ANTI-VIRAL COMPOUNDS
This application claims the benefit from and incorporates herein by references the entire content of
U.S. Provisional Application No. 61/140,262, filed December 23,2008.
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 Flaviviridac family. HCV
has enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific
proteins in one single, uninterrupted, open reading frame. The open reading frame comprises
approximately 9500 nucleotides encoding 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, 13 and ID, and pharmaceutical^/
acceptable salts thereof. These compounds and salts are capable of inhibiting the replication of HCV.
The present invention also features compositions comprising the compounds or salts of the
present invention. The compositions can also include other therapeutic agents, such as HCV helicase
inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, 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 11CV 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.

wherein:
A1 is C3-C14carbocyclyl or 3- to 14-membered heterocyclyl, and is substituted with -X1-R7,
wherein said C3-C14carbocyclyl and 3- to 14-membered heterocyclyl are optionally
substituted with one or more RA;
X1 is selected from a bond, -Ls-, -O-, -S-, or -N(RB)-;
R7 is selected from hydrogen, -LA, C5-C10carbocyclyl, or 5- to 10-membercd heterocyclyl,
wherein at each occurrence said Cs-Ciocarbocyclyl and 5- to 10-membered heterocyclyl are
each independently optionally substituted with one or more RA;
- Z1 is selected-from-a-bond, -C(RcRc)-, -O-S-or -N(RB)-;
W1 and W2 are each independently selected from N or C(RD);
R1 is selected from hydrogen or RA;
R3 and R4 are each independently selected from hydrogen or RA; or R3 and R4, taken together with
the carbon atoms to which they are attached, form a C5-C10carbocyclic or 5- to 10 membered

heterocyclic ring, wherein said C5-C10carbocyclic and 5- to 10-membered heterocyclic ring
are optionally substituted with one or more RA;
A2 is C3-C14carbocyclyl or 3- to 14-membered heterocyclyl, and is optionally substituted with one
or more RA;

B;
R5 is Rc;
R6 is Rc-, and R8 is RB; or R6 and R8, taken together with the atoms to which they are attached,
form a 3- to 10-membered heterocyclic ring which is optionally substituted with one or more
RA;
LK is a bond; C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, Rs (except hydrogen), -O-Rs, -S-Rs, -N(RsRs), -OC(O)Rs, -
C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano; or-N(RB)C(O)- or -C(O)N(RB)-;
B is C3-C10carbocycle or 3- to 10-membered heterocycle, and is optionally substituted with one or
more RA;
T is independently selected at each occurrence from a bond, -Ls-, -Ls-M-Ls—. -Ls-M-Ls—M'-
Ls-, wherein M and M' are each independently selected from a 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)CO)N(RB.)-,-
N(RB)S02N(RB)-, -N(RB)S(O)N(RB.)-, C5-C10carbocycle, or 5- to 10-membcrcd heterocycle,
and wherein at each occurrence T is independently optionally substituted with one or more
RA;
RA is independently selected at each occurrence from halogen, hydroxy, mcrcapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, -LA, or -Ls-RE;
RB and RB' are each independently selected at each occurrence from hydrogen: or C1-C6,alkyl, C2-
C6alkenyl, C2-C6alkynyl, C3-C6Carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered
heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which Ls independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
Re and Re are each independently selected at each occurrence from hydrogen; halogen; hydroxy;
mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C.-C6alkyl, C2-

C6alkenyl, C2-C6alkynyl, or C3-C6carbocyclyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
RD, RD, and RD" are each independently selected at each occurrence from hydrogen or RA
LA is independently selected at each occurrence from 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, -O-Rs, -S-Rs, -N(RSRS), -OC(O)Rs. -C(OK)Rs, nitro,
phosphate, oxo, thioxo, formyl or cyano;
Ls, Ls- and Ls- are each independently selected at each occurrence from a bond; or Ci-C<,alkylene,
C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, -O-Rs, -S-Rs, -
N(RSRS-), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs. OT(O)Rs, -
C(O)ORs, -N(RsRs.), -S(O)Rs, -S02Rs, -C(O)MRsRs.), -N(Rs)C(O)Rs-, -
N(Rs)C(O)N(Rs.RS"), -N(Rs)SO2Rs., -SO2N(RsRsO, -N(Rs)SON(R.sRs"), -
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)ORg-, -OC(O)N(RsRs0, -N(Rs)S(O)-Rs., -S(O)N(RsRs), -C(O)N(Rs)C(O)-Rs.,
C3-Ciocarbocyclyl, or 3- to 10-membered heterocyclyl, wherein said Cs-Ciocarbocyclyl and 3-
to 10-membered heterocyclyl are each independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C;-C6alkcnyl, C2-
C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -N(RBR„), OC(O)RB, -
C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano; and
Rs, Rs- and Rs- are each independently selected at each occurrence from hydrogen; or C3-C6alkyl,
C2-C6alkenyl, C2-Csalkynyl, C3-C6carbocyclyl, C3-C6CarbocyclylC1-C6alkyl, 3- to 6-
membered heterocyclyl, or (3- or 6-membered heterocyclyl)Ci-C6alkyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, -O-RB, -S-RB, -N(RBRB-), -OC(O)RB, -C(O)ORn. nitro. phosphate,
oxo, thioxo, formyl or cyano.
A1 preferably is selected from C5-C6carbocycles or 5- to 6-membered heterocycles (e.g.,
phenyl, thiazolyl, thienyl, pyrrolidinyl or piperidinyl), and is optionally substituted with one or more
RA. A1 is substituted with -X1-R7. The ring system in A1 can be identical to, or different from, that in
A2. For instance, A1 and A2 can both be phenyl, or A1 is phenyl and A2 is thiazolyl, thienyl, furanyl,
imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, benzoxazolyl, benzothienyl, benzimidazolyl, indolyl,
or N (where X is O, S or N(RB). Z1 and T can be attached to A1 via any two subsiitutable ring

atoms on A1. Two adjacent RA on A1, taken together with the ring atoms to which they arc attached,
may form a C5-C6carbocycle or a 5- to 6-membered heterocycle.
Z1 preferably is -N(RB)-, such as -NH- or -N(C1-C6alkyl)-.
R3 and R4, taken together with the carbon atoms to which they are attached, preferably form a
C5-C6carbocycle or a 5- to 6-membered heterocycle, which is optionally substituted with one or more
RA. Non-limiting examples of suitable 5- to 6-membered carbocycles or heterocycles for this purpose

independently selected from hydrogen; halog en; or C1- C6alkyl, C2-C6alkenyl, C1-C6alkynyl, C3-
C6carbocyclyl, or C3-C6carbocyclyC1-C6alkyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano. Highly preferably, R9 is selected from C1-
C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl (e.g., C3-C6cycloalkyl), or C3-C6carbocyclyC1-
Cealkyl (e.g., C3-C6cycloalkylC1-C6alkyl), each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano; and R10 and R11 are hydrogen.
R1 can be, without limitation, hydrogen or C1-C6alkyl. Preferably, R1 is hydrogen.
X1 is preferably selected from -CH2-, -O-, or -S-.
R7 can be selected, without limitation, from C5-C6carbocycles or 5- to 6-membered
heterocycles, and is optionally substituted with one or more RA. Preferably, R7 is phenyl, and is
optionally substituted with one or more RA (e.g., -N(RsRs'), such as -NH2 or -NH(C3 -C6alkyl)).
A2 can be selected, without limitation, from C5-C10carbocycles or 5- to 10-membered
heterocycles, and is optionally substituted with one or more RA. Preferably, A2 is selected from C5-

C6carbocycles or 5- to 6-membered hcterocycles, and is optionally substituted with one or more RA.
Two adjacent RA on A2, taken together with the ring atoms to which they are attached, may form a C5-
Cscarbocycle or a 5- to 6-membered heterocycle. Non-limiting examples of suitable A2 include
phenyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyL thicnyl, furanyl,
imidazolyl, pyrazolyl, triazolyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuranyl,
benzothiazolyl, indolyl, indenyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl,
quinazolinyl, or phthalazinyl, each of which is optionally substituted with one or more RA. As a non-

-T-RD preferably is -C(O)-Ls—R12 or -C(O)-Ls'-M'-LS"-R12, where R12 is i) hydrogen, (ii)
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, -O-Rs, -S-Rs, -N(RsRs-), -
OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano, or (iii) C3-C10carhocyclyl or 3-
to 10-membered heterocyclyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl. C2-C6talkynyl, Rs
(except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB.), -OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, formyl or cyano. -T-RD can also be, without limitation, -Ls-(C3-C6carbocyelyl) or -
Ls-(3- to 10-membered heterocyclyl), where said C3-Ciocarbocyclyl and 3- to 10 membered
heterocyclyl are each independently optionally substituted with one or more substitucnLs selected
from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -
N(RBRB), -OC(O)RB, -C(O)QRB, nitro, phosphate, oxo,.thioxo,formyl or cyano. In addition, -T-RD
can be, without limitation, -Ls-R& -C(O)-Ls-RE, -C(O)O-Ls-RE.


is 0, 1 or 2, m is 1 or 2, and k is 0, 1, 2, 3 or 4. Two adjacent RA, taken together with the atoms to
which they are attached, can form a C5-C6carbocycle or a 5- to 6-membered heterocycle. Rn can be,
without limitation, -LT-N(RB)-Ln-RE, -LT-N(RB)C(O)-LTT-RE, or -LT-N(RB)C(O)-Ln-RE,
wherein LT and LTT are each independently selected from (i) a bond, or (ii) C.-Coalkylene, C2-
Cealkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, C3-Ciocarbocyclyl, 3- to 10-
membered heterocyclyl, -O-Rs, -S-Rs, -N(RsRs), -OC(O)Rs, -C(O)ORs, nitro, phospliate, oxo,
thioxo, formyl or cyano. Preferably, R12 is -LT-N(RB)-LT-r-Rs, -LT-N(RB)C(O)-I .TT-Rs. or -LT-
N(RB)C(O)-LTT-Rs, where LT and LTT are as defined immediately above. R12 can also be. without
limitation, -LS-RE, such as -Ls-O-Rs, -LS-S-RS, or-Ls-N(RsRs). In addition, R;; can be, without
limitation, -Ls-(C3-Ciocarbocyclyi) or -Ls-(3- to 10-membered heterocyclyl), where said C3-
C10carbocyclyl and 3- to 10-membered heterocyclyl are each independently optionally substituted
with one or more substituents selected from CrC6alkyl, C2-C«alkenyl, C2-C6a]kynyl. Rs (except
hydrogen), halogen, -O-RB, -S-RB, -N(RBRB), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo,
formyl or cyano.

-T-RD" can be, without limitation, -C(O)-Ls-R12 or -C(O)-Ls-M'-LS'-R;, where R12 is
(i) hydrogen, (ii) 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, O. Rs, -S-Rs, -

N(RsRs), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano, or (iii) C3-
C10carbocyclyl or 3- to 10-membered heterocyclyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB.), -OC(O)RB -C(O)ORB,
nitro, phosphate, oxo, thioxo, formyl or cyano. -T-RD" can also be , without limitation, -LS-(C3-
C10carbocyclyl) or -Ls-(3- to 10-membered heterocyclyl), where said C3-C10carbocycryl and 3- to 10-
membered heterocyclyl are each independently optionally substituted with one or more substituents
selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except hydrogen), halogen, -O-Rn, -S-RB,
-N(RBRB-), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano. In addition, -T-
RD- can be, without limitation, -LS-RE, -C(O)-Ls-RE, -C(O)O-Ls-RE.

where n is 0, 1 or 2, m is 1 or 2, and k is 0, 1, 2, 3 or 4. Two adjacent RA, taken together with the
atoms to which they are attached, can form a C5-C6carbocycle or a 5- to 6-membered hcterocycle. R12
can be, without limitation, -LT-N(RB)-LTr-RE, -LT-N(RB)C(O)-LTT-RE, or-Lr-N(R„K'(O) -Ln-RE,
wherein LT and LTT are each independently selected from (i) a bond, or (ii) CVCaalkylene, C2-
Csalkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, C3-C10carbocyclyl, 3- to 10-
membered heterocyclyl, -O-Rs, -S-Rs, -N(RsRs), -OC(O)Rs, -C(O)ORs, nitro. phosphate, oxo,
thioxo, formyl or cyano. Preferably, R12 is -LT-N(RB)-LTT-RS, -Lr-N(RB)C(O)-LTT-Rs, or -LT-
N(RC(O)-L-TT-Rs, where LT and LTT- are as defined immediately above. R12 can also be, without
limitation, -LS-RE, such as -Ls-O-Rs, -LS-S-RS, OT -Ls-N(RsRs). In addition, R,.. can be, without
limitation, -Ls-(C3-Ci0carbocyclyl) or -Ls-(3- to 10-membered heterocyclyl), where said C3-
Ciocarbocyclyl and 3- to 10-membered heterocyclyl are each independently optionally substituted
with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyL Rs (except
hydrogen), halogen, -O-RB, -S-RB, -N(RBRB), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo,
formyl or cyano.
Furthermore, R2 can be, without limitation, -LK-B, where B is C3-Ciocarbocyde or 3- to 10-
membered heterocycle, and is optionally substituted with one or more RA- Non-limiting examples of



selected from (i) 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, -O-Rs, -S-Rs, -
N(RsRs), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano; (ii) -Ls-C3-
Ciocarbocyclyl or -Ls-(3- to 10-membered heterocyclyl), each of which is optionally substituted with -
one or more substituents selected from C1-C6alkyl, C1-C6alkenyl, C2-C6alkynyl, Rs (except hydrogen),
halogen, -O-RB, -S-RB, -N(RBRB-), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or
cyano; or (iii) -Ls-O-Rs, -Ls-S-Rs, or -Ls-N(RsRs-)- Alternatively, RD and RD' can join to form a
5- to 6-membered heterocycle.


Preferably, T is selected from Table 4 described below.
More preferably, T is -LS-N(RT)-LS- (e.g., -CH2-N(RT)-CH2-), or -Ls-C(RTRT )-Ls-
(e.g., -CH2-C(RTRT')-CH2-). RT is CrC6alkyl, C2-C6alkenyl, or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, -O-Rs, -S-Rs, -N(RSRS-), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or
cyano; or RT is C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered hctcrocyclyl, or (3-
or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs
(excepthydrogen), halogen,-O-RB,-S-RB,-N(RBRB),-OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, formyl or cyano. Rr is RA, and preferably Rr is hydrogen. Ls, Ls>, RA, Rn. R«\ Rs, and
Rs- are as defined above.
In one embodiment, A1 is 5- to 6-membered carbocycle or heterocycle (e.g.. phenyl, thiazolyl,
thienyl, pyrrolidinyl or piperidinyl), which is substituted with -X1-R7 and is optionally substituted
with one or mere RA; and A2 is-5- to-10-membered carbocycle or heterocycle (e.g., phenyl, pyrazmyl,- —
pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, thienyl, furanyl, imidazolyl, pyrazolyl,
triazolyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuranyl, benzothiazolyl, indolyl, indenyl,
naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, or phthalazinyl) and is
optionally substituted with one or more RA. R3 and R4, taken together with the carbon atoms to which

they are attached, form a 5- to 6-membered carbocycle or heterocycle which is optionally substituted
with one or more RA. Preferably, A2 is 5- to 6-membered carbocycle or heterocycle (e.g., phenyl),
and is optionally substituted with one or more RA; A1 is phenyl and is optionally substituted with one
or more RA; X1 is -CH2-, -O-, or -S-; and R7 is 5- to 6-membered carbocycle or heterocycle (e.g.,
phenyl) which is optionally substituted with one or more RA.
In another embodiment, Wx and W2 are N, and Z1 is -N(RB)-. Preferably, Z is selected from
-NH-, -N(CrC6alkly)-, -N(C2-C6alkenyl)-, -N(C2-C6alkynyl)- -N(C1-C6haloalkyl)-, -N(C2-
Cehaloalkenyl)-, or -N(C2-C6haloalkynyl)-. More preferably, Z1 is selected from -NH- or -N(C1-
C6alkly)-.
1
hydrogen or RA. Preferably, W1 and W2 are N, Z1 is -N(RB)- (e.g., -NH- or -N(C,-C«alkly)-), and
Xt is -CH2-, -O- or -S-. R7 preferably is phenyl, and is optionally substituted with one or more RA.
Also preferably, Ri is hydrogen; and R9, Rio, and Rn are each independently selected from hydrogen;
halogen; or C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, or C3-C6,carbocyclylC1-
C6alkyl, each of which is independently optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo,
formyl or cyano. Highly preferably, R10 and R11 are hydrogen; and R9 is selected from C; -Cialkyl, C2-
CealkenyL, C2-C6alkynyl, C3-C6carbocyclyl (e.g., C3-C6cycloalkyl), or C3-C6carbocyclyO-C6alkyl
(e.g., C3-C6CycloalkylC1-C6alkyl), and is optionally substituted with one or more substituents selected
from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano.
In yet another embodiment, R3 and R4 are each independently selected from hydrogen or RA;
and R7 is a 5- to 6-membered carbocycle or heterocycle (e.g., phenyl), which is optionally substituted
with one or more RA-
In a further embodiment, R3 and R4 are each independently selected from hydrogen or RA; A1
is 5- to 6-membered carbocycle or heterocycle (e.g., phenyl, thiazolyl, thienyl, pyrrolidinyl or
piperidinyl), which is substituted with -X1-R7 and is optionally substituted with one or more RA; and
A2 is a 5- to 10-membered carbocycle or heterocycle (e.g., phenyl, pyrazinyl, pyridinyl, pyrtmidinyl,
pyridazinyl, oxazolyl, thiazolyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, bcnzoxazolyl,
benzothienyl; benzimidazolyl, benzofuranyl- benzothiazolyl indolyl, indenyl, naphalenyl,
quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, or phthalazinyl), and is optionally
substituted with one or more RA. Preferably, A2 is 5- to 6-membered carbocycle or heterocycle (e.g.,
phenyl), and is optionally substituted with one or more RA; A1 is phenyl and is optionally substituted
with one or more RA; X1 is -CH2-, -O-, or -S-; and R7 is 5- to 6-membercd carbocycle or

heterocycle (e.g., phenyl) which is optionally substituted with one or more RA. W1 and W2 can be N,
and Z1 can be -N(RB)-, such as -NH-, -N(C1-C6alkly)-, -N(C2-C6alkenyl)-, -N(C2-C6alkynyl)-, -
N(C1-C6haloalkyl)-, -N(C2-C6haloalkenyl)-, or-N(C2-C6haloalkynyl)-.

Cgalkenyl, C2-Csalkynyl, Cs-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered
heterocyclyl, or (3- or 6-membered heterocycly^CVCsalkyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen, -O-
RB, -S-RB, -N(RBRB), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, fomiyl or cyano. X
preferably is O, S, NH orN(C1-C6alkyl).
The present invention also features compounds having Formula II or III, and
pharmaceutically acceptable salts thereof,


R7 is selected from hydrogen, -LA, C5-Ciocarbocyclyl, or 5- to 10-membered heterocyclyl,
wherein said C5-C10carbocyclyl and 5- to 10-membered heterocyclyl are each independently
optionally substituted with one or more RA;
Z1 is selected from a bond, -C(RcRc)-, -O-, -S-, or -N(RB)-;
W1, W2, W5, and W6 are each independently selected from N or C(RD), wherein RD is
independently selected at each occurrence from hydrogen or RA;
R1, R9, R11, and R15 are each independently selected at each occurrence from hydrogen or RA;
p is selected from 0, 1,2, or 3;

LK is a bond; C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is
independently optionally substituted at each occurrence with one or more substitucnts
selected from halogen, Rs (except hydrogen), -O-Rs, -S-Rs, -N(RsRsO, -OC(O)Rs, -
C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano; or -N(RB)C(O)- or -C(O)N(RB)-;
B is C3-Ciocarbocycle or 3- to 10-membered heterocycle, and is optionally substituted with one or
more RA;
T is independently selected at each occurrence from a bond, -Ls-, -Ls-M-Ls—, -Ls-M-Ls—M'-
Ly—, wherein M and M' are each independently selected from a bond, -O-, -S-, -N(RB)-, -
C(OK -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(RBK -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(C))N(RB.)-, -
N(RB)SO2N(RB0-, -N(RB)S(O)N(RB.)-, C5-Ciocarbocycle, or 5- to 10-membered heterocycle,
and wherein at each occurrence T is independently optionally substituted with one or more
RA;
RA is independently selected at each occurrence from halogen, hydroxy, mercapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, -LA, or -LS-RE;

RB and RB- are each independently selected at each occurrence from hydrogen; or C1-C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered
heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, tbioxo, formyl or cyano;
Rc and Rc- are each independently selected at each occurrence from hydrogen; halogen; hydroxy;
mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C1-C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, or C3-C6carbocyclyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
RD, RD' and RD- are each independently selected at each occurrence from hydrogen or RA
LA is independently selected at each occurrence from 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, -O-Rs, -S-Rs, -N(RsRS'), -OC(O)Rs, -C(O)ORs, nitro,
phosphate, oxo, thioxo, formyl or cyano;
Ls, Ls- and Ls- are each independently selected at each occurrence from a bond; or C1-C6alkylene,
C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, -O-Rs, -S-Rs, -
N(RsRsO),-OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano;
RE is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -
C(O)ORs, -N(RsRsO, -S(O)Rs, -S02Rs, -C(O)N(RsRs0, -N(Rs)C(O)Rs% -
N(Rs)C(O)N(Rs-Rs"), -N(Rs)S02Rs-, -SO2N(RsRs0, -N(Rs)S02N(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(RsRs0, -N(Rs)S(O)-Rs., -S(O)N(RsRs.), -C(O)N(Rs)C(O)-Rs-,
C3-Ciocarbocyclyl, or 3- to 10-membered heterocyclyl, wherein said C3-Ci0carbocyclyl and 3-
to 10-membered heterocyclyl are each independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-
C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB'), -OC(O)RB, -
C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano; and
Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-
membered heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, -O-RB, -S-RB, -N(RBRBO, -OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, formyl or cyano.
Z1 preferably is -N(RB)-, such as -NH- or -N(C1-C6alkyl)-.

X1 preferably is -CH2-, -O- or -S.
R7 can be selected, without limitation, C5-C6carbocycle or 5- to 6-membered heterocycle,
each of which is optionally substituted with one or more RA. Preferably, R7 is phenyl, and is
optionally substituted with one or more RA (e.g., -N(RsRsO such as -NH2).
A2 can be selected, without limitation, from C5-C10carbocycles or 5- to 10-membered
heterocycles, and is optionally substituted with one or more RA. Preferably, A2 is selected from C5-
C6carbocycles or 5- to 6-membered heterocycles, and is optionally substituted with one or more RA.
Two adjacent RA on A2, taken together with the ring atoms to which they are attached, may form a C5-
C6carbocycle or a 5- to 6-membered heterocycle. Non-limiting examples of suitable A2 include
phenyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, thienyl, furanyl,
imidazolyl, pyrazolyl, triazolyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuranyl,
benzothiazolyl, indolyl, indenyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl,
quinazolinyl, or phthalazinyl, each of which is optionally substituted with one or more RA. As a non-

1 or 2, and m is 1 or 2. Two adjacent RA, taken together with the atoms to which they are attached,
can form a C5-C6carbocycle or a 5- to 6-membered heterocycle.
-T-RD preferably is -C(O)-Ls—R12 or -C(O)-Ls—M'-LS—R12, where R12 is (i) hydrogen, (ii)
C1-C6alkyl, C2-C6alkenyl or C2-C6atkynyl, each of which is independently optionally substituted at
each occurrence with one or more substituents selected from halogen, -O-Rs, -S-Rs, -N(RSRS), -
OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano, or (iii) C3-Ciocarbocyclyl or 3-
to 10-membered heterocyclyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs

(except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB0, -OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, fonnyl or cyano. -T-RD can also be, without limitation, -Ls-(C3-C10carbocyclyl) or -
Ls-(3- to 10-membered heterocyclyl), where said C3-Ciocarbocyclyl and 3- to 10-membered
heterocyclyl are each independently optionally substituted with one or more substituents selected
from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -
N(RBRB-), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano. In addition, -T-RD
can be, without limitation, -LS-RE, -C(O)-Ls-RE, -C(O)O-Ls-RE.

is 0, 1 or 2, m is 1 or 2, and k is 0, 1, 2, 3 or 4. Two adjacent RA, taken together with the atoms to
which they are attached, can form a C5-C6carbocycle or a 5- to 6-membered heterocycle. R12 can be,
without limitation, -LT-N(RB)-LTT-RE, -Lr-N(RB)C(O)-LTT-RE, or -LT-N(RB)C(O)-LTT-RE,
wherein LT and LTT are each independently selected from (i) a bond, or (ii) C1-C6alkylene, C2-
C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, C3-C10carbocyclyl, 3- to 10-
membered heterocyclyl, -O-Rs, -S-Rs, -N(RSRS<), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo,
thioxo, formyl or cyano. Preferably, R12 is -Li-N(RB)-LTr-Rs, -LI-N(RB)C(O)-LTT-RS, or -Lr-
N(RB)C(O)-LTT-RS, where LT and Lrr are as defined immediately above. R12 can also be, without
limitation, -LS-RE, such as -Ls-O-Rs, -Ls-S-Rs, or -Ls-N(RsRsO- In addition, R12 can be, without
limitation, -Ls-(C3-C10carbocyclyl) or -Ls-(3- to 10-membered heterocyclyl), where said C3-
C10carbocyclyl and 3- to 10-membered heterocyclyl are each independently optionally substituted
with one or more substituents selected from C1-Csalkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except
hydrogen), halogen, -O-RB, -S-RB, -N(RBRB0, -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo,
formyl or cyano.



form a C5-C6carbocycle or a 5- to 6-membered heterocycle.
-T-RD- can be, without limitation, -C(O)-Ls—R12 or -C(O)-Ls—M'-Ls—R12, where R12 is
(i) hydrogen, (ii) 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, -O-Rs, -S-Rs. -
N(RSRS), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano, or (iii) C3-
Ciocarbocyclyl or 3- to 10-membered heterocyclyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from C1-Cealkyl, C2-C6alkenyl,
C2-C6alkynyL Rs (except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB-), -OC(O)RB, -C(O)ORB,
nitro, phosphate, oxo, thioxo, formyl or cyano. -T-RD" can also be , without limitation, -Ls-(C3-
C10carbocyclyl) or -Ls-(3- to 10-membered heterocyclyl), where said C3-C10carbocyclyl and 3- to 10-
membered heterocyclyl are each independently optionally substituted with one or more substituents
selected from C1-C6alkyl, C^-Cealkenyl, C2-C6alkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB,
-N(RBRB'), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano. In addition, -T-
RD- can be, without limitation, -LS-RE, -C(O)-Ls-RE, -C(O)O-Ls-RE.

where n is 0, 1 or 2, m is 1 or 2, k is 0, 1,2, 3 or 4. Two adjacent RA, taken together with the atoms to
which they are attached, can form a C5-C6carbocycle or a 5- to 6-membered heterocycle. R12 can be,
without limitation, -LT-N(RB)-LTT-RE, -LT-N(RB)C(O)-LTT-RE, or -LT-N(RB)C(O)-LTr-RE,
wherein LT and LTT are each independently selected from (i) a bond, or (ii) C1-C6alkylene, C2-
C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from halogen, C3-Ciocarbocyclyl, 3- to 10-
membered heterocyclyl, -O-Rs, -S-Rs, -N(RsRs), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo,
thioxo, formyl or cyano. Preferably, Ri2 is -Lr-N(RB)-LTr-Rs, -LT-N(RB)C(O)-LTI-RS, or -Lr-
N(RB)C(O)-Ln—Rs, where LT and LTT are as defined immediately above. Ri2 can also be, without
limitation, -LS-RE," such as -Ls-O-Rs, -Ls-S-Rs, or -Ls-N(RsRs')- In addition, R12 can be, without"
limitation, -Ls-(C3-Ciocarbocyclyl) or -Ls-(3- to 10-membered heterocyclyl), where said C3-
Ciocarbocyclyl and 3- to 10-membered heterocyclyl are each independently optionally substituted
with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except

substituted at each occurrence with one or more substituents selected from halogen, -O-Rs, -S-Rs, -
N(RSRS), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano; (ii) -Ls-C3-
C10carbocyclyl or -Ls-(3- to 10-membered heterocyclyl), each of which is optionally substituted with
one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Rs (except hydrogen),
halogen, -O-RB, -S-RB, -N(RBRB), -OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or
cyano; or (iii) -Ls-O-Rs, -Ls-S-Rs, or -Ls-N(RsRs). Alternatively, RD and RD' can join to form a
5- to 6-membered heterocycle.

where k is 1 or 2, R and R* are independently hydrogen or C1-C6alkyl, and R' and R" are
independently C1-C6alkyl or C6-C10aryl.
Preferably, T is selected from Table 4 described below.
More preferably, T is -LS-N(RT)-LS- (e.g., -CH2-N(RT)-CH2-), or -LS-C(RTRT')-LS-
(e.g., -CH2-C(RTRT')-CH2-). RT is CrC6alkyl, C2-C6alkenyl, or C2-C6alkynyl, each of which is
independently optionally substituted at each occurrence with one or more substituents selected from
halogen, -O-Rs, -S-Rs, -N(RsRs'), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or
cyano; or RT is C3-C.6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered heterocyclyl, or (3-
or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently optionally substituted at each
occurrence with one or more substituents selected from C1-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Rs
(excepthydrogen), halogen, -O-RB,-S-RB, -N(RBRB), -OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, formyl or cyano. Rr is RA, and preferably RT- is hydrogen. Ls, LS', RA, RB, RB', RS, and
Rs- are as defined above.

In one embodiment, A2 is 5- to 10-membered carbocycle or heterocycle (e.g., phenyl,
pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, thienyl, furanyl, imidazolyl,
pyrazolyl, triazolyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuranyl, benzothiazolyl,
indolyl, indenyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, or
phthalazinyl) and is optionally substituted with one or more RA. Preferably, A2 is 5- to 6-membered
carbocycle or heterocycle (e.g., phenyl), and is optionally substituted with one or more RAJ XI is
selected from -CH2-, -O-, or -S-; R7 is selected from 5- to 6-membered carbocycles or heterocycles,
and is optionally substituted with one or more RA; and Zi is -N(RB)- (e.g., -NH- or -N(C1-C6alkyl)-
In another embodiment, W1, W2, and W5 are N, and W6 is C(RF); RI is hydrogen; R7 is
phenyl, and is optionally substituted with one or more RA; and Rg, Rn, and RF are each independently
selected at each occurrence from hydrogen; halogen; C1-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-
Cecarbocyclyl, or C3-C6carbocyclylC1-C6alkyl, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano. Preferably, R9 is C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6carbocyclyl (e.g., C3-C6cycloalkyl), or C3-C6carbocyclyC1-C6alkyl (e.g., C3-
C6cycloalkylC1-C6alkyl), each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
phosphate, oxo, thioxo, formyl or cyano; and Ru and RF are hydrogen. Z1 can be -N(RB)- (e.g., -
NH- or -N(C1-C6alkyl)-); Xi is -CH2-, -O-, or -S-; and A2 can be 5- to 10-membered carbocycle or
heterocycle (e.g., phenyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, thienyl,
furanyl, imidazolyl, pyrazolyl, triazolyl, benzoxazolyl, benzothienyl, benzimidazolyl, benzofuranyl,
benzothiazolyl, indolyl, indenyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl,
quinazolinyl, or phthalazinyl), and is optionally substituted with one or more RA. Preferably, A2 is 5-
to 6-membered carbocycle or heterocycle (e.g., phenyl), and is optionally substituted with one or

X is 0, S or N(RB), and RB is Rs. Preferably, R13 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-
Cecarbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered heterocyclyl, or (3- or 6-membered
heterocyclyl)C1-C6alkyl, each of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen,-O-RB, -S-RB, -N(RBRB), -OC(O)RB, -
C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano; and X is O, S, NH orN(C1-C6alkyl).
The compounds of the present invention can be used in the form of salts. Depending on the
particular compound, a salt of a compound may be advantageous due to one or more of the salt's

physical properties, such as enhanced pharmaceutical stability under certain conditions or desired
solubility in water or oil. In some instances, a salt of a compound may be useful for the isolation or
purification of the compound.
Where a salt is intended to be administered to a patient, the salt preferably is pharmaceutically
acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base
addition salts, and alkali metal salts.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic
acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic
acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Examples of suitable organic acids
include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic,
and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate,
trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate,
tartaric acid, citrate, ascorbate, glucuronate, maleatc, fumarate, pyruvate, aspartate, glutamate,
benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate,
mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic. acid, b-
hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, buryrate, camphorate,
camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts
and organic salts. Non-limiting examples of suitable metallic salts include alkali metal (group la)
salts, alkaline earth metal (group Ha) salts, and other pharmaceutically acceptable metal salts. Such
salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium,
sodium, or zinc. Non-limiting examples of suitable organic salts can be made from tertiary amines
and quaternary amine, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and
procaine. Basic nitrogen-containing groups can be quaternized with agents such as alkyl halides (e.g.,
methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides), dialkyl
sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), aralkyl halides (e.g., benzyl and
phenethyl bromides), and others.
The compounds or salts of the present invention may exist in the form of solvates, such as
with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to
form, respectively, methanolate, ethanolate or acetonitrilate).
The compounds or salts of the present invention may also be used in the form of prodrugs.
Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the

invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of
the invention. Phosphate pro drags of hydroxyl groups are preferred prodrugs.
The compounds of the invention may comprise asymmetrically substituted carbon atoms
known as chiral centers. These compounds may exist, without limitation, as single stereoisomers
(e.g., single enantiomers or single diastereomer), mixtures of stereoisomers (e.g. a mixture of
enantiomers or diastereomers), or racemic mixtures. Compounds identified herein as single
stereoisomers are meant to describe compounds that are present in a form that is substantially free
from other stereoisomers (e.g., substantially free from other enantiomers or diastereomers). By
"substantially free," it means that at least 80% of the compound in a composition is the described
stereoisomer; preferably, at least 90% of the compound in a composition is the described
stereoisomer; and more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a
composition is the described stereoisomer. Where the stereochemistry of a chiral carbon is not
specified in the chemical structure of a compound, the chemical structure is intended to encompass
compounds containing either stereoisomer of the chiral center.
Individual stereoisomers of the compounds of this invention can be prepared using a variety
of methods known in the art. These methods include, _hut are not limited to, stereospecific synthesis,
chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion
of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically
separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic
resolution.
Stereospecific synthesis typically involves the use of appropriate optically pure
(enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not
cause racemization or inversion of stereochemistry at the chiral centers. Mixtures of stereoisomers of
compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for
example, by chromatographic techniques as appreciated by those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography
resins, many of which are commercially available. In a non-limiting example, racemate is placed in
solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be
separated by HPLC.
Resolution of enantiomers can also be accomplished by converting enantiomers in a mixture
to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can be separated by
column chromatography or crystallization/re-crystallization. This technique is useful when the
compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or
covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include
chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers

are separated by chromatography, the individual enantiomers can be regenerated. Frequently, the
chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases or lipases, can be useful for the resolution of
derivatives of enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl
group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes
only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be
separated from the unhydrolyzed ester.
Alternatively, salts of enantiomers in a mixture can be prepared using any method known in
the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids
or phenethylamine, followed by precipitation or crystallization/re-crystallization of the
enantiomerically pure salts. Methods suitable for the resolution/separation of a mixture of
stereoisomers, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND
RESOLUTIONS (Jacques et al.,1981, John Wiley and Sons, New York, NY).
A compound of this invention may possess one or more unsaturated carbon-carbon double
bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are
intended to be encompassed within the scope of a recited compound unless otherwise specified. In
addition, where a compound exists in various tautomeric forms, a recited compound is not limited to
any one specific tautomer, but rather is intended to encompass all tautomeric forms.
Certain compounds of the invention may exist in different stable conformational forms which
may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond,
for example because of steric hindrance or ring strain, may permit separation of different conformers.
The compounds of the invention includes each conformational isomer of these compounds and
mixtures thereof.
Certain compounds of the invention may also exist in zwitterionic form and the invention
includes each zwitterionic form of these compounds and mixtures thereof.
The compounds of the present invention are generally described herein using standard
nomenclature. For a recited compound having asymmetric center(s), it should be understood that all
of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention
unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers,
diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms,
the compound is intended to encompass all tautomeric forms. Certain compounds are described
herein using general formulas that include variables (e.g., A1, A2, Z1, T, RB, or RA). Unless otherwise
specified, each variable within such a formula is defined independently of any other variable, and any
variable that occurs more than one time in a formula is defined independently at each occurrence. If
moieties are described as being "independently" selected from a group, each moiety is selected

independently from the other. Each moiety therefore can be identical to or different from the other
moiety or moieties.
The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "Cx-Cy,"
where x is the minimum and y is the maximum number of carbon atoms in the moiety. Thus, for
example, "C1-C6alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating
further, C3-C6cycloaIkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
A prefix attached to a multiple-component substituent only applies to the first component that
immediately follows the prefix. To illustrate, the term "carbocyclylalkyl" contains two components:
carbocyclyl and alkyl. Thus, for example, C3-C6carbocyclylC1-C6alkyl refers to a C3-C6carbocyclyl
appended to the parent molecular moiety through a C1-C6alkyl group.
When words are used to describe a linking element between two other elements of a depicted
chemical structure, the leftmost-described component of the linking element is the component that is
bound to the left element in the depicted structure. To illustrate, if the chemical structure is A1-T-A2
and T is described as -N(RB)S(O)-, then the chemical will A1-N(RB)-S(O)-A2.
If a linking element in a depicted structure is a bond, then the left element in the depicted
structure is joined directly to the right element in the depicted structure. For example, if a chemical
structure is depicted as -Ls-M-Ls—, where M is selected as a bond, then the chemical structure will
be -Lg-Ls—. For another example, if a chemical moiety is depicted as -LS-RE where Ls is selected as
a bond, then the chemical moiety will be -RE.
When a chemical formula is used to describe a moiety, the dash(s) indicates the portion of the
moiety that has the free valence(s).
If a moiety is described as being "optionally substituted", the moiety may be either substituted
or unsubstituted. If a moiety is described as being optionally substituted with up to a particular
number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum number of substitutable
positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a
heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with
less than three substitutable positions will be optionally substituted by up to only as many non-
hydrogen radicals as the heterocycle has substitutable positions. To illustrate, tetrazolyl (which has
only one substitutable position) will be optionally substituted with up to one non-hydrogen radical.
To illustrate further, if an amino nitrogen is described as being optionally substituted with up to two
non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two
non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to
only one non-hydrogen radical.
The term "alkenyl" means a straight or branched hydrocarbyl chain containing one or more
double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the

alkenyl moiety, relative to groups substituted on the double bond carbons. Non-limiting examples of
alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,
1-butenyl, 2-butenyl, and 3-butenyl.
The term "alkenylene" refers to a divalent unsaturated hydrocarbyl chain which may be linear
or branched and which has at least one carbon-carbon double bond. Non-limiting examples of
alkenylene groups include -C(H)=C(H)-, -C(H)=C(H)-CH2- -C(H)=C(H)-CH2-CH2-
-CH2-C(H)=C(H)-CH2- -C(H)=C(H)-CH(CH3)-, and-CH2-(H)=:(H)-CH(CH2CH3)-.
The term "alkyl" means a straight or branched saturated hydrocarbyl chain. Non-limiting
examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-
butyl, pentyl, iso-amyl, and hexyl.
The term "alkylene" denotes a divalent saturated hydrocarbyl chain which may be linear or
branched. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -
CH2CH2CH2-, -CH2CH2CH2CH2-, and-CH2CH(CH3)CH2-.
The term "alkynyl" means a straight or branched hydrocarbyl chain containing one or more
triple bonds. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl,
decynyL 1-butynyl, 2-butynyl, and 3-butynyl.
The term "alkynylene" refers to a divalent unsaturated hydrocarbon group which may be
linear or branched and which has at least one carbon-carbon triple bonds. Representative alkynylene
groups include, by way of example, -OC-, -OC-CH2-, -OC-CH2-CH2-, -CH2-OC-CH2-, -OC-
CH(CH3)-, and -CH2-C=C-CH(CH2CH3)-.
The term "carbocycle" or "carbocyclic" or "carbocyclyl" refers to a saturated (e.g.,
"cycloalkyl"), partially saturated (e.g., "cycloalkenyl" or "cycloalkynyl") or completely unsaturated
(e.g., "aryl") ring system containing zero heteroatom ring atom. "Ring atoms" or "ring members" are
the atoms bound together to form the ring or rings. A carbocyclyl may be, without limitation, a single
ring, two fused rings, or bridged or spiro rings. A substituted carbocyclyl may have either cis or trans
geometry. Representative examples of carbocyclyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,
cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl,
cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl,
and norpinanyl. A carbocyclyl group can be attached to the parent molecular moiety through any
substitutable carbon ring atom. Where a carbocyclyl group is a divalent moiety, such as A1 and A2 in
Formula I, it can be attached to the remaining molecular moiety through any two substitutable ring
atoms.
The term "carbocyclylalkyl" refers to a carbocyclyl group appended to the parent molecular
moiety through an alkylene group. For instance, C3-C6carbocyclylC1-C6alkyl refers to a C3-
Cgcarbocyclyl group appended to the parent molecular moiety through C1-C6alkylene.

The term "cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclyl moiety
having zero heteroatom ring member. Representative examples of cycloalkenyl groups include, but
are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyL and octahydronaphthalenyl.
The term "cycloalkyl" refers to a saturated carbocyclyl group containing zero heteroatom ring
member. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.
The prefix "halo" indicates that the substituent to which the prefix is attached is substituted
with one or more independently selected halogen radicals. For example, "C1-C6haloalkyl" means a
C1-C6alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected
halogen radicals. Non-limiting examples of C1-C6haloalkyl include chloromethyl, 1-bromoethyl,
fluoromethyl, difluoromethyl, trifiuoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if
a substituent is substituted by more than one halogen radical, those halogen radicals may be identical
or different (unless otherwise stated).
The term "heterocycle" or "heterocyclo" or "heterocyclyl" refers to a saturated (e.g.,
"heterocycloalkyl"), partially unsaturated (e.g., "heterocycloalkenyl" or "heterocycloalkynyl") or
completely unsaturated (e.g., "heteroaryl") ring system where at least one of the ring atoms is a
heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently
selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can
be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group.
Where a heterocyclyl group is a divalent moiety, such as A1 and A2 in Formula I, it can be attached to
the remaining molecular moiety through any two substitutable ring atoms.
A heterocyclyl may be, without limitation, a monocycle which contains a single ring. Non-
limiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,
isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,
oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl"),
1,2,5-oxadiazolyl (also known as "furazanyl"), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-
oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-
dioxazolyl, and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl),
dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyl"),
pyrimidinyl (also known as "1,3 -diazinyl"), and pyrazinyl (also known as "1,4-diazinyl")),
piperazinyl, triazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known
1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl), oxazinyl (including 1,2,3-oxazinyl,
1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl),
isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl

(including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and
1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
A heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as,
for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl),
thiazolpyrimidinyl, thienopyrimidinyl, pyTimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,
indolizinyl, pyrindinyl, pyTanopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and
pteridinyl. Other non-limiting examples of fused-ring heterocycles include benzo-fused
heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as "pseudoindolyl"), isoindazolyl
(also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as "1-benzazinyl")
and isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, benzodiazinyl
(including cinnolinyl (also known as "1,2-benzodiazinyl") and quinazolinyl (also known as "1,3-
benzodiazinyl")), bcnzopyranyl (including "chromenyl" and "isochromenyl"), benzothiopyranyl (also
known as "thiochromenyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl,
benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"),
isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thionaphthenyl", and
"benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl", "isothionaphthenyl", and
"isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,
benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4-
benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl), and
tetrahydroisoquinolinyl.
A heterocyclyl. may comprise one or more sulfur atoms as ring members; and in some cases,
the sulfur atom(s) is oxidized to SO or SO2. The nitrogen heteroatom(s) in a heterocyclyl may or may
not be quaternized, and may or may not be oxidized to N-oxide. In addition, the nitrogen
heteroatom(s) may or may not be N-protected.
The term "pharmaceutically acceptable" is used adjectivally to mean that the modified noun is
appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
The term "therapeutically effective amount" refers to the total amount of each active
substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load.
The term "prodrug" refers to derivatives of the compounds of the invention which have
chemically or metabolically cleavable groups and become, by solvolysis or under physiological
conditions, the compounds of the invention which are pharmaceutically active in vivo. A prodrug of a
compound may be formed in a conventional manner by reaction of a functional group of the
compound (such as an amino, hydroxy or carboxy group). Prodrugs often offer advantages of
solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H., DESIGN OF
PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well

known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic
compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a
suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or
other acylated derivatives of alcohol or amine functional groups within the compounds of the
invention.
The term "solvate" refers to the physical association of a compound of this invention with one
or more solvent molecules, whether organic or inorganic. This physical association often includes
hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one
or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate"
encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not
limited to, hydrates, ethanolates, and methanolates.
The term "N-protecting group" or "N-protected" refers to those groups capable of protecting
an amino group against undesirable reactions. Commonly used N-protecting groups are described in
Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rd ed., John Wiley & Sons, NY
(1999). Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl,
propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl;
sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl
(phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfmyl groups such as p-methylphenylsulfmyl (p-
methylphenyl-S(O)-) or t-butylsulfinyl (t-Bu-S(O)-); carbamate forming groups such as
benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-
nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-
trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, dimethyl-3,5-
dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl,
allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl,
cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl;
alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; p-
methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and
benzyloxycarbonyl (Cbz).
The compounds of the present invention can be prepared by coupling a compound of Formula
TV to a compound of Formula V as showed in Scheme I, where A1, A2, Z1, W1, W2, R1, R2, R3, R4, and
T are as defined hereinabove. Compounds of Formula IV can be prepared according to the processes

described in U.S. Patent Application Publication Nos. 20070232627, 20070197558 and 20070232645
and WO2008/133753, while compounds of Formula V can be prepared according to the procedures
described in WO2004014313, WO2004014852, WO2006133326, WO2007070556, WO2007070600,
WO2008021927, WO2008021928, WO2008021936, WO2008064218, and WO2008070447.

As a non-limiting example, the compounds of the present invention can be prepared by
coupling a compound of Formula IV to a compound of Formula V as shown in Scheme II, where Ti is
a carboxylic acid as shown or an activated derivative such as an acid chloride or an activated ester
(e.g., N-hydroxysuccinimide or pentafluorophenyl esters), and T2 is an amine or substituted amine.
Amide bond coupling reagents such as DCC, EDAC, PyBOP, and HATU may be employed with the
option of adding an amine base such as triethylamine or Hunig's base in a solvent such as DMF,
DMSO, THF, or dichloromethane.


As another non-limiting example, the compounds of the present invention can be prepared by
coupling a compound of Formula IV to a compound of Formula V as shown in Scheme HI, where T1
and T2 are carboxylic acids or activated derivatives such as acid chlorides or activated esters (e.g., N-
hydroxysuccinimide or pentafluorophenyl esters) by reaction with an amine or substituted amine as
shown. Amide bond coupling reagents such as DCC, ED AC, PyBOP, and HATU may be employed
with the option of adding an amine base such as triethylamine or Hunig's base in a solvent such as
DMF, DMSO, THF, or dichloromethane. Couplings may be conducted concurrently to give
symmetric products or sequentially to give non-symmetric products. RB and RE- are as denned
hereinabove, and -C(O)N(RB)-T'-N(RB')C(O)- is T.


As yet another non-limiting example, the compounds of the present invention can be prepared
by coupling a compound of Formula IV to a compound of Formula V as shown in Scheme IV, where
T1 and T2 are independently boronic acids or esters as shown by reaction with heterocyclic or
carbocyclic halides (iodide shown in Scheme IV) or triflates and a transition metal catalyst. T' is a
heterocyclic or carbocyclic, and R can be, without limitation, independently selected at each
occurrence from hydrogen or LA, and LA is as defined hereinabove. Alternatively, alkyl stannanes
(such a tributyl- or trimethylstannanes) may be employed in place of the boronates and coupled with
halides or triflates under analogous conditions. Pd catalysts such as Pd(PPh3)4 or Pd(dppf)Cl2may be
employed or generated in situ using a Pd (II) catalyst such Pd(OAc)2 or Pd2(dba)3 and
organophosphorous ligands, such as PPh3 or P(t-Bu)3. Reactions may be conducted with addition of a
base such K2CO3 or K3PO4 in a solvent such as THF or DMF. Couplings may be conducted
concurrently to give symmetric products or sequentially to give non-symmetric products.

As still another non-limiting example, the compounds of the present invention can be
prepared by coupling a compound of Formula IV to a compound of Formula V as shown in Scheme
V, where Ti and T2 are halides (iodide as shown) by reaction with an alkyne, where R may be
trimethylsilyl (TMS) or another suitable protecting group, by Sonogashira reaction using a suitable
catalyst. Pd catalysts such as Pd(PPh3)4 or Pd(dppf)Cl2 may be employed or generated in situ using a
Pd (II) catalyst such Pd(OAc)2 or Pd2(dba)3 and organophosphorous ligands, such as PPh3 or P(t-Bu)3.
Alternatively, a Cu (I) catalyst may be employed, such as Cu (I) iodide. Reactions may be conducted
with addition of a base such K2CO3 or K3PO4 or an amine base such as triethylamine or Hunig's base
in a solvent such as THF or DMF. The TMS protecting group may be removed using a base such as
K2CO3 in a solvent such as methanol or THF. A second Sonogashira reaction with V may be
conducted under the analogous conditions to the first coupling. Couplings may be conducted
concurrently to give symmetric products or sequentially to give non-symmetric products.


As a further non-limiting example, the compounds of the present invention can be prepared
by coupling a compound of Formula IV to a compound of Formula V as shown in Scheme VI.
Formula IV and V are both aldehydes, and can be reacted with an amine to form Formula VI (step 1)
by reductive amination using a suitable reducing agent such as NaCNBH3 or NaBH(OAc)3, in a
solvent such as THF or ethanol with or without the addition of acetic acid. R may be, without
limitation, C1-C6alkyl such as tert-buyl or isopropyl, C6-C10carbocycle such as phenyl, or 6- to 10-
membered heterocycle. Alternatively, R may be a protecting group, such as benzyl or 2,4-dimethoxy
benzyl, which may be removed from VI using hydrogenolysis or by treatment with an acid, such as
TFA or HC1. Alternatively, V may contain an alkyl halidc, such as the bromide shown, and reacted
with the product of reductive amination (step 2) of aldehyde IV with the amine to form VI (step 3).
The alkylation using halide V may be conducted in the presence of a base, such as NaH, NaOH,
Hunig's base, or NaHMDS in a solvent such as THF or DMF. The halide and nitro substituted
compounds VI may be reacted with alkyl, aryl, or heteroaryl alcohols, thiols, phenols, or thiophenols
using a base such as K2CO3 or Hunig's base in a solvent such as THF or DMF. Nitro groups may be
Teduced to amino groups, using Pd or Raney Ni catalyzed hydrogenation or using Fe in the presence
of NH4CI, HC1, or acetic acid, and further functionalized to compounds I using the processes
described in U.S. Patent Application Publication Nos. 20070232627, 20070197558 and 20070232645,
and WO2008/133753, as well as those described in WO2004014313, WO2004014852,
WO2006133326, WO2007070556, WO2007070600, WO2008021927, WO2008021928,
WO2008021936, WO2008064218, and WO2008070447. T is -CH2-N(R)-CH2- or -CH2-NH-CH2-.


or an activated derivative thereof. For example, the compounds of the present invention can be
prepared from a compound of Formula VI as shown in Scheme VII, which can be prepared through
Schemes I-V by substituting chloro and/or nitro for IV and V. The halide and nitro substituted
compounds VI may be reacted with alkyl, aryl, or heteroaryl alcohols, thiols, phenols, or thiophenols
using a base such as K2C03 or Hunig's base in a solvent such as THF or DMF. Nitro groups may be
reduced to amino groups, using Pd or Raney Ni catalyzed hydrogenation or using Fe in the presence
of NH4CI, HC1, or acetic acid, and further functionalized to compounds I using the processes
described in U.S. Patent Application Publication Nos. 20070232627, 20070197558 and 20070232645,
and WO2008/133753, as well as those described in WO2004014313, WO2004014852,
WO2006133326, WO2007070556, WO2007070600, WO2008021927, WO2008021928,
WO2008021936, WO2008064218, and WO2008070447.


The compounds having Formulae II and III can be similarly prepared according to the above
schemes, as appreciated by those skilled in the art.
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.
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.


A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol
(8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90 °C for 1.5 hours,
cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture
was extracted with ethyl acetate (400 mL). The extract was washed with H2O (3 times) and brine,
dried over MgSCU, and evaporated to give the crude product as orange crystal. The crude product was
suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected
by filtration, washed with i-Pr20 and dried at 60 °C for 3 days under reduced pressure gave purified
title compound as orange crystal (18.6 g, 90% yield).
Example 1B
4-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-3-nitro-benzoic acid methyl ester

A solution of the product from Example 1A (18.5 g, 61 mmol) and di-tert-butyl dicarbonate
(26.8 g, 122 mmol) in p-dioxane (280 mL) was heated at 90 °C for 3 hours. An additional di-tert-butyl
dicarbonate (26.8 g, 122 mmol) was added and the mixture was heated at 90 °C for 3 hours. A second
additional di-tert-butyl dicarbonate (13.4 g, 61 mmol) was added and the mixture was heated at 90 °C
for 4 hours. The reaction mixture was cooled to room temperature, and then evaporated. The residue
was diluted with z'-Pr20 (250 mL) and the mixture was stirred at room temperature for 1 hour. The
resulting crystal was collected by nitration, washed with /-Pr20 and dried at 60 °C overnight under
reduced pressure gave the title compound as yellow crystal (22.8 g, 93% yield).

A suspension of the product from Example IB (22.8 g, 56 mmol), Fe powder (16.4 g, 282
mmol) and NH4CI (15.1 g, 282 mmol) in aqueous EtOH [prepared from EtOH (228 mL) and H20
(228 mL)] was gradually heated to reflux and gently refluxed for 2 hours. The reaction mixture was
cooled to room temperature and filtered through celite pad. The filtrate was evaporated. The aqueous
residue was portioned between Ethyl acetate and H20, made basic to pH 9 with K2CO3, and then
filtered through celite pad. The organic layer was separated, washed with H20 and brine, dried over
MgS04 and evaporated. The oily residue was crystallized in the treatment with z'-Pr2O (200 mL) and
stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration, washed
with z'-Pr20 and dried at 60 °C overnight under reduced pressure gave the title compound as colorless
crystal (13.9 g, 66% yield).
Example 1D
4-(4-?e^Butoxycarbonylammo-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-(i]pyrimidin-4-ylamino)-
benzoic acid methyl ester


A suspension of N'-(3-cyano-6-isopropyl-pyridin-2-yl)-Ar,A^-dimethyl-fonnamidine (2.00 g,
9.3 mmol) and the product from Example 1C (3.46 g, 9.3 mmol) in Acetic acid (40 mL) was heated at
120 °C for 20 minutes under N2. After cooling to room temperature, the reaction mixture was
portioned between ethyl acetate (150 mL) and H20 (200 mL), and then made basic to pH 9 with
K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine,
dried over MgSO4, and evaporated to give a pale brown oil. The oily residue was separated by silica
gel column chromatography (ethyl acetate/n-hexane = 5/1) gave yellow crystal. Further purification
by washing with cold ethyl acetate (15 mL) gave the title compound as slightly yellow crystal (3.27 g,
65% yield).

To a solution of the product from Example 1D (3.25 g, 6.0 mmol) in THF (32.5 mL) was
added aqueous LiOH [prepared from LiOH monohydrate (1.02 g, 24 mmol) and H2O (10 mL)]
dropwise at room temperature. The mixture was stirred at room temperature for 26 hours, and then
evaporated. The aqueous mixture was diluted with 100 mL of H2O, washed with ethyl acetate (50
mL), and then carefully acidified to pH 4-5 with 10% HCl at 5 °C under stirring. The resulting solid
was collected by filtration, washed with H2O, and dried at 60 °C overnight under reduced pressure
gave the title compound as pale yellow crystal (3.09 g, 98% yield).
Example 1F
(S)-1 -tert-butyl 2-(2-(4-nitrophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate


To a solution of BOC-L-Proline (0.485 g, 2.25 mmol) and 2-Bromo-4'-nitro acetophenone
(0.500 g, 2.05 mmol) in acetonitrile (20 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol)
dropwise at ambient temperature. After stirred for four hours, the solution was poured into brine and
extracted into ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was concentrated to
give a crude material that was used without purification (100% yield).

To a solution of the Product from Example IF (0.775 g, 2.05 mmol) in toluene (10 mL) was
added ammonium acetate (3.16 g, 41.0 mmol) in one portion. The mixture was heated at 100 °C for
16 hours. The dark red solution was poured into brine, extracted into ethyl acetate, concentrated, and
purified by combi-flash 12g column, eluting with 0-30% ethyl acetate in dichloromethane to give a
waxy solid (0.545 g, 74%).

To a solution of the Product form Example 1G (0.545 g, 1.52 mmol) in dichloromethane (15
mL) was added trifluoroacetic acid (2.34 mL, 30.4 mmol) dropwise at ambient temperature. The
solution was stirred for 16 hours then concentrated and azeotroped with toluene twice to give an
orange waxy solid TFA salt (0.367 g, 65%).
Example 1I
(S)-1 -(2-(4-(4-nitrophenyl)- lH-imidazol-2-yl)pyrrolidin-1 -yl)-2-phenylethanone


To a solution of the Product from Example 1H (0.18 g, 0.48 mmol) and HATU (0.202 g, 0.53
mmol) in DMSO (5 mL) was added diisopropyleurylamine (0.253 mL, 1.45 mmol) followed by
Phenyl acetic acid (0.066 mL, 0.53 mmol). The solution was stirred for 16 hours, then diluted with
water and the product was filtered off and purified by combi-flash 12g column, eluting with 0-5%
methanol in dichloromethane to give a solid (0.137 g, 75%).

To a solution of the Product from Example II (0.137 g, 0.36 mmol) in a mixture of water
(0.75 mL), methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added iron (0.102 g, 1.82 mmol) and
ammonium chloride (0.030 g, 0.54 mmol) and the resulting mixture was heated with vigorous stirred
at 75 °C for one hour. The warm reaction mixture was filtered through celite and rinsed well with
methanol and tetrahydrofuran. The filtrate was concentrated and partitioned between 10% NaHC03
solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated
to give a waxy solid that was used without purification (97%).
Example 1K
(S)-tert-buryl4-(2-(7-isopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4-(4-(2-(1-(2-
phenylacetyl)pyirolidin-2-yl)-1H-imidazol-4-yl)phenylcarbamoyl)phenylthio)phenylcarbamate


To a solution of the Product from Example IE (0.16 g, 0.30 mmol) and HATU (0.12 g, 0.316
mmol) in DMSO (5 mL) was added diisopropylethylamine (0.184 mL, 1.05 mmol) followed by the
Product from Example U (0.115g, 0.33 mmol). The solution was stirred at ambient temperature for
18 hours, then diluted with water and the crude product was filtered off an purified by combi-flash
12g column, eluting with 0-10% Methanol in dichloromethane to give a solid (0.092 g, 36%).
Example 1L
(S)-4-(4-ammophenylmio)-3-(7-isopropylpvrido[2,3-d]pyrimidin-4-ylamino)-N-(4-(2-(l-(2-
phenylacetyl)pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)benzamide

To a solution of the Product of Example 1K (0.092 g, 0.11 mmol) in tetrahydrofuran (1 mL)
was added 4 M HC1 in dioxane (1 mL, 4.2 mol) at ambient temperature. After stirred for four hours,
the solid HC1 salt of the product was filtered off and taken up in a small amount of methanol and

added to a NaHCO3 solution. The free amine was extracted into ethyl acetate, concentrated and
purified by combi-flash 12g column, eluting with 0-10% Methanol in dichloromethane to give a
yellow solid (0.035 g, 43%). 1H NMR (400 MHz, Solvent) d ppm 1.36 (d, J=7.02 Hz, 6 H) 1.89 -
2.36 (m, 4 H) 3.24 (dd, J=13.89, 6.87 Hz, 1 H) 3.50 - 3.81 (m, 4 H) 5.09 - 5.20 (m, 1 H) 6.66 (d,
J=8.54 Hz, 2 H) 6.98 - 7.10 (m, 2 H) 7.12 - 7.35 (m, 7 H) 7.55 (d, J=8.54 Hz, 1 H) 7.66 - 7.79 (m, 5
H) 7.96 (s, 1 H) 8.49 (s, 1 H) 8.76 (d, J=8.24 Hz, 1 H)

A solution of (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol) and 37% aqueous
formaldehyde (3.22 mL, 39.7 mmol) in methanol (22 mL) was treated with 20% Palladium on Carbon
(0.35 g, 0.66 mmol) under a hydrogen atmosphere for 5 hours. After purging with nitrogen, then
solution was filtered and concentrated. The residue was taken up in a small amount of methanol and
ether was added. The resulting solid was filtered and dried to give a white solid.

The Product of Example 2D (0.094 g, 0.10 mmol) was processed in the same manner as in
Example 1L to give a yellow solid (0.016 g, 19%). 1H NMR (400 MHz, Solvent) d ppm 1.36 (d,
J=6.71 Hz, 6 H) 1.80 - 2.12 (m, 4 H) 2.17 (s, 6 H) 3.19 - 3.26 (m, 1 H) 3.38 (s, 1 H) 3.88 (s, 1 H) 4.25
(s, 1 H) 5.06 (s, 1 H) 6.66 (d, .7=8.54 Hz, 2 H) 7.02 (d, .7=6.10 Hz, 1 H) 7.15 (d, .7=8.54 Hz, 2 H) 7.23

- 7.50 (m, 5 H) 7.55 (d, /=7.63 Hz, 1 H) 7.62 - 7.80 (m, 5 H) 7.99 (s, 1 H) 8.56 (s, 1 H) 8.77 (d,
J=7.02 Hz, 1 H)

To a solution of Carbobenzyloxy-L-proline (0.20 g, 0.80 mmol) and HATU (0.32 g, 0.84
mmol) in DMSO (6 mL) was added diisopropylethylamine ( 0.42 mL, 2.41 mmol) followed by tert-
buty-4-aminophenylcarbamate (0.175 g, 0.82 mmol). The solution was stirred at ambient temperature
for two hours, then diluted with water and the solid product was filtered off and purified by combi-
flash 12g column, eluting with 0-20% ethyl acetate in dichloromethane to give a solid (0.245 g, 70%).


To a solution of the Product from Example 3A (0.245g, 0.56 mmol) in dioxane (5 mL) was
added 4M HC1 dioxane (2.8 mL, 11.2 mol) and the mixture was stirred at ambient temperature for 17
hours. The mixture was concentrated and azeotroped with toluene to give a tan solid (0.18g, 86%).
Example 3C
(S)-benzyl2-(4-(4-(4-(tert-butoxycarbonylamino)phenylMo)-3-(7-isopropylpyrido[23-d]pyrimidin-
4-ylamino)benzamido)phenylcarbamoyl)pyrrolidine-1 -carboxylate

The product from Example 1E (0.15 g, 0.28 mmol) and the Product from Example 3B (0.134
g, 0.395 mmol) were processed in the same manner as Example 1K to give a solid (0.155g, 64%).
Example 3D
(S)-benzyl2-(4-(4-(4-ammophenylmio)-3-(7-isopropylpyrido[2,3-d]pyrimidin-4-
ylamino)benzamido)phenylcarbamoyl)pyrrolidme-1 -carboxylate


The Product of Example 3C (0.094 g, 0.10 mmol) was processed in the same manner as in
Example 1L to give a yellow solid (0.045 g, 33%). 1H NMR (300 MHz, DMSO-D6) d ppm 1.34 (d,
J=6.62 Hz, 6 H) 1.81 - 2.00 (m, 3 H) 2.16 - 2.31 (m, 1 H) 3.15 - 3.27 (m, 1 H) 3.41 - 3.56 (m, 2 H)
4.29 - 4.40 (m, 1 H) 4.92 - 5.14 (m, 2 H) 5.59 (s, 2 H) 6.64 (d, J=8.46 Hz, 2 H) 6.87 (d, J=8.82 Hz, 1
H) 7.15 (d, J=8.46 Hz, 2 H) 7.18 - 7.27 (m, 2 H) 7.34 - 7.42 (m, 2 H) 7.54 (t, J=8.09 Hz, 2 H) 7.62 -
7.72 (m, 3 H) 7.78 (d, J=7.35 Hz, 1 H) 7.95 (s, 1 H) 8.59 (s, 1 H) 8.89 (d, J=7.72 Hz, 1 H) 10.01 (d,
J=5.52 Hz, 1 H) 10.14 (d, J=5.88 Hz, 2 H)


The Product of Example 3C (0.094 g, 0.10 mmol) was processed in the same manner as in
Example 1L to give this product as a yellow solid (0.014 g, 12%). 1H NMR (300 MHz, DMSO-D6) d
ppm 1.34 (d, J=6.99 Hz, 6 H) 1.58 - 1.70 (m, 2 H) 1.70 - 1.85 (m, 1 H) 1.95 - 2.12 (m, 1 H) 2.88 (t,
J=6.62 Hz, 2 H) 3.13 - 3.26 (m, 1 H) 3.66 (dd, J=8.64, 5.33 Hz, 1 H) 5.59 (s, 2 H) 6.63 (d, J=8.46 Hz,
2 H) 6.86 (d, J=8.46 Hz, 1 H) 7.14 (d, J=8.46 Hz, 2 H) 7.63 (q, J=8.95 Hz, 5 H) 7.77 (d, J=9.19 Hz, 1
H) 7.94 (s, 1 H) 8.58 (s, 1 H) 8.88 (d, J=6.99 Hz, 1 H) 9.90 (s, 1 H) 10.13 (d, J=10.66 Hz, 2 H)
The following compounds were also prepared according to the processes described herein:

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 1b-Conl. 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. The lb-Conl replicon construct is identical to the
la-H77 replicon, except that the NS3-NS5B coding region is derived from the lb-Conl strain, and
that the replicon contains different adaptive mutations. 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 (Invitrogcn), 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 ul 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 and are then lysed for RNA extraction. For the luciferase
assay, 30 ul 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 ul, 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 IC50 and/or EC50 value can be calculated using nonlinear regression curve fitting
to the 4-paramcter logistic equation and GraphPad Prism 4 software.
When evaluated using the above method, representative compounds of the present invention
inhibited HCV replicon replication with IC50 values in the range of from about 0.1 nM to about 100
uM. IC50 refers to 50% inhibitory concentration. Cytotoxicity of the compounds of the present
invention can also be evaluated using methods known in the art. When tested, the TC50 values of
representative compounds of the present invention were often greater than the corresponding IC50
values of the compounds. TC50 refers to 50% toxicity concentration. Table 6 lists the IC50 values of
the compounds of Examples 1-18 when tested using HCV replicons.


The present invention also features pharmaceutical compositions comprising the compoundsKof the invention. A pharmaceutical composition of the present invention can comprise one or more
compounds of the invention, each of which has a formula independently selected from selected from
Formulae I, II or III.
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-HTV 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, a-interferon, P-interferon, pegylated interferon-cc, pegylated interferon-lambda,
ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025, NIM-811, R7128, R1626,

R4048, T-l 106, PSI-7851, PF-00868554, ANA-598, IDX184, IDX102, IDX375, GS-9190, VCH-759,
VCH-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052,
BMS-791325, BMS-650032, GS-9132, ACH-1095, AP-H005, A-831, A-689, AZD2836, telaprevir,
boceprevir, UMN-191, BI-201335, VBY-376, VX-500 (Vertex), PHX-B, ACH-1625, IDX136,
IDX316, VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 (Tibotec), ITMN-191
(Intermune, Roche), MK-7009 (Merck), IDX-PI (Novartis), BI-201335 (Boehringer Ingelheim),
R7128 (Roche), PSI-7851 (Pharmasset), MK-3281 (Merck), PF-868554 (Pfizer), IDX-184 (Novartis),
IDX-375 (Pharmasset), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS),
Albuferon (Novartis), 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 compounds of the present invention having Formula I, II or HI (or (or a salts, 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-HTV 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-FJIV 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 HTV
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.
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 pharmaceutical^ 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.
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 all HC V 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 or 3a. 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 la. 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 la 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.
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 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.

CLAIMS
What is claimed is:
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein:
A1 is C3-C14carbocyclyl or 3- to 14-membered heterocyclyl, and is substituted with -X1-R7,
wherein said C3-C14carbocyclyl and 3- to 14-membered heterocyclyl are optionally
substituted with one or more RA;
X1 is selected from a bond, -Ls-, -O-, -S-, or -N(RB)-;
R7 is selected from hydrogen, -LA, C5-C10carbocyclyl, or 5- to 10-membered heterocyclyl,
wherein at each occurrence said C5-C10carbocyclyl and 5- to 10-membered heterocyclyl are
each independently optionally substituted with one or more RA;
Z1 is selected from a bond, -C(RcRc)-, -O- -S-, or -N(RB)-;
W1 and W2 are each independently selected from N or C(RD);
R1 is selected from hydrogen or RA;
R3 and R4 are each independently selected from hydrogen or RA; or R3 and R4, taken together with
the carbon atoms to which they are attached, form a C5-C10carbocyclic or 5- to 10-membered
heterocyclic ring, wherein said C5-C10carbocyclic and 5- to 10-membered heterocyclic ring
are optionally substituted with one or more RA;
A2 is C3-C14Carbocyclyl or 3- to 14-membered heterocyclyl, and is optionally substituted with one
or more RA;


R6 is Rc; and R8 is RB; or R6 and R8, taken together with the atoms to which they are attached,
form a 3- to 10-membered heterocyclic ring which is optionally substituted with one or more
RA;
LK is a bond; C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, Rs (except hydrogen), -O-Rs, -S-R& -N(RSRS.), -OC(O)Rs, -
C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano; or -N(RB)C(O)- or -C(O)N(RB)-;
B is C3-Ciocarbocycle or 3- to 10-membered heterocycle, and is optionally substituted with one or
more RA;
T is independently selected at each occurrence from a bond, -Ls-, -LS-M-LS'-, -Ls-M-Ls—M'-
Ls"-, wherein M and M' are each independently selected from a bond, -O-, -S-, -N(RB)-, -
C(OK -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)S02N(RB.)-, -N(RB)S(O)N(RB-)-, C5-Ciocarbocycle, or 5- to 10-membered heterocycle,
and wherein at each occurrence T is independently optionally substituted with one or more
RA;
RA is independently selected at each occurrence from halogen, hydroxy, mercapto, amino,
carboxy, nitro, phosphate, oxo, thioxo, formyl, cyano, -LA, or -LS-RE;
RB and RB' are each independently selected at each occurrence from hydrogen; or C1-C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C3-C6Carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-membered
heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
Re and Re are each independently selected at each occurrence from hydrogen; halogen; hydroxy;
mercapto; amino; carboxy; nitro; phosphate; oxo; thioxo; formyl; cyano; or C1-C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, or C3-C6carbocyclyl, each of which is independently optionally
substituted at each occurrence with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo, formyl or cyano;
RD, RD' and RD» are each independently selected at each occurrence from hydrogen or RA
LA is independently selected at each occurrence from 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, -O-Rs, -S-Rs, -N(RsRs), -OC(O)Rs, -C(O)ORs, nitro,
phosphate, oxo, thioxo, formyl or cyano;
Ls, Ls- and LS" are each independently selected at each occurrence from a bond; or C1-C6alkylene,
C2-C6alkenylene, or C2-C6alkynylene, each of which is independently optionally substituted at

each occurrence with one or more substituents selected from halogen, -O-Rs, -S-Rs, -
N(RsRs'X -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or cyano;
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, -S02Rs, -C(O)N(RsRs.), -N(Rs)C(O)Rs., -
N(Rs)C(O)N(Rs.Rs..), -N(Rs)S02Rs-, -S02N(RsRs.), -N(Rs)S02N(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.), -C(O)N(Rs)C(O)-Rs<,
C3-Ciocarbocyclyl, or 3- to 10-membered heterocyclyl, wherein said C3-Ciocarbocyclyl and 3-
to 10-membered heterocyclyl are each independently optionally substituted at each
occurrence with one or more substituents selected from C1-C6alkyl, C2-C6alkenyl, C2-
Olkynyl, Rs (except hydrogen), halogen, -O-RB, -S-RB, -N(RBRB0, -OC(O)RB, -
C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano; and
Rs, Rs- and Rs" are each independently selected at each occurrence from hydrogen; or C1-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, C3-C6carbocyclylC1-C6alkyl, 3- to 6-
membered heterocyclyl, or (3- or 6-membered heterocyclyl)C1-C6alkyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from halogen, -O-RB, -S-RB, -N(RBRB.), -OC(O)RB, -C(O)ORB, nitro, phosphate,
oxo, thioxo, formyl or cyano.
2. The compound or salt of claim 1, wherein:
A1 is C5-C6carbocyclyl or 5- to 6-membered heterocyclyl, which is optionally substituted with one
or more RA, and A] is substituted with -XrR7;
R7 is C5-C6carbocyclyl or 5- to 6-membered heterocyclyl, and is optionally substituted with one or
more RA.
R3 and R4 are each independently selected from hydrogen or RA; or R3 and R4, taken together with
the carbon atoms to which they arc attached, form a Cs-Cecarbocyclic or 5- to 6-membered
heterocyclic ring, wherein said C5-C6carbocyclic and 5- to 6-membered heterocyclic ring are
optionally substituted with one or more RA; and
A2 is C5-Ciocarbocyclyl or 5- to 10-membered heterocyclyl, and is optionally substituted with one
or more RA.
3. The compound or salt according to one of claims 1-2, wherein A2 is Cs-Cecarbocycryl or 5- to 6-
membered heterocyclyl, and is optionally substituted with one or more RA.
4. The compound or salt according to one of claims 1-3, wherein R7 is phenyl, and is optionally
substituted with one or more RA.

5. The compound or salt according to one of claims 1-4, wherein A1 is phenyl, and is optionally
substituted with one or more RA.
6. The compound or salt according to one of claims 1-5, wherein A2 is phenyl, and is optionally
substituted with one or more RA.
7. The compound or salt according to one of claims 1-6, wherein A1, A2 and R7 are phenyl, and are
each independently optionally substituted with one or more RA.
8. The compound or salt according to one of claims 1-7, wherein R3 and R4, taken together with the
carbon atoms to which they are attached, form a C5-C6carbocyclic or 5- to 6-membered heterocyclic
ring which is optionally substituted with one or more RA.
9. The compound or salt according to one of claims 1-8, wherein W1 and W2 are N, and Z1 is-N(RB)-
10. The compound or salt according to one of claims 1-9, wherein:
W1and W2are N;
Z1 is-N(RB)-;
X1 is -CH2-, -O- or -S-;
R3 and R4, taken together with the carbon atoms to which they are attached, form

R9, R10, and R11 are each independently selected from hydrogen or RA.
11. The compound or salt according to one of claims 1-10, wherein
A1 is phenyl, and is optionally substituted with one or more RA;
R7 is phenyl, and is optionally substituted with one or more RA;
R1 is hydrogen;
R9, R10, and Rn are each independently selected from hydrogen; halogen; or C1-C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, or C3-C6carbocyclyC1-C6aIkyl, each of which is
independently optionally substituted at each occurrence with one or more substituents

selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, phosphate, oxo, thioxo,
formyl or cyano.
12. The compound or salt according to one of claims 1-11, wherein R2 is -N(RB)C(O)C(R5R6)N(Rs)-
T-RD.
13. The compound or salt of claim 12, wherein R5 is Re, and Re and Rg 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.
14. The compound or salt of claim 12, wherein:

15. The compound or salt of claim 14, wherein:
-T-RD is -C(O)-Ls-R12 or -C(O)-Ls-M'-Ls—R12; and
R12 is hydrogen; C1-Cealkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more substituents selected from halogen,
-O-Rs, -S-Rs, -N(RsRg-), -OC(O)Rs, -C(O)ORs, nitro, phosphate, oxo, thioxo, formyl or
cyano; or C3-Ciocarbocyclyl or 3- to 10-membered heterocyclyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from CrC6alkyl, C2~C6alkenyl, C2-C6alkynyl, halogen, -O-RB, -S-RB, -N(RBRB.), -
OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano.


19. The compound or salt of claim 18, wherein:
-T-RD" is -C(O)-Ls-R12 or-C(O)-Ls-M'-Ls—R12; and
R12 is 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,
-O-Rs, -S-Rs, -N(RSRS-), -OC(O)Rs, -C(O)ORs, nirro, phosphate, oxo, thioxo, formyl or
cyano; or C3-Ciocarbocyclyl or 3- to 10-membered heterocyclyl, each of which is
independently optionally substituted at each occurrence with one or more substituents
selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -O-RB, -S-RB, -N(RBRB0, -
OC(O)RB, -C(O)ORB, nitro, phosphate, oxo, thioxo, formyl or cyano.

26. A method of inhibiting HCV virus replication, comprising contacting cells infected with HCV
virus with a compound or salt according to one of claims 1-24.
27. A method of treating HCV infection, comprising administering to an HCV patient a compound or
salt according to one of claims 1-24.
28. A process of making a compound according to one of claims 1-24, comprising a step described in
one of schemes described herein.

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.