IMIDAZOLE DERIVATIVES AS ANTIVIRAL AGENTS
FIELD OF THE INVENTION:
The present invention is related to novel compounds of the general formula I,
their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their isotopes,
their N-oxides, their metabolites, their pharmaceutically acceptable salts, polymorphs,
solvates, optical isomers, clathrates, co-crystals, combinations with suitable medicament,
pharmaceutical compositions containing them, methods of making of the above
compounds , and their use as antiviral candidate, more specifically as anti-HCV.
BACKGROUND OF THE INVENTION
Persistent hepatitis C virus (HCV) infection is a major health problem globally affecting
-3% of the world population and is an important contributor to chronic liver disease
culminating with liver cirrhosis, hepatocellular carcinoma and liver failure [Szabo E,Lotz G,
et al., Pathol. Oncol. Res. 2003, 9, 215-221 ; Hoofnagle JH., Hepatology 1997, 26 15S-20].
An estimated 170 million chronic carriers worldwide are at risk of developing liver disease.
In the United States alone 3 million are chronically infected with HCV and the number of
HCV related deaths is increasing significantly over the years [Barnes E., WHO factsheet
201 0. Available at:
http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html]. Clinically,
chronic infection is often asymptomatic with latent periods lasting for decades before
manifestation by which time extensive liver damage has occurred. HCV is spread primarily
by unscreened blood transfusions and use of contaminated needles and syringes; the
highest risk groups are intravenous drug users and people who received blood
transfusions (mainly haemophiliacs) before 1990 when screening for HCV was introduced.
Factors that have been reported to influence the rate of HCV disease progression include
age (increasing age is associated with more rapid progression), gender (males have more
rapid disease progression than females), alcohol consumption (associated with an
increased rate of disease progression), HIV co-infection (associated with a markedly
increased rate of disease progression), and fatty liver.
Despite significant efforts, no vaccine exists for HCV and until a year ago the standard
therapy for HCV was a combination of pegylated interferon (PEG-IFN) a and weight based
ribavarin (RBV), which was inadequate for majority of the patients and therapy associated
side effects such as pancytopenia, flu-like symptoms or depression were commonly
observed leading to early treatment discontinuation [Fried MW, et al., N Engl J Med. 2002,
347, 975-982]. The approval of two direct acting agents (DAA) i.e. 1st generation protease
inhibitors, Incivek and Victrelis in May 201 1 ushered in the era of specifically targeted
HCV therapy[Jesudian AB, Gambarin-Gelwan M and Jacobson IM., Gastroenterology
Hepatol. 2012, 8, 9 1- 10 1.
The combination of above mentioned DAAs, Peg-IFN and RBV (triple therapy)
substantially increases the rate of sustained virologic response in treatment na 've and
experienced patients. However, a number of issue restrict the usage of these drugs - i)
complex treatment algorithms issued by the regulatory bodies; ii) they are restricted to
genotype 1; iii) low barrier to resistance mutations and iv) increased cost of therapy
leading to limited access to care. Hence, there exists a need for alternative therapeutic
strategies that ensure broader genotype coverage, better efficacy, better tolerance and
limited selection of resistant HCV variants.
The sequence diversity of HCV is complex with the virus organized into 6 distinct
genotypes and over 100 subtypes. Additionally, HCV exists as many closely related viral
sequences, termed as quasi-species, in the infected individual, making specific
pharmaceutical targeting of HCV proteins challenging due to the rapid evolution of escape
mutants. It is increasingly evident that a broad collection of specific, pan genotypic antiviral
drugs targeting multiple essential viral functions, in addition to the current viral
therapies will be required for effective global control of HCV.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a novel compound of
the general formula (I), its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its
isotopes, its N-oxides, its metabolites, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals,
(I)
wherein, R1a, R1 to R12 , m, n, Y, ring D and ring A are as defined hereinbelow.
In another aspect, the present invention provides a pharmaceutical composition,
containing the compound of the general formula (I) as defined herein, its tautomeric forms,
its stereoisomers, its analogs, its prodrugs, its isotopes, its N-oxides, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its
clathrates, or its co-crystals in combination with the usual pharmaceutically employed
carriers, diluents and the like are useful for the treatment of HCV infection.
DESCRIPTION OF THE INVENTION
HCV is a member of the Flaviviridae family of enveloped, positive stranded RNA viruses
belonging to the genus Hepacivirus. The genome is a single ~9.6kb strand of RNA and
consists of one open reading frame that encodes for a polyprotein of -3000 amino acids
flanked by untranslated regions at both 5' and 3' ends. This precursor polyprotein is then
processed by viral and cellular proteases to yield 10 separate mature viral proteins critical
for replication and assembly of progeny viral particles. The organization of the structural
and non-structural proteins in the HCV polyprotein is as follows: C-E1 -E2-P7-NS2-NS3-
NS4a-NS4b-NS5a-NS5b. The three structural proteins C, E 1 and E2 are involved in
packaging of the virus and the infectivity cycle. The function of the p7 protein is unknown.
Of the non-structural proteins, NS2 is a zinc dependent metalloproteinase that functions in
conjunction with a part of NS3 protein. NS3 protein has two catalytic activities associated
with it: a serine protease at the N-terminal end which requires NS4A as a cofactor, and an
ATPase dependent helicase activity at the C-terminal end. NS5A is a membrane anchored
phosphoprotein that is present in basally phosphorylated (56kDa) and
hyperphosphorylated (58kDa) forms. Its precise role has not been determined but it has
been shown to play a role in RNA binding, multiple host protein interactions, and interferon
resistance. Additionally recent evidence suggests that NS5A plays an important role in
replication and infectivity of HCV. The NS5B protein encodes an RNA dependent RNA
polymerase activity, key to the generation of progeny viruses. While the pathology of HCV
infection mainly affects the liver, the virus is found in other cell types in the body including
peripheral blood lymphocytes [Thomson BJ et al., Clin Microbial Infect. 2005, 1 ., 86-94;
Moriishi K et al., Antivir. Chem. Chemother. 2003, 14, 285-297]. Characterization of the
replicase machinery required for HCV RNA synthesis has defined the protease/helicase
NS3 protein, the NS4A cofactor, the NS4B integral membrane protein, the NS5A protein
and the RNA dependent RNA polymerase NS5B as being its essential components.
Hence, one of the aspects of the present invention is provision of novel compounds of the
general formula I,
(I)
their tautomeric forms, their isomers, their isotopes, their metabolites, their prodrugs, their
pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods
of making of the above compounds, and their use as antiviral compounds;
wherein,
Ring 'A' is a saturated carbocycle, which may be a monocyclic system or may be a fused
carbocycle or may be a bridged carbocycle, the said ring A may contain 5 to 10 carbons;
Ring 'D' is selected from 5 to 10 membered carbocycle and 5 to 10 membered
heterocycle, the ring 'D' may be monocyclic, fused bicyclic, bridged bicyclic or spiro
bicyclic;
Y is selected from -CH(R2a)- and -N(R2)-;
R1 is selected from the group consisting of R13aC(=0)N(R 14)-, R13aOC(=0)N(R 14)-,
R1 (R14)N-, R1 (R14)NC(=0)N(R 15)-, R1 aS0 2N(R14)-,
R1 aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-,
R1 aOC(=0)N(R 14)CRa(Rb)C(Rc)(Rd)C(=0)N(R 15)-,
R1 (R14a)NC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-, and
R1 (R14a)NC(=0)N(R 14)CRa(Rb)C(Rc)(Rd)C(=0)N(R 15)-;
R1a is selected independently at each occurrence from the group consisting of halogen,
substituted- or unsubstituted- Ci-6 alkyl, R13aC(=0)-, R13bO-, R1 aOC(=0)-, R1 aC(=0)0-,
and R1 (R14)NC(=0)-,
R2 is selected independently at each occurrence from the group consisting of substitutedor
unsubstituted- Ci-6 alkyl, R13aC(=0)-, R1 aS0 2- , R1 aOC(=0)-, R1 (R14)NC(=0)-,
R1 aOC(=0)N(R 14)C(Ra)(Rb)C(=0)-, R1 aOC(=0)N(R 14)C(Ra)(Rb)C(Rc)(Rd)C(=0)-,
R1 (R14)NC(=0)N(R 15)C(Ra)(Rb)C(=0)-, R1 (R14)NC(=0)N(R 15)C(Ra)(Rb)C(Rc)(Rd)C(=0)-,
R1 S0 2N(R14)C(Ra)(Rb)C(=0)-, R1 S0 2N(R14)C(Ra)(Rb)C(Rc)(Rd)C(=0)-, and
R1 aOC(=0)N(R 14)C(Ra)(Rb)S0 2- ;
R a is selected independently at each occurrence from the group consisting of
R1 aC(=0)N(R 14)-, R1 aOC(=0)N(R 14)-, R1 (R14)N-, R1 (R14)NC(=0)N(R 15)-,
R1 aS0 2N(R14)-, R1 aOC(=0)N(R 14)C(Ra)(Rb)C(=0)N(R 15)-,
R1 aOC(=0)N(R 14)C(Ra)(Rb)C(Rc)(Rd)C(=0)N(R 15)-,
R1 (R14a)NC(=0)N(R 14)C(Ra)(Rb)C(=0)N(R 15)-, and
R1 (R14a)NC(=0)N(R 14)CRa(Rb)C(Rc)(Rd)C(=0)N(R 15)-;
R3 is independently selected from O and N(R16) ;
R4 is selected independently at each occurrence from CRe(Rf) , O and N(R14) ; such that,
when n = 2 and R4 is selected as CRe(Rf) for both the occurrences, two Res together can
form a bond to form a alkenylene linkage or two Res and two Rfs together can form bonds
to form alkynylene linkage;
R5, R6, R7, R8, R and R10 are independently selected as hydrogen, or R5 and R6 together,
R7 and R10 together, or R8 and R together independently along with the carbon atoms to
which they are attached forming 5 to 8 membered substituted- or unsubstitutedcarbocycle,
5 to 8 membered substituted- or unsubstituted- heterocycle, 6 membered
substituted- or unsubstituted- aryl, or 5 to 6 membered substituted- or unsubstitutedheteroaryl;
with a proviso that the compound of formula I must have at least one cyclic system formed
out of either R5 and R6, R8 and R9, or R7 and R10 ; also provided that R7 and R10 take part in
formation of cyclic system only when n is 0;
R1 1 and R12 are independently selected from a group consisting of hydrogen, halogen,
substituted- or unsubstituted- Ci-6 alkyl, R13bO-, and (R1 )(R14)N-;
wherein, R13 , R14 , R14a and R15 are independently selected from hydrogen, substituted- or
unsubstituted- C -6 alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstitutedheterocyclyl;
R1 a is selected from substituted- or unsubstituted- C -6 alkyl, perhaloalkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstitutedcycloalkyl,
and substituted- or unsubstituted- heterocyclyl;
R1 b is selected from hydrogen, substituted- or unsubstituted- C -6 alkyl, perhaloalkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
R16 is selected from hydrogen or substituted- or unsubstituted alkyl group;
Ra, Rb, Rc and Rd, are independently selected from hydrogen, halogen, substituted- or
unsubstituted- C -6 alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstitutedheterocyclyl,
or Ra, Rb, Rc and Rd together with the carbon atom(s) to which they are
attached forming substituted- or unsubstituted- carbocycle, substituted- or unsubstitutedheterocycle;
m is an integer ranging between 0 to 2, selected independently at each occurrence;
n is an integer ranging between 0 and 2;
'alkyl' may be substituted with 1 to 4 substituents selected from the group consisting of
halogen, oxo, Ci-6 alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, R17aC(=0 )-,
R17aS0 2- , R17bO-, R17aOC(=0 )-, R17aC(=0)0-, (R17)(R1 )NC(=0 )-, (R17a)C(=0)N(R18)-,
(R17)(R1 )N-, (R17)(R1 )NC(=0)N(R19)-, and R17aS0 2N(R18)-;
'cycloalkyl', 'cycloalkenyl' and 'carbocycle' may be substituted with 1 to 2 substituents
selected from the group consisting of halogen, oxo, C -6 alkyl, haloalkyl, R17aC(=0)-,
R17aS0 2- , R17bO-, R17aOC(=0)-, R17aC(=0)0-, (R17)(R1 )NC(=0)-, (R17a)C(=0 )N(R18)-,
(R17)(R1 )N-, (R17)(R1 )NC(=0 )N(R19)-, and R17aS0 2N(R18)-;
'aryl' may be substituted with 1 to 2 substituents selected from the group consisting of
halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl(H)N-,
alkyl(alkyl)N-, H2N-, alkyl-S0 2- , alkyl-C(=0)(H)N-, alkyl -C(=0)(alkyl )N-, alkyl(H)NC(=0)-,
alkyl(alkyl)NC(=0)-, H2NC(=0)-, alkyl(H)NS0 2- , alkyl(alkyl)NS0 2- , and H2NS0 2- ;
'heteroaryl' may be substituted with 1 to 2 substituents selected from the group consisting
of halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl-O-, perhaloalkyl -O-, alkyl-S0 2- ,
H2N-, alkyl(H)N-, alkyl(alkyl)N-, alkyl-C(=0)(H)N-, alkyl -C(=0)(alkyl )N-, NH2C(=0)-,
alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, NH2S0 2- , alkyl (H)NS0 2- , and alkyl(alkyl)NS0 2- ;
ring carbon(s) of 'heterocycle' may be substituted with 1 to 2 substituents selected from
the group consisting of halogen, nitro, cyano, oxo, alkyl, R17bO-, R17aOC(=0)-,
R17aC(=0)0-, R17(H)NC(=0 )-, R17 (alkyl)NC(=0)-, R17(H)N-, R17(alkyl)N-, R17aC(=0)(H)N-,
R17(H)NC(=0)(H)N-, and R17(alkyl)NC(=0 )(H)N-; the substituents on ring nitrogen(s) of
'heterocycle' are selected from the group consisting of alkyl, R17aS0 2- , R17aC(=0)-,
R17aOC(=0)-, R17(H)NC(=0 )-, and R17(alkyl)NC(=0);
R17 , R18 and R1 are independently selected from hydrogen and alkyl;
R17a is selected from alkyl and perhaloalkyl;
R17b is selected from the group consisting of hydrogen, alkyl, and perhaloalkyl;
Whenever a range of the number of atoms in a structure is indicated (e.g., a C - 2, Ci-8, Ci-
6, or C -4 alkyl, alkylamino, etc.), it is specifically contemplated that any sub-range or
individual number of carbon atoms falling within the indicated range also can be used.
Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., CrC 8) , 1-6 carbon
atoms (e.g., CrC 6) , 1-4 carbon atoms (e.g., CrC 4) , 1-3 carbon atoms (e.g., CrC 3) , or 2-8
carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl,
alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof
(e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6
carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon
atoms, 1-1 1 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5
carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms,
2-10 carbon atoms, 2-1 1 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon
atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-1 0
carbon atoms, 3-1 1 carbon atoms, 3-1 2 carbon atoms, 4-5 carbon atoms, 4-6 carbon
atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-1 1
carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).
One of the embodiments of the present invention is compound of formula (I) as described
above, wherein, ring A is particularly selected as cyclopentane;
In any of the embodiments of the invention described above, Y is particularly selected as -
N(R2)-;
In any of the embodiments of the invention described above, R1 is particularly selected as
R1 aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-;
In any of the embodiments of the invention described above, m is particularly selected as 0
at all the occurrences;
In any of the embodiments of the invention described above, R2 is particularly selected as
R1 aOC(=0)N(R 14)CRa(Rb)C(=0)-;
In any of the embodiments of the invention described above, R3 is particularly selected
from NH and O;
In any of the embodiments of the invention described above, n is particularly selected as 0;
In any of the embodiments of the invention described above, R5 and R6 are independently
selected from hydrogen and halogen, or R5 and R6 together with the carbon atoms to
which they are attached form a six membered carbocycle;
In any of the embodiments of the invention described above, R7 and R10 are particularly
selected as hydrogen, or R7 and R10 together with the carbon atoms to which they are
attached form a five or six membered carbocycle, the said carbocycle is unsubstituted or
substituted with one or two alkyl groups;
In any of the embodiments of the invention described above, R and R8 are particularly
selected as hydrogen, or R and R8 together with the carbon atoms to which they are
attached form a six or seven membered carbocycle, or R9 and R8 together with the carbon
atoms to which they are attached form a seven membered heterocycle containing one
heteroatom;
In any of the embodiments of the invention described above, R1 1 and R12 are particularly
selected as hydrogen;
In any of the embodiments of the invention described above, ring D is particularly selected
as
In any of the embodiments of the invention described above, ring A is particularly selected
as cyclopentane, ring D is particularly selected as , R1 is particularly selected
as R13aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15 )-, m is particularly selected as 0 at all the
occurrences, R3 is particularly selected from NH and O, n is particularly selected as 0, R5
and R6 are independently selected from hydrogen and halogen, or R5 and R6 together with
the carbon atoms to which they are attached form a six membered carbocycle, R7 and R10
are particularly selected as hydrogen, or R7 and R10 together with the carbon atoms to
which they are attached form a five or six membered carbocycle, the said carbocycle is
unsubstituted or substituted with one or two alkyl groups, R9 and R8 are particularly
selected as hydrogen, or R9 and R8 together with the carbon atoms to which they are
attached form a six or seven membered carbocycle, or R9 and R8 together with the carbon
atoms to which they are attached form a seven membered heterocycle containing one
heteroatom, R1 1 and R12 are particularly selected as hydrogen, such that at least one cyclic
system is formed out of either R5 and R6, R8 and R9, or R7 and R10 ;
General terms used in formula can be defined as follows ; however, the meaning stated
should not be interpreted as limiting the scope of the term per se.
The term "alkyl", as used herein, means a straight chain or branched hydrocarbon
containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to 10
carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms.
Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl ,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl , neopentyl, and nhexyl.
'Alkyl' as defined hereinabove may be substituted with one or more substituents selected
independently from the group comprising of halogen, oxo, C -6 alkyl, haloalkyl, aryl ,
heteroaryl , cycloalkyi , heterocyclyl, R17aC(=0)-, R17aS0 2- , R17bO-, R17aOC(=0)-,
R17aC(=0)0-, (R17)(R1 )NC(=0)-, (R17a)C(=0)N(R 18)-, (R17)(R1 )N-,
(R17)(R1 )NC(=0)N(R 19)-, and R17aS0 2N(R18)-; wherein, R17 , R18 and R19 are
independently selected from hydrogen and alkyl, R17a is selected from alkyl and
perhaloalkyl, R17b is selected from the group consisting of hydrogen, alkyl, and
perhaloalkyl.
The term "haloalkyl" used herein means an alkyl group as defined hereinabove wherein
at least one of the hydrogen atoms of the said alkyl group is substituted with halogen . The
haloalkyl group is exemplified by monofluoromethyl, 1,2-dichloroethyl and the like. The
term "perhaloalkyl" means an alkyl group as defined hereinabove wherein all the
hydrogen atoms of the said alkyl group are substituted with halogen . The perhaloalkyl
group is exemplified by trifluoromethyl, pentafluoroethyl and the like.
The term "cycloalkyi" as used herein, means a monocyclic, bicyclic, or tricyclic nonaromatic
ring system containing from 3 to 14 carbon atoms, preferably monocyclic
cycloalkyi ring containing 3 to 6 carbon atoms. Examples of monocyclic ring systems
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl .
Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which
two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
Representative examples of bicyclic ring systems include, but are not limited to,
bicyclo[3.1 .1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,
bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane,
bicyclo[3.1 .0]hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-1 H-indene.
Tricyclic ring systems are also exemplified by a bicyclic ring system in which two nonadjacent
carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge.
Representative examples of tricyclic-ring systems include, but are not limited to,
tricyclo[3.3.1 .0 7]nonane and tricyclo[3.3.1 . 1 7]decane (adamantane). The term cycloalkyl
also include spiro systems wherein one of the ring is annulated on a single carbon atom
such ring systems are exemplified by spiro[2.5]octane, spiro[4.5]decane,
spiro[bicyclo[4.1 .0]heptane-2,1 '-cyclopentane], hexahydro-2'H-spiro[cyclopropane-1 ,1'-
pentalene].
The term "cycloalkenyl" as used herein, means a cycloalkyl group as defined above
containing at least one double bond.
The term "carbocycle" as used herein, means a cyclic system made up of carbon atoms,
which includes cycloalkyl, cycloalkenyl and aryl.
Cycloalkyl, cycloalkenyl and carbocycle as defined hereinabove may be substituted with
one or more substituents selected independently from the group comprising of halogen,
oxo, C -6 alkyl, haloalkyl, R17aC(=0)-, R17aS0 2- , R17bO-, R17aOC(=0)-, R17aC(=0)0-,
(R17)(R1 )NC(=0)-, (R17a)C(=0)N(R 18)-, (R17)(R1 )N-, (R17)(R1 )NC(=0)N(R 19)-, and
R17aS0 2N(R18)-; wherein, R17 , R18 and R1 are independently selected from hydrogen and
alkyl, R17a is selected from alkyl and perhaloalkyl, R17b is selected from the group
consisting of hydrogen, alkyl, and perhaloalkyl.
The term "aryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic
hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl,
fluorenyl, indenyl, azulenyl, and the like. Aryl group also include partially saturated bicyclic
and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene. The said aryl group
also includes aryl rings fused with heteroaryl or heterocyclic rings such as 2,3-dihydrobenzo[
1 ,4]dioxin-6-yl, 2,3-dihydro-benzo[1 ,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-
dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-
dihydro-1 H-indol-5-yl, 2,3-dihydro-1 H-indol-4-yl, 2,3-dihydro-1 H-indol-6-yl, 2,3-dihydro-1 Hindol-
7-yl, benzo[1 ,3]dioxol-4-yl, benzo[1 ,3]dioxol-5-yl, 1,2,3,4-tetrahydroquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl.
Aryl as defined hereinabove may be substituted with one or more substituents selected
independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl,
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl(H)N-, alkyl(alkyl)N-, H2N-, alkyl-S0 2- , alkyl-
C(=0)(H)N-, alkyl-C(=0)(alkyl)N-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, H2NC(=0)-,
alkyl(H)NS0 2- , alkyl(alkyl)NS0 2- , and H2NS0 2- .
The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring
system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring
atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated),
wherein at least one ring in the ring system is aromatic. Heteroaryl groups may be
optionally substituted w th one or more substituents. In one embodiment, 0, 1, 2, 3, or 4
atoms of each ring of a heteroaryl group may be substituted by a substituent. Exampies of
heteroaryl groups include pyridyi, 1-oxo-pyridyl, furanyi, thienyi, pyrroi , oxazolyi,
oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,
py mdi yi, pyrazinyl, triazinyl. triazolyl. thiadiazolyl, isoquinolinyl, benzoxazolyl,
benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyi, benzimidazolyi, benzothiazolyl.
benzothiadiazolyl, benzoxadiazolyl, indolyl. azaindolyl, imidazopyridyl. quinazolinyl.
purinyl, pyrrolo[2,3]pyrimidinyi, pyrazoio[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-
thiadiazolyl, 1H-pyrazoio[5,1 -c]-1 ,2,4-triazoiyi, pyrrolo[3,4-d]-1 ,2,3-triazolyL
cyciopentairiazolyL 3H-pyrroio[3,4-c] isoxazolyl and the like.
Heteroaryl as defined hereinabove may be substituted with one or more substituents
selected independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl,
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-S0 2- , H2N-, alkyl(H)N-, alkyl(alkyl)N-, alkyl-
C(=0)(H)N-, alkyl-C(=0)(alkyl)N-, NH2C(=0)-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-,
NH2S0 2- , alkyl(H)NS0 2- , and alkyl(alkyl)NS0 2- .
The term "heterocycle" or "heterocyclic" as used herein, means a 'cycloalkyl' group
wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2)-, -S(O)-, -N(Rm)-, -
Si(Rm)Rn- , wherein, Rm and Rn are independently selected from hydrogen, alkyl, aryl,
heteroaryl, cycloalkyi, and heterocyclyl. The heterocycle may be connected to the parent
molecular moiety through any carbon atom or any nitrogen atom contained within the
heterocycle. Representative examples of monocyclic heterocycle include, but are not
limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-
dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl. oxadiazolidinyl, oxazolinyl,
oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl. pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomorpholinyl, 1. 1 -dioxidothiomorpholinyl (thiomorpholine sulfone).
thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include, but are
not limited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3-
dihydro-1-benzofuranyl, 2,3-dihydro-1 -benzothienyl, 2,3-dihydro-1 H-indolyl and 1,2,3,4-
tetrahydroquinolinyl. The term heterocycle also include bridged heterocyclic systems such
as azabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane and the like.
Heterocyclyl group may be substituted on ring carbons with one or more substituents
selected independently from the group consisting of halogen, nitro, cyano, oxo, alkyl,
R17bO-, R17aOC(=0)-, R17aC(=0)0-, R17(H)NC(=0)-, R17(alkyl)NC(=0)-, R17(H)N-,
R17(alkyl)N-, R17aC(=0)(H)N-, R17(H)NC(=0)(H)N-, and R17(alkyl)NC(=0)(H)N-; wherein,
R17 is selected from hydrogen and alkyl, R17a is selected from alkyl and perhaloalkyl, R17b
is selected from the group consisting of hydrogen, alkyl, and perhaloalkyl.
Heterocyclyl group may further be substituted on ring nitrogen(s) with substituents
selected from the group comprising of alkyl, R17aS0 2- , R17aC(=0)-, R17aOC(=0)-,
R17(H)NC(=0)-, and R17(alkyl)NC(=0); wherein, R17 is selected from hydrogen and alkyl,
R17a is selected from alkyl and perhaloalkyl.
The term xo' means a divalent oxygen (=0) attached to the parent group. For example
oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a
cyclohexanone, and the like.
The term 'annulated' means the ring system under consideration is either annulated with
another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as
in the case of fused or spiro ring systems.
The term 'bridged' means the ring system under consideration contain an alkylene bridge
having 1 to 4 methylene units joining two non adjuscent ring atoms.
A compound its stereoisomers, racemates, pharmaceutically acceptable salt thereof as
described hereinabove wherein the compound of general formula I is selected from:
1. methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
2. methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
3. methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
4. methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
5. methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
6. methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
7. methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2
yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2
yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2
yl)carbamate.
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate.
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1 ,2-d]oxazol-8
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate.
methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 Hnaphtho[
1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate.
methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 Hnaphtho[
1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate.
26. methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
27. methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-
yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-
methyl-1-oxobutan-2-yl)carbamate.
28. methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)(ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
29. methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-
1H-imidazol-2-yl)cyclopentyl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
30. methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9H-fluoren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
3 1. methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9-dimethyl-9H-fluoren-2-yl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate.
32. methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenanthren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
According to a feature of the present invention, the compounds of general formula I where
all the symbols are as defined earlier, can be prepared by methods given in Schemes
given below or example. Representative procedures are shown below, however; the
disclosure should not be construed to limit the scope of the invention arriving at compound
of formula I as disclosed hereinabove.
Scheme 1: Halogenation of synthon 1 (could be prepared by methods well known in the
art, Tetrahedron, 2000, 56, 5225-5240) may be achieved leading to the formation of 2
which could be coupled to the protected (P = Boc, Cbz) -aminocyclopentane carboxylic
acid 3 (individual isomers RR, SS, RS and SR could be made by methods known in the
literature, Tet. Lett., 2002, 43, 5401 -5404; J. Am. Chem. Soc, 1999, 12 1, 7574-7581 ; Tet.
Asymm., 2008, 19, 2796-2803) using an appropriate base like triethylamine, 4-
methylmorpholine, diisopropylethylamine and solvents like DMF, 1,4-dioxane, THF,
acetonitrile to yield 4. Cyclization of 4 using NH4OAc could lead to the formation of 5 which
may be deprotected and coupled with (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic
acid using amide coupling reagents like carbodiimides, phosphonium salts, uronium salts,
carbonyldiimidazole in presence of a mild base like triethylamine, 4-methylmorpholine,
diisopropylethylamine in a solvent like DMF, 1,4-dioxane, THF, dichloromethane leading to
the formation of 6. Alternatively, de-protected form of 5 can be coupled to similar moieties
by methods known in the literature to furnish compounds of formula I.
Scheme 1:
Scheme 2: Reduction of 7, could be prepared by methods known in the literature, using
either of Pd/C, Pt0 2 or Raney Ni, Fe/HCI, tin(ll) chloride, titanium(lll) chloride or zinc/AcOH
could lead to the formation of 8. Diazotization followed by Sandmeyer reaction of 8 might
lead to the formation of 9 which on acidic/basic hydrolysis might result in formation of 10.
One carbon homologation followed by halogenations might lead to formation of 1 1 from
10. Intermediate 11 could further be O-alkylated with 3 in presence of a suitable base and
solvent and cyclized using NH4OAc to yield 13. Pd-catalyzed C-C coupling of 13 with 14
(ref WO2009102318 A 1) might lead to the formation of 15 which on de-protection and
coupling with (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid or similar moieties
might lead to the synthesis of 16 or compounds of formula I.
Scheme 2
Scheme 3: Diazotization followed by Sandmeyer reaction on synthon 17 may lead to the
formation of 18. Synthesis of 19 may be accomplished by halogenation of 18 with suitable
halogenating agents. O-alkylation of 19 with Boc-L-proline using an appropriate base like
triethylamine, 4-methylmorpholine, diisopropylethylamine and solvent like DMF, 1,4-
dioxane, THF, acetonitrile might lead to the formation of 20. Cyclization of intermediate 20
with NH4OAc might lead to the formation of tricyclic system 2 1. Synthon 25 might be
synthesized from 22 wherein 22 could be O-alkylated with 3 followed by cyclization using
NH4OAC and finally generation of boronate/boronic acid via Pd-catalysis. Synthons 2 1 and
25 could be linked through C-C coupling method using Pd catalysts to obtain 26. Synthesis
of the compound 27 or compounds of formula I may be accomplished by de-protection of
26 and coupling the de-protected amine to (S)-2-((methoxycarbonyl)amino)-3-
methylbutanoic acid or similar moieties using a suitable combination of coupling reagents,
bases and solvents.
Scheme 3
Scheme 4: In another process, Wittig reaction on m-halo substituted benzaldehyde 28
using the appropriate base and solvent might lead to the formation of 29 which on
reduction with Pt-based reagents amongst others may lead to the formation of acid 30
which under acidic conditions may lead to the formation of 34. Alternatively, 34 could also
be synthesized from the phenol 3 1 which on alkylation might lead to the formation of 32
which on acidic/basic hydrolysis could lead to the formation of the acid 33. Cyclization of
33 under acidic conditions might lead to the formation of 34. (J. Med. Chem., 2000, 43,
2049-2063; ibid, 2005, 48, 7351-7362; WO20091 02633 A1). On treatment with isoamyl
nitrite in an appropriate solvent, oxime 35 might be generated from 34 which upon reaction
with Boc-L-prolinal under basic conditions may lead to formation of 36. Treatment of 36
with triethyl phosphite might lead to the formation of either 37 or 38. Pd-catalyzed C-C
coupling of either 37 or 38 with 25 followed by de-protection and coupling with (S)-2-
((methoxycarbonyl)amino)-3-methylbutanoic acid might lead to the formation of 39 or 40.
Symmetrical compounds could be prepared by coupling 42 (generated from 34) with the
boronate/boronic acid of 42 through the use of Pd catalyzed C-C coupling reactions to
yield 44 or compounds of formula I.
Scheme 4
Scheme 5: Acetophenone 45, which is readily available or prepared from suitable
reagents, could be protected with a suitable protecting group to get 46 which could be then
halogenated and O-alkylated to possibly yield 48. Cyclization of 48 might be accomplished
using ammonium acetate to yield 49 which upon de-protection of benzylic hydroxyl group
followed by alkylation under basic conditions with either synthon 37 or 38 might lead to the
synthesis of 50. De-protection of 50 under acidic conditions and sequential coupling with
(S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid or similar moieties might lead to
the formation of 5 1 or compounds of formula I.
Compounds of the present invention were prepared using synthetic schemes provided
below:
Compounds 1 to 3 were prepared by following the route provided in Scheme I
Compounds 4 to 15 were prepared by following the route provided in Scheme I I
ntitative
ative
Compounds 16 to 20 were prepared by following vided in Scheme III
Compounds 2 1 to 23 were prepared by following the route provided in Scheme IV
Compounds 24 to 27 were prepared by following the route provided in Scheme V
Compounds 28 and 29 were prepared by following the route provided in Scheme VI
Compounds 30 to 32 were prepared by following the route provided in Scheme VII
Scheme VII
A further embodiment of the present invention includes pharmaceutical compositions
comprising any single compound, a combination of two or more compounds delineated
herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable
carrier or excipient.
Yet a further embodiment of the present invention is a pharmaceutical composition
comprising any single compound or a combination of two or more compounds delineated
herein, or a pharmaceutically acceptable salt thereof, in combination with one or more
agents known in the art, with a pharmaceutically acceptable carrier or excipient.
It will be further appreciated that compounds of the present invention can be administered
as the sole active pharmaceutical agent, or used in combination with one or more agents
to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
Other agents to be administered in combination with a compound or combination of
compounds of the present invention include therapies for diseases caused by HCV
infection that suppresses HCV viral replication by direct or indirect mechanisms. These
agents include, but not limited to, host immune modulators (for example, interferon-alpha,
pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG
oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such
as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines
that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin
12); a compound that enhances the development of type 1 helper T cell response;
interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvant
combinations directed against HCV; agents that interact with host cellular components to
block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated
translation step of HCV viral replication or to block viral particle maturation and release
with agents targeted toward the viroporin family of membrane proteins such as, for
example, HCV P7 and the like; and any agent or combination of agents that inhibit the
replication of HCV by targeting other proteins of the viral genome involved in the viral
replication and/or interfere with the function of other viral targets, such as inhibitors of
NS3/NS4A protease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein.
According to yet another embodiment, the pharmaceutical compositions of the present
invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including,
but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein,
and internal ribosome entry site (IRES).
Accordingly, one embodiment of the present invention is directed to a method for treating
or preventing an infection caused by an RNA-containing virus comprising co-administering
to a patient in need of such treatment one or more agents selected from the group
consisting of a host immune modulator and a second or more antiviral agents, or a
combination thereof, with a therapeutically effective amount of a compound or combination
of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
Examples of the host immune modulator are, but not limited to, interferon-alpha,
pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a
vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits
replication of HCV either by inhibiting host cellular functions associated with viral
replication or by targeting proteins of the viral genome. Example of the RNA-containing
virus includes, but not limited to, hepatitis C virus (HCV).
A further embodiment of the present invention is directed to a method of treating or
preventing infection caused by an RNA-containing virus comprising co-administering to a
patient in need of such treatment an agent or combination of agents that treat or alleviate
symptoms of HCV infection including cirrhosis and inflammation of the liver, with a
therapeutically effective amount of a compound or combination of compounds of the
present invention, or a pharmaceutically acceptable salt thereof. Example of the RNAcontaining
virus includes, but not limited to, hepatitis C virus (HCV).
Yet another embodiment of the present invention provides a method of treating or
preventing infection caused by an RNA-containing virus comprising co-administering to a
patient in need of such treatment one or more agents that treat patients for disease
caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a
compound or a combination of compounds of the present invention, or a pharmaceutically
acceptable salt thereof. An agent that treats patients for disease caused by hepatitis B
(HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir,
lamivudine or tenfovir, or any combination thereof. Example of the RNA-containing virus
includes, but not limited to, hepatitis C virus (HCV).
A further embodiment of the present invention provides a method of treating or preventing
infection caused by an RNA-containing virus comprising co-administering to a patient in
need of such treatment one or more agents that treat patients for disease caused by
human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a
compound or a combination of compounds of the present invention, or a pharmaceutically
acceptable salt thereof. The agent that treats patients for disease caused by human
immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir,
lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-1 14,
fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine,
abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1 360, enfuvirtide (T-
20) or T-1249, or any combination thereof. Example of the RNA-containing virus includes,
but not limited to, hepatitis C virus (HCV).
It can occur that a patient may be co-infected with hepatitis C virus and one or more other
viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus
(HAV) and hepatitis B virus (HBV). Thus also contemplated is combination therapy to treat
such co-infections by co-administering a compound according to the present invention with
at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
In addition, the present invention provides the use of a compound or a combination of
compounds of the invention, or a therapeutically acceptable salt thereof, and one or more
agents selected from the group consisting of a host immune modulator and a second or
more antiviral agents, or a combination thereof, to prepare a medicament for the treatment
of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C
virus. Examples of the host immune modulators include, but are not limited to, interferonalpha,
pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a
vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral
agent inhibits replication of HCV either by inhibiting host cellular functions associated with
viral replication or by targeting proteins of the viral genome.
When used in the above or other treatments, combination of compound or compounds of
the present invention, together with one or more agents as defined herein above, can be
employed in pure form or, where such forms exist, in pharmaceutically acceptable salt
thereof. Alternatively, such combination of therapeutic agents can be administered as a
pharmaceutical composition containing a therapeutically effective amount of the compound
or combination of compounds of interest, or their pharmaceutically acceptable salt thereof,
in combination with one or more agents as defined hereinabove, and a pharmaceutically
acceptable carrier. Such pharmaceutical compositions can be used for inhibiting the
replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting
said virus with said pharmaceutical composition. In addition, such compositions are useful
for the treatment or prevention of an infection caused by an RNA-containing virus,
particularly Hepatitis C virus (HCV).
Hence, a still further embodiment of the invention is directed to a method of treating or
preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus
(HCV), comprising administering to a patient in need of such treatment a pharmaceutical
composition comprising a compound or combination of compounds of the invention or a
pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove,
with a pharmaceutically acceptable carrier.
When administered as a combination, the therapeutic agents can be formulated as
separate compositions which are given at the same time or within a predetermined period
of time, or the therapeutic agents can be given as a single unit dosage form.
Antiviral agents contemplated for use in such combination therapy include agents
(compounds or biologicals) that are effective to inhibit the formation and/or replication of a
virus in a mammal, including but not limited to agents that interfere with either host or viral
mechanisms necessary for the formation and/or replication of a virus in a mammal. Such
agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor;
and an HBV inhibitor.
Other agents to be administered in combination with a compound of the present invention
include a cytochrome P450 monooxygenase inhibitor, which is expected to inhibit
metabolism of the compounds of the invention. Therefore, the cytochrome P450
monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the
compounds of the present invention. Accordingly, the CYP inhibitor is administered in an
amount such that the bioavailability of the compounds of the present invention is increased
in comparison to the bioavailability in the absence of the CYP inhibitor.
The term 'room temperature' used in the specification denotes any temperature ranging
between about 20° to about 40°C, except and otherwise it is specifically mentioned in the
specification.
The intermediates and the compounds of the present invention may obtained in pure form
in a manner known per se, for example, by distilling off the solvent in vacuum and recrystallizing
the residue obtained from a suitable solvent, such as pentane, diethyl ether,
isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations
or subjecting it to one of the purification methods, such as column chromatography (e.g.,
flash chromatography) on a suitable support material such as alumina or silica gel using
eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their
combinations. Preparative LC-MS method is also used for the purification of molecules
described herein.
Salts of compound of formula I can be obtained by dissolving the compound in a suitable
solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform
or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was
then treated with the desired acid or base as described in Berge S.M. et al.
"Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66,
page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use
by P.H.Einrich Stahland Camille G.wermuth, Wiley- VCH (2002). Lists of suitable salts can
also be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing
Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19
(1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium),
alkaline earth metal (e.g., calcium), or ammonium of salt.
The compound of the invention or a composition thereof can potentially be administered as
a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by
reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid,
nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as
formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid,
malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic
base, such as sodium hydroxide, potassium hydroxide. The conversion to a salt is
accomplished by treatment of the base compound with at least a stoichiometric amount of
an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such
as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is
added in a similar solvent. The mixture is maintained at a suitable temperature (e.g.,
between 0 °C and 50 °C). The resulting salt precipitates spontaneously or can be brought
out of solution with a less polar solvent.
The stereoisomers of the compounds of formula I of the present invention may be
prepared by stereospecific syntheses or resolution of the achiral compound using an
optically active amine, acid or complex forming agent, and separating the diastereomeric
salt/complex by fractional crystallization or by column chromatography.
The term "prodrug" denotes a derivative of a compound, which derivative, when
administered to warm-blooded animals, e.g. humans, is converted into the compound
(drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the
present invention occurs in such a manner that the proven drug form (parent carboxylic
acid drug) is released, and the moiety or moieties split off remain nontoxic or are
metabolized so that nontoxic metabolic products are produced. For example, a carboxylic
acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
When an ester is administered to a subject, the ester is cleaved, enzymatically or nonenzymatically,
reductively, oxidatively, or hydrolytically, to reveal the anionic group. An
anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are
cleaved to reveal an intermediate compound which subsequently decomposes to yield the
active compound.
The prodrugs can be prepared in situ during the isolation and purification of the
compounds, or by separately reacting the purified compound with a suitable derivatizing
agent. For example, hydroxy groups can be converted into esters via treatment with a
carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol prodrug
moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester
moieties, e.g., ethyl esters, di-lower alkylamino lower-alkyl esters, e.g.,
dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g.,
pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl
ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryllower
alkyl esters, amides, lower-alkyl amides, di-lwer alkyl amides, and hydroxy amides.
Thus the present invention further provides a pharmaceutical composition, containing the
compounds of the general formula (I) as defined above, its tautomeric forms, its
stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its
metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical
isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically
acceptable carriers, diluents and the like.
The pharmaceutically acceptable carrier (or excipient) is preferably one that is chemically
inert to the compound of the invention and one that has no detrimental side effects or
toxicity under the conditions of use. Such pharmaceutically acceptable carriers preferably
include saline (e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oil and
ethylene oxide available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor
EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50%
ethanol), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water),
polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60%
water). A preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and
particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice
of carrier will be determined in part by the particular compound chosen, as well as by the
particular method used to administer the composition. Accordingly, there is a wide variety
of suitable formulations of the pharmaceutical composition of the present invention.
The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous,
intraarterial, intramuscular, interperitoneal, rectal, and vaginal administration are merely
exemplary and are in no way limiting.
The pharmaceutical compositions can be administered parenterally, e.g., intravenously,
intraarterially, subcutaneously, intradermal^, intrathecal^, or intramuscularly. Thus, the
invention provides compositions for parenteral administration that comprise a solution of
the compound of the invention dissolved or suspended in an acceptable carrier suitable for
parenteral administration, including aqueous and non-aqueous, isotonic sterile injection
solutions.
Overall, the requirements for effective pharmaceutical carriers for parenteral compositions
are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy
Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages
238-250 ( 1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-
630 ( 1986). Such compositions include solutions containing anti-oxidants, buffers,
bacteriostats, and solutes that render the formulation isotonic with the blood of the
intended recipient, and aqueous and non-aqueous sterile suspensions that can include
suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The
compound can be administered in a physiologically acceptable diluent in a pharmaceutical
carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous
dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for
example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or
polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-1 ,3-dioxolane-
4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester
or glyceride, or an acetylated fatty acid glyceride with or without the addition of a
pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent,
such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic
oils. Specific examples of oils useful in such formulations include peanut, soybean,
sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in
parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate
and isopropyl myristate are examples of suitable fatty acid esters.
Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and
triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for
example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic
detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and
monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example,
fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene
copolymers, (d) amphoteric detergents such as, for example, alkyl- -aminopropionates,
and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically will contain from about 0.5% or less to about 25% or
more by weight of a compound of the invention in solution. Preservatives and buffers can
be used. In order to minimize or eliminate irritation at the site of injection, such
compositions can contain one or more nonionic surfactants having a hydrophile-lipophile
balance (HLB) of from about 12 to about 17. The quantity of surfactant in such
formulations will typically range from about 5% to about 15% by weight. Suitable
surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate
and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed
by the condensation of propylene oxide with propylene glycol. The parenteral formulations
can be presented in unit-dose or multi-dose sealed containers, such as ampoules and
vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition
of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions can be prepared from sterile
powders, granules, and tablets.
Topical formulations, including those that are useful for transdermal drug release, are well
known to those of skill in the art and are suitable in the context of the present invention for
application to skin.
Formulations suitable for oral administration can consist of (a) liquid solutions, such as an
effective amount of a compound of the invention dissolved in diluents, such as water,
saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each
containing a pre-determined amount of the compound of the invention, as solids or
granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
Liquid formulations can include diluents, such as water and alcohols, for example, ethanol,
benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule
forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and
cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn
starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum,
colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium
stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering
agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and
pharmacologically compatible excipients. Lozenge forms can comprise the compound
ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles
comprising a compound of the invention in an inert base, such as gelatin and glycerin, or
sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound
of the invention, such excipients as are known in the art.
An compound of the present invention, alone or in combination with other suitable
components, can be made into aerosol formulations to be administered via inhalation. A
compound or epimer of the invention is preferably supplied in finely divided form along with
a surfactant and propellant. Typical percentages of the compounds of the invention can
be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
The surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
Representative of such surfactants are the esters or partial esters of fatty acids containing
from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,
linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic
anhydride. Mixed esters, such as mixed or natural glycerides can be employed. The
surfactant can constitute from about 0.1% to about 20% by weight of the composition,
preferably from about 0.25% to about 5%. The balance of the composition is ordinarily
propellant. A carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
These aerosol formulations can be placed into acceptable pressurized propellants, such
as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated
as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
Such spray formulations can be used to spray mucosa.
Additionally, the compound of the invention can be made into suppositories by mixing with
a variety of bases, such as emulsifying bases or water-soluble bases. Formulations
suitable for vaginal administration can be presented as pessaries, tampons, creams, gels,
pastes, foams, or spray formulas containing, in addition to the compound ingredient, such
carriers as are known in the art to be appropriate.
The concentration of the compound in the pharmaceutical formulations can vary, e.g., from
less than about 1% to about 10%, to as much as 20% to 50% or more by weight, and can
be selected primarily by fluid volumes, and viscosities, in accordance with the particular
mode of administration selected.
For example, a typical pharmaceutical composition for intravenous infusion could be made
up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of
the invention. Actual methods for preparing parenterally administrable compounds of the
invention will be known or apparent to those skilled in the art and are described in more
detail in, for example, Remington's Pharmaceutical Science (17th ed., Mack Publishing
Company, Easton, PA, 1985).
It will be appreciated by one of ordinary skill in the art that, in addition to the
aforedescribed pharmaceutical compositions, the compound of the invention can be
formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or
liposomes. Liposomes can serve to target a compound of the invention to a particular
tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used
to increase the half-life of a compound of the invention. Many methods are available for
preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys.
Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871 , 4,501 ,728, 4,837,028, and 5,01 9,369.
The present invention also provides a pharmaceutical composition, containing the
compounds of the general formula (I) as defined above, its tautomeric forms, its
stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its pharmaceutically
acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates and its cocrystals
in combination with the usual pharmaceutically employed carriers, diluents and the
like, and for use in any of the methods described herein.
The compounds of the invention can be administered in a dose sufficient to treat the
disease, condition or disorder. Such doses are known in the art (see, for example, the
Physicians' Desk Reference (2004)). The compounds can be administered using
techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp.
1258-1 268 ( 1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).
Suitable doses and dosage regimens can be determined by conventional range-finding
techniques known to those of ordinary skill in the art. Generally, treatment is initiated with
smaller dosages that are less than the optimum dose of the compound of the present
invention. Thereafter, the dosage is increased by small increments until the optimum
effect under the circumstances is reached. The present method can involve the
administration of about 0.1 g to about 50 mg of at least one compound of the invention
per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 g to
about 200 mg of the compound of the invention would be more commonly used,
depending on a patient's physiological response.
By way of example and not intending to limit the invention, the dose of the
pharmaceutically active agent(s) described herein for methods of treating or preventing a
disease or condition as described above can be about 0.001 to about 1 mg/kg body weight
of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015
mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.1 5 mg, 0.2 mg, 0.25 mg, 0.5 mg,
0.75 mg, or 1 mg/kg body weight per day. The dose of the pharmaceutically active
agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg
body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10
mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg,
750 mg, or 1000 mg/kg body weight per day.
In accordance with embodiments, the present invention provides methods of treating,
preventing, ameliorating, and/or inhibiting a hepatitis C virus infection comprising
administering a compound of formula (I) or a salt thereof.
It should also be understood that the compounds of the present invention can inhibit
multiple genotypes of HCV. In one of the embodiment compound of the present invention
are active against the 1a, 1b, 2a, 2b, 3a, 4a and 5a genotypes.
The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words stemming
therefrom, as used herein, do not necessarily imply 100% or complete treatment,
prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment,
prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes
as having a potential benefit or therapeutic effect. In this respect, the inventive methods
can provide any amount of any level of treatment, prevention, amelioration, or inhibition of
the disorder in a mammal. For example, a disorder, including symptoms or conditions
thereof, may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%,
20%, or 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided
by the inventive method can include treatment, prevention, amelioration, or inhibition of
one or more conditions or symptoms of the disorder, e.g., cancer. Also, for purposes
herein, "treatment," "prevention," "amelioration," or "inhibition" can encompass delaying the
onset of the disorder, or a symptom or condition thereof.
In accordance with the invention, the term subject includes an "animal" which in turn
includes a mammal such as, without limitation, the order Rodentia, such as mice, and the
order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order
Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the
mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of
the order Perssodactyla, including Equines (horses). It is most preferred that the
mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order
Anthropoids (humans and apes). An especially preferred mammal is the human.
The term "viral infection" refers to the introduction of a virus into cells or tissues, e.g.,
hepatitis C virus (HCV). In general, the introduction of a virus is also associated with
replication. Viral infection may be determined by measuring virus antibody titer in samples
of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable
diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid
capture assay, nucleic acid sequence based amplification, and the like. A virus may infect
an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and
hepatocellular carcinoma.
The term "immune modulator" refers to any substance meant to alter the working of the
humoral or cellular immune system of a subject. Such immune modulators include
inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins,
steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
Following are the abbreviations used and meaning thereof in the specification:
ACN: Acetonitrile. Boc: tert-butyloxycarbonyl. Cbz: Carbobenzyloxy. CDCI3:
Deuterochloroform. DCM: dichloromethane. DDQ: 2,3-Dichloro-5,6-dicyano-pbenzoquinone.
DIPEA: N, N-diisopropylethylamine. DME: 1, 2-dimethoxyethane. DMF: N,
N-dimethylformamide. DMSO- 6: Dimethyl sulfoxide-d 6. EDCI: A/-(3-Dimethylaminopropyl)-
/V-ethylcarbodiimide. EtOAc: Ethyl acetate. HATU: 0-(7-Azabenzotriazol-1 -yl)-A/,A/,A/',/Vtetramethyluronium
hexafluorophosphate. HCI: hydrochloric acid. HOBt: 1-
Hydroxybenzotriazole hydrate. HPLC - High Performance Liquid Chromatography. KOAc:
potassium acetate. MeOD: Methanol-d 4. Na2S04: sodium sulphate. NaHC0 3: sodium
bicarbonate. NCS: N-chlorosuccinimide. PCy3: Tricyclohexylphosphine. Pd(PPh3)4:
Tetrakis(triphenylphosphine)palladium(0). Pd-C: Palladium on charcoal. PdCI2(dppf): [ 1 , 1 '-
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll). PdCl2(dppf)-CH 2CI2: [ 1 , 1 '-
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane.
pet-ether: petroleum ether. TFA: trifluoroacetic acid. THF: Tetrahydrofuran
The following examples are provided to further illustrate the present invention and
therefore should not be construed in any way to limit the scope of the present invention. All
1HNMR spectra were determined in the solvents indicated and chemical shifts are reported
in units downfield from the internal standard tetramethylsilane (TMS) and interproton
coupling constants are reported in Hertz (Hz). In case of mixture of the isomers, the peak
values given are for the dominant isomer (rotamer/tautomer).
Example 1: Preparation of methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (mixture of trans isomers) (Compound 1):
Step 1: 2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (trans isomers) ( 1 a):
HN-Boc
To a stirred solution of rans-2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid
(0.8 g, 3.49 mmol) [synthesized as described in J. Org. Chem., 2001 , 66 (16), 5629-5632]
and 2-bromo-1-(4-bromophenyl)ethanone (0.97 g, 3.49 mmol) in acetonitrile (50 mL)
DIPEA (0.61 mL, 3.49 mmol) was added and the reaction was stirred at rt for 2 h. The
contents were concentrated under reduced pressure and water (100 mL) was added and
extracted with ethyl acetate (2 50mL). The combined organic layers were washed with
brine, dried over anhydrous Na2S0 4 and concentrated under reduced pressure to get pale
yellow colored oily liquid ( 1 .3 g, 87 %) that was used in the next step without further
purification. 1H-NMR (400 MHz, CDCI3) , 7.81 -7.79 (m, 2H), 7.67-7.65 (m, 2H), 5.61 (bs,
1H), 5.42-5.20 (m, 2H), 4.30-4.22 (m, 1H), 3.19-3.14 (m, 1H), 2.1 5-1 .65 (m, 6H), 1.47 (s,
9H); m/z 426.30 (M++ 1) .
Step 2 : tert-butyl (2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (trans
isomers)(1 b):
To the stirred solution of 2-(4-bromophenyl)-2-oxoethyl-2-((tert-butoxycarbonyl)amino)
cyclopentanecarboxylate ( 1 .3 g, 3.05 mmol) from the previous step in toluene (20 ml_),
ammonium acetate (4.70 g, 6 1 .0 mmol) was added and the contents were heated at 110
C for 15 h. The reaction mixture was poured into 100 mL water and extracted with ethyl
acetate (2 50 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2S0 4 and purified by flash column chromatography (45% EtOAc/hexane) to
get orange colored solid ( 1 .0 g, 8 1 %). 1H-NMR (400 MHz, CDCI3) , 7.57-7.47 (m, 4H),
7.21 (s, 1H), 5.14-4.95 (m, 1H), 4.35-4.15 (m, 1H), 3.39-3.1 5 (m, 1H), 2.14-1 .65 (m, 6H),
1.43 (s, 9H); m/z 406.1 1 (M++1).
Step 3 : tert-butyl (2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate (trans isomers) (1c):
A mixture of tert-butyl (2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate ( 1 g,
2.46 mmol) from the previous step, potassium acetate (0.68 g, 6.90 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) ( 1 .3 g, 4.92 mmol) in dioxane (10
mL) was de-gassed with nitrogen for 30 min after which Pd(PPh3)4 (0.08 g, 0.07 mmol)
was added and the reaction mixture was irradiated with microwaves at 120 C for 40 min.
The contents were taken up in EtOAc (20 mL) and passed through a celite bed. The celite
bed was thoroughly rinsed with EtOAc (20 mL). The combined organic layers were
washed with brine, dried over sodium sulphate and purified by flash chromatography
(50% ethylacetate/hexane) to yield a pale yellow coloured solid (0.7 g, 62%). 1H-NMR (400
MHz, CDCI3) , 7.79-7.77 (d, J = 8.0 Hz, 2H), 7.61 -7.59 (d, J = 8.0 Hz, 2H), 7.32 (s, 1H),
5.20-5.1 0 (m, 1H), 4.30-4.25 (m, 1H), 3.39-3.30 (m, 1H), 2.14-1 .60 (m, 6H), 1.36 (s, 12H),
1.30 (s, 9H); m/z 454.28 (M++1).
Step 4 : (2S)-tert-butyl 2-(7-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (trans
isomers) (1d):
The solution of (S)-tert-butyl 2-(7-bromo-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate (0.2 g, 0.48 mmol) [synthesized as reported in ref.
WO2009/1 02633] and tert-butyl (2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (0.26 g, 0.57 mmol) [from the previous
step] in a mixture of DME-H20 (3:1 , 4 mL) was degassed using nitrogen gas for 15 min.
Potassium carbonate (0.33 g, 2.40 mmol) and Pd(PPh 3)4 (0.055 g, 0.048 mmol) were
added and irradiated using microwaves at 120 C for 40 min. The contents were taken up
in ethyl acetate and washed with water. The organic layer was dried over Na2S0 4 and
concentrated under reduced pressure to obtain the crude compound which was purified by
flash chromatography (80% EtOAc/hexane) to get a pale yellow solid (0.16 g, 50%). 1HNMR
(400 MHz, CDCI3) , 7.85-7.40 (m, 7H), 7.1 2-6.90 (m, 1H), 5.07-4.86 (m, 2H), 4.40-
4.20 (m, 2H), 3.50-3.33 (m, 3H), 3.15-2.80 (m, 4H), 2.45-1 .80 (m, 8H), 1.60-1 .51 (m, 18H);
m/z 665.40 (M++1).
Step 5 : methyl ((2S)-1-((2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (mixture of trans
isomers) (Compound 1) :
(2S)-tert-butyl 2-(7-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol-5-
yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.1 g,
0.15 mmol) [from previous step] was dissolved in DCM (4 mL) and TFA (0.2 mL) was
added to the reaction mixture at 5-1 0 C. After completion of addition, the mixture was
stirred at rt for 2 h. The mixture was evaporated to dryness and triturated with diethyl ether
to obtain the product as a TFA salt which was used in the next step without any further
purification. (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid (0.05 g, 0.30 mmol)
[synthesized as reported in ref. WO201 0/1 32538 A1] was added to acetonitrile (10 mL)
followed by EDCI hydrochloride (0.06 g, 0.30 mmol), HOBt (0.05 g, 0.30 mmol) and DIPEA
(0.18 mL, 0.9 mmol) and stirred for 20 min. Subsequently crude TFA salt from previous
step (0.070 g) was added and stirred overnight at rt. The reaction mixture was evaporated
to dryness and the required amide was precipitated out by adding water (20 mL) and
filtered. The pale yellow solid was purified by preparative HPLC (0.023 g, 20 %). 1H NMR
(DMSO-Gfe, 400 MHz), 12.10-1 1.55 (m, 2H), 7.82-7.29 (m, 9H), 7.05-6.60 (m, 2H), 5.10-
5.05 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s, 6H),
3.02-2.67 (m, 4H), 2.25-1 .65 (m, 10H), 0.99-0.51 (m, 12H); m/z 779.50 (M++1). m.p.: 148-
150 C.
Example 2 : methyl ((2S)-1-((2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (mixture of cis isomers) (Compound 2):
Step 1: 2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (cis isomers) (2a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using c/'s-2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid
[synthesized as described in Tetrahedron: Asymmetry, 2008, 19, 2796-2803]. 1H-NMR
(400 MHz, CDCI3) , 7.85-7.79 (m, 2H), 7.70-7.65 (m, 2H), 5.65 (bs, 1H), 5.35-5.20 (m,
2H), 4.35-4.22 (m, 1H), 3.25-3.14 (m, 1H), 2.20-1 .65 (m, 6H), 1.47 (s, 9H); m/z 426.30
(M++1).
Step 2 : tert-butyl (2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (cis
isomers) (2b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1 using intermediate (2a) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
7.60-7.45 (m, 4H), 7.23 (s, 1H), 5.20-4.95 (m, 1H), 4.37-4.1 5 (m, 1H), 3.40-3.1 7 (m, 1H),
2.20-1 .70 (m, 6H), 1.50 (s, 9H); m/z 406.1 1 (M++ 1) .
Step 3 : tert-butyl (2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate (cis isomers) (2c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using intermediate (2b) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
7.79-7.77 (m, 2H), 7.70-7.67 (m, 2H), 7.30 (s, 1H), 5.20-5.1 0 (m, 1H), 4.30-4.25 (m, 1H),
3.39-3.32 (m, 1H), 2.14-1 .60 (m, 6H), 1.36 (s, 12H), 1.30 (s, 9H); m/z 454.20 (M++ 1) .
Step 4 : (2S)-tert-butyl 2-(8-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol-
5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -
carboxylate (2d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using intermediate (2c) from the previous step and (S)-tert-butyl 2-(8-bromo-
3,4,5, 6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
[synthesized as described in WO2009/1 02633]. 1H-NMR (400 MHz, CDCI3) , 7.83-7.45
(m, 8H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 3H), 3.10-2.80 (m, 4H), 2.45-
1.80 (m, 10H), 1.60-1 .51 (m, 18H), m/z 679.40 (M++ 1) .
Step 5: methyl ((2S)-1-((2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(mixture of cis isomers): (Compound 2)
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using intermediate (2d) from the previous step. 1H NMR (DMSO- 6, 400 MHz),
11.88-1 1.55 (m, 2H), 8.15-8.00 (m, 2H), 7.82-7.29 (m, 9H), 5.1 5-5.02 (m, 1H), 4.40-4.32
(m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 (s, 6H), 2.94-2.80 (m, 4H), 2.14-1 .65
(m, 10H), 0.97-0.59 (m, 14H); m/z 793.50 (M++1). m.p.: 155-1 57 C.
Example 3 : Preparation of methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (mixture of cis isomers) (Compound 3):
Step 1: (2S)-tert-butyl 2-(7-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (cis
isomers) (3a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1, using intermediate 2c from Example 2, Step 3 and (S)-tert-butyl 2-(7-bromo-
4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized as
described in WO2009/1 02633]. 1H-NMR (400 MHz, CDCI3) , 7.85-7.40 (m, 7H), 7.1 2-6.90
(m, 1H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.33 (m, 3H), 3.15-2.80 (m, 4H), 2.45-
1.80 (m, 8H), 1.60-1 .51 (m, 18H); m/z 665.40 (M++1).
Step 2 : methyl ((2S)-1-((2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (mixture of cis
isomers): (Compound 3)
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using intermediate (3a) from the previous step. 1H NMR (DMSO- 6, 400 MHz),
11.88-1 1.55 (m, 2H), 7.88-7.28 (m, 9 H), 7.02-6.87 (m, 2H), 5.1 5-5.02 (m, 1H), 4.40-4.32
(m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 2H), 3.51-3.45 (m, 6H), 3.02-2.67 (m, 4H), 2.20-
1.55 (m, 12H), 1.10-0.55 (m, 12H); m/z 779.50 (M++ 1) . m.p.: 140 C.
Example 4 : Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 4):
Step 1: (1S,2R)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)amino)
cyclopentanecarboxylate (4a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using 2-bromo-1-(4-bromophenyl)ethanone and (1S,2R)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized as described in
Tetrahedron: Asymmetry, 2008, 19, 2796-2803] as starting materials. 1H-NMR (400 MHz,
CDCI3) 7.79 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H), 5.60 (bs, 1H), 5.40-5.20 (m, 2H),
4.35-4.30 (m, 1H), 3.20-3.1 5 (m, 1H), 2.20-1 .60 (m, 6H), 1.40 (s, 9H). LC-MS: m/z 326.0
[(M++1) - 100] (value observed for the de-Boc product).
Step 2 : tert-butyl ((1 R,2S)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate
(4b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1 using the intermediate (4a) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
7.60-7.56 (m, 2H), 7.49-7.45 (m, 2H), 7.21 (s, 1H), 5.0-4.95 (m, 1H), 4.35-4.30 (m, 1H),
3.40-3.35 (m, 1H), 2.40-1 .60 (m, 6H), 1.48/1 .33 (s, 9H); m/z 406.10 (M++ 1) .
Step 3 : tert-butyl ((1 R,2S)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate (4c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using the intermediate (4b) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
7.79-7.77 (m, 2H), 7.70-7.67 (m, 2H), 7.30 (s, 1H), 5.20-5.1 0 (m, 1H), 4.30-4.25 (m, 1H),
3.39-3.32 (m, 1H), 2.14-1 .60 (m, 6H), 1.36 (s, 12H), 1.30 (s, 9H); m/z 454.20 (M++ 1) .
Step 4 : (S)-tert-butyl 2-(7-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(4d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediate 4c and and (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
[synthesized as described in WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 7.83-7.45 (m,
7H), 7.20-7.10 (m, 1H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 3H), 3.1 5-3.05
(m, 2H), 2.97-2.80 (m, 2H), 2.45-1 .80 (m, 8H), 1.60-1 .51 (m, 18H), m/z 665.40 (M++1).
Step 5 : methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 4).
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (4d) from previous step. 1H NMR (DMSO- , 400 MHz),
12.1 0-1 1.55 (m, 2H), 7.82-7.29 (m, 9H), 7.05-6.60 (m, 2H), 5.1 0-5.05 (m, 1H), 4.40-4.32
(m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s, 6H), 3.02-2.67 (m, 4H), 2.20-
1.65 (m, 10H), 0.99-0.51 (m, 12H), m/z 779.50 (M++ 1) . m.p.: 162-165 C.
Example 5 : Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1, 4,5,6-
tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Example 5):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate (5a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 4 (4b) and (S)-tert-butyl 2-(8-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized as described in WO20091 02633].
1H-NMR (400 MHz, CDCI3) 7.83-7.45 (m, 8H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H),
3.50-3.43 (m, 3H), 3.10-2.80 (m, 4H), 2.45-1 .80 (m, 10H), 1.60-1 .51 (m, 18H), m/z 679.40
(M++1).
Step 2 : methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 5):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using intermediate (5a) from the previous step. 1H NMR (DMSO- 6, 400 MHz),
11.88-1 1.55 (m, 2H), 8.04-7.29 (m, 11H), 5.15-5.02 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-
4.07 (m, 2H), 3.87-3.70 (m, 4H), 3.51 -3.45 (m, 6H), 2.94-2.80 (m, 4H), 2.20-1 .65 (m, 12H),
0.97-0.71 (m, 12H), m/z 793.50 (M++1). m.p.: 165-167 C.
Example 6 : Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hbenzo[
2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-
3-methyl-1-oxobutan-2-yl)carbamate (Compound 6):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrol^
carboxylate (6a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 4 (4b) and (S)-tert-butyl 2-(8-
(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized using procedures described in
WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.30 (bs, 1H), 7.83-7.40
(m, 8H), 5.07-4.90 (m, 2H), 4.40-4.20 (m, 3H), 3.50-3.43 (m, 3H), 3.25-3.1 0 (m, 2H), 2.95-
2.90 (m, 1H), 2.45-1 .72 (m, 8H), 1.65-1 .51 (m, 18H), m/z 681 .40 (M++ 1) .
Step 2 : methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 6):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using HATU, DMF and the intermediate (6a) from previous step. 1H NMR
(DMSO-Gfe, 400 MHz), 12.00-1 1.70 (m, 2H), 8.1 4-6.90 (m, 11H), 5.05-5.02 (m, 1H), 4.40-
4.10 (m, 4H), 3.90-3.70 (m, 4H), 3.60 (s, 6H), 3.15-3.00 (m, 2H), 2.14-1 .55 (m, 12H), 0.97-
0.71 (m, 12H), m/z 795.50 (M++1). m.p.: 191 C.
Example 7 : methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 7):
Step 1: ( 1 R,2S)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (7a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using 2-bromo-1-(4-bromophenyl)ethanone and ( 1 R,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized by following the
procedures described in Tetrahedron: Asymmetry, 2008, 19, 2796-2803]. 1H-NMR (400
MHz, CDCI3) 7.80 (d, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 5.6 (bs, 1H), 5.40-5.20 (m,
2H), 4.35-4.30 (m, 1H), 3.19-3.1 5 (m, 1H), 2.20-1 .60 (m, 6H), 1.40 (s, 9H); m/z 326.2
[(M++1) - 100] (value observed for the de-Boc product).
Step 2 : tert-butyl- ((1 S,2R)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate
(7b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1, using the intermediate (7a) from the previous step. 1H-NMR (400 MHz, CDCI3)
7.60-7.56 (m, 2H), 7.49-7.47 (m, 2H), 7.20 (s, 1H), 5.05-4.95 (m, 1H), 4.40-4.31 (m, 1H),
3.40-3.35 (m, 1H), 2.40-1 .60 (m, 6H), 1.33/1 .26 (s, 9H); m/z 406.0 (M++1).
Step 3 : tert-butyl ((1 S,2R)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate (7c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using the intermediate (7b) from the previous step. 1H-NMR (400 MHz, CDCI3)
7.85-7.78 (m, 2H), 7.65-7.60 (m, 2H), 7.30 (s, 1H), 5.15-5.1 0 (m, 1H), 4.35-4.25 (m, 1H),
3.45-3.30 (m, 1H), 2.19-1 .60 (m, 6H), 1.40 (s, 12H), 1.35 (s, 9H); m/z 454.28 (M++ 1) .
Step 4 : (S)-tert-butyl 2-(8-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrolidine-1 -
carboxylate (7d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediate 7c and (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrolidine-1 -
carboxylate [synthesized as described in WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 
7.78-7.48 (m, 8H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.70-3.43 (m, 3H), 3.05-2.90 (m,
4H), 2.45-1 .90 (m, 10H), 1.50-1 .31 (m, 18H), m/z 681 .40 (M++ 1) .
Step 5 : methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 7):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (7d) from the previous step. 1H NMR (DMSO- 6, 400
MHz), 12.1 0-1 1.80 (m, 2H), 8.14-6.90 (m, 11 H), 5.05-5.02 (m, 1H), 4.40-4.10 (m, 4H),
3.90-3.70 (m, 4H), 3.60 (s, 6H), 3.15-3.00 (m, 2H), 2.14-1 .95 (m, 12H), 0.97-0.71 (m,
12H), m/z 795.30 (M++1). m.p.: 2 18 C.
Example 8 : Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1, 4,5,6-
tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 8):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-
yl)pyrrolidine-1-carboxylate (8a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 Example 7 (7b) and (S)-tert-butyl 2-(8-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized as described in WO20091 02633].
1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.20 (bs, 1H), 7.83-7.45 (m, 8H), 5.07-4.86
(m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 3H), 3.1 0-2.80 (m, 4H), 2.45-1 .80 (m, 10H),
1.60-1 .51 (m, 18H), m/z 679.40 (M++1).
Step 2 : methyl ((S)-1-(((1S,2R)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 8):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (8a) from the previous step. 1H NMR (DMSO- 6, 400
MHz), 11.88-1 1.55 (m, 2H), 8.31-6.99 (m, 11 H), 5.1 5-5.02 (m, 1H), 4.40-4.32 (m, 2H),
4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51-3.45 (s, 6H), 2.94-2.80 (m , 4H), 2.1 0-1 .40 (m,
12H), 0.95-0.54 (m, 12H), m/z 793.50 (M++ 1) . m.p.: 162-164 C.
Example 9 : Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1, 4,5,6-
tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 9):
Step 1: (1S,2S)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)amino)
cyclopentanecarboxylate (9a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using 2-bromo-1-(4-bromophenyl)ethanone and (1S,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized as described in J. Org.
Chem., 2001 , 66 ( 1 6), 5629-5632]. 1H NMR (DMSO- , 400 MHz), 7.90-7.87 (m, 2H),
7.78-7.76 (m, 2H), 7.06-7.03 (m, 1H), 5.45-5.30 (m, 2H), 4.05-3.95 (m, 1H), 2.80-2.75 (m,
1H), 1.90-1 .40 (m, 6H), 1.35 (s, 9H); m/z 326.0 [(M++ 1) - 100] (value observed for the de-
Boc product).
tert-butyl ((1 S,2S)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1 using the intermediate (9a) from the previous step. 1H-NMR (DMSO- , 400
MHz), 7.68 (d, J = 8.0 Hz, 2H), 7.57-7.54 (m, 1H), 7.48 (d, J = 8.0 Hz, 2H), 6.95 (d, J =
8.0 Hz, 1H), 4.05-3.90 (m, 1H), 3.1 0-3.02 (m, 1H), 2.1 0-1 .40 (m, 6H), 1.35 (s, 9H); m/z
406.0 (M++1).
Step 3: tert-butyl ((1 S,2S)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate (9c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using the intermediate (9b) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
7.85-7.78 (m, 2H), 7.65-7.60 (m, 2H), 7.30 (s, 1H), 5.30-5.1 0 (m, 1H), 4.30-4.20 (m, 1H),
3.45-3.30 (m, 1H), 2.25-1 .60 (m, 6H), 1.40 (s, 12H), 1.35 (s, 9H); m/z 454.28 (M++ 1) .
Step 4: (S)-tert-butyl 2-(8-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-
yl)pyrrolidine-1-carboxylate (9d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates 9c and (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-
1-carboxylate [synthesized as described in WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 
11.00 (bs, 1H), 10.50 (bs, 1H), 7.83-7.45 (m, 8H), 4.95-4.86 (m, 2H), 4.25-4.15 (m, 2H),
3.50-3.43 (m, 3H), 3.20-2.80 (m, 4H), 2.45-1 .80 (m, 10H), 1.60-1 .51 (m, 18H), m/z 679.40
(M++1).
Step 5: methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 9):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (9d) from the previous step. 1H NMR (DMSO- , 400
MHz), 11.88-1 1.55 (m, 2H), 8.31-6.99 (m, 11 H), 5.1 5-5.02 (m, 1H), 4.40-4.32 (m, 2H),
4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51-3.45 (s, 6H), 2.94-2.80 (m , 4H), 2.14-1 .50 (m,
12H), 0.97-0.70 (m, 12H), m/z 793.50 (M++ 1) . m.p.: 147 C.
Example 10: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 10):
Step 1: (S)-tert-butyl 2-(7-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(10a)
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 9 (9b) and (S)-tert-butyl 2-(7-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate [synthesized as described in WO20091 02633]. m/z 665.3
(M++1).
Step 2 : methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 10):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (10a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.55 (m, 2H), 8.08-6.96 (m, 11H), 5.1 0-5.05 (m, 1H), 4.40-4.32 (m, 2H),
4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s, 6H), 3.02-2.67 (m, 4H), 2.20-1 .45 (m,
10H), 0.97-0.68 (m, 12H), m/z 779.50 (M++ 1) . m.p.: 181 C.
Example 1 1 : Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hbenzo[
2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-
3-methyl-1-oxobutan-2-yl)carbamate (Compound 11):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-ben^
carboxylate ( 1 1a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 9 (9b) and (S)-tert-butyl 2-(8-
(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized as described in WO20091 02633].
1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.30 (bs, 1H), 7.90-7.30 (m, 8H), 5.07-4.90
(m, 2H), 4.40-4.10 (m, 3H), 3.50-3.43 (m, 2H), 3.25-3.10 (m , 3H), 2.95-2.90 (m, 1H), 2.45-
1.72 (m, 8H), 1.65-1 .51 (m, 18H), m/z 681 .40 (M++1).
Step 2 : methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 11):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate ( 1 1a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.80 (m, 2H), 8.14-7.00 (m, 11 H), 5.05-5.02 (m, 1H), 4.40-4.10 (m, 5H),
3.90-3.70 (m, 3H), 3.55-3.50 (m, 6H), 3.15-3.10 (m, 2H), 2.14-1 .95 (m, 12H), 0.97-0.71 (m,
12H), m/z 795.40 (M++1). m.p.: 172-1 74 C.
Example 12: Preparation of methyl ((S)-1-(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1, 4,5,6-
tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 12):
Step 1: ( 1R, 2R)-2-(4-bromophenyl)-2-oxoethyl-2-((tert-butoxycarbonyl)amino)
cyclopentane carboxylate ( 1 2a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using 2-bromo-1 -(4-bromophenyl)ethanone and ( 1 R,2R)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized by following the
procedures provided in J. Org. Chem., 2001 , 66 ( 1 6), 5629-5632]. 1H-NMR (400 MHz,
CDCI3) , 7.79 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H), 5.40-5.20 (m, 2H), 4.25-4.18 (m,
1H), 2.85-2.80 (m, 1H), 2.20-2.00 (m, 3H), 1.82-1 .76 (m, 2H), 1.60-1 .50 (m, 1H), 1.40 (s,
9H). m/z 326.0 [(M++1) - 100] (value observed for the de-Boc product).
Step 2 : tert-butyl ((1 R,2R)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate
(12b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1 using intermediate (12a) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
7.60-7.56 (m, 2H), 7.49-7.47 (m, 2H), 7.26 (s, 1H), 5.00-4.90 (m, 1H), 4.17-4.10 (m, 1H),
3.17-3.1 2 (m, 1H), 2.38-2.1 0 (m, 4H), 1.80-1 .55 (m, 2H), 1.50 (s, 9H); m/z 405.85 (M++1).
Step 3 : tert-butyl ((1 R,2R)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)carbamate ( 12c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using intermediate (12b) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
7.85-7.78 (m, 2H), 7.70-7.60 (m, 2H), 7.35 (s, 1H), 5.25-5.1 0 (m, 1H), 4.30-4.25 (m, 1H),
3.45-3.30 (m, 1H), 2.19-1 .60 (m, 6H), 1.45 (s, 12H), 1.35 (s, 9H); m/z 454.28 (M++ 1) .
Step 4 : (S)-tert-butyl 2-(8-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate ( 12d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates 12c and (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-
1-carboxylate [synthesized as described in WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 
7.83-7.30 (m, 8H), 5.07-4.86 (m, 2H), 4.25-4.15 (m, 2H), 3.50-3.43 (m, 2H), 3.20-2.90 (m,
5H), 2.45-1 .70 (m, 10H), 1.60-1 .51 (m, 18H), m/z 679.40 (M++ 1) .
Step 5 : methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 12):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (12d) from the previous step. 1H NMR (DMSO- , 400
MHz), 11.88-1 1.55 (m, 2H), 8.20-8.02 (m, 2H), 7.78-7.29 (m, 8H), 7.08-7.05 (m, 1H),
5.15-5.02 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s,
6H), 2.97-2.94 (m ,4H), 2.14-1 .55 (m, 12H), 0.97-0.79 (m, 12H), m/z 793.50 (M++1). m.p.:
157-162 C.
Example 13: Preparation of methyl ((S)-1-(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hbenzo[
2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-
3-methyl-1-oxobutan-2-yl)carbamate (Compound 13):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrolidine-1-
carboxylate ( 1 3a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 12 ( 12b) and (S)-tert-butyl 2-
(8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized following the procedures provided in
WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 7.83-7.40 (m, 8H), 5.07-4.90 (m, 2H),
4.40-4.20 (m, 3H), 3.50-3.43 (m, 2H), 3.25-3.10 (m, 3H), 2.95-2.90 (m, 1H), 2.45-1 .72 (m,
8H), 1.65-1 .51 (m, 18H), m/z 681 .40 (M++1).
Step 2 : methyl ((S)-1 -(((1 R,2R)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 13):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (13a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.80 (m, 2H), 8.14-7.00 (m, 11 H), 5.05-5.02 (m, 1H), 4.40-4.10 (m, 5H),
3.90-3.70 (m, 3H), 3.55-3.50 (m, 6H), 3.15-3.10 (m, 2H), 2.14-1 .95 (m, 12H), 0.97-0.71 (m,
12H), m/z 795.40 (M++1). m.p.:1 62-165 C.
Example 14: Preparation of methyl ((S)-1-(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 14):
Step 1: (S)-tert-butyl 2-(7-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(14a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 12 ( 12b) and (S)-tert-butyl 2-
(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate [synthesized following the procedures described in
WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 7.83-7.35 (m, 8H), 5.07-4.86 (m, 2H),
4.20-4.1 0 (m, 2H), 3.50-3.43 (m, 3H), 3.1 9-3.10 (m , 2H), 2.97-2.80 (m, 2H), 2.45-1 .80 (m,
8H), 1.60-1 .51 (m, 18H), m/z 665.40 (M++1).
Step 2 : methyl ((S)-1 -(((1 R,2R)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 14):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (14a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.55 (m, 2H), 8.20-8.14 (m, 1H), 7.80-6.96 (m, 10H), 5.1 0-5.05 (m, 1H),
4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51-3.45 (s, 6H), 3.02-2.67
(m, 4H), 2.20-1 .45 (m, 10H), 0.99-0.75 (m, 12H), m/z 779.50 (M++1). m.p.:142-145 C.
Example 15: Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 15):
Step 1: (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(15a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 7 (7b) and (S)-tert-butyl 2-(7-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1-carboxylate [synthesized by following procedures provided in
WO20091 02633]. 1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.50 (bs, 1H), 7.83-7.45
(m, 7H), 7.20-7.10 (m, 1H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 3H), 3.29-
3.26 (m, 2H), 2.97-2.80 (m, 2H), 2.45-1 .80 (m, 8H), 1.60-1 .51 (m, 18H), m/z 665.40
(M++1).
Step 2 : methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 15):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (15a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.55 (m, 2H), 8.08-6.96 (m, 11H), 5.10-5.05 (m, 1H), 4.40-4.32 (m, 2H),
4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s, 6H), 3.02-2.67 (m ,4H), 2.14-1 .50 (m,
10H), 0.99-0.54 (m, 12H), m/z 779.30 (M++ 1) . m.p.:163 C.
Example 16: Preparation of methyl ((S)-1-(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-
d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (Compound 16):
Step 1: (S)-tert-butyl 2-(7-bromo-3H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate
(16a):
DDQ (0.41 g, 1.79 mmol) was added to the solution of (S)-tert-butyl 2-(7-bromo-4,5-
dihydro-3H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate [synthesized by following
the procedures provided in WO20091 02633] (0.5 g, 1.19 mmol) in benzene (10 mL) and
stirred at 80 C for 3 h. Benzene was evaporated under reduced pressure and the residue
was purified by column chromatography (60% EtOAc/hexane) to afford the title compound
(0.3 g, 60%). 1H-NMR (400 MHz, CDCI3):-5 8.05-8.03 (m, 1H), 7.62-7.50 (m, 4H), 5.24-
5.23 (m, 1H), 3.61-3.50 (m, 1H), 3.1 5-3.10 (m, 1H), 2.29-2.19 (m, 2H), 2.09-2.01 (m,
2H), 1.54-1 .34 (m, 9H), m/z416.09 (M++1).
Step 2 : (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3H-naphtho[1 ,2-
d]imidazol-2-yl)pyrrolidine-1 -carboxylate ( 16b):
In a 5 - 20 mL microwave vial, 1,4-Dioxane (15 mL) was purged with nitrogen for 10 min
and (S)-tert-butyl 2-(7-bromo-3H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(16a) (0.4 g, 0.96 mmol), bis(pinacolato)diboron (0.49 g, 1.92 mmol), PCy3 (0.03 g, 0.1
mmol), KOAc (0.38 g, 3.84 mmol) were added and purged with nitrogen. Finally,
PdCI2(dppf)-CH 2Cl2 adduct (0.08 g, 0.1 mmol) was added & purged with nitrogen and
irradiated with microwaves at 115 C for 45 min. The reaction mixture was poured into
water and extracted with ethyl acetate. The organic layer was washed with saturated brine
solution, dried over anhydrous sodium sulphate and purified by column chromatography
(70% EtOAc/hexane) to afford the title compound (0.3 g, 67%). 1H-NMR (400 MHz, CDCI3)
8.46 (s, 1H), 7.97-7.95 (m, 1H),7.71 -7.47 (m, 3H), 5.23-5.22 (br s,1 H), 3.48-3.41 (m,1 H),
3.20-3.23 (m, 1H), 2.26-2.19 (m, 2H), 2.61 -2.41 (m, 2H), 1.41 (s, 9H),1 .30-1 .22 (m,12H),
m/z 464.26 (M++1).
Step 3 : (S)-tert-butyl 2-(7-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate ( 16c):
The title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates ( 16b) from the previous step and from Step 2 of
Example 12. 1H-NMR (400 MHz, CDCI3) 8.15-7.32 (m, 9H), 7.20-7.10 (m, 1H), 5.40-5.10
(m, 2H), 4.40-4.20 (m, 1H), 3.55-3.50 (m, 2H), 3.35-3.1 0 (m, 2H), 2.45-1 .80 (m, 8H), 1.60-
1.51 (m, 18H), m/z 663.40 (M++1).
Step 4 : methyl ((S)-1 -(((1 R,2R)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 16):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate ( 16c) from the previous step. 1H NMR (DMSO- , 400
MHz), 13.02-1 1.85 (m, 2H), 8.50-8.30 (m, 2H), 8.10-7.65 (m, 8H), 7.37-7.25 (m, 1H),
7.10-6.90 (m, 1H), 5.30-5.28 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m,
4H), 3.51-3.45 (s, 6H), 2.20-1 .50 (m, 10H), 0.99-0.81 (m, 12H), m/z 777.30 (M++ 1) .
m.p.:1 58-1 6 1 C.
Example 17: Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-
d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (Compound 17):
Step 1: (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate ( 17a):
The title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from the Step 2 of Example 16 ( 16b) and Step 2 of
Example 7 (7b). 1H-NMR (400 MHz, CDCI3) 7.83-7.52 (m, 10H), 5.30-5.20 (m, 2H), 4.35-
4.25 (m, 2H), 3.55-3.35 (m, 2H), 3.29-3.26 (m, 1H), 2.60-1 .72 (m, 8H), 1.65-1 .51 (m, 18H),
m/z 663.40 (M++1).
Step 2 : methyl ((S)-1-(((1S,2R)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 17):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (17a) from the previous step. 1H NMR (DMSO- , 400
MHz), 13.02-1 1.85 (m, 2H), 8.50-8.30 (m, 2H), 8.1 0-7.65 (m, 8H), 7.37-7.25 (m, 1H),
7.10-6.90 (m, 1H), 5.30-5.28 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m,
4H), 3.51-3.45 (s, 6H), 2.14-1 .65 (m, 10H), 0.99-0.51 (m, 12H), m/z 777.30 (M++ 1) .
m.p.:210 C.
Example 18: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-
d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (Compound 18):
Step 1: (S)-tert-butyl 2-(7-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate ( 18a):
The title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from the Step 2 of Example 16 ( 16b) and from Step 2
of Example 9 (9b). 1H-NMR (400 MHz, CDCI3) 7.83-7.52 (m, 10H), 5.30-5.20 (m, 2H),
4.35-4.25 (m, 2H), 3.55-3.35 (m, 2H), 3.29-3.26 (m, 1H), 2.60-1 .72 (m, 8H), 1.65-1 .51 (m,
18H), m/z 663.40 (M++1).
Step 2 : methyl ((S)-1-(((1S,2S)-2-(5 -(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 18):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (18a) from the previous step. 1H NMR (DMSO- , 400
MHz), 13.02-1 1.85 (m, 2H), 8.45-7.06 (m, 13H), 5.30-5.25 (m, 1H), 4.44-4.32 (m, 2H),
4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s, 6H), 3.1 2-3.1 0 (m , 1 H), 2.14-1 .50 (m,
9H), 0.99-0.51 (m, 12H), m/z 777.30 (M++1). m.p.:171 C.
Example 19: Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-
d]imidazol-7-yl)phenyl)-4-chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 19):
Step 1: tert-butyl ((1S,2R)-2-(5-(4-bromophenyl)-4-chloro-1 H-imidazol-2-
yl)cyclopentyl)carbamate (19a):
To the stirred solution of tert-butyl ((1S,2R)-2-(5-(4-bromophenyl)-1 H-imidazol-2-
yl)cyclopentyl)carbamate (0.1 5 g, 0.369 mmol) [7b] in DMF (2 mL) was added NCS (0.074
g, 0.55 mmol) at room temperature and the reaction was warmed to 50 ° and stirred for
20 min. The contents were diluted by water and extracted by ethyl acetate. The organic
layer was separated, dried over sodium sulphate, evaporated under reduced pressure to
get crude product which was used in the next step without further purification (0.1 g, 62%).
1H-NMR (400 MHz, CDCI3) 7.58-7.51 (m, 4H), 4.75-4.70 (m, 1H), 4.40-4.30 (m, 1H),
3.35-3.25 (m, 1H), 2.40-1 .60 (m, 6H), 1.50/1 .30 (s, 9H); m/z 440.10 (M++ 1) .
Step 2 : (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4-
chloro-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(19b):
The title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates ( 19a) from the previous step and intermediate from
Step 2 of Example 16 (16b). 1H-NMR (400 MHz, CDCI3) 8.20-7.52 (m, 9H), 5.40-5.30 (m,
1H), 4.83-4.75 (m, 1H), 4.40-4.35 (m, 2H), 3.55-3.35 (m, 2H), 3.30-3.26 (m, 1H), 2.45-1 .72
(m, 8H), 1.55-1 .31 (m, 18H), m/z 697.40 (M++1).
Step 3 : methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 19).
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (19b) from the previous step. 1H NMR (DMSO- , 400
MHz), 13.10-1 2.30 (m, 2H), 8.50-8.30 (m, 2H), 8.1 0-7.65 (m, 7H), 7.35-7.30 (m, 1H),
6.82-6.80 (m, 1H), 5.45-5.30 (m, 1H), 4.55-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m,
4H), 3.51-3.45 (s, 6H), 2.40-1 .65 (m, 10H), 0.99-0.51 (m, 12H), m/z 8 11.40 (M++ 1) .
m.p.:255-257 C.
Example 20: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-
d]imidazol-7-yl)phenyl)-4-chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 20):
Step 1: tert-butyl ((1S,2S)-2-(5-(4-bromophenyl)-4-chloro-1 H-imidazol-2-
yl)cyclopentyl)carbamate (20a):
To the stirred solution of tert-butyl ((1S,2S)-2-(5-(4-bromophenyl)-1 H-imidazol-2-
yl)cyclopentyl)carbamate (0.15 g, 0.369 mmol) (9b) in DMF (2 mL) was added NCS (0.074
g, 0.55 mmol) at room temperature and the reaction was warmed to 50 ° and stirred for
20 min. The contents were diluted by water and extracted by ethyl acetate. The organic
layer was separated, dried over sodium sulphate, evaporated under reduced pressure to
get crude product which was used in the next step without further purification (0.1 g, 62%).
1H-NMR (400 MHz, CDCI3) 12.07 (bs, 1H), 7.69-7.67 (m 2H), 7.56-7.51 (m, 2H), 4.90-
4.89 (m, 1H), 3.10-3.00 (m, 1H), 2.36-2.33 (m, 1H), 2.21 -2.18 (m, 2H), 1.83-1 .78 (m, 3H),
1.57-1 .53 (m, 9H). m/z 440.04 (M++1).
Step 2 : (S)-tert-butyl 2-(7-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4-
chloro-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
(20b):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediate (20a) from the previous step and Step 2 of Example 16
(16b). m/z 697.26 (M++1).
Step 3: methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 20):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (20b) from the previous step. 1H NMR- (400 MHz,
MeOD), 8.46-8.43 (m, 1H), 8.30-8.25 (m, 1H), 8.10 (s, 1H), 7.96-7.94 (m, 1H), 7.88-7.87
(m, 3H), 7.83-7.80 (m, 1H), 7.73-7.67 (m, 1H), 5.38-5.37 (m, 1H), 4.50-4.49 (m, 1H), 4.30-
4.29 (m , 1 H), 4.1 5-4.1 0 (m, 1H), 4.01-4.00 (m, 1H), 3.7 (s, 6H), 3.32-3.30 (m, 2H), 3.10-
3.02 (m, 1H), 2.60-2.50 (m, 1H), 2.40-2.1 5 (m, 6H), 2.10-1 .85 (m, 7H), 1.80-1 .71 (m, 2H).
1.10-0.95 (m, 6H), 0.91-0.82 (m, 6H); m/z 8 1 1.4 (M++ 1) . m.p.:185-187 C.
Example 2 1 : Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-5,6-dihydro-4Hbenzo[
3,4]cyclohepta[1,2-d]oxazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-
3-methyl-1-oxobutan-2-yl)carbamate (Compound 21):
Step 1: (S)-tert-butyl 2-(8-bromo-5,6-dihydro-4H-benzo[3,4]cyclohepta[1 ,2-d]oxazol-2-
yl)pyrrolidine-1-carboxylate (21a):
To the stirred solution of (2S)-2-(2-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-
yl) 1-tert-butyl pyrrolidine- 1,2-dicarboxylate (3.2 g, 7.04 mmol) [synthesized using
procedures described in WO2009/1 02633] in xylene (25 mL), ammonium acetate ( 10.86 g,
141 mmol) was added at room temperature and the reaction mass was heated at 130 C
for 15 h. The reaction mixture was poured into water (100 mL) and the compound was
extracted with ethyl acetate (100 mL 2), dried over sodium sulphate, concentrated under
reduced pressure and purified by flash column chromatography (45-55%
Ethylacetate/Hexane) to get the title compound as side product, orange colored solid (0.7
g, 23 % yield) along with (S)-tert-butyl 2-(8-bromo-1 ,4,5,6-
tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate as the major
compound. 1H NMR (CDCI3, 400 MHz): 7.52-7.50 (m, 1H), 7.37-7.28 (m, 2H), 4.88-4.85
(m, 1H), 3.60-3.40 (m, 2H), 2.95-2.80 (m, 4H), 2.40-1 .90 (m, 6H), 1.45/1 .25 (s, 9H); m/z
433.05 (M++1)
Step 2 : (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydro-4Hbenzo[
3,4]cyclohepta[1 ,2-d]oxazol-2-yl)pyrrolidine-1 -carboxylate (21 b):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using intermediate (21 a) from the previous step. 1H NMR (CDCI3, 400 MHz): 
7.80-7.60 (m, 2H), 7.56-7.53 (m, 1H), 4.90-4.80 (m, 1H), 3.80-3.50 (m, 2H), 2.95-2.80 (m,
4H), 2.40-1 .90 (m, 6H), 1.48/1 .44 (s, 9H), 1.25 (m, 12H); m/z 480.90 (M++ 1)
Step 3: (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1 ,2-d]oxazol-2-yl)pyrrolidine-1-
carboxylate (21c):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediate from Step 2 of Example 4 (4b) and the boronate
intermediate (21b) from the previous step. 1H-NMR (400 MHz, CDCI3) 7.78-7.45 (m, 8H),
5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.70-3.43 (m, 3H), 3.05-2.90 (m, 4H), 2.45-1 .90 (m,
10H), 1.50-1 .31 (m, 18H), m/z 680.40 (M++ 1) .
Step 4: methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1 ,2-d]oxazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Compound 21):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (21c) from the previous step. 1H NMR (DMSO- , 400
MHz), 11.85-1 1.70 (m, 1H), 7.82-7.03 (m, 11H), 5.1 5-5.02 (m, 1H), 4.44-4.32 (m, 2H),
4.1 1-4.1 0 (m, 2H), 3.90-3.75 (m, 4H), 3.51 -3.45 (s, 6H), 2.94-2.80 (m, 4H), 2.24-1 .55 (m,
12H), 0.97-0.71 (m, 12H), m/z 794.50 (M++ 1) . m.p.:138-141 C.
Example 22: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-
dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 22):
Step 1: (S)-tert-butyl 2-(8-bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-
yl)pyrrolidine-1 -carboxylate (22a):
Title compound was synthesized by following the procedure described in Step 1 of
Example 2 1 using (2S)-2-(8-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-4-yl) 1-tertbutyl
pyrrolidine- 1,2-dicarboxylate [synthesized as described in WO2009/1 02633] as the
starting material. 1H NMR (DMSO- , 400 MHz): 7.57-7.53 (m, 1H), 7.38-7.35 (m, 1H),
7.30-7.28 (m, 1H), 4.90-4.82 (m, 1H), 4.30-4.26 (m, 2H), 3.50-3.45 (m, 1H), 3.00-2.95 (m,
2H), 2.40-2.20 (m, 1H), 2.05-1 .90 (m, 4H), 1.38/1 . 1 5 (s, 9H); m/z 435.00 (M++1)
Step 2 : (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-
dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1 -carboxylate (22b):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using intermediate (22a) from the previous step. 1H NMR (CDCI3, 400 MHz): 
7.66-7.63 (m, 1H), 7.56-7.53 (m, 2H), 5.07-4.90 (m, 1H), 4.29-4.21 (m, 2H), 3.70-3.60 (m,
1H), 3.1 5-3.05 (m, 2H), 2.40-1 .70 (m, 5H), 1.48/1 .44 (s, 9H), 1.25 (m, 12H); m/z 482.98
(M++1)
Step 3 : (S)-tert-butyl 2-(8-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1-
carboxylate (22c):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using the intermediates from Step 2 of Example 9 (9b) and the boronate (22b)
from the previous step. 1H-NMR (400 MHz, CDCI3) 7.83-7.35 (m, 8H), 5.07-4.90 (m, 2H),
4.40-4.20 (m, 3H), 3.75-3.40 (m, 4H), 3.25-3.10 (m, 2H), 2.45-1 .72 (m, 8H), 1.65-1 .51 (m,
18H), m/z 682.40 (M++1).
Step 4 : methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 22):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (22c) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.80 (m, 1H), 8.14-6.90 (m, 11 H), 5.1 5-5.10 (m, 1H), 4.40-4.30 (m, 4H),
4.15-4.1 0 (m, 1H), 3.95-3.70 (m, 3H), 3.55-3.50 (m, 6H), 3.10-2.95 (m, 2H), 2.14-1 .95 (m,
12H), 0.97-0.71 (m, 12H), m/z 796.50 (M++ 1) . m.p.:220-222 C.
Example 23: Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-
dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 23):
Step 1: (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1-
carboxylate (23a):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1, using the intermediates from Step 2 of Example 4 (4b) and the intermediate
from step 2 of Example 22 (22b). 1H-NMR (400 MHz, CDCI3) 7.83-7.35 (m, 8H), 5.07-
4.90 (m, 2H), 4.40-4.20 (m, 3H), 3.75-3.40 (m, 4H), 3.25-3.10 (m, 2H), 2.45-1 .72 (m, 8H),
1.65-1 .51 (m, 18H), m/z 682.40 (M++1).
Step 2 : methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 23):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (23a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.80 (m, 1H), 8.14-6.90 (m, 11 H), 5.1 5-5.10 (m, 1H), 4.40-4.30 (m, 4H),
4.15-4.1 0 (m, 1H), 3.95-3.70 (m, 3H), 3.55-3.50 (m, 6H), 3.1 0-2.95 (m,2H), 2.14-1 .95 (m,
12H), 0.97-0.71 (m, 12H), m/z 796.50 (M++ 1) . m.p.:166-168 C.
Example 24: Preparation of methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-
4,5-dihydro-1 H-naphtho[1,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 24):
Step 1: (1S,2S)-6-bromo-1 -oxo-1 ,2,3,4-tetrahydronaphthalen-2-yl 2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (24a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using 2,6-dibromo-3,4-dihydronaphthalen-1 (2H)-one [synthesized using
procedures described in WO201 0/1 17635A1] and (1S,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized using procedures
described in J. Org. Chem., 2001 , 66 ( 16), 5629-5632] as starting materials. 1H-NMR (400
MHz, CDCI3) 8.09-8.07 (m, 1H), 7.85-7.81 (m, 1H), 7.55-7.50 (m, 2H), 5.56-5.50 (m, 1H),
4.30-4.05 (m, 2H), 3.30-3.05 (m, 4H), 2.45-1 .60 (m, 6H), 1.40 (s, 9H); m/z 352.1 0 [(M++ 1)
- 100] (value observed for the de-Boc product).
Step 2 : tert-butyl ((1S,2S)-2-(7-bromo-4,5-dihydro-3H-naphtho[1 ,2-d]imidazol-2-
yl)cyclopentyl)carbamate (24b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1, using the intermediate (24a) from the previous step. 1H-NMR (400 MHz,
CDCI3) 7.34-7.30 (m, 3H), 4.90-4.87 (m, 1H), 4.19-4.12 (m, 1H), 3.15-3.13 (m, 1H), 3.05-
2.85 (m, 4H), 2.45-2.10 (m, 2H), 1.90-1 .60 (m, 4H), 1.50 (s, 9H); m/z 432. 10 (M++1).
Step 3 : (S)-tert-butyl 2-(5-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4,5-
dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate
(24c).
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1, using the intermediates (24b) from the previous step and (S)-tert-butyl 2-(5-(4-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -
carboxylate [synthesized using procedures described in ref. WO2010/99527A1] as starting
materials. 1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.50 (bs, 1H), 7.85-7.40 (m, 7H),
7.20-7.1 0 (m, 1H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 2H), 3.1 7-3.09 (m ,
3H), 2.93-2.89 (m, 2H), 2.45-1 .80 (m, 8H), 1.60-1 .51 (m, 18H); m/z 665.40 (M++ 1) .
Step 4 : methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-
d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 24):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 1 using the intermediate (24c) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.10-1 1.55 (m, 2H), 8.13-7.46 (m, 9H), 7.31 -7.29 (m, 1H), 7.04-7.01 (m, 1H),
5.10-5.05 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s,
6H), 3.02-2.67 (m ,4H), 2.14-1 .55 (m, 10H), 0.99-0.51 (m, 12H), m/z 779.30 (M++ 1) .
m.p.:1 81-1 83 C.
Example 25: Preparation of methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-
4,5-dihydro-1 H-naphtho[1,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate (Compound 25):
Step 1: ( 1R,2S)-6-bromo-1 -oxo-1 ,2,3,4-tetrahydronaphthalen-2-yl 2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (25a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1, using 2,6-dibromo-3,4-dihydronaphthalen-1 (2H)-one [synthesized using
procedures described in WO2010/1 17635A1] and ( 1 R,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized using procedures
described in Tetrahedron: Asymmetry, 2008, 19, 2796-2803] as starting materials. 1HNMR
(400 MHz, CDCI3) 8.09-8.07 (m, 1H), 7.85-7.81 (m, 1H), 7.55-7.50 (m, 2H), 5.56-
5.50 (m, 1H), 4.30-4.05 (m, 2H), 3.30-3.05 (m, 4H), 2.45-1 .60 (m, 6H), 1.40 (s, 9H); m/z
352.1 0 [(M++ 1) - 100] (value observed for the de-Boc product).
Step 2 : tert-butyl ((1S,2R)-2-(7-bromo-4,5-dihydro-3H-naphtho[1 ,2-d]imidazol-2-
yl)cyclopentyl)carbamate (25b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1, using the intermediate (25a) from the previous step. 1H-NMR (400 MHz,
CDCI3) 7.34-7.30 (m, 3H), 5.1 9-5.16 (m, 1H), 4.90-4.87 (m, 1H), 4.40-4.30 (m, 1H), 3.36-
3.31 (m, 1H), 3.05-2.80 (m, 4H), 2.45-2.10 (m, 2H), 1.90-1 .60 (m, 4H), 1.50/1 .43 (s, 9H);
m/z 431.85 (M++1).
Step 3 : (S)-tert-butyl 2-(5-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4,5-
dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate
(25c):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1, using the intermediates (25b) from the previous step and (S)-tert-butyl 2-(5-(4-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -
carboxylate [synthesized using procedures described in ref. WO2010/99527A1] as starting
materials. 1H-NMR (400 MHz, CDCI3) 11.00 (bs, 1H), 10.50 (bs, 1H), 7.85-7.40 (m, 7H),
7.20-7.1 0 (m, 1H), 5.07-4.86 (m, 2H), 4.40-4.20 (m, 2H), 3.50-3.43 (m, 2H), 3.17-3.09 (m,
3H), 2.93-2.89 (m, 2H), 2.45-1 .80 (m, 8H), 1.60-1 .51 (m, 18H), m/z 665.40 (M++ 1) .
Step 4 : methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-
d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 25):
Title compound was synthesized following the procedure as described in Step 2 of
Example 6 using the intermediate (25c) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.55 (m, 2H), 8.13-7.46 (m, 8H), 7.41-7.29 (m, 2H), 7.04-6.90 (m, 1H),
5.10-5.05 (m, 1H), 4.40-4.32 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s,
6H), 3.02-2.67 (m ,4H), 2.14-1 .50 (m, 10H), 0.99-0.51 (m, 12H), m/z 779.30 (M++1). m.p.:
224 C.
Example 26: Preparation of methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-
1H-naphtho[1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate (Compound 26):
Step 1: (S)-tert-butyl 2-(5-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Hnaphtho[
1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (26a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 16, using the intermediate from Step 3 of Example 25 (25c). 1H-NMR (400 MHz,
CDCI3) 8.10-7.45 (m, 9H), 7.26 (s, 1H), 5.1 5-5.03 (m, 2H), 4.55-4.35 (m, 1H), 3.75- 3.35
(m, 2H), 3.25-3.15 (m, 2H), 2.55-1 .60 (m, 8H), 1.51 - 1 .30 (m, 18H), m/z 663.40 (M++1).
Step 2 : methyl ((S)-1-(((1S,2R)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 26):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (26a) from the previous step. 1H NMR (DMSO- , 400
MHz), 12.1 0-1 1.55 (m, 2H), 8.60-7.50 (m, 11H), 7.31-7.29 (m, 1H), 7.1 0-6.85 (m, 1H),
5.10-5.05 (m, 1H), 4.55-4.40 (m, 2H), 4.1 1-4.07 (m, 2H), 3.87-3.81 (m, 4H), 3.51 -3.45 (s,
6H), 2.40-1 .50 (m, 10H), 0.99-0.51 (m, 12H), m/z 777.30 (M++1). m.p.:238-240 C.
Example 27: Preparation of methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 27):
Step 1: (S)-tert-butyl 2-(5-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Hnaphtho[
1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (27a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 16, using the intermediate from Step 3 of Example 24 (24c) as starting material.
1H-NMR (400 MHz, CDCI3) 8.10-7.45 (m, 9H), 7.26 (s, 1H), 5.1 5-5.03 (m, 2H), 4.60-4.35
(m, 1H), 3.75- 3.35 (m, 2H), 3.25-3.15 (m, 2H), 2.55-1 .60 (m, 8H), 1.51 - 1 .30 (m, 18H), m/z
663.40 (M++1).
Step 2 : methyl ((S)-1 -(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-
2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-
methyl-1 -oxobutan-2-yl)carbamate (Compound 27):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 6 using the intermediate (27a) from the previous step. 1H NMR (400 MHz,
MeOD), 8.55-8.47 (m, 2H), 8.20-7.75 (m, 8H), 7.42-7.30 (m, 2H), 5.30-5.27 (m, 2H),
4.65-4.60 (m, 2H), 4.27-4.15 (m, 2H), 3.95-3.85 (m, 3H), 3.70-3.65 (m, 6H), 2.70-1 .95 (m,
10H), 0.99-0.80 (m, 12H), m/z 777.30 (M++ 1) .
Example 28: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)(ethyl)amino)-3-
methyl-1-oxobutan-2-yl)carbamate (Compound 28):
Step 1: (1S,2S)-ethyl-2-(ethylamino)cyclopentanecarboxylate (28a):
To a solution of ( 1 S,2S)-ethyl 2-aminocyclopentanecarboxylate (0.2 g, 1.27 mmol)
[synthesized using procedures described in J. Org. Chem., 2001 , 66 (16), 5629-5632] in
THF ( 10 mL), acetic acid (0.07 mL, 1.27 mmol) and acetaldehyde (0.07 mL, 1.27 mmol)
were added and stirred for 1 h at room temperature after which sodium
triacetoxyborohydride (0.4 g, 1.91 mmol) was added and stirred at room temperature for
16 h. After completion, the mixture was added to saturated NaHC0 3 solution and extracted
with EtOAc (2 35 mL). The organic layer was washed with brine, dried over Na2S04 and
concentrated under reduced pressure to get colorless oil (0.14 g, 59%) which was taken to
next step without any purification. 1H-NMR (400 MHz, CDCI3) , 4.20-4.1 0 (m, 2H), 3.56
(q, J = 7.2 Hz, 1H), 2.72 (q, J = 7.2 Hz , 1H), 2.62-2.50 (m, 2H), 1.94-1 .50 (m, 6H), 1.28-
1.23 (t, J = 7.2 Hz , 3H), 1.05-1 .02 (t, J = 7.2 Hz , 3H); m/z 186 (M++ 1) .
Step 2 : (1S,2S)-ethyl 2-((tert-butoxycarbonyl)(ethyl)amino)cyclopentanecarboxylate (28b):
To a stirred solution of (1S, 2S)-ethyl-2-(ethylamino)cyclopentanecarboxylate (28a) (0.22
g, 1.19 mmol) in 1,4-Dioxane (10 mL) was added a solution of NaHC0 3 (0.35 g, 4.16
mmol) in water (10 mL) till the solution turned basic. To this Boc anhydride (0.33 mL, 1.43
mmol) was added. The resultant mixture was stirred at room temperature for 16 h. The
reaction mixture was poured into water and extracted with ethyl acetate ( 15 ml_). The
combined organic layers were dried over sodium sulfate and concentrated under reduced
pressure to get white solid (0.2 g, 59%) which was used in the next step without any
further purification. 1H-NMR (400 MHz, CDCI3) , 4.25 (bs, 1H), 4.16-4.1 1 (m, 1H), 3.20-
3.19 (m, 2H), 2.93 (q, J = 7.2 Hz, 2H), 2.05-1 .70 (m, 6H), 1.47-1 .44 (m, 9H), 1.26 (t, J =
7.2 Hz, 3H), 1. 1 2 (t, J = 7.2 Hz, 3H); m/z 285 .2 (M+) .
Step 3: (1S,2S)-2-((tert-butoxycarbonyl)(ethyl)amino)cyclopentanecarboxylic acid (28c):
To a stirred solution of (1S, 2S)-ethyl-2-((tertbutoxycarbonyl)(
ethyl)amino)cyclopentanecarboxylate (28b) ( 1 .3 g, 4.56 mmol) in
Tetrahydrofuran (10 ml_), Ethanol ( 10 mL) and Water (10 mL) lithium hydroxide (0.44 g,
18.22 mmol) was added. The reaction mixture was stirred at room temperature for 4 h.
The reaction mixture was concentrated under reduced pressure and diluted with water and
extracted with ethyl acetate (2 35 mL). The aqueous layer was acidified by 1N HCI. and
extracted with ethyl acetate (2 10 mL) and the combined organic layers were washed
with brine, dried over sodium sulfate and concentrated under reduced pressure to yield a
white solid (0.7 g, 59%) which was used in the next step without any purification. 1H-NMR
(400 MHz, CDCI3) , 4.33-4.29 (m, 1H), 3.28-3.18 (m, 1H), 3.00-2.90 (m, 2H), 2.00-1 .65
(m, 6H), 1.47 (s, 9H), 1.13 (t, J = 7.2 Hz, 3H); m/z 257.1 8 (M+) .
Step 4: ( 1S, 2S)-2-(4-bromophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)(ethyl) amino)
cyclopentane carboxylate (28d):
To a stirred solution of (1S,2S)-2-((tertbutoxycarbonyl)(
ethyl)amino)cyclopentanecarboxylic acid (28c) (0.7 g, 2.72 mmol) in ACN
(20 mL), 2-bromo-1 -(4-bromophenyl)ethanone (0.76 g, 2.72 mmol) and DIPEA (0.35 g,
2.72 mmol) were added and stirred for 3 h at room temperature. The contents were
concentrated under reduced pressure and water (50 mL) was added to it and extracted
with DCM (20 mL 2). The combined organic layers were washed with brine, dried over
Na2S0 4 and concentrated under reduced pressure to get white foam (0.9 g, 73%) that was
used in the next step without any further purification m/z 354 [(M+) - 100].
Step 5 : tert-butyl ((1S,2S)-2-(5-(4-bromophenyl)-1 H-imidazol-2-
yl)cyclopentyl)(ethyl)carbamate (28e):
To a stirred solution of ( 1 S,2S)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)(
ethyl)amino)cyclopentanecarboxylate (28d) (0.900 g, 1.98 mmol) in
toluene (12 mL) ammonium acetate (4.58 g, 59.4 mmol) was added and heated for 18 hr
at 110 C. The mixture was added to water (100mL) and extracted with DCM (70 mL 2).
The combined organic layers were washed with brine and dried over Na2S0 4,
concentrated under reduced pressure and purified by flash chromatography using 5%
EtOAc / pet-ether to get yellow solid (0.22 g, 26%). 1H-NMR (400 MHz, CDCI3) : 7.70-
7.60 (m, 1H), 7.48-7.46 (m, 3H), 7.16 (bs, 1H), 4.90-4.80 (m, 1H), 3.30-3.20 (m, 2H),
3.10-3.00 (m, 1H), 2.50-2.40 (m, 1H), 2.00-1 .70 (m, 5H), 1.50 (s, 9H), 1.18-1 . 13 (m, 3H);
m/z 434.98 (M++1).
Step 6: (S)-tert-butyl 2-(7-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)(ethyl)amino)
cyclopentyl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate (28f):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 1 using intermediate (28e) from the previous step and (S)-tert-butyl 2-(7-(4,4,5,5-
tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1-carboxylate [synthesized using procedures described in WO2009/1 02633].
1H-NMR (400 MHz, CDCI3) : 11.00 (bs, 1H), 10.50 (bs, 1H), 7.83-7.52 (m, 8H), 5.07-4.86
(m, 2H), 3.50-3.43 (m, 3H), 3.2-3.26 (m, 2H), 3.08-3.03 (m, 2H), 2.97-2.90 (m, 2H), 2.50-
2.40 (m, 2H), 2.25-1 .72 (m, 8H), 1.60-1 .51 (m, 18H), 1.20-1 . 15 (m, 3H), m/z 693.50
(M++1).
Step 7 : methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)(ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound
28):
Title compound was synthesized by following the procedure as described in Step 5
(Example 1) using intermediate (28f) from the previous step. 1H NMR (DMSO- , 400
MHz), 11.80-1 1.75 (bs, 2H), 8.14-7.92 (m, 6H), 7.34-7.31 (m, 1H), 6.99-6.96 (m, 1H),
5.17-4.99 (m, 4H), 4.20-3.85 (m, 5H), 3.55-3.50 (m , 6H), 3.15-2.85 (m, 4H), 2.14-1 .50 (m,
12H), 0.99-0.51 (m, 15H), m/z 807.50 (M++ 1) . m.p.: 193-195 C.
Example 29: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 Hnaphtho[
1,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)(methyl)amino)-3-
methyl-1-oxobutan-2-yl)carbamate (Compound 29):
Step 1: (1S, 2S)-ethyl 2-(methylamino)cyclopentanecarboxylate (29a):
To a solution of (1S,2S)-ethyl 2-aminocyclopentanecarboxylate (2 g, 12.72 mmol) in
ethanol (30 mL), formaldehyde solution (37% v/v, 0.385 mL, 14 mmol) was added and
stirred for 1h. Then, 10% Pd-C (2.03 g, 19.1 mmol) was added to the mixture and stirred
for 2 h under H2 atmosphere. After completion of reaction, the mixture was filtered through
a pad of celite. The celite bed was washed with ethanol (20 mL). The combined organic
layers were evaporated under reduced pressure and the residue ( 1 .4 g, 64%) was taken to
next step without any purification. 1H-NMR (400 MHz, CDCI3) , 4.20-4.1 0 (m, 2H), 3.07
(q, J = 7.6 Hz, 1H), 2.70 (q, J = 7.2 Hz, 1H), 2.26 (s, 3H), 1.94-1 .50 (m, 6H), 1.27 (t, J =
7.2 Hz, 3H); m/z 171 .23 (M+)
Step 2 : ( 1S, 2S)-ethyl 2-((tert-butoxycarbonyl)(methyl)amino) cyclopentanecarboxylate
(29b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 28, using intermediate (29a) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
4.60-4.50 (m, 1H), 4.1 9-4.1 0 (m, 2H), 2.56 (q, J = 7.2 Hz, 1H), 2.05-1 .70 (m, 6H), 3.27
(s, 3H), 1.47-1 .44 (m, 9H), 1.25 (t, J = 7.2 Hz, 3H); m/z 271 .29 (M+)
Step 3: (1S, 2S)-2-((tert-butoxycarbonyl)(methyl)amino)cyclopentanecarboxylic acid (29c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 28, using intermediate 29b as starting material. 1H-NMR (400 MHz, CDCI3) , 
4.61-4.59 (m, 1H), 3.28-3.1 8 (m, 1H), 2.81 (s, 3H), 2.00-1 .65 (m, 6H), 1.47 (s, 9H); m/z
244.08 (M++1).
Step 4: (1S,2S)-2-(4-bromophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)(methyl)
amino)cyclopentanecarboxylate (29d) :
Title compound was synthesized by following the procedure as described in Step 4 of
Example 28, using intermediate 29c as starting material m/z 439.79 (M+)
Step 5 : tert-butyl ((1 S,2S)-2-(5-(4-bromophenyl)-1 H-imidazol-2-
yl)cyclopentyl)(methyl)carbamate (29e):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 28, using intermediate 29d as starting material. 1H-NMR (400 MHz, CDCI3) , 
7.60-7.45 (m, 4H), 7.20 (bs, 1H), 4.90-4.88 (m, 1H), 3.30-3.23 (m, 1H), 2.80 (s, 3H), 2.50-
2.40 (m, 1H), 2.00-1 .70 (m, 5H), 1.50 (s, 9H); m/z 420.20 (M++1).
Step 6: (S)-tert-butyl 2-(7-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)(methyl)amino)
cyclopentyl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1 -carboxylate (29f):
Title compound was synthesized by following the procedure as described in Step 6 of
Example 28, using intermediate (29e) from the previous step and (S)-tert-butyl 2-(7-
(4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-
yl)pyrrolidine-1-carboxylate [synthesized using procedures described in WO2009/1 02633].
1H-NMR (400 MHz, CDCI3) , 11.00 (bs, 1H), 10.50 (bs, 1H), 7.83-7.52 (m, 8H), 5.07-4.86
(m, 2H), 3.50-3.43 (m, 3H), 3.20-3.10 (m, 2H), 2.97-2.90 (m, 2H), 2.85 (s, 3H), 2.50-2.40
(m, 2H), 2.25-1 .72 (m, 8H), 1.60-1 .51 (m, 18H), m/z 679.50 (M++ 1) .
Step 7 : methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)(methyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound
29):
Title compound was synthesized by following the procedure as described in Step 7 of
Example 28, using intermediate 29f as starting material. 1H-NMR (400 MHz, DMSO- 6) 
11.80-1 1.75 (bs, 2H), 8.14-7.92 (m, 6H), 7.34-7.31 (m, 1H), 6.99-6.96 (m, 1H), 5.17-4.99
(m, 2H), 4.20-3.85 (m, 4H), 3.55-3.50 (m, 6H), 3.1 5-2.85 (m, 5H), 2.14-1 .50 (m, 12H),
0.99-0.51 (m, 15H), m/z 793.50 (M++1). m.p.: 162-155 C.
Example 30: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9Hfluoren-
2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (Compound 30):
Step 1: 1-(7-bromo-9H-fluoren-2-yl)ethanone (30a):
To a degassed solution of 2,7-dibromo-9H-fluorene (3.0 g, 9.3 mmol) and tributyl(1-
ethoxyvinyl)stannane (3.3 g, 9.3 mmol) in 1,4-Dioxane (20 mL) was added Pd(PPh3)4 (0.56
g, 0.463 mmol) and PdCI2(dppf) (0.34 g, 0.46 mmol) and the contents were heated at 80
C for 5 h. The reaction mixture was cooled to room temperature and water was added
and the contents were extracted with EtOAc (2 20 mL). The organic layer was washed
with brine, dried over sodium sulphate and concentrated under reduced pressure to yield
2-bromo-7-(1-ethoxyvinyl)-9,9 dimethyl-9H-fluorene as an orange liquid. To the above
product THF (6 mL) and 2M HCI (10 mL) was added and the reaction was stirred at rt for 2
h. The contents were evaporated under reduced pressure, the residue was dissolved in
water and extracted with EtOAc (2 20 mL). The organic contents were washed with
brine, dried over sodium sulphate and purified by flash chromatography (3%
EtOAc/Hexane) to yield a white colored solid (0.90g, 33.9%).
1H-NMR (400 MHz, CDCI3) : 8.1 5 (bs, 1H), 8.04-8.01 (m, 1H), 7.83-7.81 (m, 1H), 7.74-
7.70 (m, 2H), 7.57-7.55 (m, 1H), 3.96 (s, 2H), 2.67 (s, 3H); m/z 286.07 (M+) .
Step 2 : 2,2-dibromo-1-(7-bromo-9H-fluoren-2-yl)ethanone (30b):
To a solution of 1-(7-bromo-9H-fluoren-2-yl)ethanone (30a) (0.4 g, 1.4 mmol) in chloroform
(15 mL) was added bromine (0.07 mL, 1.4 mmol) at 0 C under nitrogen atmosphere. The
cooling bath was removed and the reaction mixture was warmed to rt and stirred for 2 h.
Water was added to the reaction mixture and the organic contents were washed with
sodium bisulphite solution, brine, dried over sodium sulphate and evaporated under
reduced pressure to yield a yellow colored solid that was used in the next step without
further purification (0.550, 89%). 1H-NMR (400 MHz, CDCI3) 8.27 (bs, 1H), 8.1 8-8.14 (m,
1H), 8.09-8.04 (m, 1H), 7.88-7.80 (m, 1H), 7.77-7.72 (m, 2H), 7.62-7.59 (m, 1H), 4.1 0-3.99
(m, 2H).
Step 3 : 2-bromo-1-(7-bromo-9H-fluoren-2-yl)ethanone 30c):
To a solution of 2-bromo-1-(7-bromo-9H-fluoren-2-yl)ethanone (30b) (0.35 g, 0.96 mmol)
in THF (3 mL) at 0 C was added triethylamine (0.24 ml_, 1.69 mmol) and diethyl phosphite
(0.22 mL, 1.69 mmol). The reaction was gradually warmed to room temperature and the
mixture was stirred for 1.5 h after which excess THF was removed under reduced
pressure. The crude was triturated with n-pentane to get a white solid (0.350g, 85%) that
was used in the next step without further purification. 1H NMR (DMSO- , 400 MHz), 
8.29 (bs, 1H), 8.22-8.14 (m, 2H), 8.06-8.03 (m, 1H), 7.90-7.87 (m, 1H), 7.67-7.65 (m, 1H),
4.97 (s, 2H), 4.03 (s, 2H); m/z 386 (M++23).
Step 4 : ( 1S,2S)-2-(7-bromo-9H-fluoren-2-yl)-2-oxoethyl-2-((tert-butoxycarbonyl)
amino)cyclopentanecarboxylate (30d) :
Title compound was synthesized by following the procedure as described in Step 1 of
Example 1 using intermediate (30c) from the previous step and (1S,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized using procedures
described in J. Org. Chem., 2001 , 66 ( 16), 5629-5632] as starting materials. 1H-NMR (400
MHz, CDCI3) : 8.1 1-8.1 0 (m, 1H), 7.98-7.96 (m, 1H), 7.86-7.83 (m, 1H), 7.75-7.71 (m,
2H), 7.58-7.56 (m, 1H), 5.53-5.31 (m, 2H), 3.97 (s, 2H), 3.90-3.85 (m, 1H), 2.80-2.75 (m,
1H), 2.20-2.1 0 (m, 4H), 1.90-1 .80 (m, 2H), 1.45 (s, 9H); m/z 4 14.1 0 [(M++1) - 100] (value
observed for the de-Boc product).
Step 5: tert-butyl ((1 S,2S)-2-(5-(7-bromo-9H-fluoren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)carbamate (30e):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 1 using intermediate (30d) from the previous step. 1H-NMR (400 MHz, CDCI3) : 
7.88 (bs, 1H), 7.76-7.61 (m, 4H), 7.51 -7.48 (m, 1H), 7.33 (s, 1H), 4.93-4.91 (m, 1H), 4.22-
4.18 (s, 1H), 3.91 (s, 2H), 3.20-3.18 (m, 1H), 2.50-2.20 (m, 4H), 1.90-1 .80 (m, 2H), 1.50 (s,
9H); m/z 493.99 (M++ 1) .
Step 6: tert-butyl ((1S,2S)-2-(5-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-9H-fluoren-
2-yl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (30f):
Boc
Title compound was synthesized by following the procedure as described in Step 3 of
Example 1 using intermediate (30e) from the previous step. 1H-NMR (400 MHz, CDCI3) : 
8.00 (bs, 1H), 7.85-7.77 (m, 3H), 7.71-7.66 (m, 1H), 7.58-7.47 (m, 1H), 7.36-7.32 (m, 1H),
4.89-4.87 (m, 1H), 4.20-4.1 5 (m, 1H), 3.93 (s, 2H), 3.27-3.20 (m, 1H), 2.40-1 .60 (m, 6H),
1.40 (s, 9H), 1.34 (s, 12H); m/z 542.1 2 (M++ 1) .
Step 7 : (S)-tert-butyl 2-(5-(7-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)-9H-fluoren-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-
yl)pyrrolidine-1 -carboxylate (30g):
Title compound was synthesized following the procedure as described in Step 4 of
Example 1 using the intermediates (30f) from the previous step and (S)-tert-butyl 2-(5-
bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate
[synthesized using procedures described in ref. WO201 0/096302 A1] as starting materials
maintaining a temperature of 125 C for 35 min. 1H-NMR (400 MHz, CDCI3) , 12.00 (bs,
1H), 11.50 (bs, 1H), 8.05-7.05 (m, 8H), 5.70-5.35 (m, 2H), 5.25-5.05 (m, 1H), 4.95-4.80
(m, 2H), 4.30-4.10 (m, 1H), 4.05-3.90 (m, 2H), 3.75-3.30 (m, 4H), 3.25-3.1 0 (m, 1H), 2.45-
1.72 (m, 8H), 1.65-1 .51 (m, 18H), 0.95-0.80 (m, 2H), 0.01 (s, 9H); m/ 781 .2 (M++1).
Step 8: methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9H-fluoren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 30):
To a stirred solution of (S)-tert-butyl 2-(5-(7-(2-((1S,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentyl)-1 H-imidazol-5-yl)-9H-fluoren-2-yl)-1 -((2-
(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (30g) (0.06 g, 0.07
mmol) in DCM (4 mL) was added TFA (0.143 ml_, 1.854 mmol). The resultant mixture was
stirred at 45 C for 18 h. All the volatiles were evaporated under reduced pressure. The
residue was washed with diethyl ether to get white solid [m/z 451 .20 (M++ 1)]. The solid so
obtained (0.030 g, 0.063 mmol) was taken up in DMF (2 mL) and (S)-2-
((methoxycarbonyl)amino)-3-methylbutanoic acid (0.024 g 0.13 mmol), DIPEA (0.06 mL,
0.3 mmol) and HATU (0.052 g, 0.13 mmol) was added and the resultant mixture was
stirred at room temperature for 16 h under nitrogen atmosphere. Ice cold water was added
in the reaction mixture and the off white colored precipitate was filtered off, washed with
water, dried under high vacuum and purified by preparative HPLC to yield the title
compound as a pale yellow solid (0.02 g, 25%). 1H NMR (DMSO- 6, 400 MHz): 11.80
(bs, 2H), 8.20-8.1 6 (m, 1H), 7.93-7.50 (m, 8H), 7.33-7.31 (m, 1H), 7.09-7.07 (m, 1H), 5.10-
5.05 (m, 1H), 4.40-4.32 (m, 1H), 4.10-3.85 (m, 6H), 3.55-3.45 (m, 7H), 3.20-3.1 5 (m, 2H),
2.20-1 .50 (m, 10H), 0.99-0.51 (m, 12H), m/z 765.50 (M++ 1) . m.p.: 176-178 C.
Example 3 1 : Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9-
dimethyl-9H-fluoren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-
2-yl)carbamate (Compound 31):
Step 1: 1-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone (31a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 30, using 2,7-dibromo-9,9-dimethyl-9H-fluorene as the starting material. 1H-NMR
(400 MHz, CDCI3) , 8.07-8.05 (m, 1H), 7.99-7.97 (m, 1H), 7.82-7.77 (m, 1H), 7.66 (d, J =
8 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.53-7.48 (m, 1H), 2.67 (s, 3H), 1.53 (s, 6H); m/z
316.96 (M++1).
Step 2 : 2,2-dibromo-1 -(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone
Title compound was synthesized by following the procedure as described in Step 2 of
Example 30 using intermediate (31a) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
8.08-8.07 (m, 1H), 7.99-7.97 (m, 1H), 7.85-7.79 (m, 1H), 7.66 (d, J = 8 Hz, 1H), 7.63-7.61
(m, 1H), 7.53-7.48 (m, 1H), 6.77 (s, 1H), 1.53 (s, 6H); m/z 470.5 (M++ 1) .
Step 3 : 2-bromo-1-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone (31c):
Title compound was synthesized by following the procedure as described in Step 3 of
Example 30, using intermediate (31 b) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
8.07-8.05 (m, 1H), 7.99-7.97 (m, 1H), 7.82-7.77 (m, 1H), 7.66 (d, J = 8 Hz, 1H), 7.61 (d,
J = 1.6 Hz, 1H), 7.53-7.48 (m, 1H), 4.15 (s, 2H), 1.57 (s, 6H); m/z 394.9 (M++1).
Step 4 : (1S,2S)-2-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-2-oxoethyl 2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (31d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 30, using intermediate (31c) from the previous step and (1S,2S)-2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylic acid [synthesized using procedures
described in J. Org. Chem., 2001 , 66 ( 16), 5629-5632] as starting materials. 1H-NMR (400
MHz, CDCI3) , 8.0 (s, 1H), 7.94-7.92 (m, 1H), 7.78 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz,
1H), 7.62 (s, 1H), 7.58-7.53 (m, 1H), 5.59-5.53 (m, 1H), 5.40-5.36 (m, 1H), 4.95 (bs, 1H),
4.16 (s, 1H), 2.86-2.84 (m, 1H), 2.1 2-2.06 (m, 4H),1 .80-1 .75 (m, 2H), 1.54 (s, 6H), 1.29 (s,
9H); m/z 542.5 (M++ 1) .
Step 5 : tert-butyl ((1S,2S)-2-(5-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)carbamate (31 e):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 30, using intermediate (31 d) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
7.76 (s, 1H), 7.69-7.67 (m, 2H), 7.59-7.55 (m, 2H), 7.50 (d, J = 8 Hz, 1H), 7.32 (s, 1H),
4.92 (bs, 1H), 4.23-4.21 (m, 1H), 3.25-3.21 (m, 1H), 2.48-2.45 (m, 1H), 2.25-1 .60 (m, 5H),
1.54 (s, 6H), 1.29 (s, 9H); m/z 524.1 (M++ 1) .
Step 6 : tert-butyl ((1 S,2S)-2-(5-(9,9-dimethyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)-9H-f luoren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (31 f)
Title compound was synthesized by following procedure as described in Step 6 of
Example 30, using intermediate (31 e) from the previous step. 1H-NMR (400 MHz, CDCI3) ,
7.89 (s, 1H), 7.84 (m, 2H), 7.76 (m, 1H), 7.77 (s, 1H), 7.51 (m, 1H), 7.49 (s, 1H), 4.24
(m, 1H), 4.04 (m, 1H), 3.27 (m, 1H), 2.17-1 .69 (m, 6H), 1.56 (s, 6H), 1.44 (s, 9H), 1.34 (s,
12H); m/z 570.2 (M++ 1) .
Step 7 : (S)-tert-butyl 2-(5-(7-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)-9,9-dimethyl-9H-fluoren-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 Himidazol-
2-yl)pyrrolidine-1-carboxylate (31 g):
Title compound was synthesized by following the procedure as described in Step 7 of
Example 30, using intermediate (31 f) from the previous step. 1H-NMR (400 MHz, CDCI3) , 
7.85 (s, 1H), 7.80-7.78 (m, 2H), 7.60-7.58 (m, 1H), 7.51 (s, 1H), 7.25-7.22 (m, 1H), 7.1 9 (d,
J = 8 Hz, 1H), 7.01-6.99 (m, 1H), 5.33 (s, 2H), 5.22-5.21 (m, 1H), 4.90-4.88 (m, 1H), 4.25-
4.24 (m, 1H), 3.66-3.64 (m, 1H), 3.50-3.1 3 (m, 4H), 2.39-2.06 (m, 5H), 1.95-1 .81 (m, 5H),
1.56 (s, 6H), 1.44 (s, 18H), 0.89-0.84 (m, 2H), 0.00 (s, 9H); m/z 809.5 (M++ 1) .
Step 8 : methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9-dimethyl-9H-fluoren-2-yl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 3 1) :
Title compound was synthesized by following the procedure as described in Step 8 of
Example 30, using intermediate from the previous step. 1H-NMR (400 MHz, CDCI3) , 
8.30-7.57 (m, 5H), 7.53 (s, 1H), 7.42 (s, 1H), 6.86 (s, 1H), 5.39-5.31 (m, 3H), 4.49-4.46 (m,
2H), 4.04-4.02 (m, 1H), 3.84 (s, 6H), 3.20-3.18 (m, 2H), 3.1 5-3.1 2 (m, 1H), 2.34-1 .75 (m,
12H), 1.66 (s, 6H), 1.06-0.89 (m, 12H); m/z 793.5 (M++1). m.p.: 157-1 58 C.
Example 32: Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-
(methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-
yl)phenanthren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate (Compound 32):
Step 1: 1-(7-bromophenanthren-2-yl)ethanone (32a):
Title compound was synthesized by following the procedure as described in Step 1 of
Example 30, using 2,7-dibromophenanthrene [Synthesized according to procedure
reported in WO 2010132601 A1] as starting material. 1H-NMR (400 MHz, CDCI3) : 8.74 (d,
J = 9 Hz, 1H), 8.60 (d, J = 9 Hz, 1H), 8.55 (s, 1H), 8.1 6 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H),
7.75 (d, J = 8.8 Hz, 1H), 7.58-7.51 (m, 2H), 2.56 (s, 3H); LCMS: m/z = 299.0 (M+) .
Step 2 : 2,2-dibromo-1-(7-bromophenanthren-2-yl)ethanone (32b):
Title compound was synthesized by following the procedure as described in Step 2 of
Example 30, using intermediate (32a) from the previous step. 1H-NMR (400 MHz, CDCI3) :
8.74 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 9.6 Hz, 1H), 8.55 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H),
7.81 (s, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.45 (s, 2H), 6.83 (s, 1H).
Step 3: 2-bromo-1-(7-bromophe c)
Title compound was synthesized by following the procedure as described in Step 3 of
Example 30, using intermediate (32b) from the previous step. 1H-NMR (400 MHz, CDCI3) :
8.74 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H),
8.09 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.58-7.51 (m, 2H), 4.89 (s, 2H).
Step 4: (1S,2S)-2-(7-bromophenanthren-2-yl)-2-oxoethyl 2-((tertbutoxycarbonyl)
amino)cyclopentanecarboxylate (32d):
Title compound was synthesized by following the procedure as described in Step 4 of
Example 30, using intermediate (32c) from the previous step. 1H-NMR (400 MHz, CDCI3) :
8.62-8.49 (m, 2H), 8.28 (s, 1H), 7.81-7.28 (m, 4H), 7.42-7.31 (m, 1H), 5.52-5.37 (m, 2H),
4.96 (bs, 1H), 4.32-4.27 (m,1 H), 2.92-2.86 (m, 1H), 2.32-1 .76 (m, 6H), 1.38 (s, 9H). m/z
527.5 (M++1).
Step 5: tert-butyl ((1S,2S)-2-(5-(7-bromophenanthren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)carbamate (32e):
Title compound was synthesized by following the procedure as described in Step 5 of
Example 30, using intermediate (32d) from the previous step. 1H-NMR (400 MHz, CDCI3) :
8.63-8.51 (m, 2H), 8.28 (s, 1H), 7.81-7.26 (m, 4H), 7.42-7.31 (m, 2H), 4.98-4.96 (bs, 1H),
4.29-4.22 (m, 1H), 3.29-3.209 (m, 1H), 2.88-1 .61 (m, 6H), 1.38 (s, 9H). m/z 507.5 (M++1).
Step 6: tert-butyl ((1 S,2S)-2-(5-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)phenanthren-2-yl)-1 H-i )
Title compound was synthesized by following the procedure as described in Step 6 of
Example 30, using intermediate (32e) from the previous step. 1H-NMR (400 MHz, CDCI3) :
8.71-8.64 (m, 2H), 8.37 (s, 1H), 8.02 (s, 1H), 7.80-7.56 (m, 2H), 7.45-7.35 (m, 2H), 4.29-
4.21 (m, 1H), 3.29-3.19 (m, 1H), 2.87-1 .71 (m, 6H), 1.38 (s, 9H), 1.27 (s, 12H), m/z 553.7
(M++1).
Step 7 : (S)-tert-butyl 2-(5-(7-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 Himidazol-
5-yl)phenanthren-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-
yl)pyrrolidine-1 -carboxyla
Title compound was synthesized by following procedure as described in Step 7 of
Example 30, using intermediate (32f) from the previous step m/z 795.3 (M++ 1) .
Step 8: methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenanthren-2-yl)-1 H-imidazol-2-
yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 32):
Title compound was synthesized by following the procedure as described in Step 8 of
Example 30, using intermediate (32g) from the previous step. 10.99-1 0.86 (m, 1H), 10.61 -
10.56 (m, 1H), 8.65-8.58 (m, 2H), 8.28 (s, 1H), 8.1 2-8.09 (m, 1H), 7.78-7.71 (m, 4H), 7.57-
7.49 (m, 1H), 7.41 -7.38 (m, 1H), 5.49-5.41 (m, 1H), 4.37-4.29 (m, 2H), 3.99-3.86 (m, 2H),
3.84-3.78 (m, 1H), 3.68 (s, 6H), 3.21 -3.18 (m, 2H), 2.67-2.14 (m, 5H), 1.86-1 .63 (m, 7H),
0.91 (d, 12H), m/z 777.2 (M++1), m.p.: 153-1 55 C.
Example 33: Biological Activity
Anti-viral activity of the compounds of the invention was monitored using an HCV replicon
assay. The Huh7.5/ Con1/SG-Neo(l)hRluc2aUb cell line persistently expressing a
bicistronic genotype 1b replicon in Huh 7.5 cells was obtained from Apath LLC. This cell
line was used to test inhibition of genotype 1b replicon levels by test compound using
Renilla luciferase enzyme activity readout as a measure of viral replication efficiency.
Briefly, 7000 cells were seeded in 96 well black clear bottom plates and allowed to adhere
overnight. The next day each compound was added in triplicate to the cells at the desired
concentration with a final DMSO concentration of 0.5%. Cells in media alone and cells
incubated without drug with 0.5% DMSO served as controls. The plates were incubated for
72h at 37°C prior to running the luciferase assay. Enzyme activity was measured using
Renilla-Glo Luciferase Assay kit from Promega as per the manufacturer's instructions. The
following equation was used to generate the percent inhibition value for each test
concentration.
Average Control (cells alone +0.5% DMSO) - Average compound value(cells + drug)
%Inhibition = X 100
Average Control (cells alone+0.5% DMSO)
The EC5o value was determined using GraphPad Prism and the following equation:
Y=Bottom + (Top-Bottom)/(1+1 0 ((LoglC5o-X)* HillSlope))
EC50 values/% inhibitions of compounds were determined 2-3 times in the replicon assay.
Following table 1 shows EC50 values, for inhibition of genotype 1b replicon, of the
compounds of the invention. Group A compounds exhibited EC50 value between 1 pM to
999 pM, Group B exhibited EC50 value between 1 nM to 999 nM, and Goup C exhibited
EC50 value of more than 1 .
Table 1:
CLAIMS
1. A compound of formula I, its tautomeric forms, its stereoisomers, its analogues, its
prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its Noxides,
its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical
isomers, its cl
wherein, in the compound of formula I,
Ring 'A' is a saturated carbocycle, which may be a monocyclic system or may be a
fused carbocycle or may be a bridged carbocycle, the said ring A may contain 5 to
10 carbons;
Ring 'D' is selected from 5 to 10 membered carbocycle and 5 to 10 membered
heterocycle, the ring 'D' may be monocyclic, fused bicyclic, bridged bicyclic or spiro
bicyclic;
Y is selected from -CH(R2a)- and -N(R2)-;
R1 is selected from the group consisting of R13aC(=0)N(R 14)-, R13aOC(=0)N(R 14)-,
R13(R14)N-, R13 (R14)NC(=0)N(R 15)-, R13aS0 2N(R14)-,
R1 aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-,
R1 aOC(=0)N(R 14)CRa(Rb)C(Rc)(Rd)C(=0)N(R 15)-,
R1 (R14a)NC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-, and
R1 (R14a)NC(=0)N(R 14)CRa(Rb)C(Rc)(Rd)C(=0)N(R 15)-;
R1a is selected independently at each occurrence from the group consisting of
halogen, substituted- or unsubstituted- Ci-6 alkyl, R1 aC(=0)-, R13bO-, R1 aOC(=0)-,
R1 aC(=0)0-, and R1 (R14)NC(=0)-,
R2 is selected independently at each occurrence from the group consisting of
substituted- or unsubstituted- Ci-6 alkyl, R13aC(=0)-, R13aS0 2- , R13aOC(=0)-,
R1 (R14)NC(=0)-, R1 aOC(=0)N(R 14)C(Ra)(Rb)C(=0)-,
l
R1 aOC(=0)N(R14)C(Ra)(Rb)C(Rc)(Rd)C(=0 )-,
R1 (R14)NC(=0)N(R15)C(Ra)(Rb)C(=0 )-,
R1 (R14)NC(=0)N(R15)C(Ra)(Rb)C(Rc)(Rd)C(=0 )-, R1 S0 2N(R14)C(Ra)(Rb)C(=0 )-,
R1 S0 2N(R14)C(Ra)(Rb)C(Rc)(Rd)C(=0 )-, and R1 aOC(=0)N(R14)C(Ra)(Rb)S0 2- ;
R a is selected independently at each occurrence from the group consisting of
R1 aC(=0)N(R14)-, R1 aOC(=0)N(R14)-, R1 (R14)N-, R1 (R14)NC(=0)N(R15)-,
R1 aS0 2N(R14)-, R1 aOC(=0)N(R14)C(Ra)(Rb)C(=0)N(R15)-,
R1 aOC(=0)N(R14)C(Ra)(Rb)C(Rc)(Rd)C(=0)N(R15)-,
R1 (R14a)NC(=0)N(R14)C(Ra)(Rb)C(=0)N(R15)-, and
R1 (R14a)NC(=0)N(R14)CRa(Rb)C(Rc)(Rd)C(=0)N(R15)-;
R3 is independently selected from O and N(R16) ;
R4 is selected independently at each occurrence from CRe(Rf) , O and N(R14) ; such
that, when n = 2 and R4 is selected as CRe(Rf) for both the occurrences, two Res
together can form a bond to form a alkenylene linkage or two Res and two Rfs
together can form bonds to form alkynylene linkage;
R5, R6, R7, R8, R9 and R10 are independently selected as hydrogen, or R5 and R6
together, R7 and R10 together, or R8 and R together independently along with the
carbon atoms to which they are attached forming 5 to 8 membered substituted- or
unsubstituted- carbocycle, 5 to 8 membered substituted- or unsubstitutedheterocycle,
6 membered substituted- or unsubstituted- aryl, or 5 to 6 membered
substituted- or unsubstituted- heteroaryl;
with a proviso that the compound of formula I must have at least one cyclic system
formed out of either R5 and R6, R8 and R9, or R7 and R10 ; also provided that R7 and
R10 take part in formation of cyclic system only when n is 0;
R1 1 and R12 are independently selected from a group consisting of hydrogen,
halogen, substituted- or unsubstituted- Ci-6 alkyl, R13bO-, and (R1 )(R14)N-;
wherein, R13 , R14 , R14a and R15 are independently selected from hydrogen,
substituted- or unsubstituted- C -6 alkyl, substituted- or unsubstituted- aryl,
substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl,
and substituted- or unsubstituted- heterocyclyl;
2
R1 a is selected from substituted- or unsubstituted- C -6 alkyl, perhaloalkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyi, and substituted- or unsubstitutedheterocyclyl;
R1 b is selected from hydrogen, substituted- or unsubstituted- C -6 alkyl,
perhaloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
substituted- or unsubstituted- cycloalkyi, and substituted- or
unsubstituted- heterocyclyl;
R16 is selected from hydrogen or substituted- or unsubstituted alkyl group;
Ra, Rb, Rc and Rd, are independently selected from hydrogen, halogen, substitutedor
unsubstituted- C -6 alkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyi, and substitutedor
unsubstituted- heterocyclyl, or Ra, Rb, Rc and Rd together with the carbon atom(s)
to which they are attached forming substituted- or unsubstituted- carbocycle,
substituted- or unsubstituted- heterocycle;
m is an integer ranging between 0 to 2, selected independently at each occurrence;
n is an integer ranging between 0 and 2;
'alkyl' may be substituted with 1 to 4 substituents selected from the group consisting
of halogen, oxo, Ci-6 alkyl, haloalkyl, aryl, heteroaryl, cycloalkyi, and heterocyclyl,
R17aC(=0)-, R17aS0 2- , R17bO-, R17aOC(=0)-, R17aC(=0)0-, (R17)(R1 )NC(=0)-,
(R17a)C(=0)N(R 18)-, (R17)(R1 )N-, (R17)(R1 )NC(=0)N(R 19)-, and R17aS0 2N(R18)-;
'cycloalkyi', 'cycloalkenyl' and 'carbocycle' may be substituted with 1 to 2
substituents selected from the group consisting of halogen, oxo, C -6 alkyl,
haloalkyl, R17aC(=0)-, R17aS0 2- , R17bO-, R17aOC(=0)-, R17aC(=0)0-,
(R17)(R1 )NC(=0)-, (R17a)C(=0)N(R 18)-, (R17)(R1 )N-, (R17)(R1 )NC(=0)N(R 19)-, and
R17aS0 2N(R18)-;
'aryl' may be substituted with 1 to 2 substituents selected from the group consisting
of halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl-O-, perhaloalkyl-O-,
alkyl(H)N-, alkyl(alkyl)N-, H2N-, alkyl-S0 2- , alkyl-C(=0)(H)N-, alkyl-C(=0)(alkyl)N-,
alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, H2NC(=0)-, alkyl(H)NS0 2- , alkyl(alkyl)NS0 2- ,
'heteroaryl' may be substituted with 1 to 2 substituents selected from the group
consisting of halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-S0 2- , H2N-, alkyl(H)N-, alkyl(alkyl)N-, alkyl-C(=0)(H)N-, alkyl-
C(=0)(alkyl)N-, NH2C(=0)-, alkyl(H)NC(=0)-, alkyl(alkyl)NC(=0)-, NH2S0 2- ,
alkyl(H)NS0 2- , and alkyl(alkyl)NS0 2- ;
ring carbon(s) of 'heterocycle' may be substituted with 1 to 2 substituents selected
from the group consisting of halogen, nitro, cyano, oxo, alkyl, R17bO-, R17aOC(=0)-,
R17aC(=0)0-, R17(H)NC(=0)-, R17(alkyl)NC(=0)-, R17(H)N-, R17(alkyl)N-,
R17aC(=0)(H)N-, R17(H)NC(=0)(H)N-, and R17(alkyl)NC(=0)(H)N-; the substituents
on ring nitrogen(s) of 'heterocycle' are selected from the group consisting of alkyl,
R17aS0 2- , R17aC(=0)-, R17aOC(=0)-, R17(H)NC(=0)-, and R17(alkyl)NC(=0);
R17 , R18 and R1 are independently selected from hydrogen and alkyl;
R17a is selected from alkyl and perhaloalkyl;
R17b is selected from the group consisting of hydrogen, alkyl, and perhaloalkyl.
2 . The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in claim 1, wherein ring A
is selected as cyclopentane.
The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in claim 1 or 2, wherein
ring Y is selected as -N(R2)-.
The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
4
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-3,
wherein R1 is selected as R13aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-.
5. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-4,
wherein m is selected as 0 at all the occurrences.
6. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-5,
wherein R2 is selected as R13aOC(=0)N(R 14)CRa(Rb)C(=0)-.
7. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-6,
wherein R3 is selected from NH and O.
8. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-7,
wherein n is selected as 0.
9. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-8,
wherein R5 and R6 are independently selected from hydrogen and halogen, or R5
and R6 together with the carbon atoms to which they are attached form a six
membered carbocycle.
10. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-9,
wherein R7 and R10 are selected as hydrogen, or R7 and R10 together with the
carbon atoms to which they are attached form a five or six membered carbocycle,
the said carbocycle is unsubstituted or substituted with one or two alkyl groups.
11. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-
10, wherein R and R8 are selected as hydrogen, or R and R8 together with the
carbon atoms to which they are attached form a six or seven membered carbocycle,
or R9 and R8 together with the carbon atoms to which they are attached form a
seven membered heterocycle containing one heteroatom.
12. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-
11, wherein R1 1 and R12 are selected as hydrogen.
13. The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-
12, wherein ring D is selected as
The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any on -
13, wherein ring A is selected as cyclopentane, ring D is selected as
R1 is selected as R13aOC(=0)N(R 14)CRa(Rb)C(=0)N(R 15)-, m is selected as 0 at all
the occurrences, R3 is selected from NH and O, n is selected as 0, R5 and R6 are
independently selected from hydrogen and halogen, or R5 and R6 together with the
carbon atoms to which they are attached form a six membered carbocycle, R7 and
R10 are selected as hydrogen, or R7 and R10 together with the carbon atoms to
which they are attached form a five or six membered carbocycle, the said
carbocycle is unsubstituted or substituted with one or two alkyl groups, R and R8
are selected as hydrogen, or R and R8 together with the carbon atoms to which
they are attached form a six or seven membered carbocycle, or R9 and R8 together
with the carbon atoms to which they are attached form a seven membered
heterocycle containing one heteroatom, R1 1 and R12 are selected as hydrogen; such
that at least one cyclic system is formed out of R5 and R6, R8 and R9, or R7 and R10 .
The compound of formula I, its tautomeric forms, its stereoisomers, its analogues,
its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its
N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates or its co-crystals, as claimed in any one of claims 1-
14, wherein the compound is selected from the group consisting of:
methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
8
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-
d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-
chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-
chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1 ,2-
d]oxazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-
oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
10
methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 Hnaphtho[
1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 Hnaphtho[
1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-
d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(7-(4-(2-((S)-1 -((S)-2-amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-
d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)(ethyl)amino)-3-methyl-1-oxobutan-2-
yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-
yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)(methyl)amino)-3-methyl-1 -oxobutan-
2-yl)carbamate;
11
methyl ((S)-1 -(((1 S,2S)-2-(5-(7-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9H-fluoren-2-yl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;
methyl ((S)-1 -(((1 S,2S)-2-(5-(7-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9-dimethyl-9H-fluoren-2-
yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate;
and
methyl ((S)-1 -(((1 S,2S)-2-(5-(7-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3-
methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenanthren-2-yl)-1 Himidazol-
2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate.
16. A pharmaceutical composition comprising a compound or a combination of
compounds according to any one of claims 1-15 or a pharmaceutically acceptable
salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
17. A method of inhibiting the replication of an RNA-containing virus comprising
contacting said virus with a therapeutically effective amount of a compound or
combination of compounds of any one of claims 1- 15, or a pharmaceutically
acceptable salt thereof.
18. A method of treating or preventing infection caused by an RNA-containing virus
comprising administering to a patient in need of such treatment a therapeutically
effective amount of a compound or combination of compounds of any one of claims
1-15, or a pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the RNA-containing virus is hepatitis C virus.
20. The method of claim 18, further comprising the step of co-administering one or
more agents selected from the group consisting of a host immune modulator and an
antiviral agent, or a combination thereof.
21. The method of claim 20, wherein the host immune modulator is selected from the
group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta,
interferon-gamma, consensus interferon, a cytokine, and a vaccine.
22. The method of claim 20, wherein the antiviral agent inhibits replication of HCV by
inhibiting host cellular functions associated with viral replication.
12
23. The method of claim 20, wherein the antiviral agent inhibits the replication of HCV
by targeting proteins of the viral genome.
24. The method of claim 20, wherein said antiviral agent is an inhibitor of a HCV viral
protein, a replication process or a combination thereof, wherein said targeting
protein or replication process is selected from the group consisting of helicase,
protease, polymerase, metalloprotease, NS4A, NS4B, NS5A, assembly, entry, and
IRES.
25. The method of claim 18, further comprising the step of co-administering an agent or
combination of agents that treat or alleviate symptoms of HCV infection selected
from cirrhosis and inflammation of the liver.
26. The method of claim 18, further comprising the step of co-administering one or
more agents that treat patients for disease caused by hepatitis B (HBV) infection.
27. The method of claim 18, further comprising the step of co-administering one or
more agents that treat patients for disease caused by human immunodeficiency
virus (HIV) infection.
28. The pharmaceutical composition of claim 16, further comprising an agent selected
from interferon, pegylated interferon, ribavirin, amantadine, an HCV protease
inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal
ribosome entry site inhibitor.
29. The composition of claim 16, further comprising a cytochrome P450
monooxygenase inhibitor or a pharmaceutically acceptable salt thereof.
30. A method of treating hepatitis C infection in a subject in need thereof comprising c o
administering to said subject a cytochrome P450 monooxygenase inhibitor or a
pharmaceutically acceptable salt thereof, and a compound of any one of claims 1-
15 or a pharmaceutically acceptable salt thereof