HEPATITIS C VIRUS INHIBITORS

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/241,489 filed September 11, 2009; U.S. Provisional Application No. 61/241,578 filed September 11, 2009; U.S. Provisional Application No. 61/241,595 filed September 11, 2009; U.S. Provisional Application No. 61/241,617 filed September 11, 2009; U.S. Provisional Application No. 61/241,577 filed September 11, 2009. The entire teachings of the above applications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel antiviral agents. More specifically, the present invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, methods for inhibiting HCV viral replication, methods for treating or preventing HCV infection, and processes for making the compounds. BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV.

Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30%) of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flulike symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology, 26 (suppl 1): 71S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV R A levels and normalization of liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science, 244:359-362), HCV is now widely accepted as the most common causative agent of posttransfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science, 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science, 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci., USA 87:2057-2061), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA - A Publication of the RNA

Society, 1(5): 526-537, 1995 Jul). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology, 2 ^nd Edition, p931-960; Raven Press, N.Y.). There are three structural proteins, C, El and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are several non- structural proteins. NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus. NS4A is a tightly associated but non-covalent cofactor of the serine protease. NS5A is a membrane-anchored phosphoprotein that is observed in basally phosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms. While its function has not fully been elucidated, NS5A is believed to be important in viral replication. The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. , 151 2-22) encodes an R A-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra- typically (-95-98% amino acid (aa) identity across lb isolates) and inter-typically (-85% aa identity between genotype la and lb isolates). The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al, (2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection.

Following the termination codon at the end of the long ORF, there is a 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun., 215744-749; Tanaka, T. et al (1996) J. Virology, 70:3307-3312; Yamada, N. et al (1996) Virology, 223:255-261). The 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.

Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. In particular, compounds which are effective to inhibit the function of the NS5A protein are desired. The HCV NS5A protein is described, for example, in Tan, S.-L., Katzel, M.G. Virology, 2001, 284, 1; and in Rice, C. M. Nature, 2005, 435, 374.

Based on the foregoing, there exists a significant need to identify compounds with the ability to inhibit HCV. SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds. Compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.

In its first principal aspect, the present invention provides a compound of Formula

(1-1):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

Ring B is a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

L is absent or selected from the group consisting of optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, and optionally substituted C ₂ -C ₄ alkynyl;

G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L, and Ring B, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;

J is selected from -N(R ^lc )-C(0)-, -N(R ^lc )-C(0)0- and -N(R ^lc )-C(0)-N(R ^lc )-; preferably -N(R ^lc )-C(0)-;

W at each occurrence is independently O or -N(R ^lb )-; preferably -N(R ^lb )-;

R ¹ , R ^la , R ^lb , R ^lc , R ⁹ , and R ^9a at each occurence are each independently hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R ^lb and R ^9a , or R ^lb and R ⁹ can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic ring;

R ⁶ at each occurence is independently selected from the group consisting of optionally substituted 0(C ₁ -C ₈ alkyl), optionally substituted amino, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C ₁ -C ₈ alkyl; more preferably C ₁ -C8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl);

7 R ^l» R ^9a

Q is selected from: and ;

X is absent, O, S, CH ₂ , or CH ₂ CH ₂ ;

Y is absent, O, S, C(R , C(R ¹ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ C(R ⁷ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ OC(R ¹ ) ₂ , or C(R^SC(R ¹ ) ₂ ;

Wherein at least one of X and Y is present;

Wherein at least one of X and Y is not O or S;

U is absent or independently selected from O, S, S(O), S0 ₂ , NC(0)-(C ₁ -C ₄ alkyl),

C(O), protected carbonyl, OCH ₂ , OCH ₂ CH _2, SCH ₂ , SCH ₂ CH ₂ , C(R ⁷ ) ₂ , and C(R ⁷ ) ₂ C(R ⁷ ) ₂ ; preferably CH ₂ ;

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -C ₄ alkyl; preferably hydrogen, halogen or hydroxy;

Optionally two geminal R ⁷ groups can be taken together with the cabon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6-membered heterocyclic;

R ² at each occurence is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or -NR ^a R ^b ; R ^a at each occurence is independently hydrogen or optionally substituted C ₁ -C ₈ alkyl;

R ^b at each occurence is -C(0)-R ⁶ ;

Alternatively R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₂ -C ₈ alkenyl, and optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C1-C ₄ alkyl; alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted heterocyclic;

R ⁵ is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C1-C ₄ alkyl; and

R ^7a and R ^7b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted C1-C ₄ alkyl; alternatively, CHR ^7a -U or CHR ^7b -U can be taken together to form a group selected from CH=CH, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic; or yet alternatively, U, R ^7a , and R ^7b can be taken together with the carbon atoms to which they are attached to form a bridged, optionally substituted 4- to 7- membered ring including C ₄ -C7 cycloalkyl, C ₄ -C7 cycloalkenyl and 4- to 7-membered heterocyclic.

In its second principal aspect, the present invention provides a compound of Formula (2-1)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A and Ring B are each independently a monocyclic or polycyclic group selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl; L is absent or selected from the group consisting of optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, and optionally substituted C ₂ -C ₄ alkynyl; wherein taken together is not optionally substituted phenyl-thiazolyl or 3,4'-biphenyl;

J is selected from the group consisting of -N(R ^lc )-C( O)-, -N(R ^lc )-C(0)0- and

-N(R ^lc )-C(0)-N(R ^lc )-; preferably -N(R ^lc )-C(0)-;

W at each occurrence is independently O or -N(R ^lb )-; preferably -N(R ^lb )-;

R ¹ , R ^la , R ^lb , R ^lc , R ⁹ , and R ^9a at each occurrence are each independently hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively, R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ^J and R ⁹ can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R ^lb and R ^9a , or R ^lb and R ⁹ can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;

R ⁶ at each occurrence is independently selected from the group consisting of optionally substituted 0(C ₁ -C ₈ alkyl); optionally substituted amino; C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C ₁ -C ₈ alkyl; more preferably C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl);

G is selected from the group consisting of -N(R ^lc )-C(0)-, -N(R ^lc )-C(0)0- and -N(R ^lc )-C( -N(R ^lc )-; preferably -N(R ^lc )-C(0)-;

; or alternatively G and Q are taken together to form

X is absent, O, S, CH ₂ , or CH ₂ CH ₂ ;

Y at is absent, O, S, C(R , CCR^C(R ⁷ ^, CCR^C^C^, C(R^OCCR ¹ ^, or C(R^SCCR ¹ ^; Wherein at least one of X and Y is present;

Wherein at least one of X and Y is not O or S;

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -C ₄ alkyl; preferably hydrogen, halogen or hydroxy;

R ² at each occurrence is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or -NR ^a R ^b ;

R ^a at each occurrence is independently hydrogen or optionally substituted C ₁ -C ₈ alkyl;

R ^b at each occurrence is -C(0)-R ⁶ ; and

Alternatively R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group.

In its third principal aspect, the present invention provides a compound of Formula

(3-1):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A and Ring B are each independently absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

L is absent or selected from the group consisting of optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, and optionally substituted C ₂ -C ₄ alkynyl;

Wherein at least one of Ring A, Ring B and L is present;

G and J are each independently optionally substituted 5-membered heteroaryl or optionally substituted 5/6-member fused heteroaryl; wherein the 5-membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, Ring B and L, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl; W at each occurrence is independently O or -N(R ^lb )-; preferably -N(R ^lb )-;

R ¹ , R ^la , R ^lb , R ⁹ , and R ^9a at each occurrence are each independently hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R ^lb and R ^9a , or R ^lb and R ⁹ can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;

R ⁶ at each occurrence is independently selected from the group consisting of optionally substituted 0(C ₁ -C ₈ alkyl); optionally substituted amino; C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C8 cycloalkyl, C ₃ -C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C ₁ -C ₈ alkyl; more preferably C ₁ -C8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl);

Q is selected from: , and;

X is absent, O, S, CH ₂ , or CH ₂ CH ₂ ;

Y is absent, O, S, C(R , C(R ¹ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ C(R ⁷ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ OC(R ¹ ) ₂ , or C(R^SC(R ¹ ) ₂ ;

Wherein at least one of X and Y is present;

Wherein at least one of X and Y is not O or S;

U is absent or independently selected from O, S, S(O), S0 ₂ , NC(0)-(C ₁ -C ₄ alkyl), C(O), protected carbonyl, OCH ₂ , OCH ₂ CH ₂ , SCH ₂ , SCH ₂ CH ₂ , C(R ⁷ ) ₂ , and C(R ⁷ ) ₂ C(R ⁷ ) ₂ ; preferably CH ₂ ;

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -C ₄ alkyl; preferably hydrogen, halogen or hydroxy;

Optionally two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C3-C ₈ cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;

R ² at each occurrence is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or -NR ^a R ^b ;

R ^a at each occurrence is independently hydrogen or optionally substituted C ₁ -C ₈ alkyl;

R ^b at each occurrence is -C(0)-R ⁶ ;

Alternatively R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₂ -C ₈ alkenyl, and optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C1-C ₄ alkyl; alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted heterocyclic;

R ⁵ is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C1-C ₄ alkyl; and

R ^7a and R ^7b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted C1-C ₄ alkyl; alternatively, CHR ^7a -U or CHR ^7b -U can be taken together to form a group selected from CH=CH, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic; or yet alternatively, U, R ^7a , and R ^7b can be taken together with the carbon atoms to which they are attached to form a bridged, optionally substituted 4- to 7- membered ring including C ₄ -C7 cycloalkyl, C ₄ -C7 cycloalkenyl and 4- to 7-membered heterocyclic, each optionally substituted.

In its fourth principal aspect, the present invention provides a compound of Formula (4-1):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

Ring B is a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

L is absent or selected from the group consisting of optionally substituted C1-C ₄ alkyl, optionally substituted C2-C ₄ alkenyl, and optionally substituted C2-C ₄ alkynyl;

R ¹ at each occurrence is independently hydrogen or optionally substituted C1-C ₄ alkyl;

R ⁶ at each occurrence is independently selected from the group consisting of optionally substituted 0(C ₁ -C ₈ alkyl); optionally substituted amino; C ₁ -C ₈ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C ₁ -C ₈ alkyl; more preferably C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl);

U is absent or independently selected from O, S, S(O), S0 ₂ , NC(0)-(C ₁ -C ₄ alkyl), C(O), protected carbonyl, OCH ₂ , OCH ₂ CH ₂ , SCH ₂ , SCH ₂ CH ₂ , C(R ⁷ ) ₂ , and C(R ⁷ ) ₂ C(R ⁷ ) ₂ ; preferably CH ₂ ;

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C1-C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C1-C ₄ alkyl; preferably hydrogen, halogen or hydroxy;

Optionally two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted C ₃ -C ₈ cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;

R ^7a and R ^7b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted C1-C ₄ alkyl; alternatively, CHR ^7a -U or CHR ^7b -U can be taken together to form a group selected from CH=CH, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclic;

G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L and Ring B, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;

Q is selected from: ,

Alternatively G and Q are taken together to form

V is selected from the group consisting of -N(R ^lc )-, -N(R ^lc )-C(0)-, -N(R ^lc )- C(0)0- and -N(R ^lc )-C(0)-N(R ^lc )-; preferably -N(R ^lc )- or -N(R ^lc )-C(0)-;

W is O or -N(R ^lb )-; preferably -N(R ^lb )-;

R ^la , R ^lb , R ^lc , R ^ld , R ⁹ , and R ^9a at each occurrence are each independently hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively R ^la and R ^9a , R ^la and R ⁹ , R ^ld and R ^9a , or R ^ld and R ⁹ can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R ^lb and R ^9a , or R ^lb and R ⁹ can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;

X is absent, O, S, CH ₂ , or CH ₂ CH ₂ ;

Y is absent, O, S, C(R , C(R ¹ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ C(R ⁷ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ OC(R ¹ ) ₂ , or C(R^SC(R ¹ ) ₂ ;

Wherein at least one of X and Y is present;

Wherein at least one of X and Y is not O or S;

R ² is hydrogen, optionally substituted C ₁ -C ₈ alkyl, or

R ^a is hydrogen or optionally substituted C ₁ -C ₈ alkyl;

R ^b at each occurrence is -C(0)-R ⁶ ; Alternatively R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₂ -C ₈ alkenyl, and optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted heterocyclic; and

R ⁵ is independently hydrogen, optionally substituted C ₁ -C ₈ alkyl, or optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted C ₁ -C ₄ alkyl.

In its fifth principle aspect, the present invention provides a compound of Formula

(5-1):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;

Ring B is an optionally substituted aryl or optionally substituted heteroaryl;

L is absent or selected from the group consisting of optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₂ -C ₄ alkenyl, and optionally substituted C ₂ -C ₄ alkynyl;

W at each occurrence is independently O or -N(R ^lb )-; preferably -N(R ^lb )-;

R ¹ , R ^la , R ^lb , R ^lc , R ⁹ , and R ^9a at each occurrence are each independently hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R ^lb and R ^9a , or R ^lb and R ⁹ can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;

R ⁶ at each occurrence is independently selected from the group consisting of optionally substituted 0(C ₁ -C ₈ alkyl); optionally substituted amino; C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C ₁ -C ₈ alkyl; more preferably C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl);

G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L and Ring B and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;

Q is selected from: ;

tively G and Q are taken together to form or

V is selected from the group consisting of -N(R ^lc )-, -N(R ^lc )-C(0)-, -N(R ^lc )- C(0)0- and -N(R ^lc )-C(0)-N(R ^lc )-;

X is absent, O, S, CH ₂ , or CH ₂ CH ₂ ;

Y is absent, O, S, C(R , C(R ¹ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ C(R ⁷ ) ₂ C(R ⁷ ) ₂ , C(R ¹ ) ₂ OC(R ¹ ) ₂ , or C(R^SC(R ¹ ) ₂ ;

Wherein at least one of X and Y is present;

Wherein at least one of X and Y is not O or S;

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -C ₄ alkyl; preferably hydrogen, halogen or hydroxy;

U is absent or selected from O, S, S(O), S0 ₂ , NC(0)-(C C ₄ alkyl), C(O), protected carbonyl, OCH ₂ , OCH ₂ CH ₂ , SCH ₂ , SCH ₂ CH ₂ , C(R ⁷ ) ₂ , and C(R ⁷ ) ₂ C(R ⁷ ) ₂ ; preferably CH ₂ ; Optionally two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;

R ² is hydrogen, optionally substituted C ₁ -C ₈ alkyl, or -NR ^a R ^b ;

R ^a is hydrogen or optionally substituted C ₁ -C ₈ alkyl;

R ^b is -C(0)-R ⁶ ;

Alternatively R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₂ -C ₈ alkenyl, and optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C ₁ -C ₄ alkyl; alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted heterocyclic;

R ⁵ is hydrogen, optionally substituted C ₁ -C ₈ alkyl, or optionally substituted C ₃ -C ₈ cycloalkyl; preferably hydrogen or optionally substituted C ₁ -C ₄ alkyl; and

R ^7a and R ^7b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted C ₁ -C ₄ alkyl; alternatively, CHR ^7a -U or CHR ^7b -U can be taken together to form a group selected from CH=CH, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic; or yet alternatively, U, R ^7a , and R ^7b can be taken together with the carbon atoms to which they are attached to form a bridged, optionally substituted 4- to 7-membered ring including C ₄ -C ₇ cycloalkyl, C ₄ -C ₇ cycloalkenyl and 4- to 7-membered heterocyclic, each optionally substituted.

Each preferred group stated above can be taken in combination with one, any or all other preferred groups.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient. In yet another aspect, the present invention provides a method of inhibiting the replication of a RNA-containing virus comprising contacting said virus with said pharmaceutical composition. Particularly, this invention is directed to methods of inhibiting the replication of HCV.

In still another aspect, the present invention provides 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 the present invention, or a pharmaceutically acceptable salt thereof. Particularly, this invention is directed to methods of treating or preventing infection caused by HCV.

Yet another aspect of the present invention provides the use of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically HCV. DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention have utility in inhibiting the replication of RNA- containing virus, including, for example, HCV. Other compounds useful for inhibiting the replication of RNA-containing viruses and/or for the treatment or prophylaxis of HCV infection have been described in copending U.S. Application Serial No. 12/702,673 filed February 9, 2010 entitled "Linked Dibenzimidiazole Derivatives"; U.S. Application Serial No. 12/702,692 filed February 9, 2010 entitled "Linked Dibenzimidiazole Derivatives"; U.S. Application Serial No. 12/702,802 filed February 9, 2010 entitled "Linked

Dibenzimidiazole Derivatives"; U.S. Application Serial No. 12/707,190 filed February 17, 2010 entitled "Linked Diimidazole Antivirals"; U.S. Application Serial No. 12/707,200 filed February 17, 2010 entitled "Linked Diimidazole Derivatives"; U.S. Application

Serial No. 12/707,210 filed February 17, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Application Serial No. 12/714,583 filed March 1, 2010 entitled "Novel Benzimidazole Derivatives"; and U.S. Application Serial No. 12/714,576 filed March 1, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Application Serial No. 12/816,148 filed June 15, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Application Serial No. 12/816,171 filed June 15, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/241,489 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S.

Provisional Application Serial No. 61/241,578 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/241,595 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/241,617 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/241,577 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/241,598 filed September 11, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/286,178 filed December 14, 2009 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/297,918 filed January 25, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/314,304 filed March 16, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/322,438 filed April 9, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/351,327 filed June 4, 2010 entitled "Hepatitis C Virus Inhibitors"; U.S. Provisional Application Serial No. 61/372,999 filed August 12, 2010 entitled "Hepatitis C Virus Inhibitors"; and the contents of each of which are expressly incorporated by reference herein.

As discussed above, a general strategy for the development of antiviral agents is to inactivate virally encoded proteins, including NS5A, that are essential for the replication of the virus. The relevant patent disclosures describing the synthesis of HCV NS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2004/014852; WO

2006/079833; WO 2006/1333262; WO 2007/031791; WO 2007/070556; WO

2007/070600; WO 2007/082554; WO 2008/021927; WO 2008/021928; WO

2008/021936; WO 2008/048589; WO 2008/064218; WO 2008/070447; WO

2008/144380; WO 2008/154601; WO 2009/020825; WO 2009/020828; WO

2009/034390; WO 2009/102318; WO 2009/102325; WO 2009/102694; WO

2010/017401; WO 2010/039793; WO 2010/065668; WO 2010/065674; WO

2010/065681; WO 2010/091413; WO 2010/096777; WO 2010/096462 and WO

2010/096302„the contents of each of which are expressly incorporated by reference herein.

I. Compounds having Formula (1-1)

In certain aspects, the present invention relates to compounds of Formula (1-1) as illustrated above, and pharmaceutically acceptable salts thereof. In another embodiment, the present invention relates to compounds of Formula (1- I), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-.

In still another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(0)0-.

In still another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-

NH

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.

In a further embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R ^lb and R ^9a , or R ^lb and R ⁹ are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by one of the following core groups:

wherein R ⁶ is as previously defined in Formula (1-1) and each of the above core groups is optionally substituted.

In an additional embodiment, the invention relates to compounds of Formula (1-1) and pharmaceutically acceptable salts thereof; wherein R^ is independently an optionally substituted C ₁ -C ₈ alkyl. In a further embodiment, the invention relates to compounds of Formula (1-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R ₆ is an a-amino acid residue.

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted five-membered heteroaryl containing one or more nitrogen atoms, and is C-attached.

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms and wherein the 5- membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6- membered fused heteroaryl is aryl or heteroaryl and is C-attached to group one of Ring A, L and Ring B.

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:

wherein each of the above said heteroaryl groups is optionally substituted.

In yet another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.

In yet another embodiment, the present invention relates to compounds of

Formulae (1-Ia-l ~ l-Ia-4), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^7a , R ^7b , and R ^9a are as previously defined in Formula (1-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (l-Ia-5 ~ l-Ia-6), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (1-1 ).

In yet another embodiment, the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (1-1).

In yet another embodiment, the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each independently occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C ₁ -C ₄ alkyl).

In still another embodiment, the present invention relates to compounds of Formulae (1-Ib-l ~ l-Ib-4), and pharmaceutically acceptable salts thereof: (1-lb-4)

wherein Ring B, G, J, Q, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (1-1); in Formula (1-Ib-l), Ring A and L are each present and as previously defined in Formula (1-1); in Formula (l-Ib-2), Ring A is present and as previously defined in Formula (1-1); in Formula (l-Ib-3), L is present and as previously defined in Formula (1- I)

In still another embodiment, the present invention relates to compounds of Formulae (1-Ib-l ~ l-Ib-4), and pharmaceutically acceptable salts thereof; wherein R ⁶ is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl).

In another embodiment, the present invention relates to compounds of Formula (1- Ib-1), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or optionally substituted monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In yet another embodiment, the present invention relates to compounds of Formula (l-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or bicyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In a further embodiment, the present invention relates to compounds of Formula (l-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or bicyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In another embodiment, the present invention relates to compounds of Formula (1-

Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl. In yet another embodiment, the present invention relates to compounds of Formula (l-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or bicyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In a further embodiment, the present invention relates to compounds of Formula (l-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In another embodiment, the present invention relates to compounds of Formula (1- Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or polycyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of

Formula (1-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atoms to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.

In still another embodiment, the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -C ₄ alkyl; preferably hydrogen, halogen or hydroxyl. In still another embodiment, the present invention relates to com ounds of

Formula (1-1), and pharmaceutically acceptable salts thereof; wherein at each occurence is independently illustrated by one of the following groups:

Representative compounds of the present invention are those selected from compounds 1-1 to 1-374 and 1-377 to 1-382 compiled in the following tables and/or shown below:

It is intended that the definition of any substituent or variable (e.g., R , R , etc.) a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when U is C(R ⁷ ) ₂ , each of the two R ⁷ groups may be the same or different.

It is also intended that the drawn formula of any linker or spacer (e.g., -NH- C(O)-, -OC(0)-NH-, etc.) at a particular location in a molecule be independent of its directions of attachment, unless otherwise indicated. For example, when a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments. II. Compounds having Formula (2-1)

In certain aspects, the present invention relates to compounds of Formula (2-1) as illustrated above, and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to compounds of Formula (2- I), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(O)-.

In still another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(0)0-.

In still another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(O)- NH-.

In still another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-.

In still another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(0)0-.

In still another embodiment, the present invention relates to compounds of

Formula (2-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)- NH-.

In still another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof;; wherein each of G and J is -NH-C(O)-.

In yet another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ are taken together to form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4- to 8-membered heterocyclic.

In a further embodiment, the present invention relates to compounds of Formula

(2-1), and pharmaceutically acceptable salts thereof; wherein R ^lb and R ^9a , or R ^lb and R ⁹ are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.

In yet another embodiment, the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by the one of the following core groups:

wherein R ⁶ is as previously defined in Formula (2-1) and each of the above core groups is optionally substituted.

In an additional embodiment, the invention relates to compounds of Formula (2-1) and pharmaceutically acceptable salts thereof; wherein R6 is independently an optionally substituted C ₁ -C ₈ alkyl.

In a further embodiment, the invention relates to compounds of Formula (2-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R ₆ is an a-amino acid residue.

In yet another embodiment, the present invention relates to compounds of Formulae (2-Ia-l ~ 2-Ia-2), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, ,W, X, Y, R ¹ , R ² , , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (2-1).

In yet another embodiment, the present invention relates to compounds of Formulae (2-Ia-3 ~ 2-Ia-4),and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, Y, R ¹ , R ² , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (2-1).

In another embodiment, the present invention relates to compounds of Formula (2- Ia-5), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, Y, R ¹ , R ⁶ , R ⁹ , R ^a , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (2-1).

In yet another embodiment, the present invention relates to compounds of Formula (2-Ia-5), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (2-Ia-5), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C ₁ -C ₄ alkyl).

In a further embodiment, the present invention relates to compounds of Formulae (2-Ib-l ~ 2-Ib-2), and pharmaceutically acceptable salts thereof: ) (2-lb-2)

wherein Ring A, Ring B, G, J, Q, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined; and in Formula (2-lb-l), L is present and as previously defined in Formula (2-1).

In another embodiment, the present invention relates to compounds of Formulae (2-Ib-l ~ 2-Ib-2), and pharmaceutically acceptable salts thereof; wherein R ⁶ is C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl).

In yet another embodiment, the present invention relates to compounds of Formula (2-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In still another embodiment, the present invention relates to compounds of

Formula (2-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, and the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl. In a further embodiment, the present invention relates to compounds of Formula (2-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl.

In another embodiment, the present invention relates to compounds of Formula (2- Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl.

Representative compounds of the present invention are those selected from compounds 2-1 to 2-295 compiled in the following tables and/or shown below:

It is intended that the definition of any substituent or variable (e.g., R , R , etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when Y is C(R ¹ ) ₂ , each of the two R ¹ groups may be the same or different.

It is also intended that the drawn formula of any linker or spacer (e.g., -NH- C(O)-, -OC(0)-NH-, etc.) at a particular location in a molecule be independent of its directions of attachment, unless otherwise indicated. For example, when a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.

III. Compounds having Formula (3-1)

In certain aspects, the present invention relates to compounds of Formula (3-1) as illustrated above, and pharmaceutically acceptable salts thereof.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.

In a further embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R ^lb and R ^9a , or R ^lb and R ⁹ are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.

In one embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by one of the following core groups:

wherein R ⁶ is as previously defined and each of the above core groups is optionally substituted.

In an additional embodiment, the invention relates to compounds of Formula (3-1) and pharmaceutically acceptable salts thereof; wherein R6 is independently an optionally substituted C ₁ -C ₈ alkyl.

In a further embodiment, the invention relates to compounds of Formula (3-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R ₆ is an a-amino acid residue.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each

independently an optionally substituted five-membered heteroaryl containing one or more nitrogen atoms, and are each C-attached.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each

independently an optionally substituted 5/6-membered fused heteroaryl; wherein the 5- membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-membered fused aryl is aryl or heteroaryl and is C-attached to one of Ring A, Ring B and L.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein one of G and J is an optionally substituted five-membered heteroaryl containing one or more nitrogen, and is each C-attached; the other of G and J is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-membered fused aryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B. In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each

independently illustrated by one of the following heteroaryl groups:

wherein each of the above said heteroaryl groups is optionally substituted.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each

independently optionally substituted imidazolyl or benzimidazolyl.

In yet another embodiment, the present invention relates to compounds of F rmulae (3-Ia-l ~ 3-Ia-4), or a pharmaceutically acceptable salt thereof:

wherein Ring A, Ring B, G, J, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^7a and R ^9a are as previously defined in Formula (3-1).

In yet another embodiment, the present invention relates to compounds of F rmulae (3-Ia-5 ~ 3-Ia-6), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (3-1).

In yet another embodiment, the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (3-1).

In yet another embodiment, the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C ₁ -C ₄ alkyl).

In still another embodiment, the present invention relates to compounds of Formulae 3-Ib-l ~ 3-Ib-6), and pharmaceutically acceptable salts thereof:

wherein G, J, Q, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , and R ^9a are as previously defined in Formula (3-1); in Formula (3-Ib-l), Ring A, Ring B, and L are each present and as previously defined; in Formula (3-Ib-2), Ring A and Ring B are each present and as previously defined in Formula (3-1); in Formula (3-Ib-3), Ring B and L are each present and as previously defined in Formula (3-1); in Formula (3-Ib-4), Ring A and L are each present and as previously defined in Formula (3-1); in Formula (3-Ib-5), Ring B is present and as previously defined in Formula (3-1); and in Formula (3-Ib-6), L is present and as previously defined in Formula (3-1).

In still another embodiment, the present invention relates to compounds of Formulae (3-Ib-l ~ 3-Ib-6), and pharmaceutically acceptable salts thereof; wherein R ⁶ is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl). In still another embodiment, the present invention relates to compounds of Formula (3-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or bicyclic heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of

Formulae (3-Ib-3 ~ 3-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B or Ring A is optionally substituted bicyclic aryl or bicyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of

Formulae (3-Ib-3 ~ 3-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B or Ring A is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of

Formula (3-Ib-5), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or polycyclic heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl. In still another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.

In yet another embodiment, the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ - C ₄ alkyl; preferably hydrogen, halogen or hydroxy.

In still another embodiment, the present invention relates to com ounds of

Formula (3-1), and pharmaceutically acceptable salts thereof; wherein at each occurence is independently illustrated by one of the following groups:

Representative compounds of the present invention are those selected from compounds 3-1 to 3-347compiled in the following tables and/or shown below:

It is intended that the definition of any substituent or variable (e.g., R , R , etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when U is C(R ⁷ ) ₂ , each of the two R ⁷ groups may be the same or different. It is also intended that the drawn formula of any linker or spacer (e.g., -NH- C(O)-, -OC(0)-NH-, etc.) at a particular location in a molecule be independent of its directions of attachment, unless otherwise indicated. For example, when a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.

IV. Compounds having Formula (4-1)

In certain aspects, the present invention relates to compounds of Formula (4-1) as illustrated above, and pharmaceutically acceptable salts thereof.

In still another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.

In another embodiment, the present invention relates to com ounds of Formula (4-

I), and pharmaceutically acceptable salts thereof; wherein at each occurence is independently illustrated by one of the following groups:

each of which can be optionally substituted.

In yet another embodiment, R ^la and R ^9a , R ^la and R ⁹ , R ^ld and R ^9a , or R ^ld and R ⁹ are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.

In a further embodiment R ^lb and R ^9a , or R ^lb and R ⁹ are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.

In yet another embodiment, the present invention relates to compounds of Formula

(4-1), and pharmaceutically acceptable salts thereof; wherein the moiety of

is illustrated by one of the following core groups:

wherein R ⁶ is as previously defined in Formula (4-1) and each of the above core groups is optionally substituted. In an additional embodiment, the invention relates to compounds of Formula (4-1) and pharmaceutically acceptable salts thereof; wherein R^ is independently an optionally substituted C ₁ -C ₈ alkyl.

In a further embodiment, the invention relates to compounds of Formula (4-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R ₆ is an a-amino acid residue.

In yet another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted five-membered heteroaryl containing one or more nitrogen atoms, and is C-attached.

In yet another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms and wherein the 5- membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6- membered fused heteroaryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B.

In yet another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:

wherein each of the above said heteroaryl groups is optionally substituted.

In yet another embodiment, the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.

In yet another embodiment, the present invention relates to compounds of

Formulae (4-Ia-l ~ 4-Ia-4), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^ld , R ^7a , R ^7b and R ^9a are as previously defined in Formula (4-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (4-Ia-5 ~ 4-Ia-8), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , R ^ld , R ^7a , R ^7b and R ^9a are as previously defined in Formula (4-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (4-Ia-9 ~ 4-Ia-12), and pharmaceutically acceptable salts thereof;

wherein Ring A, Ring B, G, L, R ⁶ , R ^7a and R ^7b are as previously defined in Formula (4-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (4-Ia-13 ~ 4-Ia-16), and pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, L, R ⁶ , R ^7a and R ^7b are as previously defined in Formula (4-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (4-Ia-13 ~ 4-Ia-16), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ - C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (4-Ia-13 ~ 4-Ia-16), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C ₁ -C ₄ alkyl).

In still another embodiment, the present invention relates to compounds of Formulae (4-Ib- ~ 4-Ib-4), and pharmaceutically acceptable salts thereof;

wherein Ring B, G, Q, U, R ¹ , R ⁶ , R ^7a and R ^7b are as previously defined in Formula (4-1); in Formula (4-Ib-l), A and L are each present and as previously defined; in Formula (4-1). in Formula (4-Ib-2), Ring A is present and as previously defined in Formula (4-1); and in Formula (4-Ib-3), L is present and as previously defined in Formula (4-1).

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-l ~ 4-Ib-4), and pharmaceutically acceptable salts thereof; wherein R ⁶ is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl). In still another embodiment, the present invention relates to compounds of Formula (4-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl.

In still another embodiment, the present invention relates to compounds of

Formula (4-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (4-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In yet another aspect, the present invention relates to compounds of Formula (4-Ib- 4), and pharmaceutically acceptable salts thereof; wherein R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ - C ₄ alkyl; preferably hydrogen, halogen or hydroxyl.

Representative compounds of the present invention are those selected from compounds 4-1 to 4-348 compiled in the following tables and/or are shown below:

It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substitutent at any given location.

It is intended that the definition of any substituent or variable (e.g., R ³ , R ⁷ , etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when U is C(R ⁷ ) ₂ , each of the two R ⁷ groups may be the same or different.

It is also intended that the drawn formula of any linker or spacer (e.g., -NH- C(O)-, -OC(0)-NH-, etc.) at a particular location in a molecule be independent of its directions of attachment, unless otherwise indicated. For example, when a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments. V. Compounds having Formula (5-1)

In certain aspects, the present invention relates to compounds of Formula (5-1) as illustrated above, and pharmaceutically acceptable salts thereof.

In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R ^la and R ^9a , R ^la and R ⁹ , R ¹ and R ^9a , or R ¹ and R ⁹ are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.

In a further embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R ^lb and R ^9a , or R ^lb and R ⁹ are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.

In another embodiment, the present invention relates to compounds of Formula (5-

I), and pharmaceutically acceptable salts thereof; wherein the moiety of

is illustrated by one of the following core groups:

wherein R ⁶ is as previously defined and each of the above core groups is optionally substituted.

In an additional embodiment, the invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R^ is independently an optionally substituted C ₁ -C ₈ alkyl.

In a further embodiment, the invention relates to compounds of Formula (5-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R ₆ is an a-amino acid residue.

In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; G is an optionally substituted five- membered heteroaryl containing one or more nitrogen atoms, and is C-attached. In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen and wherein the 5-membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6-membered fused heteroaryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B.

In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:

wherein each of the above said heteroaryl groups is optionally substituted.

In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.

In yet another embodiment, the present invention relates to compounds of

Form lae (5-Ia-l ~ 5-Ia-4), and pharmaceutically acceptable salts thereof;

wherein Ring A, Ring B, G, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1).

In yet another embodiment, the present invention relates to compounds of

Formulae (5-Ia-5 ~ 5-Ia-7), and pharmaceutically acceptable salts thereof;

wherein Ring A, Ring B, G, L, U, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1).

In yet another embodiment, the present invention relates to compounds of Formulae (5-Ia-8 ~ 5-Ia-9), and pharmaceutically acceptable salts thereof;

wherein Ring A, Ring B, G, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1).

In yet another embodiment, the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof;

wherein Ring A, Ring B, G, L, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1).

In yet another embodiment, the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.

In still another embodiment, the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C ₁ -C ₄ alkyl).

In still another embodiment, the present invention relates to compounds of Formulae (5-Ib-l ~ 5-Ib-4), and pharmaceutically acceptable salts thereof;

wherein Ring B, G, Q, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1); in Formula (5-Ib-l), Ring A and L are each present and as previously defined in Formula (5-1); in Formula (5-Ib-2), Ring A is present and as previously defined in Formula (5-1); and in Formula (5-Ib-3), L is present and as previously defined in Formula (5-1).

In still another embodiment, the present invention relates to compounds of Formulae (5-Ib-l ~ 5-Ib-4), and pharmaceutically acceptable salts thereof; wherein R ⁶ at each occurrence is independently C ₁ -C ₈ alkyl optionally substituted with amino, hydroxy, protected amino or 0(C ₁ -C ₄ alkyl).

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Rng B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-2) and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl. In still another embodiment, the present invention relates to compounds of Formula (5-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.

In still another embodiment, the present invention relates to compounds of Formulae (5-Ib-5 ~ 5-Ib-8), and pharmaceutically acceptable salts thereof:

wherein Ring B, Q, V, R ¹ , R ⁶ , R ⁹ , R ^la , R ^lb , R ^lc , and R ^9a are as previously defined in Formula (5-1); in Formula (5-Ib-5), Ring A and L are each present and as previously defined in Formula (5-1); in Formula (5-Ib-6), Ring A is present and as previously defined in Formula (5-1); and in Formula (5-Ib-7), L is present and as previously defined in Formula (5-1).

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-5), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-6), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-6), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-7), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In still another embodiment, the present invention relates to compounds of

Formula (5-Ib-7), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C ₂ -C ₄ alkenyl or optionally substituted C ₂ -C ₄ alkynyl.

In still another embodiment, the present invention relates to compounds of Formula (5-Ib-8), or a pharmaceutically acceptable salt thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl.

In still another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C ₃ -C ₈ cycloalkyl, C3-C ₈ cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.

In still another embodiment, the present invention relates to compounds of

Formula (5-1), and pharmaceutically acceptable salts thereof; wherein two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.

In yet another embodiment, the present invention relates to compounds of Formula

(5-1), and pharmaceutically acceptable salts thereof; wherein R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy,

0(C ₁ -C ₄ alkyl), S(C ₁ -C ₄ alkyl), amino optionally substituted with one or two C ₁ -C ₄ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C ₁ -

C ₄ alkyl; preferably hydrogen, halogen or hydroxy. In still another embodiment, the present invention relates to com ounds of

Formula (5-1), and pharmaceutically acceptable salts thereof; wherein each occurence is independently illustrated by one of the following groups:

Representative compounds of the present invention are those selected from compounds 5-1 to 5-394 compiled in the following tables and/or shown below:

It will be appreciated that the description of the present invention herein should construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substitutent at any given location.

It is intended that the definition of any substituent or variable (e.g., R ³ , R ⁷ , etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when U is C(R ⁷ ) ₂ , each of the two R ⁷ groups may be the same or different.

It is also intended that the drawn formula of any linker or spacer (e.g., -NH- C(O)-, -OC(0)-NH-, etc.) at a particular location in a molecule be independent of its directions of attachment, unless otherwise indicated. For example, when a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.

It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substitutent at any given location. It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.

It should be understood that in some embodiments, the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.

It will be further appreciated that reference herein to therapy and/or treatment includes, but is not limited to, prevention, retardation, prophylaxis, therapy and/or cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

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 disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These agents include, but are 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 R A; anti-sense R A; 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 NS5 A protein.

According to yet another embodiment, the pharmaceutical compositions of the present invention may further comprise other inhibitor(s) of 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 include, but are not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, 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. An example of the RNA-containing virus includes, but is 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. An example of the RNA-containing virus includes, but is 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. An example of the R A-containing virus includes, but is 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-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof. An example of the RNA- containing virus includes, but is 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 pharmaceutically 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 modulator include, but are 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. 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 R A-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 (also referred to herein as a CYP 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 this invention. Accordingly, the CYP inhibitor is administered in an amount such that the bioavailiablity of the protease inhibitor is increased in comparison to the bioavailability in the absence of the CYP inhibitor.

In one embodiment, the invention provides methods for improving the

pharmacokinetics of compounds of the invention. The advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, US Patent Pub. Nos. 2004/0091527; US 2004/0152625; and US 2004/0091527). Accordingly, one embodiment of this invention provides a method for administering an inhibitor of CYP3 A4 and a compound of the invention. Another embodiment of this invention provides a method for administering a compound of the invention and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2C19 ("CYP2C19"), isozyme 2D6 ("CYP2D6"), isozyme 1 A2 ("CYP1 A2"), isozyme 2C9 ("CYP2C9"), or isozyme 2E1 ("CYP2E1"). In a preferred embodiment, the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention. These CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfmavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.

It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, containing within a package insert instructing the patient to the correct use of the invention is a desirable additional feature of this invention.

According to a further aspect of the invention is a pack comprising at least a compound of the invention and a CYP inhibitor of the invention and an information insert containing directions on the use of the combination of the invention. In an alternative embodiment of this invention, the pharmaceutical pack further comprises one or more of additional agent as described herein. The additional agent or agents may be provided in the same pack or in separate packs.

Another aspect of this involves a packaged kit for a patient to use in the treatment of HCV infection or in the prevention of HCV infection, comprising: a single or a plurality of pharmaceutical formulation of each pharmaceutical component; a container housing the pharmaceutical formulation(s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.

Accordingly, this invention provides kits for the simultaneous or sequential administration of a compound of the invention and a CYP inhibitor (and optionally an additional agent) or derivatives thereof are prepared in a conventional manner. Typically, such a kit will comprise, e.g. a composition of each inhibitor and optionally the additional agent(s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.

In another embodiment, a packaged kit is provided that contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration. The instructions will typically be written instructions on a package insert, a label, and/or on other components of the kit, and the dosage form or forms are as described herein. Each dosage form may be individually housed, as in a sheet of a metal foil- plastic laminate with each dosage form isolated from the others in individual cells or bubbles, or the dosage forms may be housed in a single container, as in a plastic bottle. The present kits will also typically include means for packaging the individual kit components, i. e., the dosage forms, the container means, and the written instructions for use. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.

DEFINITIONS

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

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.

The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and idenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a

combination thereof.

The term "heteroaryl," as used herein, refers to a mono- or polycyclic ring system comprising at least one aromatic ring having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, and quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.

In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.

The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings wherein at least one ring is aromatic; and they can be fused or covalently attached.

The term "tricyclic aryl" or "tricyclic heteroaryl" refers to a ring system consisting of three rings wherein at least one ring is aromatic.

The terms "C ₁ -C ₄ alkyl," "C ₁ -C ₆ alkyl," "C ₁ -C ₈ alkyl," "C ₂ -C ₄ alkyl," or "C ₃ -C ₆ alkyl," as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and four, one and six, one and eight carbon atoms, or the like, respectively. Examples of C ₁ -Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The terms "C ₂ -C ₈ alkenyl," "C ₂ -C ₄ alkenyl," "C ₃ -C ₄ alkenyl," or "C ₃ -C ₆ alkenyl," as used herein, refer to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The terms "C ₂ -C ₈ alkynyl," "C ₂ -C ₄ alkynyl," "C ₃ -C ₄ alkynyl," or "C ₃ -C ₆ alkynyl," as used herein, refer to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "C ₃ -C8-cycloalkyl", or "Cs-Cy-cycloalkyl," as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted. Examples of C ₃ -C8-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-Cycycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like.

The term "C ₃ -C ₈ cycloalkenyl" or "C5-C7 cycloalkenyl," as used herein, refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond, and the carbon atoms may be optionally oxo-substituted. Examples of C ₃ -C ₈ cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C5-C7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

The term "arylalkyl," as used herein, refers to an aryl-substituted alkyl group. More preferred arylalkyl groups are aryl-C ₁ -C ₆ -alkyl groups.

The term "heteroarylalkyl," as used herein, refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-C ₁ -C6-alkyl groups.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.

An "aliphatic" group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are functional groups, such as, O, OH, NH, NH ₂ , C(O), S(0) ₂ , C(0)0, C(0)NH, OC(0)0, OC(0)NH, OC(0)NH ₂ , S(0) ₂ NH, S(0) ₂ NH ₂ , NHC(0)NH ₂ , NHC(0)C(0)NH, NHS(0) ₂ NH, NHS(0) ₂ NH ₂ , C(0)NHS(0) ₂ ,

C(0)NHS(0) ₂ NH or C(0)NHS(0) ₂ NH ₂ , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo- substituted. An aliphatic group may be straight chained, branched, cyclic, or a

combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and

polyimines, for example. Aliphatic groups may be optionally substituted. A linear aliphatic group is a non-cyclic aliphatic group. It is to be understood that when an aliphatic group or a linear aliphatic group is said to "contain" or "include" or "comprise" one or more specified functional groups, the aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group. In some examples, the linear aliphatic group can be represented by the formula M-V'-M', where M and M' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and V is a functional group. In some examples, V is selected from the group consisting of C(O), S(0) ₂ , C(0)0,

C(0)N(R ⁿ ), OC(0)0, OC(0)N(R ⁿ ), S(0) ₂ N(R ⁿ ), N(R ⁿ )C(0)N(R ⁿ ),

N(R ⁿ )C(0)C(0)N(R ⁿ ), N(R ⁿ )S(0) ₂ N(R ⁿ ), C(0)N(R ⁿ )S(0) ₂ or

C(0)N(R ⁿ )S(0) ₂ N(R ⁿ ); wherein R ¹¹ is as previously defined. In another aspect of the invention, an exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group such as described herein.

The term "alicyclic," as used herein, denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom, and the carbon atoms may be optionally oxo-substituted. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo

[2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.

The terms "heterocyclic" or "heterocycloalkyl" can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).

The term "substituted" when used with alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, or aliphatic as described herein refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, - OH, protected hydroxy, -N0 ₂ , -N ₃ , -CN, -NH ₂ , protected amino, oxo, thioxo, -NH-C1-C12- alkyl, -NH-C ₂ -C ₈ -alkenyl, -NH-C ₂ -C ₈ -alkynyl, -NH-C ₃ -C ₁₂ -cycloalkyl, -NH-aryl, -NH- heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O- C ₁ -C ₁₂ -alkyl, -0-C ₂ -C ₈ -alkenyl, -0-C ₂ -C ₈ -alkynyl, -0-C ₃ -C ₁₂ -cycloalkyl, -O-aryl, -O- heteroaryl, -O-heterocycloalkyl, -C(0)-C ₁ -C ₁₂ -alkyl, -C(0)-C ₂ -C ₈ -alkenyl, -C(0)-C ₂ -C ₈ - alkynyl, -C(0)-C ₃ -C ₁₂ -cycloalkyl, -C(0)-aryl, -C(0)-heteroaryl, -C(0)-heterocycloalkyl, - CONH ₂ , -CONH-C ₁ -C ₁₂ -alkyl, -CONH-C ₂ -C ₈ -alkenyl, -CONH-C ₂ -C ₈ -alkynyl, -CONH- C ₃ -C ₁₂ -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OC0 ₂ -d- C ₁₂ -alkyl, -OC0 ₂ -C ₂ -C ₈ -alkenyl, -OC0 ₂ -C ₂ -C ₈ -alkynyl, -OC0 ₂ -C ₃ -C ₁₂ -cycloalkyl, - OC0 ₂ -aryl, -OC0 ₂ -heteroaryl, -OC0 ₂ -heterocycloalkyl, -C0 ₂ -C ₁ -C ₁₂ alkyl, -C0 ₂ -C ₂ -C ₈ alkenyl, -C0 ₂ -C ₂ -C ₈ alkynyl, C0 ₂ -C ₃ -C ₁₂ -cycloalkyl, -C0 ₂ - aryl, C0 ₂ -heteroaryl, C0 ₂ - heterocyloalkyl, -OCONH ₂ , -OCONH-C ₁ -C ₁₂ -alkyl, -OCONH-C ₂ -C ₈ -alkenyl, -OCONH- C ₂ -C ₈ -alkynyl, -OCONH-C ₃ -C ₁₂ -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, - OCONH- heterocycloalkyl, -NHC(0)H, -NHC(0)-C ₁ -C ₁₂ -alkyl, -NHC(0)-C ₂ -C ₈ -alkenyl, -NHC(0)-C ₂ -C ₈ -alkynyl, -NHC(0)-C ₃ -C ₁₂ -cycloalkyl, -NHC(0)-aryl, -NHC(O)- heteroaryl, -NHC(0)-heterocycloalkyl, -NHC0 ₂ -C ₁ -C ₁₂ -alkyl, -NHC0 ₂ -C ₂ -C ₈ -alkenyl, - NHCO ₂ - C ₂ -C ₈ -alkynyl, -NHC0 ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHC0 ₂ -aryl, -NHC0 ₂ -heteroaryl, - NHC0 ₂ - heterocycloalkyl, -NHC(0)NH ₂ , -NHC(0)NH-C ₁ -C ₁₂ -alkyl, -NHC(0)NH-C ₂ -C ₈ - alkenyl, -NHC(0)NH-C ₂ -C ₈ -alkynyl, -NHC(0)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH-heterocycloalkyl, NHC(S)NH ₂ , -NHC(S)NH-C C ₁₂ -alkyl, -NHC(S)NH-C ₂ -C ₈ -alkenyl, -NHC(S)NH-C ₂ -C ₈ -alkynyl, -NHC(S)NH-C ₃ -C ₁₂ - cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, - NHC(NH)NH ₂ , -NHC(NH)NH-C ₁ -C ₁₂ -alkyl, -NHC(NH)NH-C ₂ -C ₈ -alkenyl, - NHC(NH)NH-C ₂ -C ₈ -alkynyl, -NHC(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)NH-aryl, - NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C ₁ -C ₁₂ -alkyl, - NHC(NH)-C ₂ -C ₈ -alkenyl, -NHC(NH)-C ₂ -C ₈ -alkynyl, -NHC(NH)-C ₃ -C ₁₂ -cycloalkyl, -

NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C ₁ -C ₁₂ - alkyl, -C(NH)NH-C ₂ -C ₈ -alkenyl, -C(NH)NH-C ₂ -C ₈ -alkynyl, -C(NH)NH-C ₃ -C ₁₂ - cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)- C ₁ -C ₁₂ -alkyl, -S(0)-C ₂ -C ₈ -alkenyl, - S(0)-C ₂ -C ₈ -alkynyl, -S(0)-C ₃ -C ₁₂ -cycloalkyl, -S(O)- aryl, -S(0)-heteroaryl, -S(0)-heterocycloalkyl, -S0 ₂ NH ₂ , -S0 ₂ NH-C ₁ -C ₁₂ -alkyl, -S0 ₂ NH- C ₂ -C ₈ -alkenyl, -S0 ₂ NH- C ₂ -C ₈ -alkynyl, -S0 ₂ NH-C ₃ -C ₁₂ -cycloalkyl, -S0 ₂ NH-aryl, - S0 ₂ NH-heteroaryl, -S0 ₂ NH- heterocycloalkyl, -NHS0 ₂ -C ₁ -C ₁₂ -alkyl, -NHS0 ₂ -C ₂ -C ₈ - alkenyl, - NHS0 ₂ -C ₂ -C ₈ -alkynyl, -NHS0 ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHS0 ₂ -aryl, -NHS0 ₂ - heteroaryl, -NHS0 ₂ -heterocycloalkyl, -CH ₂ NH ₂ , -CH ₂ S0 ₂ CH ₃ , -aryl, -arylalkyl, - heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C ₃ -C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C ₁ -C ₁₂ -alkyl, -S-C ₂ -C ₈ -alkenyl, - S-C ₂ -C ₈ -alkynyl, -S-C ₃ -C ₁₂ -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.

The term "halogen," as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.

The term "hydrogen" includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.

The term "hydroxy activating group," as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like. The term "activated hydroxyl," as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.

The term "hydroxy protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl,

diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t- butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl,

trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

The term "carbonyl protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a carbonyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the carbonyl protecting group as described herein may be selectively removed. Carbonyl protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

Examples of carbonyl protecting groups include acetals, ketals, cyclic acetals, cyclic ketals, mono- or dithio acetals, mono- or dithioketals, optionally substituted hydrazones or oximes.

The term "protected carbonyl," as used herein, refers to a carbonyl group protected with a carbonyl protecting group, as defined above, including dimethyl acetal, 1,3- dioxolane, 1,3-dioxane, S,S'-dimethylketal, 1,3-dithiane, 1,3-dithiolane, 1,3-oxathiolane, N,N-dimethylhydrazone, oxime, for example.

The term "amino protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

The term "protected amino," as used herein, refers to an amino group protected with an amino protecting group as defined above.

The term "substituted amino," as used herein, refers to substitution by replacement of one or two hydrogen atoms of -NH ₂ with substituents independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; alternatively, when disubstituted, the two substitutents can be optionally taken together with the nitrogen atom to which they are attached to form an optionallysubstituted heterocyclic group.

The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; hydroxy; imidazolyl; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.

The term "protic solvent," as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents

Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable," as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid

chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2 ^nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

The term "subject," as used herein, refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like. The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:

1- 19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,

dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,

2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, /?-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and

ethylsuccinates.

The term "pharmaceutically acceptable prodrugs," as used herein, refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the

zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug," as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds of Formula (1-1),

Formula (2-1), Formula (3-1), Formula (4-1) and Formula (5-1), for example hydrates.

This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention. For example, compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions of the present invention comprise a

therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term "parenteral," as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No. 5,508,269 to Smith et al, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in U.S. Pat. No. 6,014,969, incorporated herein by reference. ANTIVIRAL ACTIVITY

An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 0.1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

According to the methods of treatment of the present invention, viral infections are treated or prevented in a patient such as a human or another animal by administering to the subject a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.

The term "therapeutically effective amount" of a compound of the invention, as used herein, means an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).

The term "inhibitory amount" of a compound of the present invention means a sufficient amount to decrease the viral load in a biological sample or a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90%> or 95%, reduction in viral load). It is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit/risk ratio applicable to any medical treatment as determined by a physician. The term "biological sample(s)," as used herein, means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells. Thus, another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.

Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

When the compositions of this invention comprise a combination of a compound of the Formula (1-1), Formula (2-1), Formula (3-1), Formula (4-1) and Formula (5-1), described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally

administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The said "additional therapeutic or prophylactic agents" include, but are not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta- 2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti- muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), antioxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantadine). The compositions according to the invention may also be used in combination with gene replacement therapy.

COMBINATION AND ALTERNATION THERAPY FOR HCV

It has been recognized that drug-resistant variants of HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HCV, RNA polymerase, protease, or helicase.

Recently, it has been demonstrated that the efficacy of a drug against a viral infection, such as HIV, can be prolonged, augmented, or restored by administering the drug in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principal drug. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.

A compound of the present invention can also be administered in combination or alternation with antiviral agent. Examplary antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 53 below.

Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art. All

publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety. ABBREVIATIONS

Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for

azobisisobutyronitrile; BINAP for 2,2'-bis(diphenylphosphino)-l, -binaphthyl; Boc ₂ 0 for di-fert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for 1 -methyl- 1 -(4- biphenylyl)ethyl carbonyl; BtOH for 1-hydroxy-benzotriazole; Bz for benzoyl; Bn for benzyl; BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassium tert- butoxide; Bu ₃ SnH for tributyltin hydride; BOP for (benzotriazol-1- yloxy)tris(dimethylamino)phos-phonium Hexafluorophosphate; Brine for sodium chloride solution in water; Cbz for carbobenzyloxy; CDI for carbonyldiimidazole; CH ₂ C1 ₂ for dichloromethane; CH ₃ for methyl; CH ₃ CN for acetonitrile; Cs ₂ C0 ₃ for cesium carbonate; CuCl for copper (I) chloride; Cul for copper (I) iodide; dba for dibenzylidene acetone; dppb for diphenylphosphino butane; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC for Ν,Ν'-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or (i-Pr) ₂ EtN for Ν,Ν-diisopropylethyl amine; Dess- Martin periodinane for l,l,l-tris(acetyloxy)-l,l-dihydro-1,2-benziodoxol-3-(1H)-one ; DMAP for 4-dimethylaminopyridine; DME for 1 ,2-dimethoxy-ethane; DMF for N,N- dimethylformamide; DM SO for dimethyl sulfoxide; DMT for

methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA for diphenylphosphoryl azide; EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; EDC HCl for N-(3- dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et ₂ 0 for diethyl ether; Fmoc for 9-fluorenylmethoxycarbonyl; HATU for 0-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium Hexafluorophosphate; HCl for hydrogen chloride; HOBT for 1-hydroxybenzotriazole; K ₂ C0 ₃ for potassium carbonate; n-BuLi for n-butyl lithium; z ^' -BuLi for z ^' -butyl lithium; t-BuLi for t-butyl lithium; PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP for lithium 2,2,6, 6-tetramethylpiperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or -SO ₂ -CH ₃ ; Ms ₂ 0 for methanesulfonic anhydride or mesyl-anhydride; NaBH ₄ for sodium borohydride; NaBH ₃ CN for sodium

cyanoborohydride; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHC0 ₃ for sodium bicarbonate or sodium hydrogen carbonate; Na ₂ C0 ₃ sodium carbonate; NaOH for sodium hydroxide; Na ₂ S0 ₄ for sodium sulfate; NaHS0 ₃ for sodium bisulfite or sodium hydrogen sulfite; Na ₂ S ₂ 0 ₃ for sodium thiosulfate; NH ₂ NH ₂ for hydrazine; NH ₄ HC0 ₃ for ammonium bicarbonate; NH ₄ C1 for ammonium chloride; NMMO for N-methylmorpholine N-oxide; NaI0 ₄ for sodium periodate; Ni for nickel; OH for hydroxyl; Os0 ₄ for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB for p-methoxybenzyl; POPd for dihydrogen dichlorobis(di-tert- butylphosphinito-KP)palladate(II); Pd ₂ (dba) ₃ for tris(dibenzylidene-acetone) dipalladium (0); Pd(PPh ₃ ) ₄ for tetrakis(triphenylphosphine)palladium (0); PdCl ₂ (PPh ₃ ) ₂ for trans- dichlorobis(triphenyl-phosphine)palladium (II); Pt for platinum; Rh for rhodium; rt for romm temperature; Ru for ruthenium; SEM for (trimethylsilyl)ethoxymethyl; TBAF for tetrabutylammonium fluoride; TBS for tert-butyl dimethylsilyl; TEA or Et ₃ N for triethylamine; Teoc for 2-trimethylsilyl-ethoxy-carbonyl; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA for Ν,Ν,Ν' ,Ν'-tetramethylethylenediamine; TPP or

PPh ₃ for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Ts for tosyl or -S0 ₂ - C ₆ H ₄ CH ₃ ; Ts ₂ 0 for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; TMS for trimethylsilyl; or TMSC1 for trimethylsilyl chloride.

SYNTHETIC METHODS

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art. It will be readily apparent to one of ordinary skill in the art that the compounds defined above can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be readily apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the variables to successfully complete the syntheses below. The variables are as defined above unless otherwise noted below.

The compounds of the present invention may be prepared via several different synthetic routes from a variety of 5/6-membered fused heteroaryl, 5-membered heteroaryl, and related intermediates. A retro-synthesis of the compounds include direct formation of a suitably linked core structure (5/6-membered fused heteroaryl or 5-membered heteroaryl) followed by attachment of a suitable capping group (such as -C(0)R ⁶ ), plus some functional group manipulations in between and/or after. Various 5/6-membered fused heteroaryl or 5-membered heteroaryl intermediates are known to those skilled in the art, for example see the encyclopedic volumns edited by A. R. Katrizky, et al,

"Comprehensive Heterocyclic Chemistry" 1984; "Comprehensive Heterocyclic Chemistry II" 1996; "Comprehensive Heterocyclic Chemistry III" 2008.

A general synthesis and further elaboration of some 6-membered ring fused imidazole related intermediates are summarized in Scheme 1, in which Z is N or CH.

The synthesis starts from the construction of an optionally substituted

imidazopyridine or benzimidazole 1-2, which may be obtained by condensation of an amino acid or its derivative 1-1.1 or 1-1.2 and a 2,3-diaminopyridine or 1,2- diaminobenzene 1-1 under the conditions to those skilled in the art. The imidazole ring closure may be realized either in one pot by heat, optionally in the presence of an acid and/or with a dehydration reagent such as polyphosphoric acid; or in two steps: 1) amide formation between diamine 1-1 and amino acid 1-1.1 or 1-1.2 in the presence of a condensation reagent such as EDC C1 , DCC or the like; or through mixed anhydride approach by reacting acid 1-1.1 or 1-1.2 with a chloroformate such as methyl

chloroformate, isobutyl chloroformate, or the like, in the presence of a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like, followed by treating the mixed anhydride with diamine 1-1; and 2) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.

Optionally, the NH group in the newly formed imidazopyridine or benzimidazole ring of 1-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like. The protected imidazopyridine or benzimidazole 1-2 may be subjected to lithium-halogen exchange with various (n-, s-, or t-) butyl lithium and the resulting lithiate can be trapped with a nucleophile, i.e. a halide such as various allyl halide to give the allylated 1-6 as a key intermediate. Alternatively, 1-6 may be obtained from the Stille reaction conditions to those skilled in the art (see reviews: A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis, 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J., 2008, 14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed., 2007, 46, 2768; V. Farina, et al, Advances in Metal-Organic Chem., 1996, 5, 1), using an allylstanne such as allyltributylstanne as the allyl donor. Analogously a key vinyl intermediates 1-3 may be prepared by Stille reaction from bromide 1-2 with tributylvinylstanne. Also, Sonogashira coupling between bromide 1-2 and propargyl alcohol or trimethylsilyl-acetylene can generate propargyl alcohol 1-4 or alkyne 1-5 after removal of TMS. Further bromination of intermediate 1-4 may form the propargyl bromide 1-9. In addition, the bromide 1-2 may be converted to methyl ketone 1-7 by coupling with tributyl(l-ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis.

Further elaboration of the imidazopyridine or benzimidazole intermediates starts from the vinyl intermediate 1-3, which may be transformed to aldehyde 1-8 through ozonolysis or periodate/OsC^ cleavage or to alcohol 1-12 by hydroboration-oxidation sequence. Alcohol 1-12 may be converted to bromide 1-15 by the well-known

bromination procedure, which can be further functionalized to amine 1-20 through azide substitution followed by reduction. Aldehyde 1-8 can then either be reduced to alcohol 1- 11, or be converted to a, β-unsatuated acid 1-10 through Horner- Wadsworth-Emmons aldehyde homologation reaction followed by saponification. Alcohol 1-11 may be similarly converted to the correponding amine intermediate 1-14 and bromide intermediate 1-13 as described previously. Bromide 1-13 can be homologated to alkyne intermediate 1- 19 with a metal acetylide. In addition, bromide 1-13 may be also tranformed to thiol 1-16 through nucleophilic substitution, which can be further oxidized to sulfonic acid 1-17. Sulfonamide 1-18 may then be derived from 1-17 through the sulfonyl chloride activation process.

It should be noted that optionally the NH group of all the imidazopyridine or benzimidazole related intermediates listed above may be protected with an amino protecting group, such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like.

A typical syntheses of imidazole related intermediates are analogous to that of the imidazopyridine or benzimidazole intermediates. As shown in Scheme 2, bromo- imidazole 2-4 can be synthesized in a three-step sequence: 1) condensation between amino acid derived aldehyde 2-1.1 or 2-1.2 and glyoxal 2-1.3 in the presence of methanolic ammonia to generate imidazole 2-2; 2) bromination of 2-2 with excess amount of bromination reagent such as 2,4,4,6-tetrabromo-2,5-cyclohexadienone, NBS, etc. to afford dibromide 2-3; and 3) selective reduction of the dibromide 2-3 by heating in aq. Na ₂ S03 or aq. NaHS0 ₃ . 2-4 then may be served as a universal intermediate further elaborable to many other imidazole derivatives using the chemistry discussed in Scheme 1, some of which are listed in the table 54 below.

Optionally, the NH group of imidazole related intermediates listed above may be protected with an amino protecting group (shown in Scheme 2 as PG, theoretically the reaction will generate two regio-isomers, but only one is drawn for clarity), such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like. The protected imidazole 2-5 may be deprotonated with a strong base such as LDA, BuLi, etc to generate a carbon anion, which may either undergo a nucleophilic substitution with an activated halide such as 2- 5.2 to afford aryl or heteroaryl substituted imidazole 2-6 or couple with an aryl or heteroaryl halide 2-5.1 in the presence appropriate transition metal salt to generate bicyclic heteroaryl 2-7. Similarly, the protected bromo imidazole 2-8 may be subjected to lithium- halogen exchange with various (n-, s-, or t-) butyl lithium, the resulting lithiate may undergo similar reactions to afford 2-6 and 2-7. Also, when 2-8 is treated with metallated aryl or heteroaryl 2-8.1, in which M at each occurrence is independently a boron, tin, silicon, zinc, zirconium, or copper species, under Suzuki, Stille or related coupling conditions known to those skilled in the art (see reviews: A. Suzuki, Pure Applied Chem. 1991, 63, 419; A. Suzuki, Handbook of Organopalladium Chemistry for Organic

Synthesis, 2002, 1, 249; A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis, 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis, 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J., 2008, 14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed., 2007, 46, 2768; V. Farina, et al, Advances in Metal-Organic Chem., 1996, 5, 1), to provide coupling product 2-7. In addition to these direct coupling strategy, aryl or heteroaryl bromide 2-5.1 may be converted to methyl ketone 2-9 under Stille coupling conditions with tributyl(l-ethoxyvinyl)tin 2-9.1. 2-9 may be brominated under conditions to those skilled in the art to afford bromide 2-10, which may be either converted to the corresponding amine 2-11, or coupled with protected amino acid 1-1.1 or 1-1.2 in the presence of a base such as Et ₃ N and DIPEA to afford keto-ester 2-12. Similarly, amine 2-11 may be converted to the corresponding keto-amide 2-13 via condensation with appropriate amino acid under standard amide formation conditions. 2- 12 and 2-13 may be tranformed to key intermediate 2-14 via heating with (NH ₄ )OAc under thermal or microwave conditions.

Similarly when Q is a fused bicyclic group as previously defined, compounds of the present invention may be synthesized from intermediates 3-2 and 3-3 (as shown in Scheme 3), which may be synthesized using similar chemistry described in Schemes 1 and 2 from the bicyclic carboxylic acid 3-1. Bicyclic carboxylic acids or derivatives with various structural features are either commercially available or known in the literature, and have been extensively reviewed by S. Hanessian, et al {Tetrahedron, 1997, 53, 12789) and A. Trabocchi, et al {Amino Acids, 2008, 34, 1) which are incorporated herein by reference.

Scheme 3

Other requisite buiding blocks for the syntheses of the molecule of the present invention are various amide, carbamate or urea-related intermediates, which can be prepared from a suitable, commercially available amine through standard amide, carbamate or urea formation by direct condensation of an carboxylic acid with a dehydration and/or condensation reagent, such as HATU, DCC, BtOH, EDC or the like; or a chloroformate; or an isocyanate; in the presence of a suitable base such as pyridine, TEA, DIPEA, DMAP, NaHC0 ₃ , K ₂ C0 ₃ or the like. For example, as shown in Scheme 3a, the Boc-protected β-amino acid 3- la can be condensed with 4-bromoaniline 3-2a in the presence of HATU and DIPEA in CH ₂ C1 ₂ to afford amide 3-3a.

3-1 a 3-2a 3-3a

Other examples of some of the amide -related intermediates that may be used to construct the title compounds of the present invention are compiled in the table 55 below.

Table 55

In addition to the intermediates mentioned above, other requisite buiding blocks for the syntheses of the molecule of the present invention are various heteroaryl or aryl amine related intermediates, which can be prepared from a suitable, commercially available amine through standard nucleophilic substitution by direct condensation of a heteroaryl halide such as 5-bromo-2-chloropyrimidine, 2,6-dibromoquinazoline, 6-bromo- 2-chlorobenzothiazole, or the like; with an appropriate amine such as 2-aminomethyl-N- Boc-pyrrolidine, l-Boc-3-aminopyrrolidine, trans-N-Boc1,2-cyclopentanediamine or the like; in the presence of a suitable base such as pyridine, TEA, DIPEA, DMAP, NaHC0 ₃ , K ₂ C0 ₃ or the like; under thermal or microwave conditions. Alternatively, some of these heteroaryl or aryl amino related intermediates can be prepared through transition metal catalyzed amination process between an suitable amine as mentioned above and an aryl or heteroaryl iodide or bromide such as 5-bromo-2-iodopyridine, 1 ,4-diiodobenzene, or the like; in the presence of a suitable base such as Cs ₂ C0 ₃ , K ₃ P0 ₄ , K ₂ C0 ₃ or the like; and an appropriate transition metal catalyst such as Cul or various Pd related catalysts; and an related ligand according to the used transition metal catalyst; under inert atmosphere. For example, as shown in Scheme 3b, the Boc-protected β-diamine 3-lb can be condensed with 5-bromo-2-chloropyrimidine 3-2b in the presence of DIPEA in 1,4-dioxane under thermal or microwave conditions to afford pyrimidynyl amine 3-3b. Alternatively, 3-lb can be reacted with 5-bromo-2-iodopyridine 3-4b in the presence of Cs ₂ C0 ₃ , catalytic amount of Cul, and 2-isobutyrylcyclohexanone as ligand, in DMF under N ₂ atmosphere to yield the desired pyridinyl amine 3-5b as described by S. L. Buchwald (J. Am. Chem. Soc. 2006, 128, 8742).

3-1 b 3-4 b 3-5b

Other examples of some aryl or heteroaryl amine related intermediates that may be used to construct the title compounds of the present invention are compiled in the table 56 below.

imidazoles such as those listed in Schemes 1-3 and the amide-related derivatives such as that in Scheme 3a, and the tables above in hand, the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments, optionally with a suitable cyclic or acyclic linker or formation of a cyclic or acyclic linker. The said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, alkylation, pericyclic reaction with different variations, or the like.

An example of the strategies that may be used to prepare the compounds of the present invention is shown in Scheme 4. Both bromides 4-1 and 4-2 can be prepared using similar procedures described in Schemes 1-3 and 3a. Bromide 4-2 can be converted to the corresponding metallated aryl 4-3 (boronate or stanne) under Suzuki or Stille conditions with bis(pinacolato)diboron, hexamethylditin or hexabutylditin in the presence of Pd- catalyst. The latter may be further coupled with imidazopyridine bromide 4-1 under similar conditions to generate a core structure 4-4.

Compound 4-4 then may be served as a common intermediate for further derivatizations to 4-5 in two steps: 1) mono-deprotection of the linear or cyclic amine moiety may be accomplished, for example, treatment to hydrogenolytic conditions under Pd catalyst to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate. Various carboxylic acids including amino acids in racemic or optical form are commercially available, and/or can be synthesized in racemic or optical form, see references cited in reviews by D.

Seebach, et al, Synthesis, 2009, 1; C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry, 2007, 18, 569; 2000, 11, 645; and 1998, 9, 3517; and experimental examples compiled in patent application WO 08/021927 A2 by C. Bachand, et al, from Brisol- Myers Squibb, Co., which is incorporated herein by reference. 4-5 may be further deprotected under hydrolytic conditions in the presence of an acid such as TFA or hydrogen chloride to remove the Boc protection group and the released amine

functionality can be further derivatized to the title compounds 1-1, with a carboxylic acid using the conditions described above.

Alternatively, as shown in Scheme 4a, the compounds of the present invention (for example I-l) may also be derived from bromoimidazopyridine or bromobenzimidazole 4- la and amide 4-2a using the procedures described previously. The intermediates 4- la and 4-2a have the desired acyl groups already installed using similar sequences shown in Scheme 4.

The compounds of the present invention containing five-membered heteroaryl other than imidazole may be prepared using similar procedures described above in Schemes 1-4 and 4a. For example, some intermediates containing a desired, suitably substituted five-membered heteroaryl have been published in US 2008/0311075A1 by C. Bachand, et al from Bristol-Myers Squibb, Co., which is incorporated by reference.

Theses intermediates are compiled in the following table 57. Table 57

The synthesis of the compounds of the present invention involves 5/6-membered fused heteroaryl intermediates other than imidazopyridines or benzimidazoles, various 5/6-membered fused heteroaryl are known in the literature. The synthesis of other 5/6- membered fused heteroaryl intermediates depends on the chemical features of each structure. For example, a typical synthesis of indole intermediate is illustrated in Scheme 5. The commercially available bromoiodoaniline 5-1 may be coupled to the commercially available acetylene 5-1.1 under the Sonogashira conditions to give phenylacetylene 5-2. The latter may be cyclized to indole 5-3 under heat or microwave condition in the presence of a copper catalyst.

It will be appreciated that, with appropriate manipulation and protection of any chemical functionality, synthesis of compounds of Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts "Protective Groups in Organic Synthesis", 3rd Ed (1999), J Wiley and Sons.

In certain aspects, the invention encompasses a process of making a compound of the invention comprising:

i) preparing a compound of Formula (II): via a transition-metal catalyzed cross-coupling reaction; wherein:

G, J, U, R ¹ , R ^la , R ^lb , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined above in Formula (l-I), (2-1),

(3-1), (4-1) or (5-1);

Ring A ¹ is absent, optionally substituted aryl or optionally substituted heteroaryl;

Ring B ¹ is optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, optionally substituted C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl; and

Z ^a and Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined above;

iiii)) wwhheenn ZZ ^aa oorr ZZ ^bb iiss an amino protecting group, fully or selectively deprotecting a compound of Formula (II) to give the corresponding amine of Formula (III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (III) with LG-C(O)-

R ⁶ ,

wherein LG is a leaving group; to give the compound of Formula (IV):

wherein Z ^d is an amino protecting group -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (V):

In another aspect, the invention is a process of making a compound according to Formula (l-I) comprising:

i) preparing a compound of Formula (l-II):

via a transition-metal catalyzed cross-coupling reaction; wherein:

G, J, U, R ¹ , R ^la , R ^lb , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined in Formula (l-I);

Ring A ¹ is absent, optionally substituted aryl or optionally substituted heteroaryl; Ring B ¹ is optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, optionally substituted C2-C ₄ alkenyl or C2-C ₄ alkynyl; and

Z ^a and Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined in in Formula (1-1);

ii) when Z ^a or Z ^b is an amino protecting group, fully or selectively deprotecting a compound of Formula (l-II) to give the corresponding amine of Formula (l-III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (l-III) with LG-

C(0)-R ⁶ ,

wherein LG is a leaving group; to give the compound of Formula (1-IV):

wherein Z ^d is an amino protecting group -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (1-V):

In yet another aspect, the invention is a process of making a compound accordingormula (2-1) comprising:

i) preparing a compound of Formula (2-II):

via a transition-metal catalyzed cross-coupling reaction; wherein:

G, J, U, R ¹ , R ^la , R ^lb , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined in Formula (2-1);

Ring A ¹ and Ring B ¹ are each independently optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, optionally substituted C2-C ₄ alkenyl or C2-C ₄ alkynyl; and Z ^a and Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined in Formula (2-1);

ii) when Z ^a or Z ^b is an amino protecting group, fully or selectively deprotecting a compound of Formula 2-II) to give the corresponding amine of Formula (2-III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (2-III) with LG-

C(0)-R ⁶ ,

wherein LG is a leavin group; to give the compound of Formula (2-IV):

wherein Z ^d is an amino protecting group -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula 2-V):

In a further aspect, the invention is a process of making a compound of Formula (3-1) comprising:

i) preparing a compound of Formula (3 -II):

via a transition-metal catalyzed cross-coupling reaction; wherein:

G, J, U, R ¹ , R ^la , R ^lb , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined in Formula (3-1);

Ring A ¹ and Ring B ¹ are each independently absent or an optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, optionally substituted C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl; and

Z ^a and Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined in Formula (3-1); ii) when Z ^a or Z ^b is an amino protecting group, fully or selectively deprotecting a compound of Formula (3 -II) to give the corresponding amine of Formula (3 -III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (3 -III) with LG- C(0)-R ⁶ ,

wherein LG is a leaving group; to give the compound of Formula (3-IV):

wherein Z ^d is an amino protecting group -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (3-V):

In another aspect, the invention is a process of making a compound of Formula (4-omprising:

i) preparing a compound of Formula (4-II):

via a transition-metal catalyzed cross-coupling reaction;

wherein:

G, U, R ¹ , R ^la , R ^lb , R ^lc , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined in Formula (4-1);

Ring A ¹ is absent, or optionally substituted aryl or optionally substituted heteroaryl;

Ring B ¹ is optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, or optionally substituted C2-C ₄ alkenyl or C2-C ₄ alkynyl; and

Z ^a or Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined in Formula (4-1); ii) when Z ^a or Z ^b is an amino protecting group, fully or selectively deprotecting a compound of Formula (4-II) to give the corresponding amine of Formula (4-III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (4-III) with LG- C(0)-R ⁶ ,

wherein LG is a leaving group; to give the compound of Formula (4-IV):

wherein Z ^d is an amino protecting group or -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (4-V):

In an additional aspect, the invention is a process of making a compound of Formula (5-1) comprising:

i) preparing a compound of Formula (5-II):

via a transition-metal catalyzed cross-coupling reaction; wherein:

Ring B, G, U, R ¹ , R ^la , R ^lb , R ^lc , R ^7a , R ^7b , R ⁹ , and R ^9a are as defined in Formula (5-1);

Ring A ¹ is absent, optionally substituted aryl or optionally substituted heteroaryl;

L ¹ is absent, optionally substituted C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl; and

Z ^a and Z ^b are each independently an amino protecting group or -C(0)-R ⁶ ; wherein R ⁶ is as defined in Formula (5-1);

ii) when Z ^a or Z ^b is an amino protecting group, fully or selectively deprotecting a compound of Formula (5-II) to give the corresponding amine of Formula (5-III):

wherein Z ^c is hydrogen, an amino protecting group or -C(0)-R ⁶ ;

iii) capping the released amino group of a compound of Formula (5-III) with LG- C(0)-R ⁶ ,

wherein LG is a leaving group; to give the compound of Formula (5-IV):

wherein Z ^d is an amino protecting group or -C(0)-R ⁶ ; and

iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (5-V):

All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and

modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims. The compounds of examples 1-1 to 1-82, 1-84 to 1-256, 1-258 to 1-326 and 1-328 1-347 may be prepared using procedures similar to those described in examples 1-83, -257 and 1-327 (described below), and/or as described in the Synthetic Methods.

-1 to 1-219.

Example 1-83.

The title compound was prepared from (S)-1-(tert-butoxycarbonyl)pyrrolidine-3- carboxylic acid and 4-bromoaniline 4-iodobenzoic acid using procedures similar described in examples 1-354 and 1-355. ESIMS m/z = Ί 16.51 [M+H] ⁺ .

-257.

Step l-257a. A solution of the compound from example 1-353 (32.5 μιηοΐ at most) in

CH ₂ C1 ₂ (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 416.37 [M+H] ⁺ .

Step l-257b. A mixture of the crude compound from step l-257a (32.5 μιηοΐ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 11.4 mg, 65.0 μιηοΐ) in DMF (3 mL) was treated with HATU (23.4 mg, 61.7 μιηοΐ) in the presence of DIPEA (81 μΐ _^ , 0.650 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a light yellow solid

(16.9 mg, 3 steps 71%). ESIMS m/z = 730.63 [M+H] ⁺ .

Example 1-327.

The title compound was prepared from the compound of Example 1-366 using procedures similar to that described in example 1-359. ESIMS m/z = 740.43 [M+H] ⁺ .

-348a and l-348b.

Step l-348a. A mixture of 4-bromoaniline (0.500 g, 2.91 mmol) and trans (+/-) 2-(tert- butoxycarbonylamino)-cyclopentanecarboxylic acid (0.733 g, 3.20 mmol) in DMF (12 mL) were added EDC HCl (0.724 g, 3.78 mmol), HOBt (0.646 g, 3.78 mmol) and DIPEA (0.54 mL, 4.36 mmol). The mixture was stirred at room temperature until the

disappearence of the starting material. The mixture was partitioned (EtOAc - water) and the organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by fiash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow white solid (0.787 g, 71%). ESIMS m/z = 404.99, 406.98 [M+H+Na] ⁺ .

Step l-348b. A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and N-Boc-L- proline (3.87 g, 18.0 mmol) in CH ₃ CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by fiash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow foam (6.73 g, 91%). 1H NMR (CDC1 ₃ ) 7.76 (t, J= 8.0 Hz, 2H), 7.63 (dd, J= 5.0, 8.5 Hz, 2H), 5.51, 5.16 (2d, J= 16.0 Hz, 1H), 5.32, 5.28 (2d, J= 16.5 Hz, 1H), 4.48, 4.40 (dd, J= 5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).

Step l-348c. A solution of the compound from step l-348b (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up to 100 °C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%). ESIMS m/z = 392.24, 394.24 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 7.57 (bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99 (m, 1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H).

Step l-348d. A mixture of the compound from step 348c (1.00 g, 2.55 mmol), bis-

(pinacolato) diboron (1.35 g, 5.33 mmol) and potassium acetate (0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh ₃ ) ₄ (0.147 g, 0.128 mmol). The resultant mixture were degassed for three times and heated up to 80 °C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 1 as a light yellow solid (0.978 g, 87%). ESIMS m/z = 440.39 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 11.03, 10.55 (2s, 1H), 7.79 (m, 3H), 7.45 (m, 1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.41 (m, 2H), 3.06, 2.91 (2m, 1H), 2.17 (m, 2H), 1.97 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).

Step l-348e. A mixture of the compound from step l-348a (0.200 g, 0.522 mmol), the compound from step 348d (0.229 g, 0.522 mmol) and NaHC0 ₃ (0.175 g, 2.09 mmol) in DME (12 mL) and H ₂ 0 (4 mL) was added Pd(PPh ₃ ) ₄ (30.2 mg, 26.1 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by

chromatography (silica, hexanes-ethyl acetate) to give a mixture of the title compounds as a light yellow solid (0.180 g, 56%). ESIMS m/z = 616.30 [M+H] ⁺ .

-349a and l-349b.

Step l-349a. A solution of the compound of example 1-348 (60.0 mg, 97.5 μιηοΐ) in CH ₂ C1 ₂ (5 mL) was treated with C1 in 1,4-dioxane (4 M, 1 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 416.20 [M+H] ⁺ . Step l-349b. A mixture of the crude compound from step l-348a (97.5 μιηοΐ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 35.8 mg, 0.205 mmol) in DMF (3 mL) was treated with HATU (74.1 mg, 0.195 mmol) in the presence of DIPEA (0.24 mL, 1.95 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a white solid (63.2 mg, 2 steps 89%). ESIMS m/z = 730.33 [M+H] ⁺ .

-350a and l-350b.

Step l-350a. A mixture of 2-amino-6-bromonaphthalene (0.500 g, 2.25 mmol) and trans (+/-) 2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.567 g, 2.48 mmol) in DMF (10 mL) were added EDC C1 (0.561 g, 2.93 mmol), HOBt (0.500 g, 2.93 mmol) and DIPEA (0.42 mL, 3.38 mmol). The mixture was stirred at room temperature until the disappearence of the starting material. The mixture was partitioned (EtOAc - water) and the organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the desired compound as a red white solid (0.911 g, 93%). ESIMS m/z = 433.04, 435.04

[M+Hf.

Step l-350b. A mixture of the compound from step l-350a (0.200 g, 0.462 mmol), the compound from step 348d (0.184 g, 0.420 mmol) and NaHC0 ₃ (0.141 g, 1.68 mmol) in DME (12 mL) and H ₂ 0 (4 mL) was added Pd(PPh ₃ ) ₄ (24.2 mg, 20.9 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give a mixture of the title compounds as a light yellow white solid (0.198 g, 71%). ESIMS m/z = 666.33 [M+H] ⁺ . Examples 1-35 la and 1-35 lb.

Step l-351a. A solution of the compound from example 1-350 (50.0 mg, 75.1 μιηοΐ) in CH ₂ CI ₂ (5 mL) was treated with C1 in 1,4-dioxane (4 M, 1 mL) for 30 min. The volatiles 5 were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 466.24 [M+H] ⁺ .

Step l-351b. A mixture of the crude compound from step 1-35 la (75.1 μιηοΐ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 27.6 mg, 0.158 mmol) in DMF (3 mL) was treated with HATU (57.1 mg, 10 0.150 mmol) in the presence of DIPEA (0.19 mL, 1.50 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a yellow solid (52.1 mg, 2 steps 89%). ESIMS m/z = 780.40 [M+H] ⁺ .

Example 1-352

Step l-352a. A mixture of (i?)-(+)-tert-butyl pyrrolidin-3-ylcarbamate (0.100 g, 0.537 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO 2008/021927, 0.103 g, 0.590 mmol) in DMF (3 mL) was treated with HATU (0.204 g, 0.537 mmol) in the presence of DIPEA (0.13 mL, 1.07 mmol) for 2 hours at rt and the 20 volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CLLCb-MeOH) to give the desired compound as a colorless oil (0.194 g, ca.100%). ESIMS m/z = 344.37 [M+H] ⁺ .

Step l-352a. A solution of the compound from step l-352a (0.537 mmol at most) in CH ₂ CI ₂ (6 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles 25 were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 244.24 [M+H] ⁺ . Step l-352c. A mixture of the crude compound from step l-352b (0.537 mmol at most) and 4-iodobenzoic acid (0.146 g, 0.590 mmol) in DMF (3 mL) was treated with HATU (0.204 g, 0.537 mmol) in the presence of DIPEA (0.13 mL, 1.07 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the desired compound as a light yellow oil (0.198 g, 3 steps 78%). ESIMS m/z = 474.25 [M+H] ⁺ .

Step l-352d. A solution of the compound from step l-348c (1.500 g, 3.824 mmol) in 1,4- dioxane (12 mL) was treated with C1 in 1,4-dioxane (4 M, 24 mL) at room temperature for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step. ESIMS m/z = 292.06, 294.06

[M+H] ⁺ .

Step l-352e. A mixture of the crude compound from step l-352d (3.824 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 0.670 g, 3.824 mmol) in DMF (12 mL) was treated with HATU (1.381 g, 3.633 mmol) in the presence of DIPEA (6.66 mL, 38.24 mmol) for 1 hour at room temperature and the volatiles were evaporated off. The residue was purified by

chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the desired compound as a yellow oil (1.500 g, 87% over 2 steps). ESIMS m/z = 449.12, 451.12

[M+H] ⁺ .

Step l-352f. A mixture of the compound from step l-352e (1.50 g, 3.34 mmol), bis-

(pinacolato) diboron (1.69 g, 6.68 mmol) and potassium acetate (0.818 g, 8.35 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh ₃ ) ₄ (0.193 g, 0.167 mmol). The resultant mixture were degassed for three times and heated up to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 2 as a colorless oil (1.15 g, 69%). ESIMS m/z = 497.35 [M+H] ⁺ .

Step l-352g. A mixture of the compound from step l-350c (39.8 mg, 84.1 μιηοΐ), the compound from step l-352f (54.2 mg, 0.109 mmol) and NaHC0 ₃ (28.3 g, 0.336 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.9 mg, 4.2 μιηοΐ). The resultant mixture were degassed and heated to 85 °C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a light yellow solid (50.8 mg, 84%). ESIMS m/z = 716.51 [M+H] ⁺ .

-353.

Step l-353a. A mixture of (S)-pyrrolidin-2-ylmethanamine (0.132 g, 0.661 mmol) and 4- iodobenzoic acid (0.167 g, 0.661 mmol) in CH ₂ C1 ₂ (6 mL) was treated with HATU (0.251 g, 0.661 mmol) in the presence of DIPEA (0.16 mL, 1.32 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.256 g, 90%). ESIMS m/z = 431.22 [M+H] ⁺ .

Step l-353b. A mixture of the compound from step l-353a (49.0 mg, 0.114 mmol), the compound from step l-348d (60.0 mg, 0.137 mmol) and NaHC0 ₃ (38.3 mg, 0.456 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (6.5 mg, 5.6 μιηοΐ). The resultant mixture were degassed and heated to 85 °C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow oil (70.0 mg, ca.100%). ESIMS m/z = 616.48 [M+H] ⁺ .

-354.

Step l-354a. A mixture of l-Boc-pyrrolidine-3-carboxylic acid (0.100 g, 0.465 mmol) and 4-bromoaniline (79.9 mg, 0.465 mmol) in CH ₂ C1 ₂ (6 mL) was treated with HATU (0.177 g, 0.465 mmol) in the presence of DIPEA (0.12 mL, 0.929 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.156 g, 91%). ESIMS m/z = 369.21 , 371.25 [M+H] ⁺ .

Step l-354b. A mixture of the compound from step l-354a (50.3 mg, 0.136 mmol), the compound from step l-348d (65.8 mg, 0.150 mmol) and NaHC0 ₃ (45.8 mg, 0.545 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (7.9 mg, 6.8 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a colorless oil (72.6 mg, 89%). ESIMS m/z = 602.40 [M+H] ⁺ .

-355.

Step l-355a. A solution of the compound from example 1-354 (20.0 mg, 33.2 μιηοΐ) in CH ₂ C1 ₂ (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 402.38 [M+H] ⁺ .

Step l-355b. A mixture of the crude compound from step l-355a (max. 33.2 μιηοΐ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 12.2 mg, 69.7 μιηοΐ) in DMF (3 mL) was treated with HATU (25.2 mg, 66.4 μιηοΐ) in the presence of DIPEA (83 μΐ _^ , 0.664 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a light yellow solid (17.0 mg, 2 steps 71%). ESIMS m/z = 716.64 [M+H] ⁺ .

-356a and l-356b.

Step l-356a. A mixture of trans-N-Boc-1,2-cyclopentanediamine (60.0 mg, 0.300 mmol) and 3-iodobenzoic acid (74.3 mg, 0.300 mmol) in CH ₂ C1 ₂ (6 mL) was treated with HATU (0.114 g, 0.300 mmol) in the presence of DIPEA (75 μΐ _^ , 0.600 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.120 g, 93%). ESIMS m/z = 431.27 [M+H] ⁺ . Step l-356b. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et ₂ 0, 8.09 mL, 24.3 mmol) slowly at 0 °C for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH ₄ C1. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).

Step l-356c. The compound from step l-356b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).

Step l-356d. A mixture of the compound from step l-356c (at most 11.6 mmol) and N- Boc-L-proline (3.75 g, 17.4 mmol) in CH ₃ CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z = 462.03, 464.02 [M+H] ⁺ .

Step l-356e. A mixture of the compound from step l-356d (0.200 g, 0.452 mmol), bis(pinaco-lato)diboron (0.144 g, 0.565 mmol), PdCl ₂ (dppf) ₂ (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80°C under N ₂ for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes- ethyl acetate) to give the desired compound as a yellow solid (0.188 g, 85%). ESIMS m/z = 490.12 [M+H] ⁺ .

Step l-356f. A mixture of the compound from step l-356a (29.4 mg, 68.3 μιηοΐ), the compound from step l-356e (40.0 mg, 81.9 μιηοΐ) and NaHC0 ₃ (22.9 mg, 0.273 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (3.9 mg, 3.4 μπιοΐ). The resultant mixture were degassed and heated to 85 °C under N ₂ for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give a mixture of title compounds as a light yellow solid (42.2 mg, 93%). ESIMS m/z = 666.45 [M+H] ⁺ .

-357a and l-357b.

Step l-357a. A solution of the compound from example 1-356 (20.0 mg, 30.0 μιηοΐ) in CH ₂ CI ₂ (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 466.43 [M+H] ⁺ .

Step l-357b. A mixture of the crude compound from step l-357a (max. 30.0 μιηοΐ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 11.0 mg, 63.0 μιηοΐ) in DMF (3 mL) was treated with HATU (22.8 mg, 60.0 μιηοΐ) in the presence of DIPEA (75 μΐ _^ , 0.600 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a white solid (16.0 mg, 2 steps 69%). ESIMS m/z = 780.72 [M+H] ⁺ .

Example 1-358.

Step l-358a. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 °C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20°C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H] ⁺ . Step l-358b. A solution of the crude compound from step l-358a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50°C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J= 8.5 Hz, 1H), 7.23, 7.03 (2d, J= 8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).

Step l-358c. A mixture of the compound from step l-358b (2.010 g, 5.488 mmol), trimethylsilyl-acetylene (2.33 ml, 16.46 mmol), Cul (0.110 g, 0.576 mmol) and

Pd(PPh ₃ ) ₂ Cl ₂ (0.308 g, 0.439 mmol) in Et ₃ N (50 mL) was degased and then heated at 80°C under N ₂ overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (1.140 g, 54%). ESIMS m/z = 384.22 [M+H] ⁺ .

Step l-358d. A suspension of the compound from step l-358c (1.140 g, 2.972 mmol) and K ₂ C0 ₃ (1.027 g, 7.430 mmol) in methanol (30 ml) was stirred at rt for 2 hour. The volatiles were evaporated off. The residue was patitioned (EtOAc - H ₂ 0). The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (0.792 g, 86%>). ESIMS m/z = 312.18

[M+H] ⁺ .

Step l-358e. A mixture of the compound from step l-354a (52.6 mg, 0.143 mmol), the compound from step l-358d (48.8 mg, 0.157 mmol) in Et ₃ N (6 mL) was added Cul (0.8 mg, 4.2 μιηοΐ) and Pd(PPh ₃ ) ₄ (16.4 mg, 14.2 μιηοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (27.4 mg, 32%). ESIMS m/z = 600.45 [M+H] ⁺ . -359.

Step l-359a. A solution of the compound from example 1-358 (27.4 mg, 45.7 μιηοΐ) in CH ₂ C1 ₂ (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 400.35 [M+H] ⁺ .

Step l-359b. A mixture of the crude compound from step l-359a (max. 45.7 μιηοΐ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 16.8 mg, 95.9 μιηοΐ) in DMF (3 mL) was treated with HATU (34.7 mg, 91.4 μιηοΐ) in the presence of DIPEA (0.11 mL, 0.914 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a light yellow solid (16.8 mg, 2 steps 52%). ESIMS m/z = 714.65 [M+H] ⁺ .

-360.

Step l-360a. A mixture of (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (0.109 g, 0.544 mmol) and 3-iodobenzoic acid (0.135 g, 0.544 mmol) in CH ₂ C1 ₂ (6 mL) was treated with HATU (0.206 g, 0.544 mmol) in the presence of DIPEA (0.14 mL, 1.09 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.204 g, 87%). ESIMS m/z = 431.21 [M+H] ⁺ .

Step l-360b. A solution of the compound from step l-356d (0.120 g, 0.271 mmol) in 1,4- dioxane (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at rt for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.

Step l-360c. A mixture of the crude compound from step l-360b (0.271 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (47.5 mg, 0.271 mmol) in DMF (2 mL) was treated with HATU (98.0 mg, 0.258 mmol) in the presence of DIPEA (0.47 mL, 2.713 mmol) for 1.5 hours at rt and the volatiles were evaporated off . The residue was patitioned (EtOAc/CH ₂ Cl ₂ - H ₂ 0). The organic layer was washed with saturated NaHC0 ₃ , brine, dried (Na ₂ S0 ₄ ), filtered and concentrated. The crude product was purified by flash column chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a light yellow solid (0.132 g, 97% over 2 steps). ESIMS m/z = 498.86, 500.85 [M+H] ⁺ .

Step l-360d. A mixture of the compound from step l-360c (0.130 g, 0.260 mmol), bis(pinacolato)diboron (79.3 mg, 0.312 mmol), PdCl ₂ (dppf) ₂ (21.3 mg, 26.0 μιηοΐ) and potassium acetate (51.0 mg, 0.521 mmol) in DMSO (4 mL) was degassed and heated at 80 °C under N ₂ overnight. The mixture was allowed to cool down and partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (0.105 g, 74%). ESIMS m/z = 547.08 [M+H] ⁺ .

Step l-360e. A mixture of the compound from step l-360a (18.4 mg, 43.9 μιηοΐ), the compound from step 360d (20.0 mg, 36.6 μιηοΐ) and NaHC0 ₃ (12.3 mg, 0.146 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (2.1 mg, 1.8 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a colorless oil (32.6 mg, ca. 100%). ESIMS m/z = 723.45 [M+Hf.

-361.

The title compound was prepared from the compound of example v360 using procedures similar to that described in example 1-359. ESIMS m/z = 780.75 [M+H] ⁺ .

-362.

Step l-362a. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20°C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 °C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H] ⁺ .

Step l-362b. A solution of the crude compound from step l-362a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50°C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J= 8.5 Hz, 1H), 7.23, 7.03 (2d, J= 8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).

Step l-362c. A mixture of the compound from step l-362b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80°C under N ₂ overnight before being evaporated. The residue was purified by chromatography (silica, hexanes- ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow solid (680 mg, 60%). ESIMS m/z = 414.24 [M+H] ⁺ .

Step l-362d. A mixture of the compound from step l-354a (20.0 mg, 54.2 μιηοΐ), the compound from step l-362c (24.6 mg, 59.6 μιηοΐ) and NaHC0 ₃ (18.2 mg, 0.217 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (3.1 mg, 2.7 μπιοΐ). The resultant mixture were degassed and heated to 90°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a colorless oil (29.3 mg, 93%). ESIMS m/z = 576.41 [M+H] ⁺ . -363.

The title compound was prepared from the compound of example 1-362 using procedures similar to that described in example 1-359. ESIMS m/z = 690.54 [M+H] ⁺ .

-364.

Step l-364a. A mixture of (な ⁾ -l-N-Boc-¾eto-proline (0.100 g, 0.465 mmol) and 2-amino- 6-bromonaphthalene (0.103 g, 0.465 mmol) in CH ₂ CI ₂ (6 mL) was treated with HATU (0.177 g, 0.465 mmol) in the presence of DIPEA (0.12 mL, 0.929 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.191 g, 98%).

Step l-364b. A mixture of the compound from step l-364a (30.0 mg, 71.5 μιηιηοΐ), the compound from step l-348d (34.5 mg, 78.6 μιηιηοΐ) and NaHC0 ₃ (24.0 mg, 0.286 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.0 mg, 3.5 μπιοΐ). The resultant mixture were degassed and heated to 95°C under N ₂ for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (41.6 mg, 89%). ESIMS m/z = 652.28 [M+H]

-365.

The title compound was prepared from the compound of example 1-364 using procedures similar to that described in example 1-359. ESIMS m/z = 766.37 [M+H] ⁺ . -366.

A mixture of the compound from step l-364a (30.0 mg, 71.5 μιηιηοΐ), the compound from step l-362c (32.4 mg, 78.6 μιηιηοΐ) and NaHC0 ₃ (24.0 mg, 0.286 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.0 mg, 3.5 μιηοΐ). The resultant mixture were degassed and heated to 95°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column

chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (40.2 mg, 90%). ESIMS m/z = 626.36 [M+H] ⁺ .

-367a and l-367b.

Step l-367a. To a suspension of trans- 1 ,2-cyclopentanediamine dihydrochloride

(racemic, 0.100 g, 0.578 mmol) in THF (6 mL) at 0°C was added NaH (60% in mineral oil, 46.2 mg, 1.155 mmol). After 5 minutes at 0°C, the milky solution was stirred at room temperature for 15 minutes before 9-BBN (0.5 M in THF, 1.15 mL, 0.578 mmol) was added. After 1 hour at room temperature, a solution of 4-iodobenzoyl chloride (0.146 g, 0.548 mmol) in THF (1.2 mL) was added. The suspension was stirred at room temperature for 2 hr being quenched carefully with H ₂ 0. The mixture was partitioned (EtOAc - aqueous NaHC0 ₃ ). The organiclayer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude product as a mixture of monoamidation and diamidation products as a white semi-solid, which was used directly for next step.

Step l-367b. A mixture of the crude compound from step l-367a (0.578 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 101.2 mg, 0.578 mmol) in DMF (3 mL) was treated with HATU (0.220 g, 0.578 mmol) in the presence of DIPEA (1.00 mL, 5.778 mmol) for 1 hours at room temperature and the volatiles were evaporated off. The residue was taken up in

CH ₂ Cl ₂ /MeOH (4/1), filtered and concentrated. The residue was purified by

chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (17.0 mg). ESIMS m/z = 488.07 [M+H] ⁺ .

Step l-367c. A mixture of compound from step l-367b (17.0 mg, 34.9 μιηοΐ), the compound from step 352f (17.2 mg, 34.9 μιηοΐ), Pd(PPh ₃ ) ₄ (4.0 mg, 3.49 μιηοΐ) and NaHC0 ₃ (10.3 mg, 0.122 mmol) in DME (2.1 mL) and H ₂ 0 (0.7 mL) was degassed and heated at 97 °C under N ₂ for 15 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified first by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) and then by preparative TLC (CH ₂ Cl ₂ /MeOH 4/1) to give a mixture the title compounds as an off-white solid (8.4 mg, 33%). ESIMS m/z = 730.28 [M+H] ⁺ .

Example 1-368.

Step l-368a. A mixture of (IR, 2i?)-trans-N-Boc-1,2-cyclopentanediamine (80.0 mg, 0.399 mmol) and 4-iodobenzoic acid (100.1 mg, 0.403 mmol) in CH ₃ CN (7 mL) was treated with HATU (0.152 g, 0.399 mmol) in the presence of DIPEA (0.70 mL, 3.994 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.160 g, 93%). ESIMS m/z = 331.10 [M+H] ⁺ .

Step l-368b. A mixture of compound from step l-368a (45.0 mg, 0.105 mmol), the compound from step l-348d (46.0 mg, 0.105 mmol), Pd(PPh ₃ ) ₄ (12.1 mg, 10.5 μιηοΐ) and NaHC0 ₃ (30.8 mg, 0.366 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 97°C under N ₂ for 15 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 10% MeOH in EtOAc) to give the title compound as an off-white solid (63.2 mg, 98%). ESIMS m/z = 616.36 [M+H] ⁺ . -369.

Step l-369a. A solution of the compound of example 1-368 (63.2 mg, 0.103 mmol) in 1,4-dioxane (1.25 mL) was treated with C1 in 1,4-dioxane (4 M, 5 mL) at 30°C for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step l-368b. A mixture of the crude compound from step l-369a (0.103 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 36.0 mg, 0.205 mmol) in DMF (3 mL) was treated with HATU (74.1 mg, 0.195 mmol) in the presence of DIPEA (0.36 mL, 2.053 mmol) for 30 minutes at rt and the volatiles were evaporated off. It was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give the title compound as a yellow solid (56.0 mg, 75% over 2 steps). ESIMS m/z = 730.45 [M+H] ⁺ .

Examples l-370a and l-370b.

Step l-370a. A mixture of tran -N-Boc-1,2-cyclopentanediamine (60.0 mg, 0.300 mmol) and 4-iodobenzoic acid (75.0 mg, 0.303 mmol) in CH ₃ CN (5 mL) was treated with HATU (0.114 g, 0.300 mmol) in the presence of DIPEA (0.52 mL, 3.000 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.119 g, 92%>). ESIMS m/z = 331.10 [M+H] ⁺ .

Step l-370b. A mixture of the compound from step l-362c (0.250 g, 0.605 mmol), 1- bromo-4-iodobenzene (0.257 g, 0.908 mmol), NaHC0 ₃ (0.203 g, 2.42 mmol) and

Pd(PPh ₃ ) ₄ (34.9 mg, 30.2 μιηοΐ) in DME (12 mL) and water (4 mL) was degassed and heated to 85°C under N ₂ overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a very light yellow solid (0.246 g, 92%). ESIMS m/z = 442.00, 444.00 [M+H] ⁺ .

Step l-370c. To a mixture of the compound from step l-370b (50.0 mg, 0.113 mmol), bis-(pinacolato)-diboron (35.9 mg, 0.141 mmol), potassium acetate (22.2 mg, 0.226 mmol) in DMSO (2 mL) was added PdCl ₂ (dppf) ₂ (9.2 mg, 11.3 μιηοΐ). The resulting solution was degased and then heated at 80 °C under N ₂ overnight before being partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a colorless oil (36.4 mg, 66%). ESIMS m/z = 490.37 [M+H] ⁺ .

Step l-370d. A mixture of compound from step l-370a (32.0 mg, 74.4 μιηοΐ), the compound from step l-370c (36.4 mg, 74.4 μιηοΐ), Pd(PPh ₃ ) ₄ (8.6 mg, 7.4 μιηοΐ) and NaHC0 ₃ (21.9 mg, 0.260 mmol) in DME (2.1 mL) and H ₂ 0 (0.7 mL) was degassed and heated at 97 °C under N ₂ for 15 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 10% MeOH in EtOAc) to give a mixture of the title compounds as an off-white solid (31.7 mg, 64%). ESIMS m/z = 666.37 [M+H] ⁺ .

-37 la and 1-37 lb.

Step l-371a. A solution of the compound of example 1-370 (31.7 mg, 47.6 μιηοΐ) in 1,4- dioxane (1 mL) was treated with C1 in 1,4-dioxane (4 M, 4 mL) at 30 °C for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step l-371b. A mixture of the crude compound from step 1-37 la (47.6 μιηοΐ at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 16.7 mg, 95.2 μιηοΐ) in DMF (3 mL) was treated with HATU (34.4 mg, 90.5 μιηοΐ) in the presence of DIPEA (0.17 mL, 0.952 mmol) for 30 minutes at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give a mixture of title compounds as a white solid (31.6 mg, 85% over 2 steps). ESIMS m/z = 780.52 [M+H] ⁺ .

-372.

Step l-372a. A mixture of (5)-3-(Boc-amino)pyrrolidine (0.150 g, 0.805 mmol) and (S)- 2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO

2008/021927, 0.148 g, 0.846 mmol) in DMF (3 mL) was treated with HATU (0.306 g, 0.805 mmol) in the presence of DIPEA (1.40 mL, 8.05 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the desired compound as a yellow oil (0.680 g). ESIMS m/z = 344.21 [M+H] ⁺ .

Step l-372b. A solution of the compound from step l-372a (0.680 g, 0.805 mmol at most) in 1,4-dioxane (1.5 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at rt for 1 hours. The volatiles were evaporated off to give the crude desired compound as a yellow oil, which was used directly in the next step. ESIMS m/z = 244.17 [M+H] ⁺ .

Step l-372c. A mixture of the crude compound from step l-372b (0.805 mmol at most) and 4-iodobenzoic acid (0.200 g, 0.805 mmol) in CH ₃ CN (4 mL) was treated with HATU (0.306 g, 0.805 mmol) in the presence of DIPEA (1.40 mL, 8.05 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the desired compound as a white foam (0.232 g, 61% over 3 steps). ESIMS m/z = 474.07 [M+H] ⁺ .

Step l-372d. A mixture of compound from step l-372c (30.0 mg, 63.4 μιηοΐ), the compound from step l-352f (40.9 mg, 82.4 μιηοΐ), Pd(PPh ₃ ) ₄ (7.3 mg, 6.34 μιηοΐ) and NaHC0 ₃ (21.3 mg, 0.254 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 98 °C under N ₂ for 2.5 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give the title compound as a light brown solid (42.7 mg, 94%).

ESIMS m/z = 716.27 [M+H] ⁺ . -373.

Step l-373a. A mixture of (i?)-N-Boc-pyrrolidine-3-carboxylic acid (1.000 g, 4.646 mmol) and 4-bromoaniline (0.799 g, 4.646 mmol) in CH ₂ CI ₂ (20 mL) was treated with HATU (1.766 g, 4.646 mmol) in the presence of DIPEA (1.62 mL, 9.292 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by

chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white foam (1.699 g, 99%).

Step l-373b. A mixture of compound from step l-373a (0.100 g, 0.271 mmol), the compound from step l-348d (0.131 g, 0.298 mmol), Pd(PPh ₃ ) ₄ (31.2 mg, 27.1 μπιοΐ) and NaHC0 ₃ (91.0 mg, 1.083 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 97°C under N ₂ for 15 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the title compound as a white solid (0.111 g, 68%). ESIMS m/z = 602.30 [M+H] ⁺ .

-374.

Step l-374a. A solution of the compound of example 1-373 (0.111 g, 0.184 mmol) in 1,4- dioxane (2 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step l-374b. A mixture of the crude compound from step l-374a (0.184 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 64.6 mg, 0.369 mmol) in DMF (4 mL) was treated with HATU (0.133 g, 0.351 mmol) in the presence of DIPEA (0.64 mL, 3.689 mmol) for 1 hour at room temperature and the volatiles were evaporated off. The residue was purified by

chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give the title compound as a light yellow solid (0.122 g, 92% over 2 steps). ESIMS m/z = 716.37 [M+H] ⁺ .

Step l-375a. A mixture of trans-aminocyclopentanol hydrochloride (racemic, 0.100 g, 0.727 mmol) and 4-iodobenzoic acid (0.180 g, 0.727 mmol) in CH ₃ CN (10 mL) was treated with HATU (0.276 g, 0.727 mmol) in the presence of DIPEA (1.27 mL, 7.266 mmol) for 30 minutes at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% EtOH) to give the desired compound as a white solid (0.226 g, 94%). ESIMS m/z = 332.04 [M+H] ⁺ .

Step l-375b. A mixture of compound from step l-375a (45.0 mg, 0.136 mmol), the compound from step l-348d (46.0 mg, 0.105 mmol), Pd(PPh ₃ ) ₄ (15.7 mg, 13.6 μπιοΐ) and NaHC0 ₃ (45.7 mg, 0.544 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 97°C under N ₂ for 15 hours. The mixture was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 1% EtOH in EtOAc) to give a mixture of title compounds as a white solid (54.2 mg, 77%). ESIMS m/z = 517.31 [M+H] ⁺ .

Examples l-376a and l-376b.

Step l-376a. A solution of the compound of example 1-375 (54.2 mg, 0.105 mmol) in 1,4-dioxane (1.25 mL) was treated with C1 in 1,4-dioxane (4 M, 5 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step l-376b. A mixture of the crude compound from step l-376a (0.103 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 36.8 mg, 0.210 mmol) in DMF (4 mL) was treated with HATU (37.9 mg, 0.100 mmol) in the presence of DIPEA (0.18 mL, 1.049 mmol) for 15 minutes at rt and the volatiles were evaporated off. It was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 15% MeOH in EtOAc) to give a mixture of title compounds as a white solid (50.1 mg, 83% over 2 steps). ESIMS m/z = 574.35 [M+H] ⁺ .

-377a and l-377b.

To a solution of (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to the method described in WO 2008/021927, 17.8 mg, 0.138 mmol) and Et ₃ N (19.2 μΐ, 0.138 mmol) in THF (2 mL) at -20 °C was added z-butyl chloroformate (17.9 μΐ, 0.138 mmol) in THF (0.1 mL). After 20 minutes at -20 °C, a solution of the compound of example 1-376 (36.0 mg, 62.8 μιηοΐ) in THF (1 mL) was added. After 15 minutes at - 20°C, the mixture was stirred at room temperature overnight. The volatiles were evaporated off. The residue was purified by HPLC to give a mixture of the title compounds as a white solid (8.2 mg, 18%). ESIMS m/z = 731.40 [M+H] ⁺ .

Example 1-378.

Step l-378a. A mixture of (5)-N-Boc-pyrrolidine-3-carboxylic acid (80.0 mg, 0.372 mmol) and 2-amino-5-bromopyridine (64.3 mg, 0.372 mmol) in CH ₂ CI ₂ (3 mL) was treated with HATU (0.141 g, 0.372 mmol) in the presence of DIPEA (0.13 mL, 0.743 mmol) for 1 hours at rt. More (5)-N-Boc-pyrrolidine-3-carboxylic acid (40.0 mg, 0.186 mmol), DIPEA (0.065 mL, 0.372 mmol) and HATU (70.5 mg, 0.186 mmol) were added. The mixture was heated at 100 °C with a microwave for 30 minutes. The volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white foam (87.3 mg, 63%>).

Step l-378b. A mixture of compound from step l-378a (48.0 mg, 0.130 mmol), the compound from step l-370c (62.7 mg, 0.143 mmol), Pd(PPh ₃ ) ₄ (15.0 mg, 13.0 μιηοΐ) and NaHC0 ₃ (38.1 mg, 0.454 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 97°C under N ₂ for 15 hours. The volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the title compound as a yellow solid (61.8 mg, 79%). ESIMS m/z = 603.15 [M+H] ⁺ .

-379.

Step l-379a. A solution of the compound of example 1-378 (61.8 mg, 0.102 mmol) in 1,4-dioxane (1 mL) was treated with C1 in 1,4-dioxane (4 M, 4mL) at room temperature for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step l-379b. A mixture of the crude compound from step l-379a (0.102 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 35.9 mg, 0.205 mmol) in DMF (2 mL) was treated with HATU (74.1 mg, 0.195 mmol) in the presence of DIPEA (0.36 mL, 2.051 mmol) for 15 minutes at room temperature and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give the title compound as a light yellow solid (62.4 mg, 85% over 2 steps). ESIMS m/z = 717.15 [M+H] ⁺ .

-380.

The title compound was prepared from (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1- carboxylate using procedures similar to that described in example 1-257. ESIMS m/z = 730.43 [M+H] ⁺ .

-381.

Step l-381a. Into a mixture of (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 90 mg, 0.5 mmol) and (R)-tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (100 mg, 0.50 mmol) in acetonitrile (2 mL) was added diisopropylethylamine (0.11 mL, 0.6 mmol) and HATU (200 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 1 hour before being partitioned between water and EtOAc. The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a brown slurry, which was purified by flash column

chromatography (silica, EtOAc-hexanes) to give the desired product as a light yellow solid (144 mg, 80%). ESIMS m/z = 358.41 [M+H] ⁺ .

Step l-381b. Into a mixture of compound firm step l-381a (144 mg, 0.4 mmol) was added hydrochloric acid in 1,4-dioxane (4M, 2 mL). The resulting mixture was stirred at room temperature for 1 hour before all volatiles were removed to afford the crude desired compound, which was used directly for the next step without further purification. ESIMS m/z = 258.28 [M+H] ⁺ .

Step l-381c. The title compound was prepared from 4-iodobenzoic acid and the compound from step l-348d using procedures similar to that described in example 1-348. ESIMS m/z = 730.45 [M+H] ⁺ .

-382a and l-382b.

A mixture of the title compounds was prepared from l-(tert- butoxycarbonyl)piperidine-3-carboxylic acid using procedures similar to that described examples 1-354 and 1-355. ESIMS m/z = 730.32 [M+H] ⁺ .

The compounds of examples 2-1 to 2-293 may be prepared using procedures similar to those described in examples 2-294 and 2-295 (described below), and/or as described in the Synthetic Methods.

Examples 2-1 to 2-219.

Step 2-294a. A mixture of l-Boc-pyrrolidine-3-carboxylic acid (0.100 g, 0.465 mmol) and 4-bromoaniline (79.9 mg, 0.465 mmol) in CH ₂ CI ₂ (6 mL) was treated with HATU (0.177 g, 0.465 mmol) in the presence of DIPEA (0.12 mL, 0.929 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.156 g, 91%). ESIMS m/z = 369.21 , 371.25 [M+H] ⁺ . Step 2-294b. A mixture of the compound from step 2-294a (0.184 g, 0.499 mmol), bis- (pinacolato) diboron (0.253 g, 0.997 mmol) and potassium acetate (0.122 g, 1.25 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh ₃ ) ₄ (28.8 mg, 24.9 μιηοΐ). The resultant mixture were degassed for three times and heated up to 85°C under N ₂ for 13 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.142 g, 68%). ESIMS m/z = 439.32 [M+Na] ⁺ .

Step 2-294c. A mixture of the compound from step 2-294a (30.0 mg, 81.3 μιηοΐ), the compound from step 2-294b (40.6 mg, 97.5 μιηοΐ) and NaHC0 ₃ (27.3 mg, 0.325 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.6 mg, 4.0 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (23.5 mg, 50%). ESIMS m/z = 579.09 [M+H] ⁺ .

-295.

Step 2-295a. A solution of the compound from example 2-294 (23.5 mg, 40.6 μιηοΐ) in CH ₂ C1 ₂ (4 mL) was treated with C1 in 1 ,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 379.35 [M+H] ⁺ .

Step 2-295b. A mixture of the crude compound from step 2-295 a (40.6 μιηοΐ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 14.9 mg, 85.2 μιηοΐ) in DMF (3 mL) was treated with HATU (30.9 mg, 81.2 μιηοΐ) in the presence of DIPEA (0.10 mL, 0.812 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a white solid (22.2 mg, 2 steps 79%) and diastereomeric mixture. ESIMS m/z = 693.39 [M+H] ⁺ . The compounds of examples 3-1 to 3-335 may be prepared using procedures similar to those described in examples 3-336 to 347 (described below), and/or as described in the Synthetic Methods.

Step 3-336a. A mixture of 2,4'-dibromoacetophenone (1.00 g, 3.60 mmol) and trans (+/-) 2-(fert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.825 g, 3.60 mmol) in CH ₃ CN (12 mL) was added DIPEA (0.94 mL, 7.55 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (1.548 g, 100%). ESIMS m/z = 426.03, 428.03 [M+H] ⁺ .

Step 3-336b. A solution of the compound from step 3_-336a (1.54 g, 3.60 mmol) in toluene (20 mL) was added ammonium acetate (5.54 g, 71.9 mol) and the resultant mixture was heated up to 100 °C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 1 as a yellow brown solid (1.34 g, 91%). ESIMS m/z = 406.09, 408.09 [M+H] ⁺ .

Step 3-336c. A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and N-Boc-L- proline (3.87 g, 18.0 mmol) in CH ₃ CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow foam (6.73 g, 91 >). 1H NMR (CDC1 ₃ ) 7.76 (t, J= 8.0 Hz, 2H), 7.63 (dd, J= 5.0, 8.5 Hz, 2H), 5.51, 5.16 (2d, J= 16.0 Hz, 1H), 5.32, 5.28 (2d, J= 16.5 Hz, 1H), 4.48, 4.40 (dd, J= 5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).

Step 3-336d. A solution of the compound from step 3-336c (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up to 100°C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%). ESIMS m/z = 392.24, 394.24 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 7.57 (bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99 (m, 1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H).

Step 3-336e. A mixture of the compound from step 3-336d (1.00 g, 2.55 mmol), bis-

(pinacolato) diboron (1.35 g, 5.33 mmol) and potassium acetate (0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh ₃ ) ₄ (0.147 g, 0.128 mmol). The resultant mixture were degassed for three times and heated up to 80°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 2 as a light yellow solid (0.978 g, 87%). ESIMS m/z = 440.39 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 11.03, 10.55 (2s, 1H), 7.79 (m, 3H), 7.45 (m, 1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.41 (m, 2H), 3.06, 2.91 (2m, 1H), 2.17 (m, 2H), 1.97 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).

Step 3-336f. A mixture of the compound from step 3_ 336b (0.315 g, 0.777 mmol), the compound from step 3^3366 (0.310 g, 0.706 mmol) and NaHC0 ₃ (0.237 g, 2.82 mmol) in DME (12 mL) and H ₂ 0 (4 mL) was added Pd(PPh ₃ ) ₄ (40.8 mg, 35.3 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give a mixture of the title compounds as a light yellow solid (0.326 g, 72%). ESIMS m/z = 639.34 [M+H] ⁺ .

Examples 3 -337a and 3 -337b.

Step 3-337a. A solution of the compound of example 3-336 (80.0 mg, 0.125 mmol) in CH ₂ C1 ₂ (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 439.23 [M+H] ⁺ .

Step 3-337b. A mixture of the crude compound from step 3^337a (theo 0.125 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 46.0 mg, 0.263 mmol) in DMF (3 mL) was treated with HATU (95.2 mg, 0.251 mmol) in the presence of DIPEA (0.31 mL, 2.51 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a light yellow solid (52.6 mg, 2 steps 56%). ESIMS m/z = 753.41 [M+H] ⁺ . -338a and 3-338b.

Step 3-338a. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20°C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 °C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H] ⁺ .

Step 3-338b. A solution of the crude compound from step 3_ 338a (10.7 g, theo. 26.7 mmol) in glacial acetic acid (100 mL) was heated at 50°C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 3 as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H] ⁺ . 1H NMR (CDCls) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J= 8.5 Hz, 1H), 7.23, 7.03 (2d, J= 8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).

Step 3-338c. A mixture of the compound from 3_ ₂ 338b (0.559 g, 1.425 mmol), trimethylsilyl acetylene (0.60 ml, 4.275 mmol), Cul (28.5 mg, 0.150 mmol) and

Pd(PPh ₃ ) ₂ Cl ₂ (80.0 mg, 0.114 mmol) in Et ₃ N (15 mL) was evacuated and refilled with N ₂ three times while being cooled with an aceton-dry ice bath. The mixture was then heated at 80°C under N ₂ for 6 hr before being evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (0.484 g, 83%). ESIMS m/z = 410.24

[M+H] ⁺ . Step 3-338d. A suspension of the compound from step 3^338ΰ (0.484 g, 1.182 mmol) and K ₂ CO ₃ (0.408 g, 2.954 mmol) in methanol (12 ml) was stirred at rt for 3 hr. The volatiles were evaporated off. The residue was purified by flash column chromatography (silica, dichloromethane-ethyl acetate) to give intermediate 4 as a yellow foam (0.370 g, 93%). ESIMS m/z = 338.24 [M+H] ⁺ .

Step 3-338e. A mixture of the compound from step 3^336b (150 mg, 0.369 mmol), the compound from step 3^338(1 (127 mg, 0.406 mmol) in Et ₃ N (4 mL) and CH ₃ CN (4 mL) were added Cul (2.1 mg, 11.0 μιηοΐ) and Pd(PPh ₃ ) ₄ (21.3 mg, 18.4 μιηοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give a mixture of the title compounds as a light yellow solid (0.137 g, 58%). ESIMS m/z = 637.32 [M+H] ⁺ .

-339a and 3 -339b.

Step 3-339a. A solution of the compound of example 3^338 (0.137 g, 0.215 mmol) in CH ₂ C1 ₂ (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 437.20 [M+H] ⁺ .

Step 3-339b. A mixture of the crude compound from step 3_-339a (theo 0.215 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 79.2 mg, 0.452 mmol) in DMF (3 mL) was treated with HATU (0.164 g, 0.431 mmol) in the presence of DIPEA (0.54 mL, 4.31 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a light yellow solid (0.144 g, 2 steps 89%). ESIMS m/z = 751.34 [M+H] ⁺ . Examples 3-340a and 3-340b.

Step 3-340a. A mixture of the compound from step 3_ 338b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80°C under N ₂ overnight before being evaporated. The residue was purified by chromatography (silica, hexanes- ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow solid (680 mg, 60%). ESIMS m/z = 414.24 [M+H] ⁺ .

Step 3-340b. A mixture of the compound from step 3 ₂ 338b (0.100 g, 0.246 mmol), the compound from step 3-340a (0.102 g, 0.246 mmol) and NaHC0 ₃ (82.8 mg, 0.985 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (14.2 mg, 12.3 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give a mixture of the title compounds as a light yellow solid (0.112 g, 75%). ESIMS m/z = 613.17 [M+H] ⁺ .

-34 la and 3-34 lb.

Step 3-341a. A solution of the compound from example 3-340 (0.112 g, 0.183 mmol) in CH ₂ C1 ₂ (3 mL) was treated with C1 in 1,4-dioxane (4 M, 2 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 413.23 [M+H] ⁺ . Step 3-341b. A mixture of the crude compound from step 3-34 la (theo 0.183 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO

2008/021927, 67.3 mg, 0.384 mmol) in DMF (3 mL) was treated with HATU (0.139 g, 0.366 mmol) in the presence of DIPEA (0.46 mL, 3.66 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give a mixture of the title compounds as a light yellow solid (87.8 mg, 2 steps 66%). ESIMS m/z = 727.40 [M+H] ⁺ .

-342.

Step 3-342a. A mixture of l-Boc-pyrrolidine-3-carboxylic acid (0.159 g, 0.739 mmol), 4-bromo-1,2-diaminobenzene (0.142 g, 0.739 mmol) in DMF (6 mL) were added

EDC HCl (0.184 g, 0.960 mmol) and DMAP (9.0 mg, 73.8 μπιοΐ). The resultant mixture were stirred at rt for two days. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the desired crude compound as a brown sticky oil (0.261 g, 92%), which was directly used in the next step.

Step 3-342b. A solution of the crude compound from step 3_ ₂ 342a (0.261 g, 0.680 mmol) in glacial acetic acid (8 mL) was heated at 40°C for 14 h. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown oil (0.195 g, 78%). ESIMS m/z = 366.24, 368.24.

Step 3-342c. A mixture of the compound from step 3^342b (30.2 mg, 82.5 μιηοΐ), the compound from step 3^3366 (36.2 mg, 82.5 μιηοΐ) and NaHCOs (27.7 mg, 0.330 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.7 mg, 4.1 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow solid (28.1 mg, 60%). ESIMS m/z = 599.37 [M+H] ⁺ . Example 3-343.

The title compound was prepared from the compound from example 3-342 using

procedures similar to that described in example 3-341. ESIMS m/z = 713.68 [M+H] ⁺ .

-344.

Step 3-344a. A mixture of 2,4'-dibromoacetophenone (0.258 g, 0.929 mmol) and 1-Boc- pyrrolidine-3-carboxylic acid (0.200 g, 0.929 mmol) in CH3CN (9 mL) was added DIPEA (0.23 mL, 1.86 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow solid (0.376 g, 98%). ESIMS m/z = 412.22, 414.22 [M+H] ⁺ .

Step 3-344b. A solution of the compound from step 3-344a (0.376 g, 0.912 mmol) in toluene (15 mL) was added ammonium acetate (1.41 g, 18.2 mmol) and the resultant mixture was heated up to 100°C for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow brown oil (0.318 g, 89%). ESIMS m/z = 392.07, 394.07 [M+H] ⁺ .

Step 3-344c. A mixture of the compound from step 3-344b (0.115 g, 0.293 mmol), bis- (pinacolato) diboron (0.149 g, 0.587 mmol) and potassium acetate (71.8 mg, 0.733 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh ₃ ) ₄ (16.9 mg, 14.6 μιηοΐ). The resultant mixture were degassed for three times and heated up to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow solid (91.0 mg, 71%). ESIMS m/z = 440.30 [M+H] ⁺ . Step 3-344d. Into a mixture of 2-bromo-1-(4-iodophenyl)ethanone (5g, 15.4 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (3.48g, 16.1 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (2.4 mL, 17 mmol). The resulting mixture was stirred at rt for 3 hours before being partitioned between EtOAc and aqueous NaHC0 ₃ . The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a brown oil. It was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as light yellow oil (6.0 g, 86%). ESIMS m/z = 481.94 [M+Na] ⁺ . Step 3-344e. The mixture of compound from step 3-344d (6.0g, 12.5 mmol) and ammonium acetate (15.1g, 196 mmol) in toluene (80 mL) was stirred at 80°C for 3 hours before being partitioned between water and aqueous NaHC0 ₃ . The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a deep red oil. It was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as light yellow solid (5.34 g, 93%). ESIMS m/z = 439.83 [M+H] ⁺ .

Step 3-344f. A mixture of the compound from step 3-344c (30.0 mg, 68.3 μιηοΐ), the compound from step 3^3446 (30.0 mg, 68.3 μιηοΐ) and NaHC0 ₃ (22.9 mg, 0.273 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (3.9 mg, 3.4 μπιοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (31.2 mg, 73%). ESIMS m/z = 625.30 [M+H] ⁺ .

-345.

The title compound was prepared from the compound from example 3-344 using procedures similar to that described in example 3-341. ESIMS m/z = 739.57 [M+H] ⁺ .

Examples 3-346a and 3-346b.

Step 3-346a. To a solution of Boc-trans-2-aminocyclopentane carboxylic acid (racemic, 0.350 g, 1.526 mmol) in THF (8 mL) at 0°C was added iodomethane (0.76 mL, 12.21 mmol), followed by NaH (60% in mineral oil, 0.244 g, 6.106 mmol). The milky solution was stirred at 0°C for 15 minutes and then at room temperature for 3 hours before being quenched carefully with H ₂ 0. The volatiles were evaporated. The residue was diluted with H ₂ 0, washed with Et ₂ 0 (* 1). The aqueous layer was acidified with citric acid to pH ~3, extracted with dichloromethane. The organics were dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a yellow oil (0.389 g), which was used directly for next step. ESIMS m/z = 307.04 [M+2Na+CH ₃ CN-H] ⁺ .

Step 3-346b. A solution of the crude compound from step 3-346a (0.389 g, 1.526 mmol at most) and 2,4'-dibromoacetophenone (0.445 g, 1.603 mmol) in CH ₃ CN (7 mL) was treated with TEA (0.43 mL, 3.053 mmol) at room temperature for 1.5 hours. The volatiles were evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.530 g, 77% over 2 steps). ESIMS m/z = 439.93, 441.93 [M+H] ⁺ .

Step 3-346c. A mixture of the compound from step 3-346b (0.530 g, 1.204 mmol) and ammonium acetate (1.021 g, 13.24 mmol) in xylenes (8 mL) was heated at 140°C with a microwave for 80 minutes. The volatiles were evaporated and the residue was partitioned (dichloromethane - aqueous NaHC0 ₃ ). The organic layer was dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1%) Et ₃ N in EtOAc) to give the desired compound as a yellow foam (0.420 g, 83%). ESIMS m/z = 419.91, 421.90 [M+H] ⁺ .

Step 3-346d. A mixture of compound from step 3-346c (89.0 mg, 0.212 mmol), the compound from step 3^3366 (93.0 mg, 0.212 mmol), Pd(PPh ₃ ) ₄ (24.5 mg, 21.2 μιηοΐ) and NaHC0 ₃ (62.3 mg, 0.741 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 98°C under N ₂ for 15 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give a mixture of the title compounds as a yellow solid (0.104 g, 75%). ESIMS m/z = 653.03 [M+H] ⁺ . Examples 3-347a and 3-347b.

Step 3-347a. A solution of the compound of example 3-46 (0.104 g, 0.159 mmol) in 1,4- dioxane (1.5 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at rt for 2 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.

Step 3-347b. A mixture of the crude compound from step 3-347a (0.159 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 55.8 mg, 0.319 mmol) in DMF (3 mL) was treated with HATU (0.115 g, .0302 mmol) in the presence of DIPEA (0.55 mL, 3.186 mmol) for 1 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N and 20% MeOH in EtOAc) to give a mixture of the title compounds as a yellow solid (89.2 mg, 73% over 2 steps). ESIMS m/z = 767.02 [M+H] ⁺ .

The compounds of Examples 4-1 to 4-347 may be prepared using procedures similar to those described in Example 4-348 (described below), and/or as described in the Synthetic Methods.

Examples 4-1 to 4-219.

Step 4-348a. Into a mixture of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (486 mg, 2.26 mmol) and 5-iodopyrimidin-2-amine (500 mg, 2.26 mmol) in acetonitrile (10 mL) was added diisopropylethylamine (0.45 mL, 2.48 mmol) and HATU (859 mg, 2.26 mmol). The resulting mixture was stirred at 150°C for 1.5 hours (heating with microwave) before being partitioned between water and EtOAc. The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, EtOAc-hexanes) to give the desired product as a light yellow solid (146 mg, 15%). ESIMS m/z = 440.93 [M+Na] ⁺ .

Step 4-348b. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et ₂ 0, 8.09 mL, 24.3 mmol) slowly at 0 °C for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH ₄ C1. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).

Step 4-348c. The compound from step 4-348b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).

Step 4-348d. A mixture of the compound from step 4-348c (at most 11.6 mmol) and N- Boc-L-proline (3.75 g, 17.4 mmol) in CH ₃ CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z = 462.03, 464.02 [M+H] ⁺ .

Step 4-348e. A mixture of the compound from step 4-348d (0.200 g, 0.452 mmol), bis(pinaco-lato)diboron (0.144 g, 0.565 mmol), PdCl ₂ (dppf) ₂ (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80 °C under N ₂ for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow solid (0.188 g, 85%). ESIMS m/z = 490.12

[M+H] ⁺ .

Step 4-348f. Into a mixture of compound from step 4-348a (146 mg, 0.35 mmol) and the compound from step 4^3486 (171 mg, 0.35 mmol) in 1 ,2-dimethoxyethane (5 mL) and water (2.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol) and NaHCC"3 (371 mg, 4.42 mmol). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 1.5 hours before being partitioned between water and EtOAc. The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, ethyl acetate -hexanes) to give the desired product as a light yellow solid (38 mg, 17%). ESIMS m/z = 654.13

[M+H] ⁺ .

Step 4-348g. A solution of the compound from step 4-348f (38 mg, 0.058 mmol) in dichloromethane (1 mL) and methanol (0.1 mL) was treated with C1 in 1,4-dioxane (4 M, 2 mL) at room temperature for 2 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.

Step 4-348h. The mixture of compounds from step 4-348g (0.048 mml at most) and (S)- (methoxycarbonyl)amino-3-methyl-butyric acid (prepared according to WO 2008/021927, 20 mg, 0.11 mmol) in MeCN (2 mL) was added diisopropylethylamine (0.11 mL) and HATU (7.7 mg). The resulting solution was stirred at room temperature for 35 minutes before being partitioned between EtOAc and aqueous NaOH (0.5M). The organic phase was separated, dried (Na ₂ S0 ₄ ) and concentrated to afford a brown slurry, which was purified by HPLC (CI 8, methanol-water) to give the title compound (2.0 mg). ESIMS m/z = 768.35 [M+H] ⁺ .

The compounds of examples 5-2 to 5-82, 5-84 to 5-293, 5-295, 5-297 to 5-304, 5- 306 to 5-312, 5-314 to 5-321, 5-323 to 5-369 and 5-371 may be prepared using procedures similar to those described in examples 5-1, 5-83, 5-294, 5-296, 5-305, 5-313, 5-322, 5- 370, 5-372 to 5-378, and 5-381 to 5-394 (described below), and/or as described in the Synthetic Methods.

Examples 5-1 to 5-219.

-220 to 5-229.

Example 5-1.

Step 5-la. A mixture of 5-bromo-2-chloropyrimidine (0.101 g, 0.524 mmol) and (S)-2- (aminomethyl)-l-N-Boc- pyrrolidine (0.105 g, 0.524 mmol) in 1,4-dioxane (2 mL) were heated up to 100 °C for 5h. The mixture was cooled down and the volatiles were evaporated. The residue was purified by flash column chromatography (silica, hexanes- ethyl acetate) to give the desired compound as a colorless oil (75.5 mg, 40%). ESIMS m/z = 357.25, 359.25 [M+H] ⁺ .

Step 5-lb. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et ₂ 0, 8.09 mL, 24.3 mmol) slowly at 0 °C for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH ₄ C1. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S04), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).

Step 5-lc. The compound from step 5-lb (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S04), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).

Step 5-ld. A mixture of the compound from step 5-lc (at most 11.6 mmol) and N-Boc-L- proline (3.75 g, 17.4 mmol) in CH ₃ CN (60 mL) was added DIPEA (2.89 mL, 23.2 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS m/z = 462.03, 464.02 [M+H] ⁺ . Step 5-le. A mixture of the compound from step 5-ld (0.200 g, 0.452 mmol), bis(pinaco- lato)diboron (0.144 g, 0.565 mmol), PdCl ₂ (dppf) ₂ (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80 °C under N ₂ for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na ₂ S04), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow solid (0.188 g, 85%). ESIMS m/z = 490.12 [M+H] ⁺ .

Step 5-lf. A mixture of the compound from step 5- la (30.2 mg, 84.5 μιηοΐ), the compound from step le (53.7 mg, 0.110 mmol) and NaHC0 ₃ (28.4 mg, 0.338 mmol) in DME (6 mL) and H ₂ 0 (2 mL) was added Pd(PPh ₃ ) ₄ (4.9 mg, 4.2 μιηοΐ). The resultant mixture were degassed and heated to 85°C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S04), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow oil (47.1 mg, 87%). ESIMS m/z = 640.61 [M+H] ⁺ .

-83.

Step 5-83a. A solution of the compound of example 5-1 (20.0 mg, 31.2 μιηοΐ) in CH ₂ CI ₂ (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z = 440.47 [M+H] ⁺ .

Step 5-83b. A mixture of the crude compound from step 5-83a (max. 31.2 μιηοΐ) and (S)- (methoxycarbonyl)amino-3-methyl-butyric acid (prepared according to WO 2008/021927, 11.5 mg, 65.5 μιηοΐ) in DMF (3 mL) was treated with HATU (23.7 mg, 62.4 μιηοΐ) in the presence of DIPEA (78 μΐ _^ , 0.624 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH ₂ Cl ₂ -MeOH) to give the title compound as a white solid (18.9 mg, 2 steps 80%). ESIMS m/z = 754.81 [M+H] ⁺ .

The title compound was prepared from the compound of example 5-391 using procedures similar to that described in example 5-83. ESIMS m/z = 754.14 [M+H] ⁺ .

-296.

The title compound was prepared from the compound of example 5-378 using procedures similar to that described in example 5-83. ESIMS m/z = 753.44 [M+H] ⁺ .

-305.

The title compound was prepared from the compound of example 5-375 using procedures similar to that described in example 5-83. ESIMS m/z = 759.52 [M+H] ⁺ . Example 5-313.

Step 5-313a. The desired compound was prepared from 5-bromo-2-chloropyrimidine and (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate using procedures similar to that described in step 5-la. ESIMS m/z = 357.12 [M+H] ⁺ .

Step 5-313b. The desired compound was prepared from compound of step 5-313a and trimethylsiltyl acetylene using procedures similar to that described in steps 5 -392c and 5- 392d. ESIMS m/z = 303.14 [M+H] ⁺ .

Step 5-313c. The desired compound was prepared from the compound from step 5-313b and the compounds from step 5 -392b using procedures similar to that described in step 5- 392e. ESIMS m/z = 588.26 [M+H] ⁺ .

Step 5-313d. The title compound was prepared from the compound from step 5-313a and the compound from step 5-392d using procedures similar to that described in example 5- 83. ESIMS m/z = 702.34 [M+H] ⁺ .

-322.

The title compound was prepared from the compound of example 5-392 using procedures similar to that described in example 5-83. ESIMS m/z = 752.12 [M+H] ⁺ .

Example 5-370

The title compound was prepared from the compound of example 5-374 using procedures similar to that described in example 5-83. ESIMS m/z = 745.57 [M+H] ⁺ . Examples 5 -372a and 5 -372b.

B

B

Step 5-372a. The desired compound was prepared from trans-N-Boc-1,2- cyclopentanediamine and 5-bromo-2-chloropyrimidine using procedures similar to that described in step 5-la. ESIMS m/z = 357.12, 359.12 [M+H] ⁺ .

Step 5-372b. A mixture of the title compounds was prepared from the compound from step 5-372a using precedures similar to that described in step 5- If. ESIMS m/z = 640.49 [M+H] ⁺ .

-373 a and 5 -373b.

A mixture of the title compounds were prepared from the compounds of example 5 -372a and 5-372b using procedures similar to that described in example 5-83. ESIMS m/z = 754.72 [M+H] ⁺ .

-374.

A mixture of the compound from step 5-la (40.0 mg, 0.112 mmol), benzene- 1 ,4-diboronic acid (8.4 mg, 50.9 μιηοΐ) in toluene (3 mL), EtOH (3 mL) and 2M aqueous Na ₂ C0 ₃ (0.2 mL) was added Pd(PPh ₃ ) ₄ (5.8 mg, 5.0 μιηοΐ). The resultant mixture were degassed and heated to reflux under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (18.4 mg, 57%). ESIMS m/z = 631.31 [M+H] ⁺ .

-375.

Step 5-375a. A mixture of 6-bromo-2-chlorobenzothiazole (0.126 g, 0.508 mmol) and (5)-2-(aminomethyl)-l-N-Boc- pyrrolidine (0.102 g, 0.508 mmol) in 2-propanol (6 mL) were added K ₂ CO ₃ (70.1 mg, 0.508 mmol). The resultant mixture were degassed and heated to 85 °C under N ₂ for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (76.1 mg, 36%). ESIMS m/z = 412.15, 414.12 [M+H] ⁺ .

Step 5-375b. A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and N-Boc-L- proline (3.87 g, 18.0 mmol) in CH ₃ CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow foam (6.73 g, 91 >). 1H NMR (CDC1 ₃ ) 7.76 (t, J= 8.0 Hz, 2H), 7.63 (dd, J= 5.0, 8.5 Hz, 2H), 5.51, 5.16 (2d, J= 16.0 Hz, 1H), 5.32, 5.28 (2d, J= 16.5 Hz, 1H), 4.48, 4.40 (dd, J= 5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).

Step 5-375c. A solution of the compound from step 5-375b (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up to 100°C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%). ESIMS m/z = 392.24, 394.24 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 7.57 (bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99 (m, 1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H). Step 5-375d. A mixture of the compound from step 5-375c (1.00 g, 2.55 mmol), bis- (pinacolato) diboron (1.35 g, 5.33 mmol) and potassium acetate (0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh ₃ ) ₄ (0.147 g, 0.128 mmol). The resultant mixture were degassed for three times and heated up to 80 °C under N ₂ for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give intermediate 1 as a light yellow solid (0.978 g, 87%). ESIMS m/z = 440.39 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 11.03, 10.55 (2s, 1H), 7.79 (m, 3H), 7.45 (m, 1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.41 (m, 2H), 3.06, 2.91 (2m, 1H), 2.17 (m, 2H), 1.97 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).

Step 5-375e. The title compound was prepared from the compound from step 5-375a and the compound from step 5-375d using precedures similar to that described in step 5- If ESIMS m/z = 645.30 [M+H] ⁺ .

-376.

Step 5-376a. A mixture of the compound from step 5-375a (29.8 mg, 72.3 μιηοΐ), bis- (pinacolato) diboron (22.9 mg, 90.3 μιηοΐ) and potassium acetate (14.2 mg, 0.145 mmol) in DMSO (5 mL) was added Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (5.9 mg, 7.2 μπιοΐ). The resultant mixture were degassed for three times and heated up to 80 °C under N ₂ for 34 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (17.5 mg, 53%). ESIMS m/z = 460.29 [M+H] ⁺ .

Step 5-376b. The title compound was prepared from the compound from step 5-376a and the compound from step 5 -375 a using precedures similar to that described in step 5- If ESIMS m/z = 665.30 [M+H] ⁺ .

-377.

The title compound was prepared from the compound of example 5-376 using procedures similar to that described in example 5-83. ESIMS m/z = 779.65 [M+H] ⁺ . -378.

Step 5-378a. A mixture of 5-bromo-2-iodopyridine (0.100 g, 0.352 mmol), Cul (3.4 mg, 17.6 μιηοΐ) and Cs ₂ C0 ₃ (0.230 g, 0.704 mmol) in DMF (3 mL) were added (S)-2- (Aminomethyl)-l-N-Boc- pyrrolidine (0.104 g, 0.528 mmol) and 2- isobutyrylcyclohexanone (11.8 mg, 7.04 μιηοΐ). The resultant mixture were degassed stirred under N ₂ for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H ₂ 0). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.112 g, 90%). ESIMS m/z = 356.27, 358.27 [M+H] ⁺ .

Step 5-378b. The title compound was prepared from the compound from step 5-378a and the compound from step le using precedures similar to that described in step If ESIMS m/z = 639.44 [M+H] ⁺ .

-381.

Step 5-381a. The desired compound was prepared from l-N-Boc-3-aminopyrrolidine and 5-bromo-2-chloropyrimidine using procedures similar to that described in step 5- la. ESIMS m/z = 343.02, 345.02 [M+H] ⁺ .

Step 5-381b. The title compound was prepared from the compound from step 5-3815a and the compound from step 5-375d using precedures similar to that described in step 5- lf. ESIMS m/z = 626.35 [M+H] ⁺ .

-382.

The title compound was prepared from the compound of example 5-381 using procedures similar to that described in example 5-83. ESIMS m/z = 740.61 [M+H] ⁺ . Example 5-383.

The title compound was prepared from the compound from step 5-38 la and the compound from step 5-375d using precedures similar to that described in step 5-lf. ESIMS m/z = 576.34 [M+H] ⁺ .

-384.

The title compound was prepared from the compound from example 5-383 using procedures similar to that described in example 5-83. ESIMS m/z = 690.57 [M+H] ⁺ .

-385.

The title compound was prepared from the compound from step 5 -375 a and the compound from step 5-le using precedures similar to that described in step 5-lf. ESIMS m/z = 695.33 [M+H] ⁺ .

-386.

The title compound was prepared from the compound of example 5-385 using procedures similar to that described in example 5-83 ESIMS m/z = 809.72 [M+H] ⁺ .

-387.

Step 5-387a. The desired compound was prepared from 2-N-Boc-butane-1,2-diamine- C1 and 5-bromo-2-chloropyrimidine using procedures similar to that described in step 5- la. ESIMS m/z = 345.22, 347.23 [M+H] ⁺ . Step 5-387b. The title compound was prepared from the compound from step 5-387a and the compound from step 5-1 e using precedures similar to that described in step 5- If.

ESIMS m/z = 628.43 [M+H] ⁺ .

-388.

The title compound was prepared from the compound from example 5-387 using procedures similar to that described in example 5-83. ESIMS m/z = 742.60 [M+H] ⁺ .

-389.

Step 5-389a. A mixture of 2-N-Boc-butane-1,2-diamine-HCl (0.300 g, 1.34 mmol), Et ₃ N (0.56 mL, 4.00 mmol) in THF (5 mL) was added N-ethoxycarbonylphthalimide (0.439 g, 2.00 mmol). The resultant mixture were degassed for three times and heated to reflux under N ₂ for 5 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the desired crude compound as a white solid (0.524 g). ESIMS m/z = 319.18 [M+H] ⁺ .

Step 5-389b. A mixture of the compound from step 5-389a (1.34 mmol at most), Mel (1.25 mL, 2.00 mmol) in THF (8 mL) at 0°C was added NaH (60% in mineral oil, 0.160 g, 4.00 mmol). The resultant mixture were gradually warmed up to rt and stirred for 20 hours. The reaction was quenched by the addition of aqueous NH ₄ C1 and the volatiles were evaporated. The residue was partitioned (EtOAc - water) and the organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.305 g, 2 steps 69%). ESIMS m/z = 333.21 [M+H] ⁺ .

Step 5-389c. A solution of the compound from step 5-389b (0.150 g, 0.452 mmol) in EtOH (10 mL) was added hydrazine (71 μί, 2.26 mmol). The resultant mixture were heated to reflux for 2 hours. The volatiles were evaporated to give the desired crude compound as a white solid (97.5 mg). ESIMS m/z = 203.22 [M+H] ⁺ . Step 5-389d. The desired compound was prepared from the compound from step 5-389c and 5-bromo-2-chloropyrimidine using procedures similar to that described in step 5- la. ESIMS m/z = 359.17, 361.17 [M+H] ⁺ .

Step 5-389e. The title compound was prepared from the compound from step 5-389d and the compound from step 5-1 e using precedures similar to that described in step 5- If. ESIMS m/z = 642.52 [M+H] ⁺ .

-390.

The title compound was prepared from the compound of example 5-389 using procedures similar to that described in example 5-83. ESIMS m/z = 756.72 [M+H] ⁺ .

-391.

Step 5-391a. A suspension of 2,6-dibromoquinazoline (0.120 g, 0.417 mmol) and (S)-N- Boc-2-(aminomethyl)pyrrolidine (83.5 mg, 0.417 mmol) in z ^' -PrOH (8 mL) and DIPEA (0.15 mL, 0.833 mmol) was heated at 85 oC for 1 hour. The reaction mixture was combined with another batch of 70.0 mg of 2,6-dibromoquinazoline and concentrated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow oil (0.120 g, 45%). ESIMS m/z = 407.15, 409.15 [M+H] ⁺ . Step 5-391b. A mixture of compound from step 5-39 la (55.0 mg, 0.135 mmol), the compound from step 5-375d (59.3 mg, 0.135 mmol), Pd(PPh ₃ ) ₄ (15.6 mg, 13.5 μιηοΐ) and NaHC0 ₃ (39.7 mg, 0.473 mmol) in DME (3 mL) and H ₂ 0 (1 mL) was degassed and heated at 97 °C under N ₂ for 15 hours. The volatiles were evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the title compound as a yellow foam (64.0 mg, 74%). ESIMS m/z = 640.37 [M+H] ⁺ .

-392.

Step 5-392a. A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20°C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20°C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated to give the crude desired compound as a dark brown foam (10.7 g). ESIMS m/z = 384.18, 386.18 [M+H] ⁺ .

Step 5-392b. A solution of the crude compound from step 5-392a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50°C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHC0 ₃ ). The organics were washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H] ⁺ . 1H NMR (CDC1 ₃ ) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J= 8.5 Hz, 1H), 7.23, 7.03 (2d, J= 8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).

Step 5-392c. A mixture of the compound from step 5-392b (2.010 g, 5.488 mmol), trimethylsilyl-acetylene (2.33 ml, 16.46 mmol), Cul (0.110 g, 0.576 mmol) and

Pd(PPh ₃ ) ₂ Cl ₂ (0.308 g, 0.439 mmol) in Et ₃ N (50 mL) was degased and then heated at 80°C under N ₂ overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (1.140 g, 54%). ESIMS m/z = 384.22 [M+H] ⁺ .

Step 5-392d. A suspension of the compound from step 5-392c (1.140 g, 2.972 mmol) and K ₂ C0 ₃ (1.027 g, 7.430 mmol) in methanol (30 ml) was stirred at rt for 2 hour. The volatiles were evaporated off. The residue was patitioned (EtOAc - H ₂ 0). The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and concentrated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et ₃ N in ethyl acetate) to give the desired compound as a yellow foam (0.792 g, 86%>). ESIMS m/z = 312.18

[M+H] ⁺ .

Step 5-392e. A mixture of compound from step 5-391a (50.4 mg, 0.124 mmol), the compound from step 392d (48.2 mg, 0.15 mmol), Pd(PPh ₃ ) ₄ (7.1 mg, 6.2 μιηοΐ) and Cul (0.7 mg, 3.7 μιηοΐ) in THF (2 mL) and Et ₃ N (1 mL) was degassed and heated at 85°C under N ₂ for 15 hours. The volatiles were evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et ₃ N in EtOAc) to give the title compound as a yellow foam (44.7 mg, 57%). ESIMS m/z = 638.31 [M+H] ⁺ . Example 5-393.

The title compound was prepared from the (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1- carboxylate using procedures similar to that described in examples 5-1 and 5-83. ESIMS m/z = 754.42 [M+H] ⁺ .

-394.

The title compound was prepared from the compound from step 5-313a and the compound from step 5 -375c using procedures similar to that described in example 5-313. ESIMS m/z = 728.17 [M+H] ⁺ .

BIOLOGICAL ACTIVITY

1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolated from colonies as described by Lohman et. al. (Lohman et al. (1999) Science 285: 110-113, expressly incorporated by reference in its entirety) and used for all experiments. The HCV replicon has the nucleic acid sequence set forth in EMBL Accession No.: AJ242651, the coding sequence of which is from nucleotides 1801 to 8406.

The coding sequence of the published HCV replicon was synthesized and subsequently assembled in a modified plasmid pBR322 (Promega, Madison, WI) using standard molecular biology techniques. One replicon cell line ("SGR 11-7") stably expresses HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genes and the HCV 3'UTR. Another replicon cell line ("Huh-luc/neo-ET") described by Vrolijk et. al. (Vrolijk et. al. (2003) Journal of Virological Methods 110:201-209, expressly incorporated by reference in its entirety) stably expresses HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene, (iv) the neomycin

phosphotransferase gene (neo), (v) the IRES from encephalomyocarditis virus (EMCV), and (vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations (E1202G, T1280I, K1846T) and the HCV 3 ^* UTR.

These cell lines were maintained at 37°C, 5% C0 ₂ , 100% relative humidity in DMEM (Cat# 11965-084, Invitrogen), with 10% fetal calf serum ("FCS", Invitrogen), 1% non-essential amino acids (Invitrogen), 1% of Glutamax (Invitrogen), 1% of 100X penicillin/streptomycin (Cat# 15140-122, Invitrogen) and Geneticin (Cat# 10131-027, Invitrogen) at 0.75 mg/ml or 0.5 mg/ml for 11-7 and Huh-luc/neo-ET cells, respectively. 2. HCV Replicon Assay - qRT-PCR

EC50 values of single agent compounds and combinations were determined by HCV RNA detection using quantitative RT-PCR, according to the manufacturer's instructions, with a TAQMAN® One-Step RT-PCR Master Mix Reagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler. The TaqMan primers used for detecting and quantifying HCV RNA were obtained from Integrated DNA Technologies. HCV RNA was normalized to GAPDH RNA levels in drug-treated cells, which was detected and quantified using the Human GAPDH Endogenous Control Mix (Applied Biosystems, AB 4310884E). Total cellular RNA was purified from 96-well plates using the RNAqueous 96 kit (Ambion, Cat# AMI 812). Chemical agent

cytotoxicity was evaluated using an MTS assay according to the manufacturer's directions (Promega).

3. HCV Replicon Assay - Luciferase

Since clinical drug resistance often develops in viral infections following single agent therapies, there is a need to assess the additive, antagonistic, or synergistic properties of combination therapies. We use the HCV replicon system to assess the potential use of the compound of the present invention or in combination therapies with Interferon alpha, cyclosporine analogs and inhibitors targeting other HCV proteins. The acute effects of a single or combinations of drugs are studied in the "Huh-luc/neo-ET" replicon with each chemical agent titrated in an X or Y direction in a 6 point two-fold dilution curve centered around the EC50 of each drug. Briefly, replicon cells are seeded at 7,000 cells per well in 90 ul DMEM (without phenol red, Invitrogen Cat.# 31053-036) per well with 10%> FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 100X penicillin/streptomycin and incubated overnight at 37°C, 5% C0 ₂ , 100% relative humidity. 16-20h after seeding cells, test compounds previously solubilized and titrated in dimethyl sulfoxide ("DMSO") from each X plate and Y plate are diluted 1 : 100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 100X penicillin/streptomycin and added directly to the 96-well plate containing cells and growth medium at a 1 : 10 dilution for a final dilution of compound and DMSO of 1 : 1000 (0.2% DMSO final concentration). Drug treated cells are incubated at 37°C, 5% C0 ₂ , 100% relative humidity for 72 hours before performing a luciferase assay using 100 ul per well BriteLite Plus (Perkin Elmer) according to the manufacturer's instructions. Data analysis utilizes the method published by Prichard and Shipman (Antiviral Research, 1990. 14: 181-205). Using this method, the combination data are analyzed for antagonistic, additive, or synergistic combination effects across the entire combination surface created by the diluted compounds in combination.

The compounds of the present invention may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment, the compounds of the present invention inhibit HCV replicon and in another embodiment the compounds of the present invention inhibit NS5A.

The compounds of the present invention can be effective against the HCV lb genotype. It should also be understood that the compounds of the present invention can inhibit multiple genotypes of HCV. In one embodiment compound of the present invention are active against the la, lb, 2a, 2b, 3a, 4a, and 5a genotypes. Table 58 shows the EC50 values of representative compounds of the present invention against the HCV lb genotype from the above described qRT-PCR or luciferase assay. EC50 ranges against HCV lb are as follows: A >10 nM; B 1-10 nM; C < InM. Where two compound are indicated under the Example column (e.g., l-349a and l-349b, it is to be understood that a mixture of the two compounds was tested in the above described qRT-PCR or luciferase assay.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.