.76 (s, 4 H) 3.54
(s, 6 H) 3.82 (s, 4 H) 3.99 - 4.12 (m, 2 H) 5.10 - 5.20 (m, 2 H) 5.36 (d, J=7.59 Hz, 2 H) 5.83 - 5.95 (m,
methyl {(2S)-1 -[(2S)-2-{6-[(2R,5R)-1 -(4-tert-butylphenyl)-5-{2-[(2S)-1 -{(2S)-2-
[(methoxycarbonyl)amino] -3-methylbutanoyl}pyrrolidin-2-yl] -1,3-benzoxazol-6-yl }pyrrolidin-2-yl] -
l,3-benzoxazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
ESI+:(M+H): 890.5
N-(methoxycarbonyl)-L-valyl-N- {5-[ 1 -(4-tert-butylphenyl)-5-(2-{ (2S)-1 -[N-(methoxycarbonyl)-L-
valyl]pyn:olidin-2-yl}-lH-benzimidazol-6-yl)pyrrolidin-2-yl]-2-methoxyphenyl}-L-prolinamide
ESI+:(M+H): 921.5
methyl {(2S)-1 -[(2S)-2-{6-[(2R,5R)-l-(4-tert-butyl-2-fluorophenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)aimno]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
ESI+:(M+H): 906.4
{[(2R,5R)-1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis [ 1H-benzimidazole-6,2-diyl(2S)pyrrolidine-
2,1 -diyl] }bis [(1 -hydroxycycloheptyl)methanone]
MS (ESI) positive ion 854 (M+H)+.
(lS,4R,l'S,4'R)-l,l'-{[(2R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-
diyl(2S)pyrrolidine-2,1-diylcarbonyl] }bis(7,7-dimethylbicyclo[2.2. l]heptan-2-one)
MS (ESI) positive ion 902 (M+H)+.
l,l'-{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-
diyl(2S)pyrrolidine-2,1 -diyl] }bis(2,2-diphenylpropan-1 -one)
MS (ESI) positive ion (M+H)+. Is not observed but
MS (APCI) positive ion 990 (M+H) + observed
Example 286
(2S,2'S)-1,1'- {[(2R,5R)- l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-
diyl(2S)pyrrolidine-2,l-diyl]}bis(3,3,3-trifluoro-2-methoxy-2-phenylpropan-l-one)
MS (ESI) positive ion 1006 (M+H)+.
{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-diyl(2S)pyrrolidine-
2,1 -diyl] }bis [(1 -phenylcyclopentyl)methanone]
MS (ESI) positive ion 918.6 (M+H)+.
l,l'-{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-
diyl(2S)pyrrolidine-2,1-diyl] }bis(2-cyclopentyl-2-phenylethanone)
MS (ESI) positive ion 946 (M+H)+.
(2R,2'R)-l,l,-{[(2R,5R)-l-(4-tert-butylphenyl)pyrroUdine-2,5-diyl]bis[lH-benzimidazole-6,2-
diyl(2S)pyrrolidine-2,1 -diyl]} bis(2-hydroxy-2-phenylbutan-1 -one)
MS (ESI) positive ion (M+H)+.
{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-diyl(2S)pyrrolidine-
2,1-diyl] }bis{ [l-(trifluoromethyl)cyclopropyl]methanone}
MS (ESI) positive ion 846 (M+H)+.
Example 297
{[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-6,2-diyl(2S)pyrrolidine-
2,l-diyl]}bis[(l-phenylcyclopropyl)methanone]
MS (ESI) positive ion 862.5 (M+H)+.
Example 298
methyl {(2S)-1 -[(2S)-2-{5-[(2R,5R)-1 -[4-(difluoromethoxy)phenyl]-5-{2-[(2S)-1 -{(2S)-2-
[(methoxycarbonyl)amino] -3-mediylbutanoyl} pyrrolidin-2-yl] -1H-benzimidazol-5-yl} pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-l -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
(ESI+) m/z 898.4 (M+H)+
Example 299
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(3,5-difluoro-4-melhoxyphenyl)-5-{2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)ammo]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
(ESI+) m/z 898.4 (M+H)+
Example 300
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[4-(4,4-dimethylpiperidin-l-yl)-3-fluorophenyl]-5-{2-[(2S)-l-
{(2S)-2-[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-
yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
MS +ESI m/z (rel abundance) 962 (100, M+H); 1H NMR (400 MHz, DMSO-^J 5 7.52 (d, J = 8.2, 1H), 7.44 (d, J= 8.1, 1H), 7.35 (d, J= 8.1, 3 H), 7.26 (s, 1H), 7.14 (m, 2 H), 6.75 (s, 1H), 6.12 (m, 2
H), 5.40 (s, 2 H), 5.19 (s, 2 H), 4.12 (t, J = 8.4, 2 H), 3.88 (s, 4 H), 3.60 (s, 6 H), 2.70 (m, 5 H), 2.24
(s, 4 H), 1.99 (m, 7 H), 1.75 (s, 2 H), 1.46 (s, 3 H), 1.39 (s, 8 H), 0.89 (m, 20 H).
Example 301
methyl {(2S)-l-[(2S)-2-{6-[l-(4-tert-butylphenyl)-5-{4-fluoro-2-[(2S)-l-{(2S)-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl]-4-fluoro-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
MS (ESI) m/z 924 (M+H)+
Example 302 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-cyclopropyl-3-fluorophenyl)-5-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)aimno]-3-melthylbutanoyl}pyrrolidm-2-yl]-lH-benzimidazol-5-
yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate
MS (ESD m/z 891 (M+H)+
Example 303
methyl {(2S)-l-t(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl )pyrrolidin-2-yl]-lH-benzimidazol-6-yl} -1-{4-[2-(2-
methoxyethoxy)ethoxy]phenyl }pyrrolidin-2-yl] -1H-benzimidazol-2-yl Jpyrrolidin-1 -yl] -3-methyl-1 -
oxobutan-2-yl} carbamate
MS (ESI) m/z 950 (M+H)+, 948 (M-H)+.
Example 304
methyl{(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[3-fluoro-4-(3-methylpyrrolidin-l-yl)phenyl]-5-{2-[(2S)-l-
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-
yl}pyrrolidin-2-yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl }carbamate
1H NMR (400 MHz, DMS0-D6) δ ppm 0.76 - 0.89 (m, 12 H) 0.95 (d, J=6.72 Hz, 3 H) 1.62 - 1.72
(m, 2 H) 1.83 - 2.06 (m, 9 H) 2.09 - 2.24 (m, 6 H) 2.52 - 2.61 (m, 2 H) 2.91 - 3.15 (m, 4 H) 3.52 (s, 6
H) 3.74 - 3.86 (m, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.08 - 5.17 (m, 2 H) 5.26 - 5.38 (m, 2 H) 5.97 - 6.10
(m, 2 H) 6.35 - 6.45 (m, 1H) 7.01 - 7.08 (m, 2 H) 7.19 (s, 1H) 7.25 - 7.32 (m, 3 H) 7.36 (d, J=8.24
Hz, 1H) 7.44 (d, J=7.92 Hz, 1H) 12.01 (s, 2 H).
Example 305
methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[2,3-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(25)-l-{(25)-2-
[(memoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidm-2-
yl] -1H-benzimidazol-2-yl }pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl} carbamate
ESI+ (m/z): 951.5; 1H NMR (400 MHz, DMSO-D6) δ ppm 0.74 - 0.90 (m, 12 H) 1.35 -1.41 (m, 2 H)
1.44 -1.51 (m, 4 H) 1.73 - 1.83 (m, 2 H) 1.86 - 2.02 (m, 6 H) 2.14 - 2.23 (m, 4 H) 2.59 - 2.72 (m, 6 H)
3.53 (s, 6 H) 3.77 - 3.84 (m, 4 H) 3.97 - 4.10 (m, 2 H) 5.06 - 5.18 (m, 2 H) 5.46 - 5.56 (m, 2 H) 6.36 -
6.47 (m, 2 H) 7.03 - 7.11 (m, 2 H) 7.23 - 7.45 (m, 6 H) 11.95 -12.10 (m, 2 H)
Example 306
methyl {(25)-l-[(2^-2-{6-[(2i?,5/?)-l-(4-ethoxy-3-fluorophenyl)-5-{2-[(25)-l-{(25)-2-
[(memoxycarbonyl)amino]-3-memylbulanoyl}pyrrolidm-2-yl]-lff-benzimidazol-6-yl}pyrrolidin-2-
yl] -1 ff-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
ESI+ (m/z): 894.4
Example 307
methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-1 -[4-(^rt-butylamino)-3-fluorophenyl]-5-{2-[(2S)-1 -{(25')-2-
[(memoxycarbonyl)amino]-3-memylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2-
yl] -1H-benzimidazol-2-yl} pyrrolidin-1 -yl] -3-methyl-l -oxobutan-2-yl} carbamate
ESI+ (m/z): 922; 1H NMR (400 MHz, DMSO-D6) δ ppm 0.75 - 0.90 (m, 12 H) 0.97 (s, 9 H) 1.61 -
1.71 (m, 2 H) 1.83 - 2.04 (m, 6 H) 2.12 - 2.23 (m, 4 H) 3.52 (s, 6 H) 3.76 - 3.86 (m, 4 H) 4.01 - 4.08
(m, 2 H) 5.09 - 5.17 (m, 2 H) 5.27 - 5.37 (m, 2 H) 5.98 - 6.07 (m, 2 H) 6.56 - 6.66 (m, 1H) 7.06 (t,
J=7.92 Hz, 2 H) 7.19 (s, 1H) 7.27 (d, J=9.00 Hz, 3 H) 7.38 (d, J=8.24 Hz, 1H) 7.46 (d, J=8.13 Hz, 1
H) 12.00 (s, 1H) 12.08 (s, 1H)
Example 308
ethyl 5-{(2R,5J?)-l-(4-terf-butylphenyl)-5-[l-(ethoxycarbonyl)-2-{(25')-l-[iV-(methoxycarbonyl)-L-
valyl]pyrrolidin-2-yl)-1H-benzimidazol-5-yl]pyrrolidin-2-yl}-2-{l-[N-(methoxycarbonyl)-L-
valyl]pyrrolidm-2-yl} -1H-benzimidazole-1 -carboxylate
and
ethyl 5-{(2R,5R)-l-(4-tert-butylphenyl)-5-[l-(ethoxycarbonyl)-2-{(25)-l-[iV-(methoxycarbonyl)-L-
valyl]pyrroUdin-2-yl}-lH-benzimidazol-6-yl]pyrrolidin-2-yl}-2-{(2S)-l-[-(methoxycarbonyl)-L-
valyl]pyrrolidin-2-yl} -1H-benzimidazole-1 -carboxylate
ESI+ (m/z): 1032.5; 1H NMR (400 MHz, DMSO-D6) δ ppm 0.70 - 1.04 (m, 12 H) 1.08 (s, 9 H) 1.33
-1.46 (m, 6 H) 1.65 -1.77 (m, 2 H) 1.81 - 2.13 (m, 8 H) 2.20 - 2.28 (m, 2 H) 2.55 - 2.62 (m, 2 H) 3.53
(d, J=4.23 Hz, 6 H) 3.80 - 3.92 (m, 4 H) 4.04 - 4.13 (m, 2 H) 4.41 - 4.59 (m, 4 H) 5.38 - 5.49 (m, 2 H)
5.66 - 5.76 (m, 2 H) 6.17 - 6.33 (m, 2 H) 6.82 - 7.00 (m, 3 H) 7.18 - 7.56 (m, 5 H) 7.75 - 7.91 (m, 2 H)
The title compounds of Examples 52, 53, 54, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 74,
75,76,77, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 93, 94,95, 96,97,99,101,102, 103,109,
110, 111, 112, 113, 117, 121, 122, 123, 125, 126, 127, 128, 129, 130, 131, 132, 135, 136, 137, 138,
139, 140, 141, 144, 145, 146, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 160, 161, 162,
163, 166, 167, 168, 169, 170, 171, 173, 176, 178, 179, 180, 181, 183, 184, 185, 186, 188, 189, 191,
192, 194, 195, 197, 198, 199, 200, 201, 202, 203, 205, 207, 208, 209, 210, 211, 212, 214, 215, 216,
217, 218, 219, 220, 221, 224, 226, 227, 228, 229, 230, 231, 233, 234, 235, 236, 237, 238, 240, 241,
242, 245, 247, 248, 250, 251, 252, 254, 256, 257, 258, 262, 263, 264, 266, 267, 268, 270, 271, 272,
273, 274, 275, 276, 277, 278, 282, 294, 295, 296, 297, 298, 299, 300, 301, 302, 305, and 306 showed
an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
The tide compounds of Examples 51, 55, 56, 57, 70, 71, 72, 73, 78, 98, 100, 108, 114, 115, 116, 119,
120, 133, 134, 142, 143, 147, 164, 172, 174, 182, 196, 204, 206, 222, 223, 225, 239, 244, 249, 253,
259, 261, 265, 281, 287, 288, 292, 303, 304, 307, and 308 showed an EC50 value of from about 0.1 to
about 1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS. The title compounds of
Examples 92, 105, 106, 107, 118, 124, 158, 165, 175, 177, 187, 190, 193, 213, 232, 243, 246, 255,
260, 269, 279, 280, 283, 284, 285, 286, 289, 290, 291, and 293 showed an EC50 value of from about 1
to about 100 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.
When tested using HCV lb-Conl replicon assays in the presence of 5% FBS, each of the
5 above compounds showed an EC50 value of less than 1 nM.
In addition, the following mixtures of stereoisomers were prepared according to procedures
similar to those described above, where each compound in each stereoisomer mixture can be readily
isolated using chiral chromatography or other suitable methods as appreciated by those skilled in the
art and, therefore, the present invention also features each compound in these stereoisomer mixtures:
10
wherein A is selected from Table la, B is selected from Table lb, D is selected from Table 2, Y and Z
are each independently selected from Table 3, and is selected from Table 4, and A, B, D
and X are each independently optionally substituted with one or more RA, and wherein Lx, L^, L3 and
RA are as described above. Preferably, L1, L2 and L3 are bond.
Each compound's anti-HCV activity can be determined by measuring the activity of the
luciferase reporter gene in the replicon in the presence of 5% FBS. The luciferase reporter gene is
placed under the translational control of the poliovirus IRES instead of the HCV IRES, and HuH-7
cells are used to support the replication of the replicon.
The inhibitory activities of the compounds of the present invention can be evaluated using a
variety of assays known in the art. For instance, two stable subgenomic replicon cell lines can be
used for compound characterization in cell culture: one derived from genotype la-H77 and the other
derived from genotype lb-Conl, obtained from University of Texas Medical Branch, Galveston, TX
or Apath, LLC, St. Louis, MO, respectively. The replicon constructs can be bicistronic subgenomic
replicons. The genotype la replicon construct contains NS3-NS5B coding region derived from the
H77 strain of HCV (la-H77). The replicon also has a firefly luciferase reporter and a neomycin
phosphotransferase (Neo) selectable marker. These two coding regions, separated by the FMDV 2a
protease, comprise the first cistron of the bicistronic replicon construct, with the second cistron
containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R,
K2040R and S2204I. The lb-Conl replicon construct is identical to the la-H77 replicon, except that
the HCV 5' UTR, 3' UTR, and NS3-NS5B coding region are derived from the lb-Conl strain, and
the adaptive mutations are K1609E, K1846T and Y3005C. In addition, the lb-Conl replicon
construct contains a poliovirus IRES between the HCV IRES and the luciferase gene. Replicon cell
lines can be maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) fetal
bovine serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and 200 mg/ml
G418(Invitrogen).
The inhibitory effects of the compounds of the invention on HCV replication can be
determined by measuring activity of the luciferase reporter gene. For example, replicon-containing
cells can be seeded into 96 well plates at a density of 5000 cells per well in 100 μl DMEM containing
5% FBS. The following day compounds can be diluted in dimethyl sulfoxide (DMSO) to generate a
200x stock in a series of eight half-log dilutions. The dilution series can then be further diluted
100-fold in the medium containing 5% FBS. Medium with the inhibitor is added to the overnight cell
culture plates already containing 100 ul of DMEM with 5% FBS. In assays measuring inhibitory
activity in the presence of human plasma, the medium from the overnight cell culture plates can be
replaced with DMEM containing 40% human plasma and 5% FBS. The cells can be incubated for
three days in the tissue culture incubators after which time 30 μl of Passive Lysis buffer (Promega)
can be added to each well, and then the plates are incubated for 15 minutes with rocking to lyse the
cells. Luciferin solution (100 μL, Promega) can be added to each well, and luciferase activity can be
measured with a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA
replication can be calculated for each compound concentration and the EC50 value can be calculated
using nonlinear regression curve fitting to the 4-pararneter logistic equation and GraphPad Prism 4
software. Using the above-described assays or similar cell-based replicon assays, representative
compounds of the present invention showed significantly inhibitory activities against HCV
replication.
The present invention also features pharmaceutical compositions comprising the compounds
of the invention. A pharmaceutical composition of the present invention can comprise one or more
compounds of the invention, each of which has Formula I (or IA, IB, Ic or ID).
In addition, the present invention features pharmaceutical compositions comprising
pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of the invention. Without
limitation, pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically
acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt retains
the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation,
or allergic response, has a reasonable benefit/risk ratio, is effective for the intended use, and is not
biologically or otherwise undesirable.
The present invention further features pharmaceutical compositions comprising a compound
of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. By way of
illustration not limitation, these other therapeutic agents can be selected from antiviral agents (e.g.,
anti-HIV agents, anti-HBV agents, or other anti-HCV agents such as HCV protease inhibitors, HCV
polymerase inhibitors, HCV helicase inhibitors, IRES inhibitors or NS5A inhibitors), anti-bacterial
agents, anti-fungal agents, immunomodulators, anti-cancer or chemotherapeutic agents, anti-
inflammation agents, antisense RNA, siRNA, antibodies, or agents for treating cirrhosis or
inflammation of the liver. Specific examples of these other therapeutic agents include, but are not
limited to, ribavirin, α-interferon, β-interferon, pegylated interferon-α, pegylated interferon-lambda,
ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025, NTM-811, R7128, R1626,
R4048, T-1106, PSI-7851 (Pharmasset) (nucleoside polymerase inhibitor), PSI-938 (Phannasset)
(nucleoside polymerase inhibitor), PF-00868554, ANA-598, IDX184 (nucleoside polymerase
inhibitor), IDX102, IDX375 (non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside
polymerase inhibitor), VCH-759, VCH-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598,
GL59728, GL60667, BMS-790052 (NS5A inhibitor), BMS-791325 (protease Inhibitor), BMS-
650032, BMS-824393, GS-9132, ACH-1095 (protease inhibitor), AP-H005, A-831 (Arrow
Therapeutics) (NS5 A inhibitor), A-689 (Arrow Therapeutics) (NS5 A inhibitor), INX08189 (Inhibitex)
(polymerase inhibitor), AZD2836, telaprevir (protease Inhibitor), boceprevir (protease Inhibitor),
ITMN-191 (fntermune/Roche), BI-201335 (protease Inhibitor), VBY-376, VX-500 (Vertex) (protease
Inhibitor), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease Inhibitor), SCH 900518
(Schering-Plough), TMC-435 (Tibotec) (protease Inhibitor), ITMN-191 (fntermune, Roche) (protease
Inhibitor), MK-7009 (Merck) (protease Inhibitor), IDX-PI (Novartis), BI-201335 (Boehringer
Ingelheim), R7128 (Roche) (nucleoside polymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck)
(nucleoside polymerase inhibitor), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF-
4878691 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), PPI-461 (Presidio) (NS5A inhibitor),
BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis),
ABT-450 (Abbott/Enanta) (protease Inhibitor), ABT-333 (Abbott) (non-nucleoside polymerase
inhibitor), ABT-072 (Abbott) (non-nucleoside polymerase inhibitor), ritonavir, another cytochrome
P450 monooxygenase inhibitor, or any combination thereof.
In one embodiment, a pharmaceutical composition of the present invention comprises one or
more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more
other antiviral agents.
In another embodiment, a pharmaceutical composition of the present invention comprises one
or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more
other anti-HCV agents. For example, a pharmaceutical composition of the present invention can
comprise a compound(s) of the present invention having Formula I, IA, IB, IC, or ID (or a salt, solvate
or prodrug thereof), and an agent selected from HCV polymerase inhibitors (including nucleoside or
non-nucleoside type of polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors,
CD81 inhibitors, cyclophilin inhibitors, IRES inhibitors, or NS5A inhibitors.
In yet another embodiment, a pharmaceutical composition of the present invention comprises
one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or
more other antiviral agents, such as anti-HBV, anti-HIV agents, or anti-hepatitis A, anti-hepatitis D,
anti-hepatitis E or anti-hepatitis G agents. Non-limiting examples of anti-HBV agents include
adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir,
lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114,
fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir,
efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or other HIV
protease, reverse transcriptase, integrase or fusion inhibitors. Any other desirable antiviral agents can
also be included in a pharmaceutical composition of the present invention, as appreciated by those
skilled in the art.
In a preferred embodiment, a pharmaceutical composition of the invention comprises a
compound of the invention (e.g.., a compound of Formula I, IA, IB, Ic, or ID, or preferably a compound
selected from Examples 1-308, or a salt, solvate or prodrug thereof), and a HCV protease inhibitor. In
another preferred embodiment, a pharmaceutical composition of the invention comprises a compound
of the invention (e.g.., a compound of Formula I, IA, IB, Ic, or ID, or preferably a compound selected
from Examples 1-308, or a salt, solvate or prodrug thereof), and a HCV polymerase inhibitor (e.g., a
non-nucleoside polymerase inhibitor, or preferably a nucleoside polymerase inhibitor). In yet another
preferred embodiment, a pharmaceutical composition of the present invention comprises (1) a
compound of the invention (e.g.., a compound of Formula I, IA, IB, Ic, or ID, or preferably a compound
selected from Examples 1-308, or a salt, solvate or prodrug thereof), (2) a HCV protease inhibitor,
and (3) a HCV polymerase inhibitor (e.g., a non-nucleoside polymerase inhibitor, or preferably a
nucleoside polymerase inhibitor). Non-limiting examples of protease and polymerase inhibitors are
described above.
A pharmaceutical composition of the present invention typically includes a pharmaceutically
acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable
carriers/excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or
potato starch), cellulose or its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose or
cellulose acetate), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or
soybean oil), glycols (e.g., propylene glycol), buffering agents (e.g., magnesium hydroxide or
aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter,
pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or phosphate buffer solutions.
Lubricants, coloring agents, releasing agents, coating agents, sweetening, flavoring or perfuming
agents, preservatives, or antioxidants can also be included in a pharmaceutical composition of the
present invention.
The pharmaceutical compositions of the present invention can be formulated based on their
routes of administration using methods well known in the art. For example, a sterile injectable
preparation can be prepared as a sterile injectable aqueous or oleagenous suspension using suitable
dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be
prepared by mixing drugs with a suitable nonirritating excipient such as cocoa butter or polyethylene
glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore
melt in the rectum and release the drugs. Solid dosage forms for oral administration can be capsules,
tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be admixed
with at least one inert diluent such as sucrose lactose or starch. Solid dosage forms may also comprise
other substances in addition to inert diluents, such as lubricating agents. In the case of capsules,
tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can
additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can
include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing
inert diluents commonly used in the art. Liquid dosage forms may also comprise wetting,
emulsifying, suspending, sweetening, flavoring, or perfuming agents. The pharmaceutical
compositions of the present invention can also be administered in the form of liposomes, as described
in U.S. Patent No. 6,703,403. Formulation of drugs that are applicable to the present invention is
generally discussed in, for example, Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES
(Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS
(Marcel Decker, New York, N.Y., 1980).
Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to
prepared pharmaceutical compositions of the present invention.
In a preferred embodiment, a compound of the invention (e.g., a compound of Formula L IA,
IB, Ic, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug
thereof) is formulated in a solid dispersion, where the compound of the invention can be molecularly
dispersed in an amorphous matrix which comprises a pharmaceutically acceptable, hydrophilic
polymer. The matrix may also contain a pharmaceutically acceptable surfactant. Suitable solid
dispersion technology for formulating a compound of the invention includes, but is not limited to,
melt-extrusion, spray-drying, co-precipitation, freeze drying, or other solvent evaporation techniques,
with melt-extrusion and spray-drying being preferred. In one example, a compound of the invention
is formulated in a solid dispersion comprising copovidone and vitamin E TPGS. In another example,
a compound of the invention is formulated in a solid dispersion comprising copovidone and Span 20.
A solid dispersion described herein may contain at least 30% by weight of a pharmaceutically
acceptable hydrophilic polymer or a combination of such hydrophilic polymers. Preferably, the solid
dispersion contains at least 40% by weight of a pharmaceutically acceptable hydrophilic polymer or a
combination of such hydrophilic polymers. More preferably, the solid dispersion contains at least
50% (including, e.g., at least 60%, 70%, 80% or 90%) by weight of a pharmaceutically acceptable
hydrophilic polymer or a combination of such polymers. A solid dispersion described herein may
also contain at least 1% by weight of a pharmaceutically acceptable surfactant or a combination of
such surfactants. Preferably, the solid dispersion contains at least 2% by weight of a pharmaceutically
acceptable surfactant or a combination of such surfactants. More preferably, the solid dispersion
contains from 4% to 20% by weight of the surfactant(s), such as from 5% to 10% by weight of the
surfactants). In addition, a solid dispersion described herein may contain at least 1% by weight of a
compound of the invention, preferably at least 5%, including, e.g., at least 10%. In one example, the
solid dispersion comprises 5% of a compound of the invention (e.g., a compound of Formula I, IA, IB,
Ic, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug
thereof), which is molecularly dispersed in a an amorphous matrix comprising 7% Vitamin E-TPGS
and 88% copovidone; the solid dispersion can also be mixed with other excipients such as
mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over the other excipients can range
from 5:1 to 1:5 with 1:1 being preferred. In another example, the solid dispersion comprises 5% of a
compound of the invention (e.g., a compound of Formula I, IA, IB, Ic, or ID, or preferably a compound
selected from Examples 1-308, or a salt, solvate or prodrug thereof), which is molecularly dispersed
in a an amorphous matrix comprising 5% Span 20 and 90% copovidone; the solid dispersion can also
be mixed with other excipients such as mannitol/aerosil (99:1), the solid dispersion can also be mixed
with other excipients such as mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over
the other excipients can range from 5:1 to 1:5 with 1:1 being preferred.
Various additives can also be included in or mixed with the solid dispersion. For instance, at
least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, plasticizers,
colorants, or stabilizers may be used in compressing the solid dispersion to tablets. These additives
can be mixed with ground or milled solid dispersion before compacting. Disintegrants promote a
rapid disintegration of the compact in the stomach and keeps the liberated granules separate from one
another. Non-limiting examples of suitable disintegrants are cross-linked polymers such as cross-
linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose or sodium croscarmellose.
Non-limiting examples of suitable fillers (also referred to as bulking agents) are lactose monohydrate,
calcium hydrogenphosphate, microcrystalline cellulose (e.g., Avicell), silicates, in particular silicium
dioxide, magnesium oxide, talc, potato or corn starch, isomalt, or polyvinyl alcohol. Non-limiting
examples of suitable flow regulators include highly dispersed silica (e.g., colloidal silica such as
Aerosil), and animal or vegetable fats or waxes. Non-limiting examples of suitable lubricants include
polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium and calcium
stearates, sodium stearyl fumarate, and the like. Non-limiting examples of stabilizers include
antioxidants, light stabilizers, radical scavengers, or stabilizers against microbial attack.
The present invention further features methods of using the compounds of the present
invention (or salts, solvates or prodrugs thereof) to inhibit HCV replication. The methods comprise
contacting cells infected with HCV virus with an effective amount of a compound of the present
invention (or a salt, solvate or prodrug thereof), thereby inhibiting the replication of HCV virus in the
cells. As used herein, "inhibiting" means significantly reducing, or abolishing, the activity being
inhibited (e.g., viral replication). In many cases, representative compounds of the present invention
can reduce the replication of HCV virus (e.g., in an HCV replicon assay as described above) by at
least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.
The compounds of the present invention may inhibit one or more HCV subtypes. Examples
of HCV subtypes that are amenable to the present invention include, but are not be limited to, HCV
genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes la, lb, 2a, 2b, 2c, 3a or 4a. In one
embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs
thereof) are used to inhibit the replication of HCV genotype 1a. In another embodiment, a compound
or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the
replication of HCV genotype lb. In still another embodiment, a compound or compounds of the
present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both
HCV genotypes 1a and lb.
The present invention also features methods of using the compounds of the present invention
(or salts, solvates or prodrugs thereof) to treat HCV infection. The methods typically comprise
administering a therapeutic effective amount of a compound of the present invention (or a salt, solvate
or prodrug thereof), or a pharmaceutical composition comprising the same, to an HCV patient,
thereby reducing the HCV viral level in the blood or liver of the patient. As used herein, the term
"treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or
condition, or one or more symptoms of such disorder or condition to which such term applies. The
term "treatment" refers to the act of treating. In one embodiment, the methods comprise
administering a therapeutic effective amount of two or more compounds of the present invention (or
salts, solvates or prodrugs thereof), or a pharmaceutical composition comprising the same, to an HCV
patient, thereby reducing the HCV viral level in the blood or liver of the patient.
A compound of the present invention (or a salt, solvate or prodrug thereof) can be
administered as the sole active pharmaceutical agent, or in combination with another desired drug,
such as other anti-HCV agents, anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, anti-
hepatitis D agents, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. Any
compound described herein, or a pharmaceutically acceptable salt thereof, can be employed in the
methods of the present invention. In one embodiment, the present invention features methods of
treating HCV infection, wherein said methods comprise administering a compound of the invention
(e.g., a compound of Formula I, IA, IB, Ic, or ID, or preferably a compound selected from Examples 1-
308, or a salt, solvate or prodrug thereof), interferon and ribavirin to an HCV patient. The interferon
preferably is a-interferon, and more preferably, pegylated interferon-α such as PEGASYS
(peginterferon alfa-2a).
A compound of the present invention (or a salt, solvent or prodrug thereof) can be
administered to a patient in a single dose or divided doses. A typical daily dosage can range, without
limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight. Single
dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
Preferably, each dosage contains a sufficient amount of a compound of the present invention that is
effective in reducing the HCV viral load in the blood or liver of the patient. The amount of the active
ingredient, or the active ingredients that are combined, to produce a single dosage form may vary
depending upon the host treated and the particular mode of administration. It will be understood that
the specific dose level for any particular patient will depend upon a variety of factors including the
activity of the specific compound employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug combination, and the severity of the
particular disease undergoing therapy.
The present invention further features methods of using the pharmaceutical compositions of
the present invention to treat HCV infection. The methods typically comprise administering a
pharmaceutical composition of the present invention to an HCV patient, thereby reducing the HCV
viral level in the blood or liver of the patient. Any pharmaceutical composition described herein can
be used in the methods of the present invention.
In addition, the present invention features use of the compounds or salts of the present
invention for the manufacture of medicaments for the treatment of HCV infection. Any compound
described herein, or a pharmaceutically acceptable salt thereof, can be used to make medicaments of
the present invention.
The compounds of the present invention can also be isotopically substituted. Preferred
isotopic substitution include substitutions with stable or nonradioactive isotopes such as deuterium,
13C, 15N or 18O. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can
give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at
least 5 mol % (e.g., at least 10 mol %) of hydrogen in a compound of the present invention is
substituted with deuterium. In another example, at least 25 mole % of hydrogen in a compound of the
present invention is substituted with deuterium. In a further example, at least 50, 60,70, 80 or 90 mole
% of hydrogen in a compound of the present invention is substituted with deuterium. The natural
abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved,
without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with
enriched or substituted starting materials. Other methods known in the art can also be used for
isotopic substitutions.
The foregoing description of the present invention provides illustration and description, but is
not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and
variations are possible in light of the above teachings or may be acquired from practice of the
invention. Thus, it is noted that the scope of the invention is defined by the claims and their
equivalents.
What is claimed is:
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
X is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA;
L1 and L2 are each independently selected from bond; or C1-C6alkylene, C2-C6alkenylene or
C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more RL;
L3 is bond or -Ls-K-Ls'-, wherein K is selected from bond, -O-, -S-, -N(RB)-, -C(O)-, -
S(O)2- -S(O)-, -OS(O)-, -OS(O)2- -S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -
OC(O)O-, -C(O)N(RB)-, -N(RB)C(Oh -N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-,
-N(RB)S(O)2- -S(O)N(RB)-, -S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -
N(RB)SO2N(RB')-, or -N(RB)S(O)N(RB')-;
A and B are each independently C3-C12carbocycle or 3- to 12-membered heterocycle, and are
each independently optionally substituted with one or more RA;
D is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA; or D is hydrogen or RA;
Y is selected from -T'-C(R1R2)N(R5)-T-RD, -T'-C(R3R4)C(R6R7)-T-RD, -LK-T-RD, or -
LK-E;
R1 and R2 are each independently RC, and R5 is RB; or R1 is Rc, and R2 and R5, taken together
with the atoms to which they are attached, form a 3- to 12-membered heterocycle which
is optionally substituted with one or more RA;
R3, R4, R6, and R7 are each independently Rc; or R3 and R6 are each independently Rc, and R4
and R7, taken together with the atoms to which they are attached, form a 3- to 12-
membered carbocycle or heterocycle which is optionally substituted with one or more RA;
Z is selected from -T'-C(R8R9)N(Ri2)-T-RD, -T'-C(R10Rii)C(R13R14)-T-RD, -LK-T-RDI or
-LK-E;
R8 and R9 are each independently Rc, and R12 is RB; or R8 is Rc, and R9 and R12, taken
together with the atoms to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more RA;
R10, R11, R13, and R14 are each independently Rc; or R10 and R13 are each independently Rc,
and R11 and R14, taken together with the atoms to which they are attached, form a 3- to
12-membered carbocycle or heterocycle which is optionally substituted with one or more
RA;
T and T are each independently selected at each occurrence from bond, -Ls-, -Ls-M-Ls'-,
or -Ls-M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each
occurrence from bond, -O-, -S-, -N(RB)-, -C(O)-, -S(O)2- -S(O)-, -OS(O)-, -
OS(O)2- -S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -
N(RB)C(O)-, -N(RB)C(O)O-, -OC(O)N(RB)- -N(RB)S(O)-, -N(RB)S(O)2-, -
S(O)N(RB)-, -S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -
N(RB)SO2N(RB')-, -N(RB)S(O)N(RB')- C3-C12carbocycle or 3- to 12-membered
heterocycle, and wherein said C3-C12carbocycle and 3- to 12-membered heterocycle are
each independently optionally substituted at each occurrence with one or more RA;
LK is independently selected at each occurrence from bond, -Ls-N(RB)C(O)-Ls'- or -Ls-
C(O)N(RB)-Ls'-; or C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which
is independently optionally substituted at each occurrence with one or more RL; or C3-
C12carbocycle or 3- to 12-membered heterocycle, each of which is independently
optionally substituted at each occurrence with one or more RA;
E is independently selected at each occurrence from C3-C12carbocycle or 3- to 12-membered
heterocycle, and is independently optionally substituted at each occurrence with one or
more RA;
RD is each independently selected at each occurrence from hydrogen or RA.
RA is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -LS-RE, wherein two adjacent RA, taken together with the
atoms to which they are attached and any atoms between die atoms to which they are
attached, can optionally form carbocycle or heterocycle;
RB and RB' are each independently selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-
membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle;
wherein each 3- to 6-membered carbocycle or heterocycle in RB or RB' is independently
optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-
C6haloalkenyl or C2-C6haloalkynyl;
RC is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C1-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-
C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RsRs'), -S(O)Rs, -SO2Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs', -
N(Rs)C(O)N(Rs'Rs"), -N(Rs)SO2Rs', -SO2N(RsRs'), -N(Rs)SO2N(Rs'Rs"), -
N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O)2-Rs, -S(O)2ORs, -S(O)ORs, -OC(O)ORs, -
N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(O)-Rs' -S(O)N(RsRs') or -
C(O)N(Rs)C(O)-Rs'; or CrC6alkyl, C2-C6alkenyl or C2-C5alkynyl, each of which is
independendy optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RSRS'), -
S(O)Rs, -SO2Rs, -C(O)N(RSRS') or -N(Rs)C(O)Rs'; or C3-C6carbocycle 3- to 6-
membered heterocycle, each of which is independently optionally substituted at each '
occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
Ls, Ls' and Ls" are each independendy selected at each occurrence from bond; or C1-
C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently
optionally substituted at each occurrence with one or more RL; and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; C1-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs , Rs' or Rs'
is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-
C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
2. The compound or salt of claim 1, wherein:
A is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,
and is optionally substituted with one or more RA;
B is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,
and is optionally substituted with one or more RA;
D is selected from C5-C6carbocycle or 5- to 6-membered heterocycle, and is optionally
substituted with one or more RA; or D is hydrogen or RA;
Z1 is independently selected at each occurrence from O, S, NH or CH2;
Z2 is independently selected at each occurrence from N or CH;
Z3 is independently selected at each occurrence from N or CH;
Z4 is independently selected at each occurrence from O, S, NH or CH2; and
W1, W2, W3, W4, W5 and W6 are each independently selected at each occurrence from CH or
N..
3. The compound or salt of claim 1, wherein:
A is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,
and is optionally substituted with one or more RA;
B is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,
and is optionally substituted with one or more RA;
D is selected from C5-C6carbocycle or 5- to 6-membered heterocycle, and is optionally
substituted with one or more RA; or D is hydrogen or RA;
Z1 is independently selected at each occurrence from O, S, NH or CH2;
Z2 is independendy selected at each occurrence from N or CH; and
W1, W2, W3, W4, W5 and W6 are each independently selected at each occurrence from CH or
N.
4. The compound or salt of claim 1, wherein:
A and B are each independendy C5-C6carbocycle or 5- to 6-membered heterocycle, and are
each independendy optionally substituted with one or more RA;
D is selected from C5-C6carbocycle or 5- to 6-membered heterocycle, and is optionally
substituted with one or more RA; and
X is wherein X3 is N and is directly linked to -L3-D, and
X is optionally substituted with one or more RA, and two adjacent RA on X, taken
together with the ring atoms to which they are attached, optionally form a 5- to 6-
membered carbocycle or heterocycle.
5. A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
X is wherein the nitrogen ring atom is directly linked to -L3-D, and wherein
X is optionally substituted with one or more RA; L1, L2 and L3 are bond;
A and B are each independently and are each independently optionally
substituted with one or more RA;
D is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA;
Y is -G-C(R1R2)N(R5)-T-RD, -G-C(R3R4)C(R6R7)-7-RD, -N(RB)C(O)C(R1R2)N(R5)-T-
RD, or -N(RB)C(O)C(R3R4)C(R6R7)-T-RD;
Z is -G-C(R8R9)N(R12)-T-RD, -G-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(R8R9)N(R12)-
T-RD, or -N(RB)C(O)C(R10R11)C(R13R14)-T-RD;
R1 is RC, and R2 and R5, taken together with the atoms to which they are attached, form a 3- to
12-membered heterocycle which is optionally substituted with one or more RA;
R3 and R6 are each independently Rc, and R4 and R7, taken together with the atoms to which
they are attached, form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more RA;
R8 is Rc, and R9 and R12, taken together with the atoms to which they are attached, form a 3-
to 12-membered heterocycle which is optionally substituted with one or more RA;
R10 and R13 are each independently Rc, and R11 and R14, taken together with the atoms to
which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more RA;
G is each independendy C5-C6carbocycle or 5- to 6-membered heterocycle, and is each
independendy optionally substituted with one or more RA;
T is each independendy selected at each occurrence from bond, -Ls- -Ls-M-Ls'-, or -Ls-
M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each occurrence
from bond, -O-, -S-, -N(RB)-, -C(O)-, -S(O)2- -S(O)-, -OS(O)-, -OS(O)2- -
S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -N(RB)C(O)-, -
N(RB)C(O)O-, -OC(O)N(RB)-, -N(RB)S(O)-, -N(RB)S(O)2- -S(O)N(RB)-, -
S(O)2N(RB)- -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -N(RB)SO2N(RB')-, -
N(RB)S(O)N(RB')-, C3-C12carbocycle or 3- to 12-membered heterocycle, and wherein
said C3-C12carbocycle and 3- to 12-membered heterocycle are each independently
optionally substituted at each occurrence with one or more RA;
RD is each independently selected at each occurrence from hydrogen or RA;
RA is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -LS-RE;
RB and RB' are each independently selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-
membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle;
wherein each 3- to 6-membered carbocycle or heterocycle in RB or RB' is independently
optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-
C6haloalkenyl or C2-C6haloalkynyl;
RC is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C1-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-
C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RsRs'), -S(O)Rs, -SO2Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs\ -
N(Rs)C(O)N(Rs'Rs"), -N(Rs)SO2Rs; -SO2N(RsRs'), -N(Rs)SO2N(Rs'Rs"), -
N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O)2-Rs, -S(O)2ORs, -S(O)ORs, -OC(O)ORs, -
N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(O)-Rs', -S(O)N(RsRs') or -
C(O)N(Rs)C(O)-Rs'; or CrC6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RsRs'), -
S(O)Rs, -SO2Rs, -C(O)N(RsRs') or -N(Rs)C(O)Rs'; or C3-C6carbocycle 3- to 6-
membered heterocycle, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6aloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
Ls, Ls' and Ls" are each independendy selected at each occurrence from bond; or C1-
C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independendy
optionally substituted at each occurrence with one or more RL; and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; C1-
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs, Rs' or Rs'
is independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-
C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.
The compound or salt of claim 5, wherein:
T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"- or -N(RB)C(O)-
Ls'-M'-Ls"-; and
Ls' is each independently C1-C6alkylene, and is independently optionally substituted at each
occurrence with one or more RL.
The compound or salt of claim 5, wherein:
Y is -N(RB)C(O)C(R1R2)N(R5)-T-RD;
Z is -N(RB)C(O)C(R8R9)N(R12)-T-RD;
T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"-; and
D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is
substituted with one or more RA.
8. The compound or salt of claim 7, wherein T is independently selected at each occurrence
from-C(O)-Ls'-N(RB)C(O)-Ls"- or -C(O)-LS'-N(RB)C(O)O-LS"-; and R2 and R5, taken together
with the atoms to which they are attached, form which is optionally substituted with one
or more RA; and R9 and R12, taken together with the atoms to which they are attached, form
which is optionally substituted with one or more RA.
9. The compound or salt of claim 5, wherein:
Y is -G-C(R1R2)N(R5)-T-RD;
Z is -G-C(R8R9)N(R12)-T-RD;
G is each independendy and is each independently optionally substituted with one
or more RA;
T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"-; and
D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is
substituted with one or more RA.
10. The compound or salt of claim 9, wherein T is independently selected at each occurrence
from -C(O)-Ls'-N(RB)C(O)-Ls"- or -C(O)-Ls'-N(RB)C(O)O-Ls"-; and R2 and R5, taken together
with the atoms to which they are attached, form which is optionally substituted with one
or more RA; and R9 and Ri2, taken together with the atoms to which they are attached, form
which is optionally substituted with one or more RA.
11. A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
X is wherein the nitrogen ring atom is directly linked to -L3-D, and wherein
X is optionally substituted with one or more RA; L1, L2 and L3 are bond;
A and B are each independentlyand are each independently optionally
substituted with one or more RA;
D is C3-C12carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with
one or more RA;
Y is -G-C(R1R2)N(R5)-T-RD, -G-C(R3R4)C(R6R7)-T-RD, -N(RB)C(O)C(R1R2)N(Rs)-T-
RD, or -N(RB)C(O)C(R3R4)C(R6R7)-T-RD;
Z is -G-C(R8R9)N(R12)-T-RD, -G-C(R10R11)C(R13R14)-T-RD, -N(RB)C(O)C(RsR9)N(R12)-
T-RD, or -N(RB)C(O)C(R10R11)C(R13R14)-T-RD;
R1 is RC, and R2 and R5, taken together with the atoms to which they are attached, form a 3- to
12-membered heterocycle which is optionally substituted with one or more RA;
R3 and R6 are each independently Rc, and R4 and R7, taken together with the atoms to which
they are attached, form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more RA;
R8 is Rc, and R9 and Ri2, taken together with the atoms to which they are attached, form a 3-
to 12-membered heterocycle which is optionally substituted with one or more RA; R10 and R13 are each independently Rc, and Ru and R14, taken together with the atoms to
which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more RA;
G is each independendy C5-C6carbocycle or 5- to 6-membered heterocycle, and is each
independently optionally substituted with one or more RA;
T is each independently selected at each occurrence from bond, -Ls- -Ls-M-Ls'-, or -Ls-
M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each occurrence
from bond, -O- -S-, -N(RB)- -C(O)-, -S(O)2- -S(O)-, -OS(O)-, -OS(O)2- -
S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-, -N(RB)C(O)-, -
N(RB)C(O)O-, -OC(O)N(RB)- -N(RB)S(OK -N(RB)S(O)2- -S(O)N(RB) -
S(O)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, -N(RB)SO2N(RB')-, -
N(RB)S(O)N(RB')-, C3-C12carbocycle or 3- to 12-membered heterocycle, and wherein
said C3-C12carbocycle and 3- to 12-membered heterocycle are each independendy
optionally substituted at each occurrence with one or more RA;
RD is each independendy selected at each occurrence from hydrogen or RA;
RA is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -LS-RE;
RB and RB' are each independently selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-
membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle;
wherein each 3- to 6-membered carbocycle or heterocycle in RB or RB' is independently
optionally substituted at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-
C6haloalkenyl or C2-C6haloalkynyl;
RC is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Cr
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,C1-
C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RsRs'), -S(O)Rs, -SO2Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs' -
N(Rs)C(O)N(Rs'Rs"), -N(Rs)SO2Rs\ -SO2N(RsRs'), -N(Rs)SO2N(Rs'Rs"), -
N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O)2-Rs, -S(O)2ORs, -S(O)ORs, -OC(O)ORs, -
N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(O)-Rs', -S(O)N(RsRs') or -
C(O)N(Rs)C(O)-Rs'; or CrC6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RSRS'), -
S(O)Rs, -SO2Rs, -C(O)N(RsRs') or -N(Rs)C(O)Rs'; or C3-C6carbocycle 3- to 6-
membered heterocycle, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl;
Ls, Ls' and Ls" are each independently selected at each occurrence from bond; or C1-
C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently
optionally substituted at each occurrence with one or more RL; and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; C1
C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,
cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or
heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs, Rs' or Rs'
is independendy optionally substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
phosphono, thioxo, formyl, cyano, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-
C6haloalkyl, C2-Cshaloalkenyl or C2-C6haloalkynyl.
12. The compound or salt of claim 11, wherein:
T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"- or -N(RB)C(O)-
Ls'-M'-Ls"-; and
Ls' is each independendy C1-C6alkylene, and is independently optionally substituted at each
occurrence with one or more RL.
13. The compound or salt of claim 11, wherein:
Y is -N(RB)C(O)C(R1R2)N(R5)-T-RD;
Z is -N(RB)C(O)C(R8R9)N(R12)-T-RD;
T is independendy selected at each occurrence from -C(O)-Ls'-M'-Ls"-; and
D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is
substituted with one or more RA.
14. The compound or salt of claim 13, wherein T is independently selected at each occurrence
from-C(O)-Ls'-N(RB)C(O)-Ls"- or -C(O)-Ls'-N(RB)C(O)O-Ls"-; and R2 and R5, taken together
with the atoms to which they are attached, form which is optionally substituted with one
or more RA; and R9 and R12, taken together with the atoms to which they are attached, form
which is optionally substituted with one or more RA.
15. The compound or salt of claim 11, wherein:
Y is -G-C(RiRa)N(R5)-T-RD;
Z is -G-C(R8R9)N(R12)-T-RD;
G is each independently selected at each occurrence and is each independently
optionally substituted with one or more RA;
T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"-; and
D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is
substituted with one or more RA.
16. The compound or salt of claim 15, wherein T is independently selected at each occurrence
from-C(O)-LS-N(RB)C(O)-Ls"- or -C(O)-Ls'-N(RB)C(O)O-Ls"-; and R2 and R5, taken together
with the atoms to which they are attached, form which is optionally substituted with one
or more RA; and R9 and Ri2, taken together with the atoms to which they are attached, form
which is optionally substituted with one or more RA.
17. A pharmaceutical composition comprising a compound or salt according to claim 1.
18. A pharmaceutical composition comprising a compound or salt according to claim 1 and
another anti-HCV agent.
19. A method of treating HCV infection, comprising administering to an HCV patient a
compound or salt according to claim 1.
20. A process of making a compound according to claim 1, comprising a step described in one of
the schemes or examples described hereinabove.
Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") are described. This invention also relates
to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds
to treat HCV infection.