Hepatitis C virus inhibitors

专利摘要:
H:ftintcnvovenNRPortblDCCFMT5O70377_3.DOC-12/04/2013 The present invention discloses compounds or pharmaceutically acceptable salts, esters, or prodrugs thereof, which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
公开号:AU2013204195A1
申请号:U2013204195
申请日:2013-04-12
公开日:2013-05-02
发明作者:Yat Sun Or；Xiaowen Peng；Yao-Ling Qiu；Ce Wang；Lu Ying
申请人:Enanta Pharmaceuticals Inc；
IPC主号:A01N43-52

专利说明:
H:fmitntenvovenNRPortblDCCFMT5070377_ .DOC-12/04/2013 HEPATITIS C VIRUS INHIBITORS RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 61/156,131 filed February 27, 2009 and U.S. Provisional Application No. 61/158,071 filed March 6, 5 2009. The entire teachings of the above applications are incorporated herein by reference. This is a divisional of Australian Patent Application No. 2010217797, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present invention relates to novel antiviral agents. More specifically, the 10 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 15 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 20 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. 25 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: flu 30 like 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 - 1- WO 2010/099527 PCT/US2010/025741 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 RNA levels and normalization of 5 liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the intmduction 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 10 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 post-transfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) 15 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 20 244:359-362; 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) 25 (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 30 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 PAGE 2 OF 222 WO 2010/099527 PCT/US2010/025741 proteinases (Rice, C.M. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 "d 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 5 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 10 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 RNA-dependent RNA polymerase (RdRp) activity and contains 15 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. 20 (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 25 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 30 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 PAGE 3 OF 222 WO 2010/099527 PCT/US2010/025741 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. A general strategy for the development of antiviral 5 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 2009/020828; WO 2009/020825; WO 2009/102318; WO 2009/102325; WO 2009/102694; WO 2008/144380; WO 2008/021927; WO 2008/021928; WO 10 2008/021936; WO 2006/133326; WO 2004/014852; WO 2008/070447; WO 2009/034390; WO 2006/079833; WO 2007/031791; WO 2007/070556; WO 2007/070600; WO 2008/064218; WO 2008/154601; WO 2007/082554; and WO 2008/048589; the contents of each of which are expressly incorporated by reference herein. 15 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 20 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-I) (RI). R1 D-A-T-E-Z Ji Q N (1-1) 25 or a pharmaceutically acceptable salt thereof, wherein: D and Z are are each independently absent or optionally substituted linear aliphatic group containing zero to eight carbon atoms; A and E are are each independently absent or a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3
-C
8 cycloalkyl, and C 3
-C
8 30 cycloalkenyl, each optionally substituted; PAGE 4 OF 222 WO 2010/099527 PCT/US2010/025741 T is absent or an optionally substituted aliphatic group; Wherein one to four of A, D, E, T and Z is absent; Ring B is a five-membered heteroaryl wherein said heteroaryl is optionally substituted; preferably, a five-membered heteroaryl containing one or more nitrogen 5 atoms; more preferably, imidazolyl that is C-attached to group J and one of groups Z, E, T, A and D; R at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1
-C
4 alkyl, -O-R 11 , -NR aR, -C(O)R", -C0 2 R", and -C(O)NRaRb; preferably, hydrogen, halogen and 10 optionally substituted C 1
-C
4 alkyl; R" at each occurrence is independently hydrogen or optionally substituted CI-Cs alkyl; and Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C-Cs alkyl, and optionally substituted 15 C 2
-C
8 alkenyl; or Ra and Rb can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u at each occurrence is independently 1, 2, or 3; Q and J are each independently selected from:
(R
7 ). R3 R4 7 -X NRS - N 20 R ,and R6
R
3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C-Cs alkyl, optionally substituted C 2 C 8 alkenyl, and optionally substituted C 3
-C
8 cycloalkyl; preferably hydrogen or optionally substituted C-C 4 alkyl; or alternatively, R3 and R! can be taken together 25 with the carbon atom to which they are attached to form optionally substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic; R at each occurrence is independently hydrogen, optionally substituted Cj
C
8 alkyl, or optionally substituted C 3
-C
8 cycloalkyl; preferably hydrogen or optionally substituted C 1
-C
4 alkyl; 30 R at each occurrence is independently selected from the group consisting of
-C(O)-R
12 , -C(O)-C(O)-R 12 , -S(O) 2 -R12, and -C(S)-R 12 , preferably -C(O)-R, 12 more preferably an optionally substituted amino acid acyl; PAGE 5 OF 222 WO 2010/099527 PCT/US2010/025741 R12 at each occurrence is independently selected from the group consisting of
-O-R
1 , -NRaRb, -R", and -NR'Rd, preferably optionally substituted C 1
-C
8 alkyl and -O-R" 1 ;
R
13 at each occurrence is independently selected from the group consisting of 5 hydrogen, 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, optionally substituted phenyl, protected amino, or
O(C-C
4 alkyl); and 10 R and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R1 3 , -C(O)-R 13 , -C(O)-OR 1 3 , -S(0) 2
-R
13 , -C(O)N(R1 3
)
2 , and -S(0) 2 N(R13) 2 ; m is 0, 1, or 2, preferably 1; n is 1, 2, 3, or 4, preferably 1 or 2; 15 X at each occurrence is independently selected from 0, S, S(O), SO 2 , and
C(R
7
)
2 , preferably CH 2 or CHR 7 ; provided that when m is 0, X is C(R 7
)
2 ; and
R
7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -O-R 11 , -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -CI-C 4 alkyl; preferably, hydrogen, 20 methyl or halogen; or two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic ring; preferably, a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally 25 substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl. In its second principal aspect, the present invention provides a compound of Formula (2-I) Q &D-A-T-E-Z J (2-1) 30 or a pharmaceutically acceptable salt thereof, wherein: D and Z are are each independently absent or optionally substituted linear aliphatic group containing zero to eight carbon atoms; PAGE 6 OF 222 WO 2010/099527 PCT/US2010/025741 A and E are are each independently absent or a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3
-C
8 cycloalkyl, and C 3
-C
8 cycloalkenyl, each optionally substituted; T is absent or an optionally substituted aliphatic group; 5 Wherein one to four of A, D, E, T and Z is absent; Ring B is a five-membered heteroaryl or a 5/6-membered fused heteroaryl, wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups Z, E, T, A and D, and the 5-membered ring of said 5/6 membered fused heteroaryl is attached to group J and contains one or more nitrogen atoms; 10 wherein said five-membered heteroaryl or 5/6-membered fused heteroaryl is optionally substituted; preferably imidazolyl or benzimidazolyl, wherein said imidazolyl or benzimidazolyl are C-attached to group J and one of groups Z, E, T, A and D; Ring G is a 5/6-membered fused heteroaryl other than benzimidazolyl, 15 wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups D, A, T, E and Z, and the 5-membered ring of said 5/6-membered fused heteroaryl is attached to group Q and contains one or more nitrogen atoms; and wherein said 5/6-membered fused heteroaryl is optionally substituted; Q and J are each independently selected from: RR)
D
3
D
4 RITk XN R5 _XN~ 20 R , and A ;
R
3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C-Cs alkyl, optionally substituted C 2 C 8 alkenyl, and optionally substituted C 3
-C
8 cycloalkyl; preferably hydrogen or optionally substituted C-C 4 alkyl; or alternatively, R 3 and R 4 can be taken together 25 with the carbon atom to which they are attached to form optionally substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic;
R
5 at each occurrence is independently hydrogen, optionally substituted C
C
8 alkyl, or optionally substituted C 3 -CS cycloalkyl; preferably hydrogen or optionally substituted C 1
-C
4 alkyl; 30 R 6 at each occurrence is independently selected from the group consisting of -C(O)-R, -C(O)-C(O)-R , -S(O) 2 -R, and -C(S)-R, preferably -C(O)-R, more preferably an optionally substituted amino acid acyl; PAGE 7 OF 222 WO 2010/099527 PCT/US2010/025741 R at each occurrence is independently selected from the group consisting of -O-R", -NRaRb, -R 13 , and -NR"Rd, preferably optionally substituted C 1
-C
8 alkyl and -O-R"; R" at each occurrence is independently hydrogen or optionally substituted 5 C 1 -C8 alkyl; and Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C 1
-C
8 alkyl, and optionally substituted
C
2
-C
8 alkenyl; or Ra and Rb can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally 10 substituted heteroaryl group;
R
13 at each occurrence is independently selected from the group consisting of hydrogen, 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-C 8 alkyl optionally 15 substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or
O(C
1
-C
4 alkyl); and R* and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R 3 , -C(O)-R 3 , -C(O)-OR 3 , -S(0) 2
-R
13 , -C(O)N(R 13
)
2 , and -S(0) 2
N(R
13
)
2 ; 20 m is 0, 1, or 2, preferably 1; n is 1, 2, 3, or 4, preferably I or 2; X at each occurrence is independently selected fiom 0, S, S(O), SO 2 , and
C(R)
2 , preferably CH 2 or CHR 7 ; provided that when m is 0, X is C(R 7
)
2 ; and
R
7 at each occurrence is independently selected from the group consisting of 25 hydrogen, halogen, cyano, -O-R", -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C-C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally 30 substituted cyclopropyl; or alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3
-C
8 cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl. PAGE 8 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 a 10 therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof. 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 15 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 20 or combination of compounds of the present invention, or a therapeutically acceptable salt thereof, as defied 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 25 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 Dibenzimidazole 30 Antivirals"; U.S. Application Serial No. 12/702,692 filed February 9, 2010 entitled "Linked Dibenzimidazole Derivatives"; U.S. Application Serial No. 12/702,802 filed February 9, 2010 entitled "Linked Dibenzimidazole Derivatives"; U.S. Application Serial No. 12/707,190 filed February 17, 2010 entitled "Linked PAGE 9 OF 222 WO 2010/099527 PCT/US2010/025741 Diimidazole Antivirals"; U.S. Application Serial No. 12/707,200 filed February 17, 2010 entitled "Linked Diimidazole Derivatives"; and U.S. Application Serial No. 12/707,2 10 filed February 17, 2010 entitled "Hepatitis C Virus Inhibitors"; the contents of each of which are expressly incorporated by reference herein. 5 I. Compounds having Formula (1-I) In certain aspects, the present invention relates to compounds of Formula (1 I) as illustrated above, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to compounds of Formula 10 (1-Ia), or a pharmaceutically acceptable salt thereof: (RS1 R N D-A-T-E-Z J Q N (1-1a) wherein A, D, E, T, Z, Q, J, u, and R 1 are as previously defined in Formula (1-I) and Ring B 1 is a five-membered heteroaryl that is C-attached to J and to one of Z, E, T, A and D. 15 In another embodiment, the present invention relates to compounds of Formula (1-Ib), or a pharmaceutically acceptable salt thereof: (R1) R D-A-T-E-Z & J Q N (1-1b) wherein A, D, E, T, Z, Q, J, u, and R' are as previously defined in Formula (1-I) and Ring B 2 is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and 20 isoxazolyl; and Ring B 2 is C-attached to J and to one of Z, E, T, A and D. In yet another embodiment, the present invention relates to compounds of Formulae (1-Ic-1 to 1-Ic-4), or a pharmaceutically acceptable salt thereof: (RNA. )3T4 (R). ) (R). R6 RN D-A-T-E-Z NR R N- D-A--E RR N (1-Ic-) RB Rs' R (1-Ic-2) R
R
4
R
3
R
4
R
3 (R') )u (R) )u (R 7). R NN--ART-R RE R N D-A-T-E-Z-O-C ). N (1-Ic-3) R6N (1--4) R 8
(R
7 ) (R 7 ) PAGE 10 OF 222 WO 2010/099527 PCT/US2010/025741 wherein A, D, E, T, Z, Ring B, X, u, m, n,R% R', R 4 , R', R 6 and R 7 are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formulae (1-Id-1 to 1-Id-4), or a pharmaceutically acceptable salt thereof: R1 OH D-A-T-E-Z N-RS R OH D-A-T-E-Z
NN-R
5 H Rs .N (1-id-1) 0= R6 N.-' (1-id-2) 12R,
R
4 R12 t 3 R OHN D-A-T-E-Z NR R12fO H ) D-A-T-E-Z N (1-Id -3) O < NN (1-Id 4)R 5 xx wherein A, D, E, T, Z, Ring B, R 3 , R, R', and R 12 are as previously defined in Formula (1-I) and X 1 is independently CH2, CHF, CH(OH), or CF 2 . In still another embodiment of the present invention, the absolute 10 stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine or five membered heteroarylmethylamine moiety is represented by Formulae (1-Ie-1 to 1 Ie-4): R OHN -A-T-EZ -Ra OHN 0-A-EZ R12 O HN D-A-T-E-Z -RaR2OH D-A-T-E-Z- B ) N N RS NMr (-92 N(1-Ie-3) Oi N N (1-le-4) N R12 R 15 wherein A, D, E, T, Z, Ring B, R 3 , R 5 , and R 12 are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-If), or a pharmaceutically acceptable salt thereof: R-AO O D-A-T-E-Z B _R6' (1-If) O ORM 20 wherein A, D, E, T, Z, Ring B, and R 1 ' are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-Ig), or a pharmaceutically acceptable salt thereof: PAGE 1 1 0F 222 WO 2010/099527 PCT/US2010/025741 R' Rb o D-A-T-E-Z-( " Rb N (1-Ig) O N-Rb Ra wherein A, D, E, T, Z, Ring B, Ra and Rb are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-Ih), or a pharmaceutically acceptable salt thereof: Re R/ N D-A -T- E-Z d . (1-1h) N R 5 R" wherein A, D, E, T, Z, Ring B, R' and Rd are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-1i), or a pharmaceutically acceptable salt thereof: R oH D-A-T-E-Z /N (1-II) 0 RO 10 wherein A, D, E, T, Z, Ring B, and R 1 3 are as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-Ij), or a pharmaceutically acceptable salt thereof: R1 0 D-A-T-E-Z-( "' ~N N -IN (1j) 0 RI a wherein A, D, E, T, Z, Ring B are as previously defined in Formula (1-I) and R1 3 a at 15 each occurrence is independently an optionally substituted C1-Cs alkyl; preferably
C
1
-C
8 alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or
O(CI-C
4 alkyl). In still another embodiment, the present invention relates to compounds of Formula (1-Ia), or a pharmaceutically acceptable salt thereof: (RI). RtYTQJ 20 Qt N (1-ila) wherein Q, J, Ring B, u, and R 1 are as previously defined in Formula (1-I) and T is present and as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-I1b), or a pharmaceutically acceptable salt thereof: PAGE 12 OF 222 WO 2010/099527 PCT/US2010/025741 (R), RN A J Q N (1-lib) wherein Q, J, Ring B, u, and RI are as previously defined in Formula (1-I) and A is present and as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of 5 Formula (1-Ic), or a pharmaceutically acceptable salt thereof: R N T o N (1-lc) wherein Q, J, Ring B, u, and RI are as previously defined in Formula (1-I) and T' is a linear aliphatic group, optionally containing one or more of an olefinic double bond and an alkynic triple bond and further, optionally comprising one or more 10 groups selected from the group consisting of 0, N(R"), C(O), S(0) 2 , C(0)O, C(O)N(R 1), OC(0)O, OC(O)N(R 1), S(0) 2 N(R"), N(R")C(O)N(R"),
N(R
1 ")C(0)C(0)N(R"), N(R")S(0) 2 N(R'l), C(O)N(R" )S(0) 2 and C(O)N(R")S(0) 2 N(R"). In still another embodiment, the present invention relates to compounds of 15 Formula (1-IHd), or a pharmaceutically acceptable salt thereof: (R) RN T2 i o N (1-ld) wherein Q, J, Ring B, u, and R' are as previously defined in Formula (1-I) and T 2 is an aliphatic group comprising a C 3 -Cs cycloalkyl or C 3
-C
8 cycloalkenyl and optionally contains one or more of an olefinic double bond and an alkynic triple 20 bond and further, optionally comprises one or more groups selected from the group consisting of 0, N(R"), C(O), S(0) 2 , C(0)O, C(O)N(R"), OC(0)O, OC(O)N(R"), S(0) 2 N(R"), N(R")C(O)N(R"), N(R")S(0) 2 N(R"), N(R")C(0)C(0)N(R 1 1), C(O)N(R")S(0) 2 and C(O)N(R")S(0) 2 N(R"). In still another embodiment, the present invention relates to compounds of 25 Formulae (1-lIa-1 and 1-lIa-2), or a pharmaceutically acceptable salt thereof: (R'). (R'). R N AT J RN T-E BJ (1lla-1) QO N (1-Illa-2) PA GE 13 OF 222 WO 2010/099527 PCTIUS2010/025741 wherein Q, J, Ring B, u, and Ri are as previously defined in Formula (1-I); in Formula (1-IHa-1) A and T are each present and as previously defined in Formula (1-I); and in Formula (1-IHa-2), T and E are each present and as previously defined in Formula (1-I). 5 In still another embodiment, the present invention relates to compounds of Formula (1-Ila-3), or a pharmaceutically acceptable salt thereof: R12OHN T-E (R 7)'n, X 7 (1-Illa-3) R 1 wherein n is 1 or 2; T is absent or optionally substituted C 2
-C
4 alkenyl or optionally substituted C 2
-C
4 alkynyl; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or 10 bicyclic heteroaryl, each optionally substituted; X at each occurrence is independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7
)
2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro, optionally substituted C 3
-C
8 cycloalkyl; or yet alternatively, two vicinal R 7 groups 15 are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3
-C
8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted C 1
-C
8 alkyl. In certain aspects, the invention is a compound of Formula (1 -HIa-3) wherein R at each occurrence is independently
C
1
-C
8 alkyl substituted with -NHCO 2
(C
1
-C
4 alkyl) or O(C 1
-C
4 alkyl). 20 In still another embodiment, the present invention relates to compounds of Formula (1-IHa-3), or a pharmaceutically acceptable salt thereof; wherein two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; and R 12 at each occurrence is independently C 1
-C
8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(C-C 4 alkyl). 25 In still another embodiment, the present invention relates to compounds of Formula (1-IHa-3), or a pharmaceutically acceptable salt thereof, wherein two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R 12 at each occurrence is independently
C
1
-C
8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(CI-C 4 30 alkyl). PAGE 14 OF 222 WO 2010/099527 PCT/US2010/025741 In still another embodiment, the present invention relates to compounds of Formulae (1-IH-a) to (1-IH-d), or a pharmaceutically acceptable salt thereof: R12 O HN . R12 (R x 1-Ill-a R x R~ RRf O2 R12 P HN .. N / (R) N N1-Il-d R 7) wherein n is 1 or 2; X at each occurrence is each independently CHl 2 , CHF, CH(OH), 5 CHMe, CF 2 , or C(R 7
)
2 ; wherein R at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R" groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R2 at each occurrence is independently 10 Ci-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or O(C 1
-C
4 alkyl). In still another embodiment, the present invention relates to compounds of Formulae (1-Ill-a) to (1-IHI-d); wherein R' 2 at each occurrence is independently C 1 Cs alkyl substituted with -NHCO 2
(C
1
-C
4 alkyl) or O(C 1
-C
4 alkyl); or a 15 pharmaceutically acceptable salt thereof. In still another embodiment, the present invention relates to compounds of Formula (1-Ifib), or a pharmaceutically acceptable salt thereof: Q N (1-Illb) wherein Q, J, Ring B, u, and R 1 are as previously defined; A and E are each present 20 and as previously defined in Formula (1-I). PAGE 15 OF 222 WO 2010/099527 PCT/US2010/025741 In still another embodiment, the present invention relates to compounds of Formulae (1-IVa-1 and 1-IVa-2), or a pharmaceutically acceptable salt thereof: (R'). (R'). N: D-A-T-R N- 7 I JT-E-ZTBJ Q N (1-WVa-1) Q N (1-IVa-2) wherein Ring B1, Q, J, u, and R 1 are as previously defined in Formula (1-I); in 5 Formula (1-IVa-1), A, D, and T are each present and as previously defined in Formula (1-I); and in Formula (1-IVa-2), E, T, and Z are each present and as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formula (1-IVb), or a pharmaceutically acceptable salt thereof: R N A-T-E &J 10 Q N (1-lVb) wherein Ring B1, Q, J, u, and R1 are as previously defined in Formula (1-I); A, E, and T are each present and as previously defined in Formula (1-I). In still another embodiment, the present invention relates to compounds of Formulae (1-Va-1 and 1-Va-2), or a pharmaceutically acceptable salt thereof: ( ) (R )N 'N,rDD-A-T-E_& J R A-T-E-Z J 15 Q N (1-Va-I) Q N (1-Va-2) wherein Ring B', Q, J, u, and R' are as previously defined in Formula (1-I); in Formula (1-Va-1), D, A, T and E are each present and as previously defined in Formula (1-I); in Formula (1-Va-2), A, E, T, and Z are each present and as previously defined in Formula (1-I). 20 In still another embodiment, the present invention relates to compounds of R7 N N )m Formula (1-I), or a pharmaceutically acceptable salt thereof; wherein J- at each occurrence is independently illustrated by one of the following groups: M Me F F Me Me Me OH PAGE 16 OF 222 WO 2010/099527 PCT/US2010/025741 Representative compounds of the present invention are those selected from compounds 1-1-1, 1-2-1, and 1-2-2 (shown below), and compounds 1-1 to 1-545 compiled in Tables 1-9: - compound 1-1-1 NH O MeO 2 CHN compound 1-2-1 NHCO 2 Me MeOC N Ph/ MeO2P NhN O-& NHCO 2 Me compound 1-2-2 H 5 Table 1: Compounds 1-1 to 1-219. R HN Q Q ON R Entry 1- R91 Entry 1- R91 Entry 1- R 2 3 N O__OPhPh 4 5 6 OH OH 7 0 8 0 9 10 11 12 N 1O 000 13 14 15 SCF OH 16 Ph 17 Ph 18 0 O 19 Ph, 20 Ph 21 Ph OH 0Me OH 0 22 N D.4 23 24 Ph'NY-1 OH 25 26 27 PAGE 17 OF 222 WO 2010/099527 PCT/US2010/025741 28 29 30 N 31 2N Boo, N'()"1' 3 B"cNJ H 0H______ o 34 35 36 N 37 38 39 N N N 40 0 0 NH 43 N 44 4 4 6 O 4 7 4 8 N &-NH 0 Hr.y0t 50 0 5N 1 U. 52 53 N 54 000 Ph ~A 57 Phyrtj 55 56 57 OMe MeO CF, Ph 58 59 60 Ph2K4 58 1 HO 61 Oygyli 62 * 63 *%AyNyfl 01 0 0 64 65 66 0 NH O NH 00 7 77 PAGE 18 OF 222 WO 2010/099527 PCT/US2010/025741 76 * rNXUI 77 78 Ho H 0 79 80 -O0 N 81 -oIrX7I 0 OH
CO
2 Bn
CONH
2 H0 HL 0..~l~ 82 ,Oy 83 84 N 85 86 87 O NH NH H pO O 88 89 90 91 0 J92 93 0 ONH -OYNH 94 *95 ION4 96 97 *y9 P A9 *yN o Ph Cl NHCO 2 Me 100 101 102 N A N AH Me 2 N NH N NH ~0 oQ 0 1031104 M 2C10N 106 107 108 0j 0 0 CN NHCO2Me ,"NHCO2Me N,0 NHCO2Me 109 N Me N CNH NHCO2Me NHC Ir 9 N!3 112 113 114 Me0 2 CHN'%A Me 2 CHN" NHCO Me HN N ,NN 115 116 117
NHCO
2 Me 2 MO NHCOMe PAGE 19 OF 222 WO 2010/099527 PCT/US2010/025741 MeO 0 118 119 120 0Y NH lOy NH 0F 0
NHCO
2 Me OBn Fmoe N 121 122 123 1
NHCO
2 Me
NHCO
2 Me
NHCO
2 Me H 0 124 125 N 126 0 0 00 127 " 0 sNH128 0 sNH 0 129 N 0 61128 13 0 H HN 130 0 * O 131 132 133 1HN35 0 0 0 0 0 MeO NH 0 MeO NH 0 0 ANH 0 136 137 138 0 0 139 *%NyJ 14N0| Ph Ph 140 141 PhNyli *N 0 142 143 144 ON|.|. 4b Ph 145 N F NJ 145 P 4 5 146 14 Ph Ph Ph 148 N N 149 N 153 N Ph Ph Ph 15 -) ,m L. 152____ Phy J 153____ Ph 154 155 156 F 3 CQ: rAI
CF
3 *N *N PAGE 20 OF 222 WO 2010/099527 PCT/US2010/025741 157 158 159 N N 160 161 Y,161 162 N C NN 163 164 9fkA 165 F .N. CI .N.N 166 167 168 F F .N.~F .N._____ 169 F 170 171 .N N 172 173 174 N N 175 176 177 178 PhN Jtj 179 180 N LO 181 N 182 18 18NbC 184 185 186 Ph N N N 187 -N 188 N, 189 00l 190 191 192 'Y N -A N0 N Oa 193 N 194 195 196 PhNY 197 N 198 199 200 N 201 N 202 203 204 AGN 21 OF22 PAGE 21 OF 222 WO 2010/099527 PCT/US2010/025741 H H 0 205 HN ,J ' 206 N07 N H N $_ H 7O 0 208 N 209 210 Ho 0H0 211 212 213 O H 2 1 6 214 215 216 0 -00 217 218 219 __ _ _ _ _ __ _ _ _ _ _ _ _ _ _ F F Table 2: Compounds 1-220 to 1-229. Ph Nk A 1 R MeO2CHN fo O W NHC0 2 Me Entry 1- R R' R" X Entry 1- R R' R" X 220 Me H H CH 2 221 H H H CF 2 222 Me H H S 223 H H HF 224 Me H H 0 225 H H H 226 H Ph H CH 2 227 H H H tO 1 H OH 228 H H Ph CH 2 229 H H H H
NHCO
2 Me NHC0 2 M, M hPh MeO2CPh Ph Compound 1-230 NCompound 1-231
SNHC
2 M P NHCO 2 M MeO 2 CHN -,NPh MeO2CH HO O Ph 5 Compound 1-232 4.- Compound 1-231 3 PAGE 22 OF 222 WO 2010/099527 PCT/US2010/025741 Table 3: Compounds 1-234 to 1-243. MeO 2 CHN NHCO2Me R' R" Entry 1- R R' R" Entry 1- R R' R" 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Et Me H 242 Me CHMe 2 H 243 Me Et H Table 4: Compounds 1-244 to 1-263. R N 5 R' Entry l- R R' Entry 1- R R' 244 MeO 2 CHN MeO 2 CHNy 245 Ph Ph Ph 248 M2CN MeO2CHN 247 MeO 2 CHNy, ON 24 Ph Ph 250 N251 MeO 2 CHN~ O..
1 N) O Ph p 252 N253 N~y~I O 1 .i Meo 2 CHN MeO 2 CHN MeO 2 CHN e21 A PhO Ph MeO 2 CHN MeO 2 CHN H co--j~N~r CNA 21 - %Ny NA 256 257 0 Ph 2 MeO 2 CHN., 259 MMO 2 CHN N N 2584 Ji~ 259 ~ y MeO 2 CHN MeO 2 CHN MeCHN Me2CN r 260 261 g oy MeOCHN ,A -A NON~e Me0 2 CHN CHO 2 CHN 262 MeO 2 CHN -,A263 -e N PAGE 23 OF 222 WO 2010/099527 PCT/US2010/025741 Table 5: Compounds 1-264 to 1-273. R R' Ph J ' MeO2CHN' MeO 2 CHN Ph Entry 1- R R' R" R'" Entry 1- R R' R" R'" 264 F H H H 265 F F H H 266 Me H H H 267 Me Me H H 268 H H Me Me 269 H H Et Et 270 CF 3 H H H 271 CF 3 H CF 3 H 272 Cl H H H 273 Cl H Cl H Table 6: Compounds 1-274 to 1-299. R' R" R MeO RN& N& M2CN "N R". R ,: 5 MeO 2 CHN Ph Entry 1- R R' R" R'" Entry 1- R R' R" R'" 274 Me H H H 275 H CO 2 H H H 276 H F H H 277 H H CO 2 H H 278 H H F H 279 H H H CO 2 H 280 H H H F 281 H CO 2 Me H H 282 H Cl H H 283 H H CO 2 Me H 284 H H Cl H 285 H H H CO 2 Me 286 H H H Cl 287 H CONH 2 H H 288 H Me H H 289 H H CONH 2 H 290 H H Me H 291 H H H CONH 2 292 H H H Me 293 H OMe H H 294 H CF 3 H H 295 H H OMe H 296 H H CF 3 H 297 H H H OMe 298 H H H CF 3 299 CO 2 Me H H H Table 7: Compounds 1-300 to 1-434.
MO
2 CHIAA N MeO 2 CHN Ph PAGE 24 OF 222 WO 2010/099527 PCT/US2010/025741 Entry Aa Entry Aa Entry Aa 1- 1- 1 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 N N 317 N N 318 Y 319 AOyNkA 320 0 0 321 322 N2 , 324 /1ovA 325 326 327 - 328 329 330 * o 331 332 0 0 ISHN 333N 334 -N 335 I-NH 336 N337 -N N-/ 338 N- NI 339 340 341 N 342 343 344 345 I-NOLN x 346 347 N O H ~ NH 348 % j 349 3-N .eO- 350 351 352 353 354 -N 355 356 357 358 359 HNA HNi O 360 361 o 362 HN o- HN_ HN 363 - 364 365 HN PAGE 25 OF 222 WO 2010/099527 PCT/US2010/025741 366 367 368 N I-NH 368 369 No / 370 371 /o . 372 O 0 373 374 p0 375 0 376 377 378 0 379 -N -O- 380 381 Ao',y 382 /,, .. N 383 /N N 384 Ao^, *O 385 /0,op"o 386 l-Vpo- 387 J- 388 389 390 - 391 oNNol 392 _ _ _ __0_ 0 0 HNA HN
HN
393 394 o 395 ~ o _ 0 0S 396 397 t-N N-1 398 399 400 401 240N N N 402 43 404 I-NQ--'0 N 0 405 _406 407 408 409 410 N!) N N 411 412 N 413 N 'N-I 00 414 415 416 0N, N 417 N 418 419 N PAGE 26 OF 222 WO 2010/099527 PCT/US2010/025741 420 421 %N, 422 00 423 N424 425 N N 426 427 4-N N28O 429 430 -o4o 431 N 432 433o -CjI-o 433 434 Table 8: Compounds 1-435 to 1-440. PPh MeO 2 CHN Entry Bb Entry Bb Entry Bb 435 436 )y- 437 N-NH N-N N-N 438 439 440 5 Table 9: Compounds 1-441 to 1-545. 1-441 N O 1-443 e2C N N 0 HOM Ph 144 h ~NHC 2 MO 1-444 0CH1f -, -- II e NPh Ph 1-443 Me2CHN Y NHCO 2 Me PAGE/- 27OF22 1-444 Xofo- Ni0 o Ph 1-445 MOCN oH- ]N H0M U Ph PAGE 27 OF 222 WO 2010/099527 PCT/US2010/025741 Ph 1-446 Ij N MN 2CH N N I andlor 1-447 BOC
MGO
2 CHN
CO
2 MeN MeO 2 CHN 4 N
NHC
2 MG N 2 1-44 2N I NHCO 2 Me NC2 1-454 N NHC2Me 1NHCO2Me 1-455 N N a N N NHO HN 8 O 1-454 "ANN , H0M H
NHC
2 S NHCO0M N N ; aEla 1-4535H N N PA00 28 NF22 WO 2010/099527 PCTUS2O1O/025741 NN 1-456 NHC0 2 MG AHC0 2 MG NH'M NHHO 2 M 1-457 0N >~ C-> N
NHCO
2 Me NHCO 2 Me 1-458 1-459 _02-N, H0M ome M2CT 1-462 MIN HNM MOO 1-4641e 2 H INIOM 1-462 NH)_CI* _OM HN N C) 146MeO 2 CHey M 1-4637, NIH ,NH.M jNN -48Me2kHfQ O4-V N ~ ~ ,MeO 2 PA Q2 o 2 WO 2010/099527 PCT[US2O1O/025741 1-47 N 1-479 M&0 2 CIN)" HN --- -I & I ~H N H 2 MQ
N
4 G N U, Ole N N! ,~HOM NN 1-478 0 N 1-479 ~MeO 2 CHN0 Hll~ H Nn.0M -471 OINH COMe 1-482 e2H IN HNH N NC e 0 JS 1-83M0 2 CH NH NHC0 2 MQ PAE 30OF22 WO 2010/099527 PCT/US2010/025741 1-484 _ = iOVe 1-4 5 OO 2 HNfr$t/N NHC% 2 Me 1-48561N N0 1-486 N P1 H d: NC0M D D 1-4878M~C~ H N HOM U 1 each D Is deuterium 1-490 N 1-488 o02CH HN C0 2 Me 1-49OJH Y 61NCH NH Ve 2 H 0 HN HN N, C 2 M 1-494 HINH"! MO N sNSN NHC 2 MG 1-49151,-NL 1-4926N PAEOC 31 HF 222 WO 2010/099527 PCT/US2010/025741 1-497-a tentative 1-497-b /0O N HCO2M MeO 2 CHN 0 NHC 2 Me < H H 1-497-b N ( N tentative MeN 2 CHN 1-401
NHICO
2 Me M00264 0 N HC0 2 M 1-503 M2CHN 9_
NHCO
2 M 1-504
NHICO
2 Me MoD 2 CHN 05 1-506 1-507
SHCO
2 Me Me0 2 CHN M-O2CHN N N NH HC0 2 MO 1-509 N 0H NHCO 2 Me 1-507 N PA508F N NH0 NHCMe MoO 2 CHN 1-5092= r~ N0 <13 NHC0 2 M M90 2 CHN 0 Nr 1-5104 , k _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(H 0 M PMGE02HN 22 WO 2010/099527 PCTUS2010/025741 MeO 2 CHN 1-511 NN ,jo NHAG MeO 2 CHN 1-5 12"1 SP H ofN No M00 2 CIN 1-513 o-YS U.- NHCO 2 rve M O 2 CH N H 0N 1-5 14 N1 NHC0 2 Me 1-515 /0C 2 M 1-516 & N F)' Me0 2 CHYj (S) 0 N 1-517 " f r 0 0 HON NHOM 1-518 N N 7 1-519 rl 1-520D NH C 2 M o 0o MeO 2 CHN0 1-5213 AHC0 2 Me PAGE 3 OF 22 WO 2010/099527 PCT/US2010/025741 1-524 N N%4 NN 00o MeO2CHU 1-525 H NHCOMe 1-526 Me
HHCO
2 Me MeO 2 CHNH 1-5282me MeO 2 CHN H HC2M NON 1-528 5N N2M 1-529 MeO 2 C HNl H H~CO 2 Me N N 1-530NH MeO 2 CHN 1-5312M 1-532 N O 2M MeO 2 CHNH 1-532 en N O HCO2Me MeO 2 CHN H
NHCO
2 Me 1-535 N MeO 2 CHN H MOCN( N -0-~= i 4 NH(s 1-534 2me 1-53 N MeO 2 CHN H ___________________________________Ph
HCO
2 Me 1-537 2H MeO 2 CHN -Ph PAGE 34 OF 222 WO 2010/099527 PCT/US2010/025741
NHCO
2 Me 1-538 N MeO 2 CHN 0-Ph 1-539 N H2Me S MeO 2 CHN H Me NHCO 2 Me 1-540 MeO 2 CHN F
NHCO
2 Me l-541 MeO(sl 1-542 N NO ( NN M e, 2 H H H O M MeO 2 CHN F1 1-544 (- N 2Me N J/ N MeO 2 CHN H NHCO 2 Me 1-545 N MeO 2 CHN F- . MeO NHCO 2 Me 1-544 MeO 2 CHN NH O 2 Me 1-545
M
eOCHt$ II. Compounds having the Formula (2-I) The present invention relates to compounds of Formula (2-I) as illustrated above, or a pharmaceutically acceptable salt thereof. 5 In one embodiment, the present invention relates to compounds of Formula (2-Ia), or a pharmaceutically acceptable salt thereof: (2-Ia) wherein A, D, E, Ring G, T, Z, Q, and J are as previously defined in Formula (2-I) and Ring B' is an optionally substituted five-membered heteroaryl; and Ring B' is 10 C-attached to J and one of Z, E, T, A and D. In some aspects, Ring B 1 is an optionally substituted five-membered heteroaryl that contains one or more nitrogen atoms. PAGE 35 OF 222 WO 2010/099527 PCTUS2010/025741 In another embodiment, the present invention relates to compounds of Formula (2-Iaa), or a pharmaceutically acceptable salt thereof: Q &D-A-T-E-Z Ji (2.4aa) wherein A, D, E, Ring G, T, Z, Q, and J are as previously defined in Formula (2-1) 5 and Ring B 2 is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B2 is C-attached to each of J and one of Z, E, T, A and D. In yet another embodiment, the present invention relates to compounds of Formula (2-Ib), or a pharmaceutically acceptable salt thereof: Q &D-A-T-E-Z Ji (2-Ib) 10 wherein A, D, E, Ring G, T, Z, Q, and J are as previously defined in Formula (2-1) and Ring B 3 is an optionally substituted 5/6 fused heteroaryl, wherein the 6 membered ring of said 5/6-fused heteroaryl is C-attached to one of groups Z, E, T, A and D, and the 5-membered ring is C-attached to group J and containing one or more nitrogen atoms. 15 In still another embodiment, the present invention relates to compounds of Formula (2-Ibb), or a pharmaceutically acceptable salt thereof: Q &D-A-T-E-Z Ji (2-Ibb) wherein A, D, E, Ring G, T, Z, Q, and J are as previously defined in Formula (2-1) and Ring B4 is selected from the group consisting of: H1 H H N~ NN 200 ACN NQ~ N N1 N 20 H In yet another embodiment, the present invention relates to compounds of Formula (2-Ic), or a pharmaceutically acceptable salt thereof: PAGE 36 OF 222 WO 2010/099527 PCT/US2010/025741 Q &D-A-T-E-Z Ji (2-Ic) wherein A, Ring B, D, E, T, Z, Q, and J are as previously defined in Formula (2-I) and Ring G 1 is an optionally substituted 5/6 fused heteroaryl other than benzimidazolyl, with the 6-membered ring C-attached to one of groups D, A, T, E 5 and Z and the 5-membered ring C-attached to group J and containing one or more nitrogen atoms. In still another embodiment, the present invention relates to compounds of Formula (2-Icc), or a pharmaceutically acceptable salt thereof: Q - D-A-T-E-Z- J (2-Icc) 10 wherein A, Ring B, D, E, T, Z, Q, and J are as previously defined in Formula (2-I) and Ring G 2 is selected from the group consisting of: H N~C N2tIh H N NH N N RN D---- N-R RGN DA-- "N DATE Z% N- /DAT- 0 H NN H In still another embodiment, the present invention relates to compounds of Formulae (2-d- to 2-d-4), or a pharmaceutically acceptable salt thereof:
R
6 -n R 3 D, E g n T , R 6 3 , R7 R IQD-A-T-E-Z 4 NI - G DA-T-E-Z0 B R K :' N -R' R6
(R
7 )., X/r;T V- N-R 5 X/ R T N j wherein A, D, E, Ring B, Ring G, T, Z, X, mn, n, R 3 , R , W 5 , R 6 and R 7 are as previously defined in Formula (2-I). PAGE 37 OF 222 WO 2010/099527 PCT/US2010/025741 In still another embodiment, the present invention relates to compounds of Formulae (2-Ie-I to 2-Ie-4), or a pharmaceutically acceptable salt thereof: R12l R( R- D-A-T-E- NR R D-A-T-E-Z (2-Ie-1) O < (2-le-2) R5R R2 R- 0 N r D-A-T-E- N-R __rD-A-T-E-Z (2-le-3) O= ' (2-le-4) 0 1 wherein A, Ring B, D, E, Ring G, T, Z, R3, R 4 , Ri, and R" are as previously defined 5 in Formula (2-I) and X 1 is independently CH 2 , CHF, CH(OH), or CF 2 . In still another embodiment of the present invention, the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine or five membered heteroarylmethylamine moiety is represented by Formulae (2-If-1 to 2 If-4): R12 R1 R N R 3 R D-A-T-E-Z- N"-R' D-A-T-E-Z R2(2-If ) 0 '2R 12~ (24f2) ozdtR 12 10 (2-If-3) O=( (2-If4) -R wherein A, B, D, E, G, T, Z, R 3 , R, and R 12 are as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of Formula (2-Ig), or a pharmaceutically acceptable salt thereof: CY-( ID-D-A-T-E-Z EB 15 R11O0 (2-Ig) OR" wherein A, D, E, T, Z, Ring B, Ring G and R" are as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of Formula (2-Ih), or a pharmaceutically acceptable salt thereof: PAGE 38 OF 222 WO 2010/099527 PCT/US2010/025741 D-A-T-E-Z B Ra'N >O (2-1h) O%( N-Ra Rb wherein A, Ring B, D, E, Ring G, T, Z, Ra and R are as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of 5 Formula (2-Ii), or a pharmaceutically acceptable salt thereof: D-A-T-E-Z B RcN O (2-l1) O N-Rc 1W Rd wherein A, Ring B, D, E, Ring G, T, Z, R* and Rd are as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of 10 Formula (2-Ij), or a pharmaceutically acceptable salt thereof: D-A-T-E-Z B R1 R wherein A, Ring B, D, E, Ring G, T, Z, and R1 3 are as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of 15 Formula (2-Ik), or a pharmaceutically acceptable salt thereof: GD-A-T-E-Z B Ria O (2-1k) 0Rua wherein A, Ring B, D, E, Ring G, T, and Z are as previously defined in Formula (2 I) and R at each occurrence is independently an optionally substituted C 1
-C
8 alkyl; preferably C 1
-C
8 alkyl optionally substituted with amino, hydroxy, phenyl, protected 20 amino, or O(C 1
-C
4 alkyl). In still another embodiment, the present invention relates to compounds of Formula (2-I1a), or a pharmaceutically acceptable salt thereof: Q &TJ (2-1la) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I) and T 25 is present and as previously defined in Formula (2-I). PAGE 39 OF 222 WO 2010/099527 PCT/US2010/025741 In still another embodiment, the present invention relates to compounds of Formula (2-Ib), or a pharmaceutically acceptable salt thereof: (2-11b) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I) and A 5 is present and as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of Formula (2-Ic), or a pharmaceutically acceptable salt thereof: (2-1ic) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I) and T' 10 is a linear aliphatic group, optionally comprising one or more of an olefinic double bond, an alkynic triple bond, 0, N(R"), C(0), S(0) 2 , C(0)0, C(O)N(R"), OC(0)O, OC(0)N(R"), S(0) 2 N(R"), N(R")C(0)N(R"), N(R")C(O)C(0)N(R"),
N(R")S(O)
2 N(R"), C(O)N(R")S(O) 2 and C(O)N(R")S(O) 2
N(R
1 ). In still another embodiment, the present invention relates to compounds of 15 Formula (2-I1d), or a pharmaceutically acceptable salt thereof: Q-O T2-3j (2-i1d) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I) and T 2 is an aliphatic group comprising a C 3
-C
8 cycloalkyl or C 3
-C
8 cycloalkenyl and optionally comprising one or more of an olefinic double bond, an alkynic triple 20 bond, 0, N(Rr), C(0), S(O) 2 , C(0)0, C(0)N(R"), OC(0)0, OC(O)N(R 1 ), S(0) 2 N(R"), N(R")C(O)N(R"), N(R")S(0) 2 N(R"), N(R")C(0)C(0)N(R"), C(0)N(R")S(0) 2 and C(0)N(R")S(0) 2 N(R"). In still another embodiment, the present invention relates to compounds of Formulae (2-lIa-1 and 2-IIIa-2), or a pharmaceutically acceptable salt thereof: Q A-T J Q T-E J 25 (2-Illa-1) (2-i1na-2) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I); in Formula (2-lIa-1), A and T are each present and as previously defined in Formula (2-1); and in Formula (2-Il~a-2), T and E are each present and as previously defined in Formula (2-I). PAGE 40 OF 222 WO 2010/099527 PCT/US2010/025741 In still another embodiment, the present invention relates to compounds of Formula (2-IlIa-3), or a pharmaceutically acceptable salt thereof: (R R)7, T </O R12 O 2Il-3)OY (RI)
R
12 wherein Ring G is as previously defined in Formula (2-1); n is 1 or 2; T is absent or 5 optionally substituted C 2
-C
4 alkenyl or optionally substituted C 2
-C
4 alkynyl; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; X at each occurrence is independently CH 2 , CHF, CH(OH), CHMe,
CF
2 , or C(R 7
)
2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R 7 groups are taken together with the carbon to which 10 they are attached to form a spiro, optionally substituted C 3
-C
8 cycloalkyl; or yet alternatively, two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3
-C
8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted C 1
-C
8 alkyl. 15 In still another embodiment, the present invention relates to compounds of Formula (2-IIa-3), or a pharmaceutically acceptable salt thereof; wherein two geminal R7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; and R 12 at each occurrence is independently C 1
-C
8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(C 1
-C
4 alkyl). 20 In still another embodiment, the present invention relates to compounds of Formula (2-IIla-3), or a pharmaceutically acceptable salt thereof; wherein two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R 12 at each occurrence is independently C1-C 8 alkyl optionally substituted with amino, hydroxy, protected 25 amino, or O(C 1
-C
4 alkyl). In still another embodiment, the present invention relates to compounds of Formulae (2-III-a) to (2-III-d), or a pharmaceutically acceptable salt thereof: PAGE 41 OF 222 WO 2010/099527 PCT/US2010/025741
R
7 0 (R7). NH O (R) N N Ru ~2411-ba (~ R12211-c R), R70 (R).- GH 1R R7~ R24II-d R wherein Ring G is imiidazolpyridyl; n is 1 or 2; X at each occurrence is each independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7
)
2 ; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R 7 5 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and Rdat each occurrence is independently Cr-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or O(Cr-C 4 alkyl). 10 In still another embodiment, the present invention relates to compounds of Formulae (2-III-a) to (2-III-d); wherein R' 2 at each occurrence is independently Cr Cs alkyl substituted with -NHCO 2 (Cr-C 4 alkyl) or O(Cr -C 4 alkyl); or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention relates to compounds of 15 Formula (2-IIub), or a pharmaceutically acceptable salt thereof: Q A -Eh (2-IlIb) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I); A and E are each present and as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of 20 Formulae (2-Ia- and 2-Iva-2), or a pharmaceutically acceptable salt thereof: G 42 (2-I2-)2 2 C8 alkylsubstittedPAGE -NC2 -42 OFyl 222 C-C lyl;o WO 2010/099527 PCT/US2010/025741 wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I); in Formula (2-Ia-1), D, A, and T are each present and as previously defined in Formula (2-I); and in Formula (2-IVa-2), E, T, and Z are each present and as previously defined in Formula (2-I). 5 In still another embodiment, the present invention relates to compounds of Formula (2-IVb), or a pharmaceutically acceptable salt thereof: Q &A-T-E &J (2-IVb) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I); A, E, and T are each present and as previously defined in Formula (2-I). 10 In still another embodiment, the present invention relates to compounds of Formulae (2-Va-1 and 2-Va-2), or a pharmaceutically acceptable salt thereof: Q& D-A-T-E- J Q A-T-E-Z J (2-Va-1) (2-Va-2) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-I); in Formula (2-Va-1), D, A, T and E are each present and as previously defiend in 15 Formula (2-I); and in Formula (2-Va-2), A, E, T, and Z are each present and as previously defined in Formula (2-I). In still another embodiment, the present invention relates to compounds of (R 7). R7 V N Formula (2-I), or a pharmaceutically acceptable salt thereof; wherein A at each occurrence is independently illustrated by one of the following groups: SN Me F F Me Me OH Representative compounds of the present invention are those selected from compounds 2-1 to 2-516 compiled in Tables 10-20: Table 10: Compounds 2-1 to 2-219. PAGE 43 OF 222 WO 2010/099527 PCT/US2010/025741 0 0 0 Entry 2- R Entry 2- R Entry 2- R) 2 AyNy)j3 N 0 Ph Ph 0 00 4 5 6 6H 6H 00 0 7 o kg 8 S NAI 9 10 11 12 N 0 OH 0 0 0 0 13 VAN 14 15 16 Ph-Al 17 Ph -114 18 0 0 0 19 20Ph Ph J OH Ome 6__ H 22 23 Ph 6 25 826 927 0 40 NO 43 NN 44 4* 00 0 46 N 0 PAGE 44 OF 222 WO 2010/099527 PCT/US2010/025741 0 N- NH 0F 0 49 N 50 51 52 N53 N- O . -(54 O 54 55 Ph 56 57 Ph OMe Me CF Ph 58 59 60 P H 0H 02 0 61 OyNy<j 62 -yN,,ru% 63 NYNy~l 0 0 0 0 HO 0 64 O NH 65 NH 66 Y y 0 67 - 0 i t'' 68 69 70 71 72 0o 0 H H H 76 o N,.77o N 78 o N 80 80 ooy.( t~ 81 ooN.( 7O H CO 2 Bn CONH 2 82 83 84 N O OLO 85 86 87 0aOY NH jOy NH O NH 88 89 90 _ _N_ _ _ OTBS OTBS 91 92 93 0O NH O NH 94 0 0 PE96 PAGE 45 OF 222 WO 2010/099527 PCTIUS2010/025741 97 y 98 99 NH 9 0 Ph CI NHCO 2 Me >N 100I Y 0~ 101 102 .0Ny NH Me 2 N yNHI-IN N 01I 0 0 109 v-NH NCO 2 Me 11 112 103 114
MOCN"~
1 MeONH KEloN 115 107~ %~J 117 C' rNHC 2 Me NHC 2 M GOM 00 121 12212 N4 COMe N NHC 2 M NHCO Me 114 HN:L~J 1251j16 N 117 9 0look&N 0 ~OSA 0 117 ~ YA 128 129 1 0~i 0 0 NHC02M 130 1312 0 130 PAGE46 O 22 WO 2010/099527 PCT/US2010/025741 133 H 134 H 135 HN eo o o o0 MeO H MeO LH 0 136 137 138 139 N 140 141 N Ph Ph Ph %N 0 142 143 N 144 N 4t:7 4'-,-7Ph 145 N 0 146 F4N 7 F 148 N 149 H N 150 Ph Ph Ph 154 BnOItN 1552c~%.JI 156 6 PhPhh 154o Bn NO o 155, 1503 157 N 158 159 N N N 160 CjA.#KrAI 161 162 N Ci N.N F54 NCI N N 166 167 168 F N%% F N 169 N 170 171 N N 172 173 174 N N N < 175 176 1 '1 177 N PAGE 47 OF 222 WO 2010/099527 PCT/US2010/025741 178 P 179 180 N 181 182 183 N 60 184 185 186 Ph* N N NN 1 0 0H0 187 -N 88 N8 189 190 0 190 191 192 0L 00 193 N 194 195 0 196 1 97 N 8 N NH2 199 200 Nj 201 N 0 H 00 H N N .)tH 202 N2N 0N 204 205 HNY 206 2N )r-Y
H
2 2N 208 H N 29 N 211 H 2 212 213 N 214 F 215 216 217 218 N~'g219F Table 11: Compounds 2-220 to 2-229. 0 N N 0 H 0 P . 48 - 222 M'ACH H Co2M 2PAG 482 OF 222 WO 2010/099527 PCT/US2010/025741 Entry 2- R R' R" X Entry 2- R R' R" X 220 Me H H CH 2 221 H H H CF 2 222 Me H H S 223 H H HF 224 Me H H 0 225 H H H H 226 H Ph H CH 2 227 H H H I OH ON 228 H H Ph CH 2 229 H H H H
NHCO
2 M P NHCO 2 M. MeO2CHNPh Me2CHN 'Ph NHC2eNC2 M0O2CHN Ph MeO2CHN4 Nj' S Compound 2-230 ( Compound 2-231 (S) (i~ (3) hG P R" NHC 2 M (M 'N N . P M' VPh CH N~H /r M - 0 2 C H N M 2CNH N MN 2 HN N N'~ N H. Compound 2.232 0 S)~ Compound 2-233 5 Table 12: Compounds 2-234 to 2-243. M0 2 CHN'f! HN NR R 4 ~N N R' R" p Entry 2- R R' R" Entry 2- R R' R" 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Et Me H 242 Me CHMe 2 H 243 Me Et H Table 13: Compounds 2-244 to 2-263. R N Entry 2- R R' Entry 2- R R' MeO 2 CHNyN Me 2 CHN 4 - N 244 Ph 245 PAGE 49 OF 222 WO 2010/099527 PCT/US2010/025741 246 N MeO 2 CHN Y 247 MeO 2
CHN
9 N Ph Ph 248 M0O2CHN MaO 2 CHN 249 MaO 2 CHN MO2CHN Ph Ph 250 N251 MeONCHNA2 OyNA Ph 0 0 Ph ph 252 253 Ny O Ph 0 MaOCHNt MeO 2 CHN MeO 2 CHN Ph H 254 255 OCi N N 0 Ph MeOCHNA MeO2CHN 27H N 256 25Ph MMeO 2 CHN 259 M N MeOCHN.A MQO2CHN. Me0 2 CHN MeO 2 CHN 260 261N A ~ OMe M0 2 CHNA MoO2CHN,,A H 262 Me 2 CHN 263 Table 14: Compounds 2-264 to 2-273. Ph R R'I MeO2CHN N - -NH yPh R" R" NHCO2Me Entry 2- R R' R" R'" Entry 2- R R' R" R!" 264 F H H H 265 F F H H 266 Me H H H 267 Me Me H H 268 H H Me Me 269 H H Et Et 270 CF 3 H H H 271 CF 3 H CF 3 H 272 Cl H H H 273 Cl H Cl H 5 Table 15: Compounds 2-274 to 2-291. NR Nk MN OCHNHC 2 MG ~ N R"' R N P Entry 2- R R' R" Entry 2- R R' R" 274 Me H H 275 H CO 2 H H 276 H F H 277 H H CO 2 H 278 H H F 279 H CO 2 Me H PAGE 50 OF 222 WO 2010/099527 PCT/US2010/025741 280 H C1 H 281 H H CO 2 Me 282 H H Cl 283 H CONH 2 H 284 H Me H 285 H H CONH 2 286 H H Me 287 H OMe H 288 H CF 3 H 289 H H OMe 290 H H CF 3 291 CO 2 Me H H Table 16: Compounds 2-292 to 2-426. MeO 2 CHN~' Aa 7 (. N~~ NH L.pNHCO 2 Me Ph Entry Aa Entry AaEntry Aa 2- 2- 2 292 293 294 295 V 1 296 297 298 299 300 301 302 303 304 - ~ 305 306 307 N308 NN 309 N 310 Y311 312 0 325 'NH 326 O N327 H-. N - ( N 328 329 - N 330N 331 332 Ab 333 N 334 N 335 N 336 337 lN 338 339 N PAGE 51 OF 222 WO 2010/099527 PCT/US2010/025741 340 341 I-Oa o" 342 343 'NN344 345 346 3-N / A 347 348 N N 349 350 351 HN-i HN-i 54H 352 -353 354 H HN-j HN 355 o-( 356 357 HN ri ri HN4 358 -- NH 359 _S 360 ____ I-NH 00 361 362 363 364 V* o 365 366 367 0 368 O N 369 0 370 0 371 N/ 372 373 374 N 375 -N N 376 AoI% 0 N 377 * 378 o 379 I-N 04 380 381 382- 383 / 384 0 ~10 0 HN- N HN 385 _ 386 o 37 [-so.-- 387 HN-S% 0 0 388 389 -N - 390 0 391 392 393 394 N { 395 396 397 -N 398 399 PAGE 52 OF 222 WO 2010/099527 PCT/US2010/025741 400 401 402 NN 403 404 405 406 407 408 N N 409 J-N N-i 410 411 N 412 413 N414 415 0 416 417 N /N IN 418 0419 N N O 421 d o 422 * o 423 NN' 424 o o 425 -,o0VN 426 Table 17: Compounds 2-427 to 2-477. Ph) MN N N H MaO 2 CHN H(N A. % (8 N Entry 2- Aa Entry 2- Aa Entry 2- Aa 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 PAGE 53 OF 222 WO 2010/099527 PCT/US2010/025741 445 446 447 N 448 449 450 N 451 N 452 N 453 NN N 454 455 456 N-0,NH s 457 458 459 460 461 N 4 463 464 465 466 467 1-N- 468 469 - 470 I-Nj- 471 I-N N] 472 -0 473 - 4"4 N I-N - 47N[AN 475 -N 476 I-No ' 1 477 Table 18: Compounds 2-478 to 2-497. MeO 2 - HN' j G& N (N O NHCO2Me PI Ph Entry Bb Entry Bb Entry Bb 2- 2- 2 478 A 479 480 N-NH N-N N-N 481 482 483 484 - 485 486 >-4 487 488 489 NN N 0 490 491 492 /N ~ H 493 494 495222 PAGE 54 OF 222 WO 2010/099527 PCT/US2010/025741 496 497 N H Table 19: Compounds 2-498 to 2-508. Ph MeO 2 CHN 0 -rl NHCO2Me Entry Entry G Entry Gg 2- 2- 2 498 499 - 500 $ N 501 502 503 504 505 506 507 508 5 Table 20: Compounds 2-509 to 2-516 2-509 2-5 10 MeO2CHCO2Me 2 -5 1 1 NH_ 0 2-512 ' 2-514 Me02CH HCO2MG 2-5 15 PAGE 55 OF 222 WO 2010/099527 PCT/US2010/025741 MeO2CH
-
2-516 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 5 accommodate a substitutent at any given location. It is intended that the definition of any substituent or variable (e.g., R, W, X, u, m, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when u is 2, each of the two Ri groups may be the same or different. 10 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. 15 It should be understood that 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 cure of the disease. It will further be appreciated that references herein to treatment or 20 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 or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, with a 25 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 30 acceptable carrier or excipient. PAGE 56 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 oligonucleo-tides and the like); 10 antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen 15 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 20 combination of agents that inhibit the replication of HCV by targeting other proteins of the viral genome involved in the viral replication and/or interfere with the function of other viral targets, such as inhibitors of NS3/NS4A protease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein. According to yet another embodiment, the pharmaceutical compositions of 25 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 30 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 PAGE 57 oF 222 WO 2010/099527 PCT/US2010/025741 are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting 5 proteins of the viral genome. A non-limiting example of the RNA-containing virus is 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 10 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 A non-limiting example of the RNA-containing virus is hepatitis C virus (HCV). 15 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 20 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. A non-limiting example of the RNA-containing virus is hepatitis C virus (HCV). 25 Another 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 30 the present invention, or a pharmaceutically acceptable salt thereof The agent that treats patients for disease caused by human immuno-deficiency 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, PAGE 58 OF 222 WO 2010/099527 PCT/US2010/025741 efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T- 1249, or any combination thereof A non-limiting example of the RNA containing virus is hepatitis C virus (HCV). It can occur that a patient may be co-infected with hepatitis C virus and one 5 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 herein 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. 10 In addition, the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt thereof, and one or more agents selected from the group consisting of a host immune modulator and one or more additional antiviral agents, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA 15 containing virus in a patient, particularly hepatitis C virus. Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant. Preferably, said additional antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated 20 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, or as a pharmaceutically acceptable salt thereof. Alternatively, such combination of 25 therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt thereof, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be used for inhibiting the replication of an RNA 30 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). PAGE 59 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 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 15 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 that can 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 20 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 sufficient to improve one or more pharmacokinetic (PK) features including, but not limited to, plasma concentration, bioavailiablity, area under the plasma 25 concentration time curve (AUC), elimination half-life, and systemic clearance, of a compound of the invention when one or more of its PK features of said compound is improved in comparison to that in the absence of the CYP inhibitor. In one embodiment, the invention provides methods for improving the pharmaco-kinetics of compounds of the invention. The advantages of improving the 30 pharmacokinetics of drugs are recognized in the art (see, for example, US Patent Pub. No.'s. 2004/0091527; US 2004/0152625; and US 2004/0091527). Accordingly, one embodiment of this invention provides a method comprising administering an inhibitor of CYP3A4 and a compound of the invention. Another embodiment of this invention provides a method comprising administering a compound of the invention PAGE 60 OF 222 WO 2010/099527 PCT/US2010/025741 and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2C19 ("CYP2C19"), isozyme 2D6 ("CYP2D6"), isozyme 1A2 ("CYPlA2"), isozyme 2C9 ("CYP2C9"), or isozyme 2E I ("CYP2E 1"). In a preferred embodiment, the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the 5 pharmacokinetics of the relevant compound of the invention 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, nelfinavir, 10 amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, ditiazem, 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, 15 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 and an information insert containing directions on the use of the combination of the invention. In an alternative 20 embodiment of this invention, the 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 25 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 30 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 a compound of the invention and optionally the additional agent (s) in a pharmaceutically acceptable PAGE 61 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 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 15 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 20 part of a larger group. The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls 25 can comprise fused rings, covalently attached rings or a combination thereof. The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, 0 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, 30 pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. PAGE 62 OF 222 WO 2010/099527 PCT/US2010/025741 In accordance with the invention, 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 the two rings can 5 be fused or covalently attached. The terms "CI-C 4 alkyl," "Ci-C alkyl," "C1-Cs 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 CI-C 8 alkyl radicals include, but are not 10 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 "C3-C6 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 15 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, 1 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 alkynyl," as used herein, refer to straight- or branched-chain hydrocarbon radicals 20 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 -Cs-cycloalkyl", or "C5-C7-cycloalkyl," as used herein, refers to 25 a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted. Examples of C 3 -Cs-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 5
-C
7 -cycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like. 30 The term "C 3 -Cs cycloalkenyl" or "C 5
-C
7 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 PAGE 63 OF 222 WO 2010/099527 PCT/US2010/025741 like; and examples of C 5
-C
7 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. 5 The term "heteroarylalkyl", as used herein, refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-Ci-C 6 -alkyl groups. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group. 10 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, 0, OH, NH, NH 2 , C(O), S(0) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , 15 S(0) 2 NH, S(0) 2
NH
2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(0) 2 NH, NHS(0) 2
NH
2 , C(O)NHS(0) 2 , C(O)NHS(0) 2 NH or C(O)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 20 atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched or cyclic 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 25 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 linear aliphatic group can, for example, be selected from one or more of 30 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 aliphatic group can be represented by the formula M-Y-M', where M and M' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and Y is a PAGE 64 OF 222 WO 2010/099527 PCT/US2010/025741 functional group. In some examples, Y is selected from the group consisting of C(O), S(0) 2 , C(0)O, C(O)N(R"), OC(0)O, OC(O)N(R"), S(0) 2 N(R"), N(R")C(O)N(R"), N(R")C(O)C(O)N(R"), N(R")S(0) 2 N(R"), C(O)N(R")S(0) 2 or C(0)N(R")S(0) 2
N(R
1 ); wherein R 1 is as previously defined. In another aspect 5 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 10 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 15 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 20 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, 25 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 30 herein can also be a divalent group when used as a linkage to connect two groups or substituents, which can be at the same or different atom(s). The term "substituted" refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected PAGE 65 OF 222 WO 2010/099527 PCTIUS2010/025741 amino, oxo, thioxo, -NH-Cl-C 12 -alkl, -NH-C 2 -C8-alkenyl, -NH-C 2 -C8-aflk)YI, NH-C 3 -C 12 -cycloatkyl, -NH-aryl, -N-H-heteroaryl, -NH-heterocycloalkyl, dialkylamino, -diarylamino, -diheteroarylamino, -O-C 1
-C
12 -alkyl, -O-C 2 -C8-alkenyl,
-O-C
2 -C8-aflkPYn, -O-C 3
-C
12 -cycloalkyl, -0-aryl, -0-heteroaryl, -0 5 heterocycloalkyl, -C(0)-C-C, 2 -alkl, -C(O)-C 2 -C8-atkenyl, -C(O)-C 2 -C8-alkynyl,
C(O)-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 heterocycloalkl, -0C0 2
-C-C,
2 -alkyl, -0C0 2
-C
2 -C8-alkenyl, -0C0 2
-C
2
-C
8 10 alkynyl, -0C0 2
-C
3
-C
1 2 -cycloajkl, -0C02-aryl, -0C0 2 -heteroaryl, -0C0 2 heterocycloatkyl, -C0 2 -Cl-CI 2 alkyl, -C0 2
-C
2 -C8 alkenyl, -C0 2
-C
2
-C
8 aflkynyl, C0 2 C 3
-C
12 -CYCloalkyl, -C0 2 - aryl, C0 2 -heteroaryl, C0 2 -heterocyloalkyl, -OCONH 2 , OCONH-C 1-C 12 -atkyl, -OCONH-C 2 -C8-alkenyl, -OCONH-C 2 -C8-aknYl, OCONH-C 3
-C
12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH 15 heterocyclo-alkyl, -NHC(O)H, -NHC(O)-C-C, 2 -alkyl, -NHC(O)-C 2 -C8-alkenyl, NHC(O)-C 2 -C8-alkynyl, -NHC(0)-C 3
-C
1 2 -cycloalkyl, -NHC(0)-aryl, -NHC(O) heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO 2
-C
1
-C
1 2 -alkyl, -NHCO 2
-C
2
-C
8 alkenyl, -NHCO 2 - C 2 -C8-alkynyl, -NHCO 2
-C
3
-C
12 -cycloalkl, -NHCO 2 -aryl, NHCO 2 -heteroaryl, -NHCO 2 - heterocycloalkyl, -NHC(O)NH 2 , -NHC(O)NH-C 1
-C
1 2 20 alkyl, -NHC(O)NH-C 2 -C8-atkenyl, -NHC(0)NH-C 2 -C8-alkynyl, -NHC(0)NH-C 3 C 12 -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH heterocycloalkyl, NHC(S)NH 2 , -NHC(S)NH-Cl-C 12 -atkYl, -NHC(S)NH-C 2
-C
8 alkenyl, -NHC(S)NH-C 2 -C8-alkynyl, -NHC(S)NH-C 3
-C
1 2 -cycloalcyl, -NHC(S)NH aryl, -NHC(S)NH-heteroaryl, -NHC(S)NHi-heterocycloalkyl, -NHC(NH)NH 2 , 25 NHC(NH)NH-Cl-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 i2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-Cl-C 12 -alkyl, -NHC(NH)
C
2 -C8-atkenyl, -NHC(NH)-C 2 -C8-alkynyl, -NHC(NH)-C 3
-C
12 -cycloalkyl, NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH 30 Cl-C 12 -alkl, -C(NH)NH-C 2 -C8-atkenyl, -C(NH)NH-C 2 -C8-alkynyl, -C(NH)NH-C 3 C 1 2-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH heterocycloalkyl, -S(0)-C 1 -C 12 -alkyl, -S(O)-C 2 -C8-alkenyl, - S(O)-C 2 -C8-AlkYty, S(0)-C 3 -Circycloalkyl, -S(0)-aiyl, -S(O)-heteroaryl, -S(0)-heterocycloalkyl, SO 2
NH
2 , -SO 2 NH-Cl-C 1 2 -allcyl, -SO 2
NH-C
2 -C8-atkenyl, -SO 2 NH- C 2
-C
8 -alkynyl, PAGjE 66 OF 222 WO 2010/099527 PCT/US2010/025741
SO
2
NH-C
3
-C
12 -cycloalkyl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -SO 2
NH
heterocycloalkyl, -NHSO 2
-C
1
-C
1 2 -alkyl, -NHSO 2
-C
2 -Cs-alkenyl, - NHSO 2
-C
2
-C
8 alkynyl, -NHSO 2
-C
3
-C
12 -cycloalkyl, -NHSO 2 -aryl, -NHSO 2 -heteroaryl, -NHSO 2 heterocycloalkyl, -CH 2
NH
2 , -CH 2
SO
2
CH
3 , -aryl, -arylalkyl, -heteroaryl, 5 heteroarylalkyl, -heterocycloalkyl, -C 3
-C
1 2 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-Cl-C 12 -alkyl, -S-C 2
-C
8 alkenyl, -S-C 2 -Cs-alkynyl, -S-C 3 -C 2 -cycloalkyl, -S-aryl, -S-heteroaryl, -S heterocycloalkyl, or methylthio-methyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted. 10 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. 15 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. 20 The term "activated hydroxy", 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 25 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 30 benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, 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, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, PAGE 67 OF 222 WO 2010/099527 PCT/US2010/025741 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, 5 acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. The term "hydroxy prodrug group", as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as 10 described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992). The term "amino protecting group," as used herein, refers to a labile 15 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 & 20 Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 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. 25 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; and acyloxy groups, such as acetoxy, 30 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, PAGE 68 OF 222 WO 2010/099527 PCTIUS2010/025741 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 5 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., 10 edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term eroticc 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 15 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 20 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 25 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 30 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. PAGE 69 OF 222 WO 2010/099527 PCT/US2010/025741 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 "d Ed. Wiley-VCH (1999); T.W. Greene 5 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. 10 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 15 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 20 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 25 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 30 the compounds described herein contain olefinic 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 PAGE 70 OF 222 WO 2010/099527 PCT/US2010/025741 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. 5 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 10 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 15 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 20 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 25 exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2 30 hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pirate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. PAGE 71 OF 222 WO 2010/099527 PCT/US2010/025741 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, 5 sulfate, phosphate, nitrate, alkyl having from I 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, 10 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. 15 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 20 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.), 25 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 ofDrug Deliver Reviews, 8:1-38(1992); Bundgaard, J. ofPharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, 30 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 the invention, for example, hydrates. PAGE 72 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methyihistidine, 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 15 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 20 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. 25 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 30 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 PAGE 73 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 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. 15 The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucc ally, 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 20 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 25 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 30 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 PAGE 74 OF 222 WO 2010/099527 PCT/US2010/025741 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 ac cording to the known art using suitable dispersing 5 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 10 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 15 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 20 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 25 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 30 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 PAGE 75 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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, carboxymethycellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as 10 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 15 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 20 well as high molecular weight polyethylene glycols and the like. 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 25 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, 30 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. PAGE 76 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 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. 15 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 20 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 98/43 650 by Montgomery, all of which are incorporated herein by reference). A discussion of 25 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 1 to 30 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, conditions are treated or prevented in a patient such as a human or PAGE 77 OF 222 WO 2010/099527 PCT/US2010/025741 another animal by administering to the patient 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. By a "therapeutically effective amount" of a compound of the invention is 5 meant 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). An effective amount of the compound described above may range from about 0.1 10 mg/Kg to about 500 mg/Kg, preferably from about I to about 50 mg/Kg. 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 15 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 20 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, 25 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 30 single or multiple doses. The compounds of the present invention described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a PAGE 78 OF 222 WO 2010/099527 PCT/US2010/025741 dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between I mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the 5 desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about I to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically exipients or carriers to produce a single dosage form will vary 10 depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. Specific 15 dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the 20 treating physician. 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 25 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 described herein and one or more additional therapeutic 30 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 PAGE 79 OF 222 WO 2010/099527 PCT/US2010/025741 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" includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic 5 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), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin 10 and amantidine). 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 15 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 20 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 25 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 30 with any of the anti-HCV drugs listed in Table 21 below. PAGE 80 OF 222 WO 2010/099527 PCT/US2010/025741 Table 21 Table of anti-Hepatitis C Compounds in Current Clinical Development Drug name Drug category Pharmaceutical Company PEGASYS pegylated interferon Long acting interferon Roche alfa-2a inrfern facon-l Long acting interferon InterMune OMNIFEron Long acting interferon Viragen ALBUFERON Long acting interferon Human Genome Sciences nterfon beta-la Interferon Ares-Serono Omega Interferon Interferon BioMedicine Oral Interferon alpha Oral Interferon Amarillo Biosciences Interferon gamma-lb Anti-fibrotic InterMune IP-501 Anti-fibrotic InterMune IMPDH inhibitor Merimebodib VX-497 (inosine monophosphate Vertex dehydrogenase) AMANTADINEBroad Antiviral Agent Endo Labs (Symmetrel) Solvay IDN-6556 Apotosis regulation Idun Pharma. XTL-002 Monclonal Antibody XTL HCV/MF59 Vaccine Chiron CIVACIR Polyclonal Antibody NABI Therapeutic vaccine Innogenetics VIRAMIDINE Nucleoside Analogue ICN ZADAXIN (thymosin alfa-1) Immunomodulator Sci Clone CEPLENE (histamine) Immunomodulator Maxim VX 950/LY 570310 Protease inhibitor Vertex/Eli Lilly ISIS 14803 Antisense Isis Pharmaceutical/Elan IDN-6556 Caspase inhibitor Idun Pharmaceuticals JTK 003 Polymerase Inhibitor AKROS Pharma Tarvacin Anti-Phospholipid Therapy Peregrine HCV-796 Polymerase Inhibitor ViroPharma/Wyeth CH-6 Protease inhibitor Schering ANA971 Isatoribine ANADYS ANA245 Isatoribine ANADYS CPG 10101 (Actilon) Immunomodulator Coley Rituximab (Rituxam) Anti-CD2o Genetech/IDEC Monoclonal AntibodyGeechDE NM283 (Valopicitabine) Polymense Inhibitor Idenix Pharmaceuticals HepXE-C Monoclonal Antibody XTL IC41 Therapeutic Vaccine Intercell Medusa Interferon Longer acting interferon Flamel Technology E-1 Therapeutic Vaccine Innogenetics Multiferon Long Acting Interferon Viragen BILN 2061 Protease inhibitor Boehringer-Ingelheim TMC435350 Protease inhibitor Tibotec/Medivir Telaprevir (VX-950) Protease inhibitor Vertex Boceprevir (SCH 503034) Protease inhibitor Schering-Plough ACH-1625 Protease inhibitor Achillion ABT-450 Protease inhibitor Abbott/Enanta BI-201335 Protease inhibitor Boehringer-Ingelheim PHX-1766 Protease inhibitor Phenomix PAGE 81 OF 222 WO 2010/099527 PCT/US2010/025741 VX-500 Protease inhibitor Vertex MK-7009 protease inhibitor Merck R7227 (ITMN-191) protease inhibitor InterMune Narlaprevir (SCH 900518) Protease inhibitor Schering/Merck Alinia (nitazoxanide) To be determined Romark ABT-072 Polymerase Inhibitor Abbott ABT-333 Polymerase Inhibitor Abbott Filibuvir (PF-00868554) Polymerase Inhibitor Pfizer VCH-916 Polymerase Inhibitor Vertex R7128 (PS16130) Polymerase Inhibitor Roche/Pharmasset IDX184 Polymerase Inhibitor Idenix R1626 Polymerase inhibitor Roche MK-3281 Polymerase inhibitor Merck PSI-7851 Polymerase inhibitor Pharmasset ANA598 Polymerase inhibitor Anadys Pharmaceuticals BI-207127 Polymerase inhibitor Boehringer-Ingelheim GS-9190 Polymerase inhibitor Gilead VCH-759 Polymerase Inhibitor Vertex Clemizole NS4B inhibitor Eiger Biopharmaceuticals A-832 NS5A inhibitor ArrowTherapeutics BMS-790052 NS5A inhibitor Bristol-Myers-Squibb ITX5061 Entry inhibitor iTherx GS-9450 Caspase inhibitor Gilead ANA773 TLR agonist Anadys CYT107 immunomodulator Cytheris SPC3649 (LNA-antimiRr4- microRNA Santaris Pharma 122) Debio 025 Cyclophilin inhibitor Debiopharm SCY-635 Cyclophilin inhibitor Scynexis Unless otherwise defied, 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 5 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)-1,1'-binaphthyl; 10 Boc 2 0 for di-tert-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 15 chloride solution in water; Cbz for carbobenzyloxy; CDI for carbonyldiimidazole;
CH
2 Cl 2 for dichloromethane; CH 3 for methyl; CH 3 CN for acetonitrile; Cs 2
CO
3 for PAGE 82 OF 222 WO 2010/099527 PCT/US2010/025741 cesium carbonate; CuCI 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 NN'-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIBAL-H for 5 diisobutylaluminium hydride; DIPEA or (i-Pr) 2 EtN for N,N-diisopropylethyl amine; Dess-Martin periodinane for 1,1,1 -tris(acetyloxy)- 1,1 -dihydro- 1,2-benziodoxol-3 (1H)-one; DMAP for 4-dimethylaminopyridine; DME for 1,2-dimethoxy-ethane; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT for di(p methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA for diphenylphosphoryl 10 azide; EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; EDC HCI 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; Grubbs- I catalyst for benzylidene bis(tricyclohexylphosphine)dichlororuthenium; HATU for O-(7-azabenzotriazol-1 15 yl)-N,NN',N'-tetramethyluronium hexafluorophosphate; HCl for hydrogen chloride; HOBT for 1-hydroxybenzotriazole; K 2
CO
3 for potassium carbonate; n BuLi for n-butyl lithium; i-BuLi for i-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 20 methoxymethyl; Ms for mesyl or -S0 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; NaHCO 3 for sodium bicarbonate or sodium hydrogen carbonate; Na 2
CO
3 sodium carbonate; NaOH for sodium 25 hydroxide; Na 2
SO
4 for sodium sulfate; NaHSO 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
HCO
3 for ammonium bicarbonate; NH 4 Cl for ammonium chloride; NMMO for N-methylmorpholine N-oxide; NaIO 4 for sodium periodate; Ni for nickel; OH for hydroxyl; Os04 for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB for p 30 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); PdC 2 (PPh 3
)
2 for trans dichlorobis(triphenyl-phosphine)palladium (11); Pt for platinum; Rh for rhodium; rt PAGE 83 OF 222 WO 2010/099527 PCT/US2010/025741 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 N,N,N',N' 5 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 TMSCI for trimethylsilyl chloride. SYNTHETIC METHODS 10 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 15 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 20 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 those title 25 compounds include direct formation of a suitably linked 5/6-membered fused heteroaryl with a 5/6-membered fused heteroaryl or 5-membered heteroaryl core structure followed by attachment of a suitable R 6 group, 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 30 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. PAGE 84 OF 222 WO 2010/099527 PCT/US2010/025741 A general synthesis and further elaboration of some benzimidazole related intermediates are summarized in Scheme 1. The synthesis starts from the construction of an optionally substituted benzimidazole la-2, which may be obtained by condensation of an amino acid or its 5 derivative la-1I.1 or la-1.2 and an o-phenylenediamine la-I under the conditions to those skilled in the art. The benzimidazole 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 la-I and amino acid la-1I.1 or la-1.2 in the presence of a condensation reagent such 10 as EDC HCI, DCC or the like; or through mixed anhydride approach by reacting acid la-1.1 or la-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 la-1; and 2) the heterocyclic ring closure in the presence of an acid such as 15 acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat. PAGE 85 OF 222 WO 2010/099527 PCTIUS2010/025741 Scheme I (R 7 )t Boc H 2 N Br R
HO
2 CH NP~ Q o r J NR C O2 H 2 N C bz ia-6 H (R)a"" - I""-""-" - -- - .2 1Q - (RI Q1orJ QrorrJ r*R* Q orJ OHR) 1a-7 H (R)u1-2 R b1a--4 (R ). H 1 0 N 1 1 la-S HH a- HlaJ N H Q1 orJQ o J1 1 or JBr H ( ) (RR la-Il 1 H (R-)u H HRR) Qor J1.I Of H Q or J N NH2~""'B Q 1 or JQ 1 r H la-17 H (RI13 H 1-19 (4 la-0 H H ni rN 2 Q orJN NO2 Q4 or N NH QirorJ.OH la-21 H la-I 2 H la-I1a2 Ha(R H QiorJ ~e _ _H Q or J OHi a-2-2 H (RI)ua-a31H NNB E ~ ~ N- N (RI). a-13 (I).-(R Optionally, the NH group in the newly formed benzimidazole ring of 1a-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-CI, NaH)D, 5 Boc, Cbz, Teoc, Troc, or the like. The protected benzimidazole la-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 la-6 as a key intermediate. Alternatively, la-6 may PAGE 86 OF 222 WO 2010/099527 PCT/US2010/025741 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; 5 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 la-3 may be prepared by Stille reaction from bromide la-2 with tributylvinylstanne. Also, Sonogashira coupling between bromide la-2 and propargyl alcohol or 10 trimethylsilylacetylene can generate propargyl alcohol la-4 or alkyne la-5 after removal of TMS. Further bromination of intermediate la-4 may form the propargyl bromide la-9. In addition, benzimidazole bromide la-2 may be converted to methyl ketone 1 a-7 by coupling with tributyl(1 -ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis. 15 Further elaboration of the benzimidazole intermediates starts from the vinyl intermediate la-3, which may be transformed to aldehyde la-8 through ozonolysis cleavage or to alcohol la-12 by hydroboration-oxidation sequence. Alcohol la-12 may be converted to bromide la-15 by the well-known bromination procedure, which can be further functionalized to amine la-20 through azide substitution 20 followed by reduction. Aldehyde la-8 can then either be reduced to alcohol la-11, or be converted to a, 0-unsatuated acid la-10 through Horner-Wadsworth-Emmons aldehyde homologation reaction followed by saponification. Alcohol la-11 may be similarly converted to the correponding amine intermediate la-14 and bromide intermediate la-13 as described previously. Bromide la-13 can be homologated to 25 alkyne intermediate la-19 with a metal acetylide. In addition, bromide la-13 may be also tranformed to thiol la-1 6 through nucleophilic substitution, which can be further oxidized to sulfonic acid la- 17. Sulfonamide la-18 may then be derived from la-1 7 through the sulfonyl chloride activation process. The compounds of the present invention may also be derived from 30 nitrobenzimidazole la-2 1, which can be prepared from the corresponding 4-nitro 1,2-diaminobenzene using the similar procedures described above. Intermediate la 21 can be converted to amine la-22 through N0 2 -reduction (i.e. H 2 , catalytical Pd). Diazotization of amine la-22 with a nitrite such as sodium nitrite, isobutyl nitrite, or the like, in an aqueous acid such as acetic acid, hydrochloric aicd, sulfuric acid, or PAGE 87 OF 222 WO 2010/099527 PCT/US2010/025741 the like, optionally in the presence of a copper or copper salt, may afford hydroxy la-23. Analogously, benzimidazolecarboxylate la-24, which can be prepared from the corresponding 4-methyl-1,2-diaminobenzoate using the procedures described 5 above, may be hydrolyzed to the corresponding carboxylic acid la-25. It should be noted that optionally the NH group of all the benzimidazole related intermediates listed above may be protected with an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like. R5- Bo 0 Scheme2 related intermediates R3 H H.ISH N # 2a-1.1 0 , Q1 or J1 Br... . N - QQ or orJ 2a-1.3 N /N (R H Br H Br H 2a-2 2a-3 2a-4 Ox H k Ab-Br Ab-MNy Cbz N35 Nf QJ 2a-8.1 or 2a-1.2Cb Br Ql or J1 Ab5. l > Q1 or i 2% Br Q 1or J Br 11 Ab Brf Ab-/ PG PG PG 2a-52 2a-5 2a-7 2a-8 Ab = aryl, heteroaryl 01 ' ( Q or J 1 B N-R 5 PG,,f - > A NH2 2a-10.1 or 2a-10.2 Ab PG2a-1 I NH 2
R
4 _NH 2a-6 2a-13 1 or J (W)R t J or b Q t HOrN R4OH Jj)Qlor J1 2a-10. 0 Bu3Sn'kOEt ,.2a-10.2 cbz 2-.1 O Ab H A-Br Ab 4 Ab 0 1 Ab 2a-14 2a-5.1 _ Br 2a-10.1 or 2a-10.2 0 _ 2a-9 2a-10 Br 2a-12 Q1 or J1 10 A typical synthesis of imidazole related intermedaites are analogous to that of the benzimidazole intermediates. As shown in Scheme 2, bromo-imidazole 2a-4 can be synthesized in a three-step sequence: 1) condensation between amino acid derived aldehyde 2a-1.1 or 2a-1.2 and glyoxal 2a-1.3 in the presence of methanolic 15 ammonia to generate imidazole 2a-2; 2) bromination of 2a-2 with excess amount of bromination reagent such as 2,4,4,6-tetrabromo-2,5-cyclohexadienone, NBS, etc. to afford dibromide 2a-3; 3) selective reduction of the dibromide 2a-3 by heating in aq. Na 2
SO
3 or aq. NaHSO 3 . 2a-4 then may be served as a universal intermediate further elaborable to many other imidazole derivatives using the chemistry discussed in 20 Scheme 1, some of which are listed in the table below. PAGE 88 OF 222 WO 2010/099527 PCT/US2010/025741 Q1 or J Q or J 1 Q or J 1 Q or J 1
H.
2 N..AQN ori B r ,:Q1 orJ 1 HO.JQN> orJ 1 HON Q orJ 1 H H HA H O orJi O, O Ji orJ glorJ 1 Q orJ 1 HO H H 2 N H H HO H_ H Qi or J' B %>-Q1 or Ji HOQ' or J M or
H
2 N -f HdBr N HON H H .Q or 1 HO-Qi or J 1 H %>-Q or Jf%>.QlorJI Br 00N ,J>-Q or J1 " 1 >-Qi rJ1Q or J >Qo~ or HO NJ H H H H Optionally, the NH group of imidazole related intermediates listed above may be protected with an amino protecting group (shown in Scheme 2 as PG), such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like. The protected 5 imidazole 2a-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 2a-5.2 to afford aryl or heteroaryl substituted imidazole 2a-6 or couple with an aryl or heteroaryl halide 2a-5.1 in the presence appropriate transition metal salt to generate bicyclic heteroaryl 2a-7. Similarly, the protected 10 bromo imidazole 2a-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 2a-6 and 2a-7. Also, when 2a-8 is treated with metalated aryl or heteroaryl 2a-8. 1, in which M at each occurrence is independently a boron, tin, silicon, zinc, zirconium, or copper species, under Suzuki or Stille conditions to those skilled in the 15 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. 20 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 2a-7. In addition to these direct coupling strategy, aryl or heteroaryl bromide 2a-5.1 may be converted to methyl ketone 2a-9 under Stille coupling conditions with tributyl(1-ethoxyvinyl)tin PAGE 89 OF 222 WO 2010/099527 PCT/US2010/025741 2a-9.1. 2a-9 may be brominated under conditions to those skilled in the art to afford bromide 2a- 10, which may be either converted to the corresponding amine 2a- 11, or coupled with protected amino acid 2a-10.1 or 2a-10.2 in the presence of a base such as Et 3 N and DIPEA to afford ketoester 2a-12. Similarly, amine 2a-1 1 may be 5 converted to the corresponding keto-amide 2a-13 via condensation with appropriate amino acid under standard amide formation conditions. 2a-12 and 2a-13 may be tranformed to key intermediate 2a- 14 via heating with (NH4)OAc under thermal or microwave conditions. With a variety of suitably substituted benzimidazoles and imidazoles in hand, 10 such as those listed in Scheme 1, Scheme 2 and the table above, 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, 15 Heck coupling, Buchwald amidation, Buchwald amination, amide coupling, ester bond formation, William etherification, Buchwald etherification, 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 3, wherein R 2 is independently R 1 . Both 20 bromides 3a-1 and 3a-2 can be prepared using the procedures described in Scheme 1 and Scheme 2. Bromide 3a-2 can be converted to the corresponding metalated aryl 3a-3 under Suzuki or Stille conditions, which may be further coupled with benzimidazole bromide 2a- 1 under similar conditions to generate a structural core 3a-4. 25 Compound 3a-4 may then serve as a common intermediate for further derivatizations to 3a-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 in the presence of a base such as potassium carbonate to remove the Cbz protection group; and 2) the released amine functionality may be 30 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 PAGE 90 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 2008/021927A2 by C. Bachand, et al, from BMS, which is incorporated herein by reference. 3a-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 la-I using the conditions described above.
(R
7 ). (R ), R)m MI-M 1 m + RS -N Br N N N + R1~ Br 3a-2 M 3a-3 3a-I M= boron or tin species R6, NBoc Scheme 3 RXN HN. 3a-4 Cbz R12 Rs N- -O R, NBoo RR R N XR N R N NN +N 10 ia-1 R12 3a-5 R12 1000 Other examples of some of the linkers that can be used to construct the title compounds of the present invention are compiled in the table below, in which PG and PG' at each occurrence are each independently amino or alcohol protecting group, such as Boc, Cbz, Troc, Teoc, PMB, TMS etc. These linkers are either 15 commercially available or may be synthesized in several steps through strategies which are known to those skilled in the art. Br- S-r BrPGN Br BrB Br Br Br r Br Br Br S Br Br Br Br Br Br BrPG . ONBr bBr PGO" N.X.OP _________ Br N-PG PG.N IN PG-NoI -Br PG' PAGE 91 OF 222 WO 2010/099527 PCT/US2010/025741 H2N S Br O r B P.B BBrBr Br C1 HO0 OH O HO OH NH HO -OH PG-N HN P Br Br -':~~--BrHO Br NHPG NHpG B r Br R Br NHPG Alternatively, as shown in Scheme 4, the compounds of the present invention (for example Ia-1) may also be derived from bromobenzimidazoles 4a-1 and imidazole 4a-2 using the procedures described previously. The intermediates 4a-1 5 and 4a-2 have the desired acyl groups already installed as seen in amino acid derivatives 2a-10. lb and 2a-10.2b, which can be prepared from protected amino acids 2a-10.1a and 2a-10.2a through the sequences shown in Scheme 1 and 2. H2N Br R12 R12 R 12 O >=O H 2 N
R
5 -N OPG R6-N - R-N N Br R3* R3- CO2H R3 I
R
4 04 R b H (R) 2a-10.1a 2a-10.1b 4a-1
(R
7 )t (R 7 )t (R) PG1 7 I X R I 0NR7I+ PGaH02C:RN 1 02a-102a 0 4a- R 2a-10.22b PG is carb oxylic acid protecting gro up R.'N O
R
2 lgIndependently R1 Rs 5 N'U R Scheme 4 R N R12 The compounds of the present invention containing benzimidazole linked 10 with other five-membered heteroaryl other than imidazole may be prepared using similar procedures described above in Schemes 1-4. For example, some intermediates containing a desired, suitably substituted five-membered heteroaryl have been published in US 2008/0311075AI by C. Bachand, et al from BMS, which is incorporated by reference. Theses intermediates are compiled in the following 15 table. PAGE 92 OF 222 WO 2010/099527 PCT/US2010/025741 H H N Br ~, oc oc ocIpo N NH N N 0 Nj. 7 N% N~ Hoc B oc Br .oc B l, N Poc B oc The synthesis of the compounds of the present invention involves 5/6 membered fused heteroaryl intermediates other than benzimidazoles, various 5/6 membered fused heteroaryl are known in the literature. For example, it may be 5 possible to prepare various 3H-imidazo[4,5-b]pyridine intermediates following similar procedures described in Scheme 1 by replacing 4-bromo-1,2 diaminobenzene la-1 with 5-bromo-2,3-diaminopyridine as starting material. 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 10 intermediate is illustrated in Scheme 5. The commercially available bromoiodoaniline 5b-I may be coupled to the commercially available acetylene 5b 1.1 under the Sonogashira conditions to give phenylacetylene 5b-2. The latter may be cyclized to indole 5b-3 under heat or microwave condition in the presence of a copper catalyst. Br Br N + H - N r b-2
NYH
2 N -N I I 5b-1 Boc
NH
2 Boc 6b-1.1 Scheme 5 Br5b-3 N4 1 15 Boc In one aspect, the invention is a process of making a compound of Formula (1-I) comprising the steps of: i) Preparing a compound of Formula (1-I1-a): N. H N T-E(U (RN~ ( 1l-). Z XNN(I 20 via a transition-metal catalyzed cross-coupling reaction; wherein: PAGE 93 OF 222 WO 2010/099527 PCT/US2010/025741 E is optionally substituted aryl or optionally substituted heteroaryl; T, X, n, u, R1, and R 7 are as defined in claim 1; Za and Zb are each independently an amino protecting group or -C(O)-R 12 ; R 12 is CI-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or O(C-C 4 5 alkyl); ii) When Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (1-I-a) to give the corresponding amine of Formula (1-II b): ZG HN_. T-E-( zNI R (RH) , (RI)( l-) HI 10 wherein Z' is hydrogen, an amino protecting group or -C(O)-R1; iii) Capping the released amino group of a compound of Formula (1-II-b) with
LG-C(O)-R
12 , wherein LG is a leaving group; to give the compound of Formula (I II-c): Zd HN (R7)" . 1-l0-c) N-.4(R7)n R12 15 wherein Zd is an amino protecting group -C(O)-R 12 ; and iv) Repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (1-II-d): R12f R f T-E_ C/1 (R 7 N' H In another aspect, the invention is a process of making a compound of 20 Formula (2-I) comprising the steps of: i. Preparing a compound of Formula (2-II-a): H-f (2-Il) ZbN.., R)n via a transition-metal catalyzed cross-coupling reaction; wherein: E, G, T, X, n, u, v, R 1 , and R 7 are as defined in claim 22; PAGE 94 OF 222 WO 2010/099527 PCT/US2010/025741 Za and Zb are each independently an amino protecting group or -C(O)-R 12 ; R 12 is
C
1
-C
8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(C 1
-C
4 alkyl); ii. When Za or Z is an amino protecting group, fully or selectively deprotecting 5 a compound of Formula (2-IT-a) to give the corresponding amine of Formula (2-II b): (RI~G T-E . (2-ll-b) ,N - (R) wherein Z" is hydrogen, an amino protecting group or -C(O)-R1; iii. Capping the released amino group of a compound of Formula (2-IT-b) with 10 LG-C(O)-R, wherein LG is a leaving group; to give the compound of Formula (2 (2-I4c) N (R) X R7 R wherein Zd is an amino protecting group -C(O)-R 12 ; and iv. Repeated reaction sequence of deprotecting and capping (step v-vii) to give 15 the compound of Formula (2-II-d): (RI). T-E7 R 12 OY(2-l-d Nc(R') R 12 It will be appreciated that, with appropriate manipulation and protection of any chemical functionality, synthesis of compounds of Formula (1-I) or (2-I) is accomplished by methods analogous to those above and to those described in the 20 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. All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their 25 entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications. PAGE 95 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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. 10 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. Example 1-1. *N B HNQQC 15 Bo Step 1-la. 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 20 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
SO
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 1-lb. A solution of the crude compound from step 1-la (10.7 g, 26.7 mmol at 25 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 NaHCO 3 ). The organics were 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 brown foam (5.78 g, 59%). ESIMS m/z= 366.17, 368.17 30 [M+H]*. 'H NMR (CDC 3 ) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, IH), 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). PAGE 96 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-1c. A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol), N-Boc-L proline (3.87 g, 18.0 mmol) and in CH 3 CN (60 mL) was treated with TEA (5.40 mL, 37.8 mmol) at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The 5 organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow foam (6.73 g, 91%). 'H NMR (CDCl 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, IH), 4.48, 4.40 (dd, J= 5.0, 8.5 Hz, 1H), 3.56 (m, IH), 3.43 10 (m, 1H), 2.30 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H). Step 1-id. A solution of the compound from step 1-ic (6.73 g, 16.3 mmol) in toluene (100 mL) was treated with ammonium acetate (25.1 g, 0.327 mol) at 100 *C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered 15 and evaporated. The residue was purified by 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]*. 'H NMR (CDCl 3 ) 7.57 (bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99 (m, lH), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H). 20 Step 1-le. A mixture of the compound from step 1-id (1.00 g, 2.55 mmol), bis(pinacolato) diboron (1.35 g, 5.33 mmol), Pd(PPh 3
)
4 (0.147 g, 0.128 mmol) and potassium acetate (0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was degassed and heated at 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 25 (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow solid (0.978 g, 87%). ESIMS m/z = 440.39 [M+H]*. 'H NMR (CDC 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, IH), 1.49 (s, 9H), 1.35 (s, 12H). 30 Step 1-if. A mixture of compound from step i-lb (0.188 g, 0.512 mmol), the compound from step 1-le (0.150 g, 0.342 mmol) Pd(PPh 3
)
4 , (39.4 mg, 34.1 pmol) and NaHCO 3 (0.115 g, 1.37 mmol) in DME (6 mL) and H 2 0 (2 mL) was degassed and heated at 80 '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 PAGr 97 OF 222 WO 2010/099527 PCT/US2010/025741 (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white needle crystal (0.106 g, 52%). ESIMS m/z = 599.59 [M+H]*. Example 1-2. 2H NHCO 2 Me *O ' N *Ph 1- 2 GNf H~~~J~ M0N'5 N' H N) Step 1-2a. A solution of the compound of example 1-1 (20.0 mg, 33.4 pmol) in 1,4 dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 30 minutes. 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 = 399.35 [M+H]*. 10 Step 1-2b. A mixture of the crude compound from step 1-2a (33.4 ptmol at most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 20.9 mg, 0.100 mmol) in DMF (3 mL) was treated with HATU (31.7 mg, 83.5 gmol) in the presence of DIPEA (83.0 pL, 0.668 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by 15 chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a yellow solid (23.8 mg, 2 steps 91%). ESIMS m/z = 781.67 [M+H]+. Example 1-1-1. (AN OX~ Step 1-1-la. A mixture of the compound from step 1-id (0.559 g, 1.425 mmol), 20 trimethylsilyl-acetylene (0.60 ml, 4.275 mmol), Cul (28.5 mg, 0.150 mmol) and Pd(PPh 3
)
2
C
2 (80.0 mg, 0.114 mmol) in Et 3 N (15 mL) was heated at 80 C under N 2 for 6 hours 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 (0.484 g, 83%). ESIMS m/z = 410.24 [M+H]+. 25 Step 1-1-1b. A suspension of the compound from step 1-1-la (0.484 g, 1.182 mmol) and K 2 C0 3 (0.408 g, 2.954 mmol) in methanol (12 ml) was stirred at rt for 3 hour. The volatiles were evaporated off. The residue was purified by chromatography (silica, dichloromethane-ethyl acetate) to give the desired compound as a yellow foam (0.370 g, 93%). ESIMS m/z = 338.24 [M+H]*. PAGE 98 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-1-1c. A mixture of the compound from step 1-1-lb (80.0 mg, 0.2371 mmol), the compound from step 1-lb (86.8 mg, 0.2371 mmol), CuI (2.2 mg, 0.01185 mmol) and Pd(PPh 3
)
2
C
2 (16.6 mg, 0.02371 mmol) in Et 3 N (0.3 mL) and CH 3 CN (2 mL) was heated at 85 "C under H 2
/N
2 mixed gas for 2 hours before being evaporated. The 5 residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the title compound as a yellow solid (48.3 mg, 33%). ESIMS m/z= 623.32 [M+H]*. Example 1-2-1. Me2CHN
NHCO
2 Me 10 Step 1-2-la. A solution of the compound of example 1-1-1 (48.3 mg, 0.0776 mmol) in 1,4-dioxane (1.5 mL) was treated with HCI in 1,4-dioxane (4 M, 6 mL) at rt 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 1-2-1b. A mixture of the crude compound from step 1-2-la (0.127 mmol at 15 most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 40.6 mg, 0.194 mmol) in DMF (1.5 mL) was treated with HATU (67.8 mg, 0.178 mmol) in the presence of DIPEA (0.27 mL, 1.551 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a 20 yellow solid (36.2 mg, 2 steps 58%). ESIMS m/z = 805.29 [M+H]*. Example 1-2-2. M 'V N )- 4 NHCOzMe N / Ph A solution of the compound of example 1-2-1 (23.0 mg, 0.0286 mmol) in ethanol (2 mL) was treated with Pd(OH) 2 (20wt% on carbon, 23 mg) at rt with a hydrogen 25 balloon for 7 hourr. The mixture was filtered through a short pad of Celite. The volatiles were evaporated off. The residue was purified by chromatography (silica,
CH
2 Cl 2 -MeOH) to give the title compound as a white solid (16.0 mg, 70%). ESIMS m/z = 809.40 [M+H] 4 . The remaining compounds of examples 1-3 to 1-356 and 1-358 to 1-440 may 30 be prepared using procedures similar to those described in examples 1-1, 1-2, 1-1-1, PAGE 99 OF 222 WO 2010/099527 PCT/US2010/025741 1-2-1, 1-2-2, 1-357, and 1-441 to 1-545, and/or as described in the Synthetic Methods. Table la: Examples 1-3 to 1-219. R.. HN R Entry 1- R Entry 1- Entry 1- RAI 3 N l Ph 0 00 4 5 6 6H 6H ____ 7 O 8 9 10 11 12 N 0 OH 0 13 1 4 15 16 Ph 17 Ph 18 0 0 0 19 Ph20 Ph 21 Ph iA 0-O H OMe OH~ 22 N .0 23 24 Ph 0 0 0 25 26 27 28 29 30 31 Bo N BocN'O2( 33 BoN HH 34 35 36 H ____OX N) 379 37 N8 N22 PAGE 100 OF 222 WO 2010/099527 PCT/IUS2010/025741 40 41 42 H NH0 H0I 0 43 N44 4 46 N 47 N 4N 'N-NH 0F 0 49 NN - 50 rlr 51 1 51 52 53 54 55h56 57 Ph O~~e M90 CF, P 58 59 60 Ph2Jt 61 _ 62 *y -LAi 63 N0 yN. Ji 64 65 -A 66 y Or Y NH yNH 67 - 68 AYN 69 p Hp 0 72 70 - 71 lN72 73 y74 y75 o )ro NH 7 6 - 4 N X N 7 7 - o Y 7 8 H O 0 H 0 79 N 80 , N, 81 e . OH
CO
2 Bn 0 CONH 2 82 OYN j 83 84 O 85 O NH 86 NH 87 OyNH PAGE 10 1 OF 222 WO 2010/099527 PCT/US2010/025741 H O O O 88 N 89 90 91NA OTBSN OTBS 91 092 93 ,ONH -oo NH N~N 94 /* N2Ji 95 AyNQ4 96 OyNH8 . 0 00 97 /* N.rJj 98 O Ph CI NHCO 2 Me CH112 100 101 M 103 104 M O C105Bo N 106 107 108 .olN y NHCO2MNe NHCOM Nl N / NHCOM ~NH NHCO 2 Me (S NHOMe S N0 112 0 113 0 114 MeOzCHN MeO 2 CHN NHCOMe N NN 115 H11 10 117
NHCO
2 Me NHCO 2 Me NHCO 2 MB HO 4 IJ~) MeO 0 o 0 dNHCO 2 Me OBn
NHCO
2 Me NHCOMe 120 13014N0 124 125 126 O PAGE 102 OF 222 WO 2010/099527 PCT/US2010/025741 00 0I kNH0 NH0 ~ONH 0 127 .
0 N 128 NH 129 0 00A 130 / 131 132 0 NH 0 00 133 134 H - 135H Me0 NH 0 MeO NH 0 O NH 139 N Y14 140 N 141 N Ph ______Ph Ph NO 142 143 N 144 N 4b Ed Ph 145 N 1F N 47 FIC N..A Ph Ph Ph 148 Ph N 149 H N 150 H Ph HN O OO O ON 151 N-%N yJj 152 153 IPhPh 154 BnO AN O 155 156 F3C YJ4CF3.N N1 N% 157 N158 159 N No No N % 160 C161 162N oN CN 163 164 165 F N% CI N. N________ 166 167 168 F N F , N N 169 F 170 OzN 171 oo %% oNN% PAGE 103 OF 222 WO 2010/099527 PCT/US2010/025741 172 173 174 175 176 177 178 Ph.N Nlj 179 180 N 181 182 183 I 0 184 185 186 Ph N N, N 187 N 188 N189 0 0 190 191 192 193 N 194 195 a 196 N 197 198 199 200 Nrj~ 20 N NN 202 N203 -N N ' 0
H
2 N H HO 205 H N N 206 N N>~ 20 208 A~~i' 209 210
H
2 NY H H 0 28H N ! N 214 N tj 215 216 Nj F F 217 218 219F PAGE 104 OF 222 WO 2010/099527 PCT/US2010/025741 Table 2: Examples 1-220 to 1-229. M2C HNR --- R __ -NHO2Me Entry 1- R R' R" X Entry 1- R R' R" X 220 Me H H CH 2 221 H H H CF 2 222 Me H H S 223 H H HF 224 Me H H 0 225 H H H H 226 H Ph H CH 2 227 H H H JfOH OH' 228 H H Ph CH 2 229 H H H H
NHCO
2 Me NHCO 2 Me Ph M2Ph P xampe Example 1231
NHCO
2 Me NHCO 2 Me Ph Ph MC P MeO 2 CHN N P Example 1-230 )4 Example 1.233 Table 3: Examples 1-234 to 1-243. M e O 2 C H N N H C O 2 M e R' R" Entry1- R R' R" Entry1- R 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Ft Me H 242 Me CHMe 2 H 243 Me Ft H 10 PAGE 105 HF 222 WO 2010/099527 PCT[US201/025741 Table 4: Examples 1-244 to 1-263. Entry I- R R! Entry I- R R 244 MeOCHN,k MeOCHN J 245 Ph Ph NIr MeO2CHN, I 246 .0MeO 2 CHNy 247 Nr ,A PhPh Ph, 248 2CHN!A MoO2CHN.T 249 Me 2
CHN,
9 M002HNA l; Ph Ph, 250 N NT 251 Ne2HN~ .. %IA., ________ Ph Ph 0_____ 252 0 253 O(r% 0 NN.,, Ph. 0 254CN A MeO 2 CHN 25 M00 2 CHN~ HN A0 A0 P Ph Me2HNt M00 2 CHN., _Y~ _H H1 258 ~~2597 e 2 H.) 260~ Ph0a 6 26 MO 2 0N. Me0 2 CHN.A 26 M0 2 CHN, NN 502H., 02CN, eN, MeO 2 CHN PhA 2640 26 FN 266 Me H HNH 263 e M 270bCF H 5H Hxme 121 t CF2 3 HCF 272~ ~~~ R'HH H 23 l H C PA 0 O 2 WO 2010/099527 PCT/US2010/025741 Table 6: Examples 1-274 to 1-299. R' R" R ORN MeO2CHN N /Jf MeO 2 CHN Ph Entry 1- R R' R" R"' Entry 1- R R' R" R'" 274 Me H H H 275 H CO 2 H H H 276 H F H H 277 H H CO 2 H H 278 H H F H 279 H H H CO 2 H 280 H H H F 281 H CO 2 Me H H 282 H Cl H H 283 H H CO 2 Me H 284 H H Cl H 285 H H H CO 2 Me 286 H H H Cl 287 H CONH 2 H H 288 H Me H H 289 H H CONH 2 H 290 H H Me H 291 H H H CONH 2 292 H H H Me 293 H OMe H H 294 H CF 3 H H 295 H H OMe H 296 H H CF 3 H 297 H H H OMe 298 H H H CF 3 299 CO 2 Me H H H 5 Table 7: Examples 1-300 to 1-434. Ph ' MeO 2 CHNAa N MeO 2 CHN Ph Entry Aa Entry Aa Entry Aa 1- 1- 1 300 301 302 303 304 305 306 307 308 N 309 310 311 312 313 314 315 316 N N 317 N PAGE 107 OF 222 WO 2010/099527 PCT/US2010/025741 318 Y 319 / 320 321 322 N 323 0 324 /,ovA 325 NA 326 327 /vov/mA 328 329 330 331 332 o 333N 334 -N 335 HN-S.. 334 0 -NH 336 N 337 I-N N-( 338 336 N 339 340 341 N 342N 343 N 344 345 N N 346 347 N 348 7T 349 t-No o- 350 351 jN 'NN/ 352 3 5-N 354 I-N 355 356 N N 357 358 359 HN-j HN-1O 360 361 - 362 HN o-i HNA HNi 363 o-( 364 365 HN 366 HNNH-1S36 -NH 367 N- o 36 369 o- f 370 371 372 oo A 373 374 N N 375 376 377 378 379 N 380 381 o of 382 N 383 N N 384 No vo, 385 AoIJ -2of 386 o 387 I-N 388 389 PAGE 108 OF 222 WO 2010/099527 PCT/US2010/025741 390 391 o 392 HN-j HN HN-1 sr, HN 393 394 o 395 oN-0 396 - 397 -N 0-39 399 400 401 4020N9N 1-_,(O H 0o/-1 402 - 4/~ 403 N- 404 N 405 _N 406 407 408 S 409 i-K IJ 410 N NN 411 412 N 413 N 414 N 415 416 .N /N 417 -N N- 418 419 N 420 o 42421 N 422N 423 o - N--aj 424 425 426 SN y 427 N N 428 429 430 -4vy oA 431 432 o 433 434 N PAGE 109 OF 222 WO 2010/099527 PCT/US2010/025741 Table 8: Examples 1-435 to 1-440. NPP M O 2 2CH N~/ MeO 2 CHN Entry Bb Entry Bb Entry B 1- I- I 435 ___ -N 436 N)y 437 N-NH N-N N 438 439 440 A Example 1-357. MOCN 0 -NHCO 2 Me 5 Me Step 1-357a. A solution of the compound of example 1-491 (0.122 g, 0.196 mmol) in 1,4-dioxane (2 mL) was treated with HCI in 1,4-dioxane (4 M, 8 mL) at rt 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. 10 Step 1-357b. A mixture of the crude compound from step 1-357a (0.196 mmol at most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 0.102 g, 0.490 mmol) in DMF (3 mL) was treated with HATU (0.171 g, 0.451 mmol) in the presence of DIPEA (0.68 mL, 3.920 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was 15 patitioned (EtOAc - H 2 0). The organic layer was washed with brine, dried (Na 2
SO
4 ), filtered and concentrated. The crude was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a yellow solid (0.144 g, 91% over 2 steps). ESIMS m/z= 806.96 [M+H] . Example 1-441. 20 A mixture of (S)-tert-butyl 2-(3-(4-iodophenyl)- IH-1,2,4-triazol-5-yl)pyrrolidine-1 carboxylate (prepared according to US 2008/0311075, 84.9 mg, 0.193 mmol), the compound from step 1-515d (66.0 mg, 0.212 mmol), Cul (1.1 mg, 5.7 gmol) and Pd(PPh 3
)
2
C
2 (6.7 mg, 9.6 gmol) in CH 3 CN (5 mL) and triethylamine (5 mL) was PAGE 110 OF 222 WO 2010/099527 PCT/US2010/025741 degassed and heated to 50 'C under N 2 for 3 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as 5 a light yellow oil (94.0 mg, 78%). ESIMS m/z = 624.34 [M+H]*. Example 1-442. MeOCHN NHC O N -N Ph Step 1-442a. A solution of the compound of Example 1-441 (90.0 mg, 0.144 mmol) in 1,4-dioxane (1 mL) was treated with HCI in 1,4-dioxane (4 M, 4 mL) at rt for 30 10 minutes. 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 = 424.11 [M+H]*. Step 1-442b. A mixture of the crude compound from step 1-442a (0.144 mmol at most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 75.4 mg, 0.361 mmol) in DMF (3 mL) was treated with HATU 15 (0.126 g, 0.332 mmol) in the presence of DIPEA (0.36 mL, 2.89 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a very light yellow solid (98.1 mg, 2 steps 80%). ESIMS m/z = 806.16 [M+H]*. Example 1-443. Ph N / Me 2 CHNR NHCO2Me 20 <Ph A mixture of the title compound of example 1-442 (51.6 mg, 63.3 pmol) and Pd(OH) 2 on carbon (20%, 50.0 mg) in ethanol (3 mL) was treated with H2 balloon overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) 25 to give the title compound as a white solid (42.5 mg, 82%). ESIMS m/z = 810.23 [M+H]*. Example 1-444. PAGE 111 OF 222 WO 2010/099527 PCT/US2010/025741 A mixture of (S)-tert-butyl 2-(3-(4-iodophenyl)-1H-pyrazol-5-yl)pyrrolidine-1 carboxylate (prepared according to US 2008/0311075, 85.0 mg, 0.213 mmol), the compound from step 1-515d (66.2 mg, 0.213 mmol), CuI (1.1 mg, 5.8 gmol) and Pd(PPh 3
)
2 Cl 2 (6.7 mg, 9.6 gmol) in CH 3 CN (5 mL) and triethylamine (5 mL) was 5 degassed and heated at 60 '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
SO
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 (91.1 mg, 76%). ESIMS m/z = 623.20 [M+H]*. 10 Example 1-445.
MO
2 C HN NHCO2Me N Ph The title compound was synthesized from the compound of Example 1-444 using procedures similar to that described in Example 1-442. ESIMS m/z 805.36 [M+H]*. 15 Example 1-446. MeO2CHN'hN'HCO2M The title compound was synthesized from the compound of Example 1-445 using procedures similar to that described in Example 1-443. ESIMS m/z = 809.42 [M+H]*. 20 Example 1-447. Boc j Boc H H N - N N anlor.N N N Step 1-447a. A mixture of the compound of step 1-lb (0.250 g, 0.683 mmol), allyltributyl-stannane (0.26 mL, 0.820 mmol) and Pd(PPh 3
)
4 (39.4 mg, 34.1 pmol) in toluene (6 mL) was degassed and heated at 110 'C under N 2 overnight. The volatiles 25 were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
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 (0.127 g, 60%). ESIMS m/z = 328.23 [M+H]*. PAGE 112 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-447b. A mixture of the compound of step 1-Id (0.180 g, 0.459 mmol), the compound of step 1-447a (0.150 g, 0.459 mmol), triethylamine (0.64 mL, 4.59 mmol), tri-o-tolylphosphine (18.0 mg, 57.3 gmol) and Pd(OAc) 2 (5.1 mg, 22.9 gmol) in CH 3 CN (8 mL) was degassed and heated to 90 'C under N 2 overnight. The 5 volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compounds as a light yellow solid (0.165 g, 70%). The regio- and stereochemistry of the olefinic double bond was not 10 determined. ESIMS m/z= 639.36 [M+H]*. Example 1-448.
NHCO
2 Me NHCO 2 Me N PNI N N and/or N N N MeO 2 CHN MeO 2 CHN Step 1-448a. A solution of the compound of Example 1-447 (0.104 g, 0.163 mmol) in 1,4-dioxane (1 mL) was treated with HCI in 1,4-dioxane (4 M, 4 mL) at rt for 30 15 minutes. 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= 439.24 [M+H]'. Step 1-448b. A mixture of the crude compound of step 1-448a (0.163 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 71.3 mg, 0.408 mmol) in DMF (3 mL) was treated 20 with HATU (0.142 g, 0.375 mmol) in the presence of DIPEA (0.41 mL, 3.26 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compounds as a white solid (89.5 mg, 2 steps 73%). The regio- and stereochemistry of the olefinic double bond was not determined. ESIMS m/z= 25 753.39 [M+H]*. Example 1-449.
NHCO
2 Me 0 N N ND -1y % , I Nj MeO 2 CHN PAGE 113 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was synthesized from the compound of Example 1-448 using procedures similar to that described in Example 1-443. ESIMS m/z= 755.47 [M+H]*. Example 1-450. 5 SEM Step 1-450a. The compound of step 1-le (0.200 g, 0.455 mmol) in THF (5 mL) was treated with a mixture of 30% aqueous H 2 0 2 (0.5 mL) and 1N aqueous NaOH (1 mL) for 30 minutes. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and 10 evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (0.144 g, 96%). ESIMS m/z= 330.15 [M+H]*. Step 1-450b. The mixture of (S)-i -(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5 g, 23.2 mmol) in acetonitrile (40 mL) was added 1,1 '-carbonyldiimidazole 15 (3.95 g, 24.5 mmol). The resulting mixture was stirred at room temperature for 20 min before being added methyl 3,4-diaminobenzoate (3.86g, 23.2 mmol). The solution was stirred at room temperature for another 3 hours before being partitioned between water and EtOAc. The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown slurry, which was purified by flash column 20 chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow oil (8.14g, 98%). ESIMS m/z = 364.17 [M+H]. Step 1-450c. The solution of compound from step 1-450b in acetic acid (150 mL) was stirred at 60 "C for three days before all volatiles were removed. The resulting residue was partitioned between aqueous NaHCO 3 and EtOAc. The organic phase 25 was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown oil, which was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow solid (2.02 g, 28%). ESIMS m/z = 346.15 [M+H]. Step 1-450d. The solution of compound from step 1-450c (2.02g, 5.8 mmol) in DMF (50 mL) was added sodium hydride (55% in mineral oil, 269 mg, 6.4 mmol). 30 The reaction was stirred at room temperature for 1.5 hours before being added 2 (Trimethylsilyl)ethoxymethyl chloride (1.02 mL, 5.8 mmol). The mixture was stirred at room temperature for another 3 hours before being partitioned between PAGE 114 OF 222 WO 2010/099527 PCT/US2010/025741 water and EtOAc. The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a biown oil, which was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow solid (2.6g, 94%). ESIMS m/z = 475.97 [M+H]+. 5 Step 1-450e. The solution of compound from step 1-450d ( 2 .6g, 5.47 mmol) in THF (50 mL) and water (25 mL) was added lithium hydroxide monohydrate (690 mg, 16.4 mmol). The resulting mixture was stirred at room temperature for 3 hours before being partitioned between water, AcOH (10 mL) and EtOAc. The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown oil, which 10 was directly used for the next step without further purification (2.6 g, crude, 100%). ESIMS m/z= 462.02 [M+H]*. Step 1-450f. The solution of compound from step 1- 4 50e ( 2 .0g, 4.3 mmol) in THF (45 mL) was added triethylamine (1.85 mL, 12.9 mmol) and ethyl chloroformate (1.05 mL, 10.8 mmol) at 0 C. The resulting mixture stirred at 0 *C for 20 minutes 15 before all volatiles were removed by rotavap. The residue was dissolved in THF (70 mL) before being added sodium borohydride (1 g, 26.4 mmol). The mixture was stirred at 0 C for another 2 hours before being partitioned between water and EtOAc. The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown oil, which was purified by flash column chromatography (silica, EtOAc 20 methanol) to give the desired product as a light yellow solid (1.57g, 81%). ESIMS m/z = 448.13 [M+H]*. Step 1-450g. The compound from step 1-450a (70.0 mg, 0.213 mmol) in THF (5 mL) was treated with the compound from step 1-450f (95.1 mg, 0.213 mmol), PPh 3 (83.6 mg, 0.319 mmol) and DEAD (50.2 gL, 0.319 mmol) overnight before being 25 evaporated to dryness. The residue was partitioned (EtOAc - water) and the organics were washed with brine, dried (Na 2
SO
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 (22.6 mg, 14%). The regiochemistry of the SEM group was not determined. ESIMS m/z = 759.39 [M+H]*. 30 Example 1-451.
MNHCO
2 Me P N H PAGE 115 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was synthesized from the compound of Example 1-450 using procedures similar to that described in steps 1-497a and 1-448b. ESIMS m/z 743.32 [M+H]*. Example 1-452. NY N: NH s k 5 N Step 1-452a. A mixture of 2-bromo-1-(5-bromothiophen-2-yl)ethanone (1.00 g, 3.52 mmol) and N-Boc-L-proline (0.758 g, 3.52 mmol) in CH 3 CN (12 mL) was added TEA (1.06 mL, 7.40 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue 10 was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow sticky oil (1.47 g, 100%). 'H NMR (CDCl 3 ) 7.49 (t, J= 4.0 Hz, 1H), 7.13 (dd, J= 4.5, 6.0 Hz, 1H), 5.36, 5.04 (2d, J= 16.0 Hz, 1H), 5.22, 5.15 (2d, J= 16.5 15 Hz, 1H), 4.45, 4.38 (dd, J= 5.5, 7.5 Hz, 1H), 3.56 (m, 1H), 3.41 (m, 1H), 2.25 (m, 2H), 2.05 (m, 1H), 1.90 (m, 1H), 1.46, 1.42 (2s, 9H). Step 1-452b. A solution of the compound of step 1-452a (1.47 g, 3.52 mmol) in toluene (22 mL) was added ammonium acetate (5.42 g, 70.3 mmol) and the resultant mixture was heated at 100 'C for 16 hours. The volatiles were evaporated and the 20 residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown yellow foam (0.586 g, 42%) with a recovery of the compound from step 1-452a (0.616 g, 42%). ESIMS m/z = 398.16, 400.16 [M+H]+. 'H NMR (CDCl 3 ) 25 10.55 (bs, 1H), 7.07 (s, 1H), 6.94 (m, 2H), 4.92 (m, 1H), 3.40 (m, 2H), 2.96 (m, 1H), 2.12 (m, 2H), 1.92 (m, 1H), 1.49 (s, 9H). Step 1-452c. A mixture of the compound of step 1-452b (0.150 g, 0.377 mmol), the compound from step 1-491a (0.118 g, 0.377 mmol), triethylamine (0.52 mL, 3.77 mmol), tri-o-tolyl-phosphine (14.8 mg, 47.1 gmol) and Pd(OAc) 2 (4.2 mg, 18.8 30 gmol) in CH 3 CN (6 mL) was degassed and heated to 110 IC in sealed tube for 36 hours. The volatiles were evaporated and the residue was partitioned (EtOAc saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO4), PAGE 116 OF 222 WO 2010/099527 PCT/US2010/025741 filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow oil (64.1 mg, 27%). ESIMS m/z= 631.26 [M+H]*. Example 1-453. HCO2Me N C N N e.tV N 5 N NHC0 2 Me The title compound was synthesized from the compound from Example 1-452 using procedures similar to that described in Example 1-448. ESIMS m/z= 745.43 [M+H]*. Example 1-454. NHCO2Me HN N~ N S 10 N O 2 Me The title compound was synthesized from the compound from Example 1-453 using procedures similar to that described in Example 1-443. ESIMS m/z= 747.40 [M+H]*. Example 1-455. NH NH d- 0 15 N O nO NN O A mixture of the compound from step 1-452b (0.150 g, 0.377 mmol), the compound from step 1-447a (0.123 g, 0.377 mmol), triethylamine (0.52 mL, 3.77 mmol), tri-o tolylphosphine (14.8 mg, 47.1 gmol) and Pd(OAc) 2 (4.2 mg, 18.8 gmol) in CH 3 CN 20 (6 mL) was degassed and heated to 110 'C in sealed tube for 36 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compounds as a yellow oil (52.7 mg, 22%). 25 The regio- and stereochemistry of the olefinic double bond was not determined. ESIMS m/z = 645.27 [M+H]*. PAGE 117 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-456.
NHCO
2 Me
NHCO
2 Me NHCOMe NHCO 2 Me The title compound was synthesized from the compound from Example 1-455 using procedures similar to that described in Example 1-448. The regio- and 5 stereochemistry of the olefinic double bond was not determined. ESIMS m/z= 759.51 [M+H]*. Example 1-457.
VHCO
2 M2 N HN IKSI N The title compound was synthesized from the compound from Example 1-456 using 10 procedures similar to that described in Example 1-443. ESIMS m/z 761.41 [M+H]*. Example 1-458. Step 1-458a. 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to 15 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 O, 8.09 mL, 24.3 mmol) slowly at 0 'C for I hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH 4 Cl. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), 20 filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%). Step 1-458b. The compound from step 1-458a (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 25 aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g). Step 1-458c. A mixture of the compound from step 1-458b (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 PAGE 118 OF 222 WO 2010/099527 PCT/US2010/025741 of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
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]*. 5 Step 1-458d. A solution of the compound from step 1-458c (at most 11.6 mmol) in toluene (60 mL) was added ammonium acetate (13.4 g, 0.174 mol) and the resultant mixture was heated up at 100 *C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash 10 column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow brown powder (3.14 g, 4 steps, 61%). ESIMS m/z = 442.02, 444.02 [M+H]*. Step 1-458e. A mixture of the compound from step 1-lb (1 g, 2.73 mmol), bis (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 15 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]*. 20 Step 1-458f. A mixture of the compound from step 1-458d (0.100 g, 0.226 mmol), the compound from step 1-458e (93.4 mg, 0.226 mmol), Pd(PPh 3
)
4 , (13.1 mg, 11.3 pmol) and NaHCO 3 (76.0 mg, 0.905 mmol) in DME (6 mL) and H20 (2 mL) was degassed and heated at 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 25 brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (92.0 mg, 59%). ESIMS m/z= 649.54 [M+H] . Example 1-459. Me2CH O NH NHCO 2 Me 30 The title compound was synthesized from the compound from Example 1-458 using procedures similar to that described in Example 1-448. ESIMS m/z = 763.21 [M+H]*. PAGE 119 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-460. Me M NO 2 CH N
NHCO
2 Me ao Step 1-460a. A solution of the compound of example 1-458 (92.0 mg, 0.142 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 nL) rt for 30 5 minutes. 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 = 449.39 [M+H] t . Step 1-460b. A mixture of the crude compound from step 1-460a (0.142 mmol at most) and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (prepared according to WO 2008/021927, 56.9 mg, 0.298 mmol) in DMF (3 mL) was treated 10 with HATU (0.108 g, 0.284 mmol) in the presence of DIPEA (0.35 mL, 2.84 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a yellow solid (60.3 mg, 2 steps 54%). ESIMS m/z = 795.68 [M+H]*. 15 Example 1-461. o o~HNJX /V O O Step 1-461a. The desired compound was prepared from 4-bromo-1,2 diaminobenzene and N-Cbz-L-proline using procedures similar to that described in steps 1-la and 1-lb. ESIMS m/z = 400.11, 402.11 [M+H]*. 20 Step 1-461b. A mixture of the compound from step 1-461a (1.00 g, 2.50 mmol), bis(pinacolato)diboron (1.27 g, 5.00 mmol) and potassium acetate (0.613 g, 6.25 mmol) in 1,4-dioxane (25 mL) was added Pd(PPh 3
)
4 (0.144 g, 0.125 mmol). The resultant mixture were degassed and heated up at 85 'C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The 25 organics were washed with brine, dried (Na 2
SO
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 (0.801 g, 72%). ESIMS m/z= 448.18 [M+H]*. Step 1-461c. A mixture of the compound from step 1-458d (0.790 g, 1.79 mmol), 30 the compound from step 1-461b (0.800 g, 1.79 mmol), Pd(PPh 3
)
4 , (0.103 g, 89.4 PAGE 120 OF 222 WO 2010/099527 PCT/US2010/025741 jmol) and NaHCO 3 (0.601 g, 7.16 mmol) in DME (24 mL) and H 2 0 (8 mL) was degassed and heated at 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
SO
4 ), filtered and evaporated. The residue was purified by 5 chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.854 g, 70%). ESIMS m/z= 683.14 [M+H]*. Example 1-462. O O N 0 HC Me MeO The title compound was synthesized from the compound of Example 1-461 using 10 procedures similar to that described in Example 1-460. ESIMS m/z= 756.26 [M+H]*. Example 1-463. MeO2CHNH
NHC
2 Me Me0 Step 1-463a. A mixture of the compound from example 1-462 (0.314 g, 0.416 15 mmol) and Pd(OH) 2 (20wt % on carbon, 150 mg) in methanol (6 mL) was adjusted pH to 3 with aqueous 6N HCl and then treated with hydrogen (60 psi) for 24 hours. The mixture was filtered through Celite and the filtrate was concentrated to give the crude desired compound as a light yellow solid (0.401 g). ESIMS m/z= 622.13 [M+H]*. 20 Step 1-463b. The title compound was synthesized from the compound from step 1 463a using procedures similar to that described in Example 1-442. ESIMS m/z= 813.32 [M+H]*. Example 1-464. MeO2CH O HC2M NHH MeO 25 The title compound was synthesized from the compound of step 1-463a using procedures similar to that described in Example 1-448. ESIMS m/z = 779.33 [M+H]*. PAGE 121 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-465. O1H MeO 2 CHN
NHCO
2 Me N~ 04 MeO A mixture of the crude compound from step 1-463a (0.104 mmol at most) and (2S,3R)-3-hydroxy-2-(methoxycarbonylaniino)butanoic acid (prepared according to 5 WO 2008/021927, 20.2 mg, 0.114 mmol) in DMF (3 mL) was treated with HATU (35.5 mg, 93.5 gmol) in the presence of DIPEA (0.13 mL, 1.04 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a yellow white solid (12.8 mg, 2 steps 16%). ESIMS m/z 781.30 [M+H]*. 10 Example 1-466. ~oHN4Y(} NIA2 MeO 2 CHN N N S N H 0,4 5
HCO
2 M e MeO A mixture of the crude compound from step 1-463 a (0.104 mmol at most) and (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (prepared according to WO 2008/021927, 21.6 mg, 0.114 mmol) in DMF (3 mL) was treated with HATU 15 (35.5 mg, 93.5 pmol) in the presence of DIPEA (0.13 mL, 1.04 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a light yellow solid (15.6 mg, 2 steps 19%). ESIMS m/z= 793.33 [M+H]. Example 1-467. N N 20 Step 1-467a. (S)-tert-butyl 2-(5-bromo-IH-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared according to WO 2008/021927, 0.500 g, 1.58 mmol) in CH 2 Cl 2 (16 mL) was treated with triethyl amine (0.66 mL, 4.75 mmol), di-tert-butyl dicarbonate (0.518 g, 0.237 mmol) and DMAP (38.7 mg, 0.316 mmol) for 1 hours before being 25 evaporated to dryness. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.650 g, 98%). ESIMS m/z= 416.11, 418.11 [M+H]*. PAGE 122 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-467b. A mixture of the compound from step 1-467a (0.650 g, 1.56 mmol), ethynyl-trimethylsilane (2.16 mL, 15.6 mmol), CuI (8.9 mg, 46.8 ptmol) and Pd(PPh 3
)
4 (90.3 mg, 78.1 Imol) in CH 3 CN (5 mL) and triethylamine (10 mL) was degassed and heated at 80 'C under N 2 overnight. The volatiles were evaporated and 5 the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
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 (0.560 g, 83%). ESIMS m/z = 434.22 [M+H]. Step 1-467c. The compound from step 1-467b (0.560 g, 1.29 mmol) in MeOH (30 10 mL) was treated with potassium carbonate (0.535 g, 3.88 mmol) for 30 minutes before being evaporated to dryness. The residue was partitioned (EtOAc - water), and the organics were washed with brine, dried (Na 2
SO
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 (0.312 g, 92%). ESIMS 15 m/z = 262.15 [M+H]*. Step 1-467d. A mixture of the compound from step 1-467c (0.103 g, 0.395 mmol), 1,4-diiodo-benzene (62.0 mg, 0.188 mmol), CuI (2.1 mg, 11.2 Imol) and Pd(PPh 3
)
4 (21.6 mg, 18.7 ptmol) in CH 3 CN (1 mL) and triethylamine (4 mL) was degassed and heated to 60 'C under N 2 for 4 hours. The volatiles were evaporated and the residue 20 was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
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 (20.0 mg, 23%). ESIMS m/z = 464.06 [M+H] 4 . Step 1-467e. A mixture of the compound from step 1-467d (20.0 mg, 43.1 ptmol), 25 the compound from step 1-458e (17.8 mg, 43.1 pmol), Pd(PPh 3
)
4 , (9.9 mg, 8.6 Amol) and NaHCO 3 (14.5 mg, 0.172 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 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
SO
4 ), filtered and evaporated. The residue was purified by 30 chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (26.1 mg, 86%). ESIMS m/z= 623.28 [M+H] 4 . PAGE 123 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-468. M0O2CHM) HCO2MeIj The title compound was synthesized from the compound of Example 1-467 using procedures similar to that described in Example 1-448. ESIMS m/z = 737.26 5 [M+H]*. Example 1-469. M0 2 CH21 HN-1/ & Z N_ MNH2CHNHC 2 Me The title compound was synthesized from the compound of Example 1-468 using procedures similar to that described in Example 1-443. ESIMS m/z= 741.23 10 [M+H]*. Example 1-470. r~ 0 HN / N__ Step 1-470a. A mixture of the compound of step 1-467c (0.150 g, 0.575 mmol), 2,6-dibromo-naphthalene (98.6 mg, 0.345 mmol), CuI (3.3 mg, 17.2 Amol) and 15 Pd(PPh 3
)
4 (33.2 mg, 28.7 gmol) in CH 3 CN (1 mL) and triethylamine (4 mL) was degassed and heated to 90 '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
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a 20 very light yellow oil (67.6 mg, 25%). ESIMS m/z = 466.00, 467.99 [M+H]*. Step 1-470b. A mixture of the compound from step 1-470a (67.6 mg, 0.145 mmol), the compound from step 1-458e (59.9 mg, 0.145 mmol), Pd(PPh 3
)
4 , (16.8 mg, 14.5 gmol) and NaHCO 3 (48.7 mg, 0.580 mmol) in DME (6 mL) and H 2 0 (2 mL) was degassed and heated at 90 *C under N 2 for 14 hours. The volatiles were evaporated 25 and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (78.8 mg, 81%). ESIMS m/z = 673.14 [M+H]*. PAGE 124 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-471. 0~ N N MeO2CH OP HN N o N NHNO
HC
2 Me The title compound was synthesized from the compound of Example 1-470 using procedures similar to that described in Example 1-448. ESIMS m/z = 787.26 5 [M+H] 4 . Example 1-472. MeO 2 CHN HN N H 2
N,
4 ~~,~~'NH 4
LNHC
2 MG N '' The title compound was synthesized from the compound of Example 1-471 using procedures similar to that described in Example 1-443. ESIMS m/z = 791.23 10 [M+H] 4 . Example 1-473. MeO2CH A H HCO2Me ~01 The title compound was synthesized from the compound of Example 1-1-1 using procedures similar to that described in Example 1-460. ESIMS m/z = 769.37 15 [M+H]*. Example 1-474. N Step 1-474a. A mixture of the compound from step 1-515d (0.200 g, 0.643 mmol), 2,6-dibromonaphthalene (0.368 g, 1.29 mmol), Cul (3.6 mg, 19.2 gmol) and 20 Pd(PPh 3
)
4 (37.1 mg, 32.1 Amol) in CH 3 CN (6 mL) and triethylamine (6 mL) was degassed and heated at 90 '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
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a 25 light yellow oil (214 mg, 65%). ESIMS m/z= 516.08, 518.08 [M+H]+. PAGE 125 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-474b. A mixture of the compound from step 1-474a (0.214 g, 0.415 mmol), bis-(pinacolato) diboron (0.211 g, 0.829 mmol) and potassium acetate (0.102 g, 1.04 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh 3
)
4 (23.9 mg, 20.7 pmol). The resultant mixture were degassed and heated up at 85 'C under N 2 for 14 hours. The 5 volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
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 (0.163 g, 60% purity). ESIMS m/z= 564.17 [M+H]*. 10 Step 1-474c. A mixture of the compound from step 1-474b (0.163 g, 0.290 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared according to WO 2008/021927, 0.137 g, 0.434 mmol), Pd(PPh 3
)
4 , (33.4 mg, 28.9 pimol) and NaHCO 3 (97.2 mg, 1.16 mmol) in DME (6 mL) and H 2 0 (2 mL) was degassed and heated at 90 'C under N 2 for 14 hours. The volatiles were evaporated 15 and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.122 g, 60% purity). ESIMS m/z = 673.29 [M+H]*. Example 1-475. MO2CHNO HN P, N 20NNH NHCO2Me 20 The title compound was synthesized from the compound from Example 1-474 using procedures similar to that described in Example 1-448 after HPLC purification. ESIMS m/z 787.20 [M+H]*. Example 1-476. )r'otHN 08) N1(E 25 N The title compound was obtained as an impurity in the compound of example 1-474. ESIMS m/z= 675.30 [M+H]*. PAGE 126 OF 222 WO 2010/099527 PCTUS2010/025741 Example 1-477. N)
M
2 CHN H N NHCO 2 Me The title compound was synthesized and purified as a minor product in example 1 475. ESIMS m/z = 789.21 [M+H] 4 . 5 Example 1-478. Step 1-478a. A mixture of 2,4'-dibromoacetophenone (1.59 g, 5.71 mmol) and N Boc-glycine (1.00 g, 5.71 mmol) in CH 3 CN (20 mL) was added DIPEA (1.42 mL, 11.4 mmol) slowly. The mixture was stirred at rt until the disappearence of the 10 starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
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 (2.02 g, 95%). ESIMS m/z = 394.15, 396.15 [M+Na]. 15 Step 1-478b. A solution of the compound from step 1-478a (2.02 g, 5.43 mmol) in toluene (30 mL) was added ammonium acetate (8.35 g, 0.108 mol) and the resultant mixture was heated up at 100 'C for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash 20 column chromatography (silica, hexanes-ethyl acetate) to the desired compound as a yellow brown solid (1.62 g, 85%). ESIMS m/z= 352.14, 354.14 [M+H]+. Step 1-478c. A mixture of the compound from step 1-478b (80.0 mg, 0.227 mmol), the compound from step 1-515d (77.8 mg, 0.250 mmol), CuI (1.3 mg, 6.8 Amol) and Pd(PPh 3
)
4 (26.2 mg, 22.7 pmol) in triethylamine (6 mL) was degassed and heated at 25 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
SO
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 (50.9 mg, 39%). ESIMS m/z = 583.37 [M+H] 4 . PAGE 127 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-479. MeH N HCO2Me The title compound was synthesized from the compound of Example 1-478 using procedures similar to that described in Example 1-448. ESIMS m/z = 697.64 5 [M+H] 4 . Example 1-480. kO f &I NHC 2 Me Step 1-480a. A solution of the compound of example 1-500 (10.0 mg, 14.7 Amol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt for 30 10 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 = 580.55 [M+H]*. Step 1-480b. A mixture of the crude compound from step 1-480a (14.7 pmol at most) and (S)-2-(methoxycarbonyloxy)-3-methylbutanoic acid (prepared according to Chemical & Pharmaceutical Bulletin, 1985, 33, 3922-3928, 2.8 mg, 16.1 Amol) 15 in DMF (3 mL) was treated with HATU (5.6 mg, 14.7 pmol) in the presence of DIPEA (37.0 jpL, 0.294 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica,
CH
2 Cl 2 -MeOH) to give the title compound as a yellow solid (8.3 mg, 2 steps 76%). ESIMS m/z= 738.64 [M+H]*. 20 Example 1-481. O HCO2Me A mixture of the crude compound from step 1-480a (14.7 pmol at most) and (S)-2 (ethoxy-carbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 3.0 mg, 16.1 jpmol) in DMF (3 mL) was treated with HATU (5.6 mg, 25 14.7 pmol) in the presence of DIPEA (37.0 pL, 0.294 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a very yellow solid (10.2 mg, 2 steps 91%). ESIMS m/z= 751.67 [M+H] 4 . PAGE 128 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-482. O O Step 1-482a. A mixture of N-Boc-L-proline (0.210 g, 0.976 mmol) and TEA (0.14 mL, 0.976 mmol) in THF (10 mL) at -20 'C was treated with iso-butyl 5 chloroformate (0.13 mL, 0.976 mmol) for 30 minutes before a slow addition of 5 bromo-3-fluorobenzene-1,2-diamine (0.200 g, 0.976 mmol) in THF (2 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
SO
4 ), filtered and 10 evaporated to give the crude desired compound as a brown foam (0.436 g). ESIMS m/z = 402.23, 404.23 [M+H]'. Step 1-482b. A solution of the crude compound from step 1-482a (0.976 mmol at most) in glacial acetic acid (10 mL) was heated at 65 'C for 24 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous 15 NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
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 (0.327 g, 2 steps 87%). ESIMS m/z= 384.16, 386.16 [M+H]+. Step 1-482c. A mixture of the compound from step 1-482b (60.0 mg, 0.156 mmol), 20 the compound from step 1-1-1b (58.0 mg, 0.172 mmol), CuI (0.9 mg, 4.6 nol) and Pd(PPh 3
)
4 (9.0 mg, 7.8 munol) in triethylamine (4 mL) and CH 3 CN (4 mL) was degassed and heated to 90 '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
SO
4 ), filtered and evaporated. The residue was purified by flash column 25 chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (54.2 mg, 54%). ESIMS m/z = 641.22 [M+H] 4 . Example 1-483. OHN N HC 2 Me PAE 1 NO NH22 PAGE 129 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was synthesized from the compound of Example 1-482 using procedures similar to that described in Example 1-448. ESIMS m/z = 755.55 [M+H]*. Example 1-484. 0~ / P00 5 Step 1-484a. A mixture of 4-bromo-5-chlorobenzene-1,2-diamine (0.3 g, 1.19 mmol) and tin(II) chloride dihydrate (1.08 g, 4.77 mmol) in DMF (10 mL) was heated at 80 'C for 2 hours. The reaction was cooled and then neutralized by the addition of aqueous 2N NaOH. The resultant mixture were partitioned (EtOAc 10 water) and the organics were washed with brine, dried (Na 2
SO
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 brown solid (0.256 g, 96%). Step 1-484b. The compound from step 1-484a (0.250 g, 1.13 mmol) in DMF (10 15 mL) was treated with N-Boc-L-proline (0.243 g, 1.13 mmol), EDC-HCl (0.281 g, 1.47 mmol) and DMAP (27.6 mg, 0.226 mmol) for 12 hours before being partitioned (EtOAc - water). The organics were washed with aqueous IN HCI, brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a light red brown foam (0.401 g). ESIMS m/z= 418.20, 420.20 [M+H]*. 20 Step 1-484c. A solution of the crude compound from step 1-484b (1.13 mmol at most) in glacial acetic acid (10 mL) was heated at 50 'C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, 25 hexanes-ethyl acetate) to give the desired compound as a yellow brown solid (0.326 g, 2 steps 85%). ESIMS m/z = 400.21, 402.21 [M+H]*. Step 1-484d. A mixture of the compound from step 1-484c (55.0 mg, 0.140 mmol), the compound from step 1-1-lb (56.5 mg, 0.168 mmol), CuI (0.8 mg, 4.1 Amol) and Pd(PPh 3
)
4 (8.0 mg, 6.9 gmol) in triethylamine (3 mL) and CH 3 CN (3 mL) was 30 degassed and heated to 95 '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
SO
4 ), filtered and evaporated. The residue was purified by flash column PAGE 130 OF 222 WO 2010/099527 PCT/US2010/025741 chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (49.7 mg, 55%). ESIMS m/z = 657.40 [M+H]+. Example 1-485. MeO2CHHCO2Me 5 The title compound was synthesized from the compound of Example 1-484 using procedures similar to that described in Example 1-448. ESIMS m/z= 771.63 [M+H]*. Example 1-486. MeO 2 CH2) O HN & ISN N NHOHC 2 Me 0 10 A solution the compound of example 1-517 (38.6 mg, 51.3 pmol) in CH 2 Cl 2 (3 mL) was treated with camphorsulfonic acid (23.8 mg, 0.103 mmol) and Dess-Martin periodinane (0.131 mg, 0.308 mmol) for 5 hours before being quenched with satuated aqueous NsS 2 0 3 and NaHCO 3 . The mixture was partitioned (EtOAc water) and the organics were washed with brine, dried (Na 2
SO
4 ), filtered and 15 evaporated. The residue was purified by flash column chromatography (silica, MeOH-CH 2 Cl 2 ) to give the title compound as a yellow brown solid (33.2 mg, 86%). ESIMS m/z 751.54 [M+H] . Example 1-487. O O 0 / N. 0 ND D ea.ch D is deuterium 20 Step 1-487a. A solution of 4'-bromoacetophenone-d 7 (0.500 g, 2.43 mmol) in AcOH (10 mL) was treated with bromine (0.12 mL, 2.43 mmol) for 24 hours before being evaporated to dryness. The residue was partitioned (EtOAc - aqueous satuated NaHCO 3 ) and the organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the desired compound as a white crystal (0.672 g, 25 98%). Step 1-487b. A mixture of the compound from step 1-487a (0.670 g, 2.38 mmol) and N-Boc-L-proline (0.511 g, 2.38 mmol) in CH 3 CN (20 mL) was added DIPEA PAGE 131 OF 222 WO 2010/099527 PCT/US2010/025741 (0.59 mL, 4.75 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
SO
4 ), filtered and evaporated to give the crude desired compound as a yellow brown oil 5 (1.06 g). ESIMS m/z= 416.32, 418.32 [M+H]*. Step 1-487c. A solution of the compound from step 1-487b (at most 2.38 mmol) in toluene (24 mL) was added ammonium acetate (3.66 g, 47.5 mmol) and the resultant mixture was heated up at 100 'C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with 10 brine, dried (Na 2
SO
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 powder (0.749 g, 2 steps, 78%). ESIMS m/z = 396.20, 398.20 [M+H]*. Step 1-487d. A mixture of the compound from step 1-487c (200 mg, 0.505 mmol), 15 the compound from step 1-515d (0.188 g, 0.606 mmol), CuI (2.9 mg, 15.1 pmol) and Pd(PPh 3
)
4 (29.1 mg, 25.2 pmol) in triethylamine (5 mL) and CH 3 CN (5 mL) was degassed and heated at 95 *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
SO
4 ), filtered and evaporated. The residue was purified by flash 20 column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.151 g, 48%). ESIMS m/z= 627.58 [M+H]*. Example 1-488. Me2C 0 I HCO2Me N'W'40 D 0 - each D Is deuterium The title compound was synthesized from the compound from Example 1-487 using 25 procedures similar to that described in Example 1-448. ESIMS m/z = 741.70 [M+H]*. Example 1-489. C1 O Step 1-489a. A mixture of the compound from step 1-458d (0.200 g, 0.452 mmol), 30 bis(pinaco-lato)diboron (0.144 g, 0.565 mmol), PdC 2 (dppf) 2 (36.9 mg, 0.0452 PAGE 132 OF 222 WO 2010/099527 PCT/US2010/025741 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
SO
4 ), filtered and evaporated. The residue was 5 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 1-489b. A mixture of the compound from step 1-484c (50.0 mg, 0.125 mmol), the compound from step 1-489a (73.2 mg, 0.150 mmol), Pd(PPh 3
)
4 , (7.2 mg, 6.2 jmol) and NaHCO 3 (41.9 mg, 0.499 mmol) in DME (6 mL) and H 2 0 (2 mL) was 10 degassed and heated at 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
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (21.3 mg, 25%). ESIMS m/z= 683.52 [M+H]*. 15 Example 1-490. CI MeO2CHI
NHCO
2 Me The title compound was synthesized from the compound from Example 1-489 using procedures similar to that described in Example 1-448. ESIMS m/z = 797.62 [M+H]. 20 Example 1-491. O40HN)K ~L.NH o,_,_ Step 1-491a. A mixture of the compound of step 1-lb (1.600 g, 4.369 mmol), tributyl(vinyl)-tin (1.53 ml, 5.242 mmol) and Pd(PPh 3
)
4 (5 mol%, 0.250 g, 0.218 mmol) in toluene (20 mL) was degassed and then refluxed under N 2 for 18 h before 25 being allowed to cool to rt. The mixture was directly purified by flash column chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a pink foam (0.912 g, 67%). ESIMS m/z = 314.18 [M+H]+. Step 1-491b. A mixture of the compound from step 1-491a (1.251 g, 3.191 mmol), the compound of step 1-1d (1.000 g, 3.191 mmol), Pd(OAc) 2 (5 mol%, 35.8 mg, 30 0.160 mmol) and P(o-tolyl) 3 (0.121 g, 0.399 mmol) in Et 3 N (4.45 mL) and CH 3 CN PAGE 133 OF 222 WO 2010/099527 PCT/US2010/025741 (30 mL) was degassed and refluxed under N 2 gas for 20 hours before being evaporated. The residue was taken up in dichloromethane and filtered through a short pad of Celite. The filtrate was purified by chromatography (silica, hexanes ethyl acetate with 1% Et 3 N in ethyl acetate) to give the title compound as a yellow 5 solid (1.471 g, 74%). ESIMS m/z = 625.05 [M+H]*. Example 1-492. %4 HN () MeO 2 CHN
NHCO
2 Me The title compound was prepared from the compound of example 1-491 using procedures similar to that described in example 1-448. ESIMS m/z = 739.15 10 [M+H] 4 . Example 1-493. MeO2C
HC
2 Me The title compound was obtained as a minor product (- 2%) in example 1-492. ESIMS m/z = 739.03 [M+H] 4 . 15 Example 1-494. MeO 2 CHN 0_ NHC0 2 Me Pd(OH) 2 (20% on carbon, 10.8 mg) was added into a solution of the compound from example 1-492 (10.8 mg, 0.0146 mmol) in EtOH (1.5 mL). The suspension was purged with H 2 3 times and stirred at rt for 6 h under H 2 (60 psi) before being 20 filtered through a short pad of Celite. The filtrate was concentrated. The crude was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a white solid (7.2 mg, 59%). ESIMS m/z 741.13 [M+H]. Example 1-495. (y EM SEM 25 To a solution of the compound from example 1-491 (0.268 g, 0.430 mmol) in DMF (6 mL) was added NaH (60% in mineral oil, 36.0 mg, 0.902 mmol) at rt. The PAGE 134 OF 222 WO 2010/099527 PCT/US2010/025741 suspension was stirred at rt for 1 hour. SEMC1 (0.154 mL, 0.868 mmol) was added dropwise at rt. After 1.5 hour at rt, the reaction was quenched with saturated NH 4 Cl solution and extracted with EtOAc. The organic layer was washed with saturated NaHCO 3 , brine, dried (Na 2
SO
4 ), filtered and concentrated. The crude was purified 5 by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow foam (0.290 g, 76%). The regiochemistry of the SEM groups was not determined. ESIMS m/z= 885.25 [M+H]. Example 1-496. EM SEM O 10 To a solution of the compound from example 1-495 (0.150 g, 0.169 mmol) in THF (1.5 mL) was added Pd(OAc) 2 (3.8 mg, 0.0 169 mmol) at 0 "C. Excess diazomethane (solution in ether) was added with a plastic pipette until the starting material was consumed. The suspension was concentrated. The residue was taken up in dichloromethane and filtered through a short pad of celite. The filtrate was purified 15 by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compounds as a colorless oil (0.106 g, 70%). The regiochemistry of the SEM group and the stereochemistry of the cyclopropyl ring were not determined. ESIMS m/z 899.07 [M+H]*. Example 1-497. MeO 2 MN te taLe A s"IN1-497-b MeO2 tentative 20
NHCO
2 Me Step 1-497a. A solution of the compound of example 1-496 (0.106 g, 0.118 mmol) in 1,4-dioxane (2 mL) was treated with HCl in 1,4-dioxane (4 M, 12 mL) at 50 "C for 4 hour. The volatiles were evaporated off to give the crude desired compounds as a yellow solid which was used directly in the next step. 25 Step 1-497b. A mixture of the crude compound from step 1-497a (0.118 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (41.3 mg, 0.236 mmol) in DMF (3 mL) was treated with HATU (85.2 mg, 0.224 mmol) in the presence of DIPEA (0.41 mL, 2.360 mmol) for 1 hours at rt and the volatiles were PAGE 135 OF 222 WO 2010/099527 PCT/US2010/025741 evaporated off to provide a brown syrup. The residue was patitioned (EtOAc - H20). The organic layer was washed with brine, dried (Na 2
SO
4 ), filtered and concentrated. The residue was purified by RP-HPLC (NH 4
HCO
3 buffer-MeOH) to give the title compounds: the major diastereomer (497-a, tentative) as a yellow solid (19.4 mg), 5 ESIMS m/z = 753.12 [M+H]+; and the minor diastereomer (497-b, tentative) as a yellow solid (3.1 mg), ESIMS m/z = 753.12 [M+H]+. The stereochemistry of the cyclopropyl rings was not determined. Example 1-498. 10 Step 1-498a. A mixture of the compound from step 1-458e (0.250 g, 0.605 mmol), 1-bromo-4-iodobenzene (0.257 g, 0.908 mmol), NaHCO 3 (0.203 g, 2.42 mmol) and Pd(PPh 3
)
4 (34.9 mg, 30.2 pmol) 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, 15 dried (Na 2
SO
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 1-498b. A mixture of the compound from step 1-le (81.1 mg, 0.185 mmol), the compound from step 1-498a (85.8 mg, 0.194 mmol), Pd(PPh 3
)
4 , (21.4 mg, 18.5 20 pmol) and NaHCO 3 (62.1 mg, 0.739 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 80 0 C under N 2 for 22 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give 25 the title compound as a yellow solid (0.100 g, 8 1%). ESIMS m/z= 675.17 [M+H]+. Example 1-499. MeO 2 CHN
NHCO
2 Me The title compound was prepared from the compound of example 1-498 using procedures similar to that described in example 1-448. ESIMS m/z = 789.06 30 [M+H]1. PAGE 1 36 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-500. ON * HCO 2 Me Step 1-500a. A solution of the compound from step 1-515b (2.000 g, 4.553 mmol) in 1,4-dioxane (25 mL) was treated with HCl in 1,4-dioxane (4 M, 50 mL) at rt for 5 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 = 339.89 [M+H]*. Step 1-500b. A mixture of the crude compound from step 1-500a (4.553 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.798 g, 4.553 mmol) in DMF (15 mL) was treated with HATU (1.644 g, 4.325 mmol) in the 10 presence of DIPEA (7.93 mL, 45.53 mmol) for 1.5 hours at rt and the volatiles were evaporated off. The residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2
SO
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 title compound as a yellow foam (2.026 g, 90% over 2 steps). 15 ESIMS m/z= 496.90 [M+H]*. Step 1-500c. A mixture of compound from step 1-500b (0.800 g, 1.612 mmol), the compound from step 1-515d (0.501 g, 1.612 mmol), Pd(PPh 3
)
4 , (5 mol%, 93.1 mg, 80.6 pmol) and CuI (3 mol%, 9.2 mg, 48.3 pmol) in Et 3 N (4 mL) and THF (12 mL) was degassed and stirred at 40 'C under N 2 for 18 hours. The volatiles were 20 evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the title compound as a yellow solid (0.705 g, 64%). ESIMS m/z = 680.09 [M+H]*. Example 1-501. MeO 2 CHN 4fHN I~N NN
NHCO
2 Me 25 The title compound was prepared from the compound of example 1-500 and (S)-2 (methoxy-carbonylamino)propanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z= 709.05 [M+H]*. Example 1-502. MeO 2 CHI
NHCO
2 MO PAGE 137 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was prepared from the compound of example 1-500 and (S)-2 (methoxycarbonylamino)butanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z = 723.05 [M+H]*. Example 1-503. MeO2CHN 5
NHCO
2 Me The title compound was prepared from the compound of example 1-500 and (S)-2 (methoxycarbonylamino)pentanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z = 737.09 [M+H]*. Example 1-504. MeO 2 CHN C NH 10 NHCO 2 Me The title compound was prepared from the compound of example 1-500 and (R) (methoxycarbonyl)amino phenyl acetic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z= 771.06 [M+H]*. Example 1-505. M0O 2 CHN /0 N 15 NHCO 2 Me The title compound was prepared from the compound of example 1-500 and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z= 753.05 [M+H]. Example 1-506. AcHN 0" 20 NHCO 2 Me The title compound was prepared from the compound of example 1-500 and (S)-2 acetamido-3-methylbutanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z 721.48 [M+H]*. Example 1-507. 25 NHCO 2 Me PAGE 138 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was prepared from the compound of example 1-500 and (R)-3 methyl-2-phenylbutanoic acid using procedures similar to that described in steps 1 500a and 1-500b. ESIMS m/z = 740.50 [M+H]*. Example 1-508. Me2CHN N NH 5
NHCO
2 Me The title compound was prepared from the compound of example 1-500 and (R)-2 (methoxy-carbonylamino)-3-methylbutanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z = 737.49 [M+H]*. Example 1-509. Me2CHN 10 NHCO 2 Me The title compound was prepared from the compound of example 1-500 and (S)-2 (methoxy-carbonylamino)-2-phenylacetic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z= 771.40 [M+H]*. Example 1-510. Me2CHN 15 Step 1-510a. A solution of the compound fromthe compound from step 1-515d (1 g, 3.21 mmol) in dichloromethane (20 mL) was treated with HCI in 1,4-dioxane (4 M, 12 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. 20 Step 1-510b. The mixture of compounds from step 1-510a (3.21 mm1 at most) and the compound from step 1-515g (562 mg, 3.21 mmol) in DMF (12 mL) was added diisopropylethylamine (4.56 mL, 32 mmol) and HATU (1.22g, 3.21 mmol). The resulting solution was stirred at room temperature for 1 hour before all volatiles were removed to provide a brown slurry, which was partitioned between EtOAc and 25 aqueous NaOH (0.5M). The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown oil, which was purified by flash column chromatography (silica, EtOAc-methanol) to give the desired compound. PAGE 139 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-510c. The title compound was prepared from the compound from step 1 51Ob and 1-515b using procedures similar to that described in step 1-500c. ESIMS m/z= 680.36 [M+H]*. Example 1-511. Me02CHN 00 5 AHAc The title compound was prepared from the compound of example 1-510 and (S)-2 acetamido-3-methylbutanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z =721.49 [M+H]*. Example 1-512. Me02CHV 10 Ph The title compound was prepared from the compound of example 1-510 and (R)-3 methyl-2-phenylbutanoic acid using procedures similar to that described in steps 1 500a and 1-500b. ESIMS m/z= 740.51 [M+H]+. Example 1-513. Me 2 CHN HN7.' 15 ''"
NHCO
2 Me The title compound was prepared from the compound of example 1-510 and (R)-2 (methoxycarbonylamino)-3-methylbutanoic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z= 737.50 [M+H]*. Example 1-514. MeO2CHN 20 NHCO 2 Me The title compound was prepared from the compound of example 1-510 and (S)-2 (methoxycarbonylamino)-2-phenylacetic acid using procedures similar to that described in steps 1-500a and 1-500b. ESIMS m/z = 771.49 [M+H]*. Example 1-515. NHCO2Me H O 25 Me2CHN H PAGE 140 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-515a. Into a mixture of 2-bromo- 1 -(4-iodophenyl)ethanone (5g, 15.4 mmol) and (S)-I-(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 5 EtOAc and aqueous NaHCO 3 . The organic phase was separated, dried (Na 2
SO
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 1-515b. The mixture of compound from step 1-515a (6.0g, 12.5 mmol) and 10 ammonium acetate (15.lg, 196 mmol) in toluene (80 mL) was stirred at 80 *C for 3 hours before being partitioned between water and aqueous NaHCO 3 . The organic phase was separated, dried (Na 2
SO
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]*. 15 Step 1-515c. A mixture of the compound from step 1-lb (2.010 g, 5.488 mmol), trimethyl-silylacetylene (2.33 ml, 16.46 mmol), CuI (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 20 the desired compound as a yellow foam (1.140 g, 54%). ESIMS m/z = 384.22 [M+H]*. Step 1-515d. A suspension of the compound from step 1-515c (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). 25 The organic layer was washed with brine, dried (Na 2
SO
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 1-515e. The mixture of compounds from step 1-515b (9.lg, 20.7 mmol) and 30 step l-515d (6.
4 5g, 20.7 mmol) in THF (200 mL), triethylamine (60 mL) and acetonitrile (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.15g, 1 mmol) and copper(I) iodide (119 mg, 0.62 mmol). The resulting mixture was purged with nitrogen before being stirred at room temperature for 12 hours, at 50 *C for 2 hours and at 60 "C for 1 hour. After addition of aqueous NaOH (1 M, 100 mL), the PAGE 141 OF 222 WO 2010/099527 PCT/US2010/025741 organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown slurry, which was absorbed with silica and purified by flash column chromatography (silica, EtOAc-methanol) to give the desired compound as light yellow solid (10.8 g, 84%). ESIMS m/z= 623.07 [M+H]+. 5 Step 1-515f. A solution of the compound from step 1-5t5e (3g, 4.58 mmol) in dichloromethane (50 mL) and MeOH (5 mL) was treated with HCI in 1,4-dioxane (4 M, 40 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. ESIMS m/z= 423.06 [M+H]+. 10 Step 1-515g. The mixture of L-valine (50g, 0.427 mol) in 1,4-dioxane (140 mL) was added water (630 mL), NaOH (54.7g, 1.4 mol) and methyl chloroformate (65.7 mL, 0.85 mol). The resulting solution was stirred at 60 "C for 22 hours before being added dichloromethane (400 mL). The aqueous phase was separated and extracted with dichloromethane (400 mL) before acidification with hydrochloric acid (37% in 15 water, 90 mL). The cloudy suspension was extracted with EtOAc (500 mL) twice and the combined organic phases were dried (Na 2
SO
4 ) and concentrated to afford a white solid, which was recrystalized with hexane and EtOAc to afford the desired product as colorless needle like crystals (54g, 72%). 'H NMR (d 6 -DMSO) 12.52 (s, 1H), 7.33 (d, 1H), 3.85 (dd, 1H), 3.56 (s, 3H), 2.06 (m, 1H), 0.98 (m, 6H). 20 Step 1-515h. The mixture of compounds from step 1-515f (4.58 mml at most) and step 1-515g (1.61g, 9.16 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (5.21 mL, 39 mmol) and HATU (3.31 g, 8.7 mmol). The resulting solution was stirred at room temperature for 35 minutes before being partitioned between EtOAc (500 mL) and aqueous NaOH (0.5M, 50 mL). The 25 organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, EtOAc methanol) to give the title compound as light yellow solid (2.3 1g, 65% over 2 steps). ESIMS m/z 737.12 [M+H]+. Example 1-516. )(.OHNI/ ~4. - N ) NN 30 PAGE 142 OF 222 WO 2010/099527 PCT/US2010/025741 The title compound was prepared from (2S, 4R)- 1 -(tert-butoxycarbonyl)-4-hydroxy pyrrolidine-2-carboxylic acid using procedures similar to that described in steps I 515a to 1-515e. ESIMS m/z= 639.36 [M+H]*. Example 1-517. MeO 2 CHN HNN N ~ ~ N 5 HO WNHCO 2 Me The title compound was prepared from the compound of example 1-516 using procedures similar to that described in example 1-448. ESIMS m/z= 753.46 [M+H]*. Example 1-518. >rf HN- N F N 10 F The title compound was prepared from (2S)-1-(tert-butoxycarbonyl)-4,4 difluoropyrrolidine-2-carboxylic acid using procedures similar to that described in steps 1-515a to 1-515e. ESIMS m/z=659.35 [M+H]*. Example 1-519. MeO 2 CHN N -NH 15 FNHCO 2 Me The title compound was prepared from the compound of example 1-518 using procedures similar to that described in example 1-448. ESIMS m/z = 773.34 [M+H]*. Example 1-520. 20 *j_0 The title compound was prepared from the compound from step 1-1-1b, 4-bromo 1,2-diaminobenzene and (6S)-5-[(tert-butoxy)carbonyl]-5-azaspiro[2.4]heptane-6 carboxylic acid (prepared according to WO 2009/102325) using procedures similar to that described in examples 1-1 and 1-1-1. ESIMS m/z = 649.30 [M+H]*. PAGE 143 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-521. MeO 2 CHN
NHCO
2 Me The title compound was prepared from the compound of Example 1-521 using procedures similar to that described in example 1-448. ESIMS m/z= 763.30 5 [M+H]. Example 1-522. O H N N __ ( N N The title compound was prepared from 2,4'-dibromoacetophenone, the compound from step 1-515d and (6S)-5-[(tert-butoxy)carbonyl]-5-azaspiro[2.4]heptane-6 10 carboxylic acid (prepared according to WO 2009/102325) using procedures similar to that described in examples 1-1 and 1-515. ESIMS m/z= 649.35 [M+H]*. Example 1-523. MeO 2 CHN
NHCO
2 Me The title compound was prepared from the compound of Example 1-522 using 15 procedures similar to that described in example 1-448. ESIMS m/z= 763.44 [M+H]. Example 1-524. NH The title compound was prepared from 2,4'-dibromoacetophenone, 4-bromo-1,2 20 diamino-benzene and (6S)-5-[(tert-butoxy)carbonyl]-5-azaspiro[2.4]heptane-6 carboxylic acid (prepared according to WO 2009/102325) using procedures similar to that described in examples 1-1 and 1-515. ESIMS m/z= 675.35 [M+H]*. PAGE 144 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-525. MeO 2 CHN HN_
NHCO
2 Me The title compound was prepared from the compound of Example 1-524 using procedures similar to that described in example 1-448. ESIMS m/z 789.47 5 [M+H]. Example 1-526. HCO2M MeO 2 CHN A mixture of the crude compound from step 1-515f (0.105 mmol at most) and (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (prepared by procedure 10 similar to that in step 515g, 35 mg, 0.21 mmol) in acetonitrile (2 mL) was treated with HATU (79 mg, 0.21 mmol) in the presence of DIPEA (0.15 mL, 1.05 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown oil. It was purified by flash column chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a yellow solid (60 mg, 2 steps 75%). ESIMS m/z= 765.14 [M+H]*. 15 Examvle 1-527.
NHCO
2 Me OH MeO 2 CHN A mixture of the crude compound from step 1-515f (0.1Ommol at most) and (2S,3R)-3-hydroxy-2-(methoxycarbonylamino)butanoic acid (prepared by procedure similar to that described in step 1-515g, 35 mg, 0.20 mmol) in DMF (2 mL) was 20 treated with HATU (76 mg, 0.20 mmol) in the presence of DIPEA (0.12 mL, 0.80 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown oil. It was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a yellow solid (64 mg, 2 steps 86%). ESIMS m/z 741.07 [M+H]*. 25 Example 1-528.
NHCO
2 Me MeO 2 CHN PAGE 145 oF 222 WO 2010/099527 PCT/US2010/025741 A mixture of the crude compound from step 1-480a (0.015 mmol at most) and (S)-2 cyclopropyl-2-(methoxycarbonylamino) acetic acid (prepared by procedure similar to that described in step 1-515g, 2.6 mg, 0.015 mmol) in acetonitrile (2 mL) was treated with HATU (5.7 mg, 0.015mmol) in the presence of DIPEA (0.03 mL, 0.15 5 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown oil. It was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a yellow solid (7.6 mg, 2 steps 69%). ESIMS m/z = 735.22 [M+H]*. Example 1-529.
NHCO
2 Me N N1( 10 MeO 2 CHN H The title compound as a yellow solid (7.9 mg, 2 steps 71%) was prepared from the crude compound from step 1-480a (0.015 mmol at most) and (S)-2 (methoxycarbonylamino)-3,3-dimethylbutanoic acid (2.8 mg, 0.015 mmol) using the procedures similar to that described in example 1-528. ESIMS m/z= 751.55 15 [M+H]*. Example 1-530.
NHCO
2 Me MeO 2 CHN The title compound as a yellow solid (7.3 mg, 2 steps 65%) was prepared from the crude compound from step 1-480a (0.015 mmol at most) and (S)-3-hydroxy-2 20 (methoxycarbonyl-amino)-3-methylbutanoic acid (2.8 mg, 0.015 mmol) using the procedures similar to that described in example 1-528. ESIMS m/z = 753.36 [M+H]*. Example 1-531. NHC0 2 Me H _H MeO 2 CHN 25 The title compound as a yellow solid (4.0 mg, 2 steps 36%) was prepared from the crude compound from step 1-480a (0.015 mmol at most) and (2S,3S)-3-hydroxy-2 (methoxy-carbonylamino)butanoic acid (2.6 mg, 0.0 15 mmol) using the procedures similar to that described in example 1-528. ESIMS m/z = 739.26 [M+H]*. PAGE 146 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-532.
NHCO
2 Me MeO2C (HsP The title compounds as a yellow solid (5.5 mg, 2 steps 46%) was prepared from the crude compound from step 1-480a (0.015 mmol at most) and 2 5 (methoxycarbonylamino)-2-phenylbutanoic acid (2.6 mg, 0.015 mmol) using the procedures similar to that described in example 1-528. ESIMS m/z = 799.46 [M+H]*. Example 1-533.
NHCO
2 Me Ph$~P 0 MeO 2 CHN P 10 Step 1-533a. A mixture of (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2 yl)pyrrolidine-1-carboxylate (prepared according to US2008/311075A1, 47.5 mg, 0.12 mmol) and the compound from step 1-515d (38 mg, 0.12 mg) in triethylamine (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.0 12 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting mixture was purged with 15 nitrogen before being stirred at 100 *C for 12 hours. The mixture was partitioned between water and EtOAc and the organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow solid (56 mg, 59%). ESIMS mz= 623.95 [M+H]*. 20 Step 1-533b. The desired product was prepared from the compound of step 1-533a using procedures similar to that described in step 1-2-la. ESIMS m/z= 424.02 [M+H]*. Step 1-533c. The title compound was prepared from the compound of step 1-533b using procedures similar to that described in step 1-2-lb. ESIMS m/z = 805.92 25 [M+H]*. Example 1-534. MeO 2 CHN h Ph US V2) Ij N NHC0 2 Me The title compound was prepared from the compound of example 1-533 using procedures similar to that described in example 1-2-2. ESIMS m/z = 810.10 [M+H]. PAGE 147 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-535. HO
NHCO
2 Me O N N ( MeO 2 CHN Step 1-535a. The desired product was prepared from (2S,4R)-1-(tert butoxycarbonyl)-4-hydroxypyrrolidine-2-caiboxylic acid using procedures similar to 5 that described in step 1-515a. ESIMS m/z = 476.14 [M+H]*. Step 1-535b. The desired product was prepared from the compound of step 1-535a using procedures similar to that described in step 1-515b. ESIMS m/z= 455.99 [M+H]. Step 1-535c. The desired product was prepared from the compound of step 1-535b 10 and the compound of step 1-515d using procedures similar to that described in step 1-515e. ESIMS m/z = 639.30 [M+H]*. Step 1-535d. The desired product was prepared from the compound of step 1-535c using procedures similar to that described in step 1-515f. ESIMS m/z = 439.26 [M+H]*. 15 Step 1-535e. The title compound was prepared from the compound of step 1-535d and the compound of step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z 753.40 [M+H]*. Example 1-536. (s N 02Me MeO 2 CHN Ph 20 Step 1-536a. The mixture of (R)-2-benzyl- I -(tert-butoxycarbonyl)pyrrolidine-2 carboxylic acid (200 mg, 0.66 mmol) and 4-bromo-1,2-diaminobenzene (135 mg, 0.73 mmol) in acetonitrile (2 mL) was added EDC (138 mg, 0.73 mmol) and 4 dimethylaminopyridine (40 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 1 hour before being partitioned between water and EtOAc. 25 The organic phase was separated, dried (Na 2
SO
4 ) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow solid (190 mg, 61%). ESIMS m/z= 474.18 [M+H]*. PAGE 148 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-536b. The desired product was prepared from the compound of step 1-536a using procedures similar to that described in step 1-lb. ESIMS m/z = 456.17 [M+H]*. Step 1-536c. The desired product was prepared from the compound of step 1-536b 5 and the compound from step 1- 1-lb using procedures similar to that described in step 1-1-1c. ESIMS m/z = 713.46 [M+H]*. Step 1-536d. The desired product was prepared from the compound of step 1-536c using procedures similar to that described in step 1-515f. ESIMS m/z= 513.30 [M+H]*. 10 Step 1-536e. The title compound was prepared from the compound of step 1-536d and the compound from step 1-515g using procedures similar to that described in step l-515h. ESIMS m/z = 827.49 [M+H]*. Example 1-537. NHC0 2 Me MeO 2 CHN '-Ph 15 Step 1-537a. The desired product was prepared from (2S,4R)-1-(tert butoxycarbonyl)-4-phenoxypyrrolidine-2-carboxylic acid using procedures similar to that described in step 1-536a. ESIMS m/z= 476.14 [M+H]*. Step 1-537b. The desired product was prepared from the compound of step 1-537a using procedures similar to that described in step 1-lb. ESIMS m/z = 458.16 20 [M+H]*. Step 1-537c. The desired product was prepared from the compound of step 1-537b and the compound of step 1-1-lb using procedures similar to that described in step 1-1-1c. ESIMS m/z = 715.36 [M+HJ. Step 1-537d. The desired product was prepared from the compound of step 1-537c 25 using procedures similar to that described in step 1-515f. ESIMS m/z= 515.19 [M+H]*. Step 1-537e. The title compound was prepared from the compound from step 1 537d and the compound from step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z = 829.35 [M+H]*. PAGE 149 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-538.
NHCO
2 Me 0N O MeO 2 CHN -Ph The title compound was prepared from (2S,4S)-1-(tert-butoxycarbonyl)-4 phenoxypyrroli-dine-2-carboxylic acid using procedures similar procedures similar 5 to that described in example 1-537. ESIMS m/z= 829.42 [M+H]*. Example 1-539. NH 02Me MeO 2 CHN M The title compound was prepared from (S)- 1 -(tert-butoxycarbonyl)-2 methylpyrrolidine-2-carboxylic acid using procedures similar procedures similar to 10 that described in example 1-536. ESIMS m/z = 751.34 [M+H]*. Example 1-540.
NHCO
2 Me MeO 2 CHN F Step 1-540a. The desired product was prepared from (2S,4R)-1-(tert butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid using procedures similar to 15 that described in step 1-536a. ESIMS m/z = 402.07 [M+H]*. Step 1-540b. The desired product was prepared from the compound from step 1 540a using procedures similar to that described in step 1-lb. ESIMS m/z = 384.09 [M+H]*. Step 1-540c. The desired product was prepared from the compound from step 1 20 540b and the compound from step 1-1-lb using procedures similar to that described in step 1-1-1c. ESIMS m/z = 641.32 [M+H]*. Step 1-540d. The desired product was prepared from the compound from step 1 540c using procedures similar to that described in step 1-515f. ESIMS m/z = 441.13 [M+H]*. 25 Step 1-540e. The title compound was prepared from the compound from step 1 540d and the compound from step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z = 755.31 [M+H]*. PAGE 150 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-541.
NHCO
2 Me N NO MeO 2 CHN H Step 1-541a. The desired product was prepared from (lR,3S,5R)-2-(tert butoxycarbonyl)-2-azabicyclo[3. 1.0]hexane-3-carboxylic acid (prepared according 5 to W02009/102325) using procedures similar to that described in step 1-536a. ESIMS m/z= 396.13 [M+H]*. Step 1-541b. The desired product was prepared from compound 1-541a using procedures similar to that described in step lb. ESIMS m/z = 378.11 [M+H]*. Step 1-541c. The desired product was prepared from the compound from step 1 10 54 lb and the compound from step 1-1-lb using procedures similar to that described in step 1-1-Ic. ESIMS m/z = 635.43 [M+H]*. Step 1-541d. The desired product was prepared from the compound from step 1 541c using procedures similar to that described in step 1-515f. ESIMS m/z= 435.31 [M+H]*. 15 Step 1-541e. The title compound was prepared from the compound from step 1 541d and the compound from step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z = 749.45 [M+H]*. Example 1-542.
NHCO
2 Me MeO 2 CHN 20 Step 1-542a. The desired product was prepared from (2S,5S)-1-(tert butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (prepared according to Journal ofMedicinal Chemistry 2009, 49, 3250) using procedures similar to that described in step 1-536a.. ESIMS m/z = 398.07 [M+H]*. Step 1-542b. The desired product was prepared from the compound from step 1 25 542a using procedures similar to that described in step 1-lb. ESIMS m/z = 380.01 [M+H]*. Step 1-542c. The desired product was prepared from the compound from step 1 542b and the compound from step 1-1-lb using procedures similar to that described in step 1-1-1c. ESIMS m/z= 637.39 [M+H]*. PAGE 151 OF 222 WO 2010/099527 PCT/US2010/025741 Step 1-542d. The desired product was prepared from the compound from step 1 542c using procedures similar to that described in step 1-515f. ESIMS m/z = 437.26 [M+H]*. Step 1-542e. The title compound was prepared from the compound from step 1 5 542d and the compound from step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z= 751.44 [M+H]*. Example 1-543.
NHCO
2 Me MeO 2 CHN F The title compound was prepared from (2S,4S)-1 -(tert-butoxycarbonyl)-4 10 fluoropyrrolidine-2-carboxylic acid using procedures similar procedures similar to that described in example 1-540. ESIMS m/z= 755.42 [M+H]*. Example 1-544. o O
HCO
2 Me MeO 2 CHN H Step 1-544a. The desired product was prepared from (S)-1 -(tert 15 butoxycarbonyl)pyrrolidine-2-carboxylic acid and 4-bromo-5-methoxybenzene- 1,2 diamine (prepared according to Journal ofMedicinal Chemistry 1997, 40, 730) using procedures similar procedures similar to that described in step 1-536a. ESIMS m/z = 414.10 [M+H]. Step 1-544b. The desired product was prepared from the compound from step 1 20 544a using procedures similar procedures similar to that described in step 1-lb. ESIMS m/z= 396.06 [M+H]*. Step 1-544c. The desired product was prepared from the compound from step 1 544b and the compound from step 1-1 -lb using procedures similar procedures similar to that described in step 1-1-1c. ESIMS m/z = 653.39 [M+H]*. 25 Step 1-544d. The desired product was prepared from the compound from step 1 544c using procedures similar procedures similar to that described in step 1-515f. ESIMS m/z= 453.27 [M+H]*. Step 1-544e. The title compound was prepared from the compound from step 1 544d and the compound from step 1-515g using procedures similar procedures 30 similar to that described in step 1-515h. ESIMS m/z= 767.47 [M+H]. PAGE 152 OF 222 WO 2010/099527 PCT/US2010/025741 Example 1-545.
NHCO
2 Me NN 0HM MeO 2 CHN (S)'. (P) Step 1-545a. The desired product was prepared from (1 S,2S,5R)-3-(tert butoxycarbonyl)-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid (prepared according 5 to J. Org. Chem, 1999, 64, 547) using procedures similar to that described in step 1 536a. ESIMS m/z = 396.25 [M+H]*. Step 1-545b. The desired product was prepared from the compound from step 1 545a using procedures similar to that described in step 1-lb. ESIMS m/z = 378.21 [M+H]*. 10 Step 1-545c. The desired product was prepared from the compound from step 1 545b and the compound from step 1-1-lb using procedures similar to that described in step 1-1-1c. ESIMS m/z = 635.33 [M+H]*. Step 1-545d. The desired product was prepared from the compound from step 1 545c using procedures similar to that described in step i f. ESIMS m/z = 435.28 15 [M+H]*. Step 1-545e. The title compound was prepared from the compound from step 1 545d and the compound from step 1-515g using procedures similar to that described in step 1-515h. ESIMS m/z = 749.44 [M+H]. Example 2-1. Boc HN 3 N__ 20 N Step 2-1a. A mixture of N-Boc-L-proline (2.289 g, 10.6 mmol) and 5-bromo-2,3 diamino-benzene (2.00 g, 10.6 mmol) in DMF (40 mL) were treated with EDC-HCl (2.651 g, 13.8 mmol) and DMAP (0.130 g, 1.06 mmol) at rt for 12 hours and then at 60 IC for another 12 hours. The resultant dark mixture was partitioned (EtOAc 25 water). The combined organics were washed with brine, dried over Na 2
SO
4 , filtered and evaporated to give the crude desired compound as a dark brown foam which was directed used in the next step. ESIMS m/z = 385.23, 387.23 [M+H]*. Step 2-1b. A solution of the crude compound from step 2-1a (theo. 10.6 mmol) in glacial acetic acid (100 mL) was heated at 50 'C for 24 hours. The volatiles were 30 evaporated and the resultant dark mixture was partitioned between EtOAc and PAGE 153 OF 222 WO 2010/099527 PCT/US2010/025741 saturated aqueous NaHCO 3 . The organics were washed with brine, dried over Na 2
SO
4 , filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (200 mg). ESIMS m/z= 267.07, 269.07 [M+H-Boc]*. 5 Step 2-1c. A mixture of the compound from step 2-lb (78 mg, 0.21mmol), 1,4 bis(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzene (33 mg, 0.10 mmol), Pd(PPh 3
)
4 (11.5 mg, 0.01 mmol), and NaHCO 3 (50.4 mg, 0.60 mmol) in 1,2 dimethoxyethane (1 mL) and water (0.5 mL) was heated at 90 *C for 6 hours under
N
2 before partition (EtOAc - water). The organics were washed with aqueous 10 NaHCO 3 , dried (Na 2
SO
4 ) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the title compound (8 mg). ESIMS m/z= 651.30 [M+H]*. Example 2-2. MeO 2 CHN P04'f HN N___' P , N Ph
NHCO
2 Me A solution of the compound from example 2-1 (8 mg, 0.012 mmol) in CH 2 Cl 2 (1 15 mL) was treated with hydrogen chloride (4M in dioxane, 5 mL) at rt for 40 minutes before all volatiles were removed by rotavap. The residue was redissolved in DMF (2 mL) and was added DIPEA (0.3 mL, 2.1 mmol), HATU (20 mg, 0.053 mmol) and (R)-(methoxycarbonyl)-aminophenyl acetic acid (prepared according to WO 2008/021927, 16 mg, 0.053 mmol). The resulting mixture was stirred at rt for 40 20 minutes before all volatiles was removed by N 2 flow. The residue was chromatographed (silica, CH 2
CI
2 -MeOH) to give the title compound (1.2 mg). ESIMS m/z = 833.38 [M+H]+. The remaining compounds of examples 2-3 to 2-508 may be prepared using procedures similar to that described in examples 2-1, 2-2, and 2-509 to 2-516, and/or 25 as described in the Synthetic Methods. Table 1Oa: Examples 2-3 to 2-219. R 0 N R Entry 2- R Entry 2- R Entry 2- R' t 1 0 3 N PAGE 154 OF 222 WO 2010/099527 PCT/US2010/025741 0 00 4 5 6 OH OH 7 8 9 10 11 12 N 0 OH 0 13 14 15 O 00 16 Ph-'j 17 Ph ---N 18 O 0 0 19 PhJj 20 Ph 21 Ph%..4 _____HOH ____ Me 6OH 22 23 24 6 H 0 0 25 0-A 26 27 28 O29 30 N 00 0 31 Bo N 32 BocN BocN H H 34 N O N H 37 N8 N9 O N 40 41 42 NlI OH 43 44 45 46 N 47 48 49 50 51 52 NfrAj 53 54 PAGE 155 OF 222 WO 2010/099527 PCT/US2010/025741 55 56 57 Ph OMe MO CF 3 Ph 58 59 60 Ph 61 62 -y1 63 N"04 0 0 64 NH 65 0 66 67 N 68 OYN 4I 69 70 71 72 H H 0 H 0 H 82 4eO N 71 4O N 4O N, 73 72 H H 0 0. 0 ii.yN 8889 8 82 92~j 8 93~ 0H Hj SH Oy N H O H N0 7,, 888 0 90 91 92 96 8 OH C02B 0 OyNH2 0____ 00 J 97 -*yNyJj 9 0 Ph C NHCO 2 Me PAGE 156 OF 222 WO 2010/099527 PCT/US2010/025741 100 NH1 Me 2 N NH 102 NNH .eNy NH M2 H%.NyN 0 0 0 103 0 J 104 MeO 2 C 105 0,Nyr.NH 'Boe 0 0 106 107 2Me 108 N Me 109 NN H' 2M0(p$NK02Me N ~~( 0 0 112 113 114 MeMeO 2 CHNO2 HNHNHC2 M a NN HN NN 115 .2G 116 2G 117
NHCO
2 Me NHCO 2 Me NHCO 2 Mo HO 4 118 0119 120 AO NH O yNH 0 NHC0 2 Me OBn Fmoc N 121 122 123 1 NHC0 2 Me NHC0 2 Me NHC0 2 Me 0 0 124 125 126 O 0~ N 0 0 127H 0 12 ..
0 3 NH 0 0 ANH 0 127 128 * 129 130 0131 0 1 0 NH 0 133 HN 134 HN 135 HN;NI AGEo 157OF22 PAGE 157 OF 222 WO 2010/099527 PCT/US2010/025741 MeO NH 0 MoO NH 0 O NH 0 136 137 138 139 NyJ. 140 N 141 N14 Ph Ph Ph 142 143 144 N i 7 47Ph 145 N146 FJ J14 F4 7 148 N 49 N 150 HO PhPh Ph HN O O" O O 151 , N 152 N 153 N PhPh Ph 154 BnO N O 155 156 F 3 CQNIAI
CF
3 ,N .N 157 N 158 159 N N 160 cjDe 161 162 l: N CI N N 163 164 165 F .N CI N N 166 167 168 F N F N 169 170 17N1 N 172 173 174 175 176 7 177 N 178 Ph ... e N.J 179 180 PAGE 158 OF 222 WO 2010/099527 PCT/US2010/025741 181 N182 183 00 184 185 186 187 - NA 1o 0 187 188 .. N188 189 'y fl~%i4. 0 190 191 -Y,192 ' . 0 ~ 00 193 N4 194 195 0 NHN 196 h NN! N NH 199 200 N 201 H 0 H H 0 N N NN0 202 203 N 24N 205 HN. 206 N : N20 20N )--N 210l H2N H 0 00 2 0 8 H 7 N N " -.
9 211 N212 213 Nr 214 F 215 216 F F1 H 217 218 219 __ __ __F F Table 11: Examples 2-220 to 2-229. MeO 2 CHN O HN N ''' -. N R-N NH O ,NHCO2Me RPAG 19 N 0 x ~R Ph PAGE 159 OF 222 WO 2010/099527 PCT/US2010/025741 Entry 2- R R' R" X Entry 2- R R' R" X 220 Me H H CH 2 221 H H H CF 2 222 Me H H S 223 H H H 224 Me H H 0 225 H H H F 226 H Ph H CH 2 227 H H H OH OH 228 H H Ph CH 2 229 H H H H
NHCO
2 Me NHCO 2 M. Me h Ph MN2C PhYPhNCI (V Compound 2-230 (R)Compound 2-231 (S Me2H Ph Me2CN N O P Compound 2-232 (R) Compound 2-233 5 Table 12: Examples 2-234 to 2-243. MCNPh N4 HC0M NH NHCO 2 Me R R" Ph Entry 2- R R' R" Entry 2- RR' " 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Et Me H 242 Me CHMe 2 H 243 Me Et H Table 13: Examples 2-244 to 2-263. f N NN R N 0 Entry 2- R R' Entry 2- R R ' 244 MeO 2 CHN MeO 2 CHN 245 44lPh Ph 245 P PAGE 160 OF 222 WO 2010/099527 PCT/US2010/025741 246 M.O2CHNA 247 MeOCHNIN Ph Phh 248 MeO 2 CHN, M.zCHN 249 MeO 2 CHN MeCH Ph Ph H Me 2
CHN.
9 4 100 Y NI 4 250 oyN 251 Me CH O N ___ __ _O Ph p____ ______ 0 hPh 0 254 2 CHN, MeO 2 CHN MeO 2 CHN C 254 255 OCI N N n- O Ph MeO 2 CHNA MG 2 CHNA 257 H H 256 257 C N N,,y r 2 Ph O Me 2 CHNA Ma 2 CHN NN 258 259 Y MeO 2 CHN Me 2 CHN.. Me 2 CHN., MeO 2 CHNA 260 261 MOCHNA Me 2 CHNA H 262 MeOzCHN263 N N 2O63 Table 14: Examples 2-264 to 2-273. Ph R R Me02CHN HNv--H Ph N 0 R' R"'
NHCO
2 Me Entry 2- R R' R" R'" Entry 2- R R' R" R"' 264 F H H H 265 F F H H 266 Me H H H 267 Me Me H H 268 H H Me Me 269 H H Et Et 270 CF 3 H H H 271 CF 3 H CF 3 H 272 Cl H H H 273 Cl H Cl H 5 Table 15: Examples 2-274 to 2-291. M0 2 CHN-- 'N/ MeN 2CHNhNHCOzMe Entry 2- R R' R" Entry 2- R R' R" 274 Me H H 275 H CO 2 H H 276 H F H 277 H H CO 2 H 278 H H F 279 H CO 2 Me H PAGE 161 OF 222 WO 2010/099527 PCT/US2010/025741 280 H Cl H 281 H H CO 2 Me 282 H H Cl 283 H CONH 2 H 284 H Me H 285 H H CONH 2 286 H H Me 287 H OMe H 288 H CF 3 H 289 H H OMe 290 H H CF 3 291 CO 2 Me H H Table 16: Examples 2-292 to 2-426. Ph MooCHN HN A N__ NW,,11-31a-C (Si N N NH 0,, NHC0 2 Me Ph Entry Aa Entry Aa Entry Aa 2- 2- 2 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 N 308 "N N--Y 309 310 " 311 / THO.. -- Ak 312 0__0 0 313 314 315 00 0 316 /o 317 318 319 320 /No 321 322 323 vo o 324 325 v-NH 326 S-NH 327 1-0 I-NH i0 328 1---DN 329 -N N-</ 330 331 1-0-O - 332 333 N 334 N 335 / N 336 337 /-N 338 339 PAGE 162 OF 222 WO 2010/099527 PCT/US2010/025741 340 0 341 342 343 ' N344 345 346 -N 347 348 N N 349 350 351 352 >354 HN o-i HNA HN 355 356 357 HN 358 S-NH 359 0N I-H -' -"'a 361 Y, 362 363 364 O o 365 366 N N 367 0 368 O N 369 O a 370 0 371 7N2 - 372O 373 374 N 375 N N 376 o- * 377 0 378 379 |-N 380 381 382 - 383 384 HN HN HN-1 385 386 387 N O 388 - 389 390 -N 391 I 392 393 394 N 395 .4 396 N 397 _N98 N 399 PAGE 163 OF 222 WO 2010/099527 PCT/US2010/025741 400 401 402 N N N 403 404 405 406 N- 407 408 N N 409 0 N /'N- 410 411 Nx 412 413 -O/"c N./ 414 415 o -(N-(} 416 417 N N H '-N N 0 418 419 420 421 422 o 423 424 0 0 425 N 426 Table 17: Examples 2-427 to 2-477. Me 2 CHN f HN ,a._ N N NH NHCO 2 Me Entry 2- Aa Entry 2- Aa Entry 2- Aa 427 428 429 430 431 32 432 433 434 435 436 437 438 439 440 441 442 443 444 PAGE 164 OF 222 WO 2010/099527 PCT/US2010/025741 445 446 447 448 7 449 450 451 452 453 454 455 456 Nl; NH 457 458 459 460 461 N462 463 464 465 466 -N 467 - 468 469 -- 0 470 -N 71 -N N 0 472 - 473 -N 74 475 |-N 476 -N77 Table 18: Examples 2-478 to 2-497. MeO2CHN N N O NHCO2Me Ph Entry Bb Entry Bb Entry Bb 2- 2- 2 478 479 /-N, 480 N-NH N-N 481 482 1-()A 483 'r /N TN 484 485 }-4 486 487 48 I 489 0 490 491 492 493 494 /, 495) PAGE 165 OF 222 WO 2010/099527 PCT/US2010/025741 496 497 Table 19: Examples 2-498 to 2-508. Ph MeO2CHN O N NHCO2Me Entry G Entry G Entry G 2- 2- 2 498 499 500 >- 501 N502 50 504 505 H 506 507 508 5 Example 2-509. Step 2-509a. A mixture of N-Boc-L-proline (0.229 g, 1.06 mmol) and TEA (0.15 mL, 1.06 mmol) in THF (10 mL) at -20 0 C was treated with iso-butyl chloroformate (0.14 mL, 1.06 mmol) for 30 minutes before a slow addition of 6-bromopyridine 10 2,3-diamine (prepared according to WO 2004/002986 and WO 2008/021851, 0.200 g, 1.06 mmol) in THIF (2 mL). It was then kept at -20 0 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
SO
4 ), filtered and evaporated to give the crude desired compound as a 15 very light brown solid (0.430 g). ESIMS mz/z = 385.17, 387.17 [M+IH]+. Step 2-509b. A solution of the crude compound from step 2-509a (1.06 mmol at most) in glacial acetic acid (12 mL) was heated at 80 0 C for 3 days. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organic were washed with brine, dried (Na 2
SO
4 ), filtered and 20 evaporated. The residue was purified by flash column chromatography (silica, PAGE 166 OF 222 WO 2010/099527 PCT/US2010/025741 hexanes-ethyl acetate) to give the desired compound as a light yellow solid (0.161 g, 2 steps 41%). ESIMS n/z = 367.21, 369.21 [M+H]+. Step 2-509c. A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol), N-Boc L-proline (3.87 g, 18.0 mmol) and in CH 3 CN (60 mL) was treated with TEA (5.40 5 mL, 37.8 mmol) 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
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as alight yellow foam (6.73 g, 91%). 'HNMR (CDC 3 ) 7.76 (t, J 10 = 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, IH), 1.46, 1.43 (2s, 9H). Step 2-509d. A solution of the compound from step 2-509c (6.73 g, 16.3 mmol) in toluene (100 mL) was treated with ammonium acetate (25.1 g, 0.327 mol) at 100 *C 15 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%). ESIMS n/z = 392.24, 394.24 [M+H]*. 'H NMR (CDC 3 ) 7.57 (bs, 1H), 7.48 (m, 3H), 7.23 (s, 20 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 2-509e. A mixture of the compound from step 2-509d (0.559 g, 1.425 mmol), trimethyl-silylacetylene (0.60 ml, 4.275 mmol), CuI (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 heated at 80 C underN2 25 for 6 hours 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 (0.484 g, 83%). ESIMS n/z = 410.24 [M+H]*. Step 2-509f. A suspension of the compound from step 2-509e (0.484 g, 1. 182 mmol) and K 2 C0 3 (0.408 g, 2.954 mmol) in methanol (12 ml) was stirred at rt for 3 30 hour. The volatiles were evaporated off. The residue was purified by chromatography (silica, dichloromethane-ethyl acetate) to give the desired compound as a yellow foam (0.370 g, 93%). ESIMS rn/z = 338.24 [M+H]*. Step 2-509g. A mixture of the compound from step 2-509b (23.0 mg, 62.6 pmol), the compound from step 2-509f (23.2 mg, 68.8 pmol), Cul (0.3 mg, 1.8 pmol) and PAGE 167 OF 222 WO 2010/099527 PCT/US2010/025741 Pd(PPh 3
)
4 (3.6 mg, 3.1 smol) in triethylamine (3 mL) and CH 3 CN (3 mL) was degassed and heated to 95 C under N 2 for 2 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by flash 5 column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (24.2 mg, 62%). ESIMS m/z= 624.48 [M+H]. Example 2-510. M2NH C
NHC
2 Me Step 2-510a. A solution of the compound of Example 2-509 (38.0 mg, 60.9 smol) 10 in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt 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 = 424.33 [M+H]*. Step 2-510b. A mixture of the crude compound from step 2-510a (60.9 smol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared 15 according to WO 2008/021927, 22.4 mg, 0.129 mmol) in DMF (3 mL) was treated with HATU (46.3 mg, 0.122 mmol) in the presence of DIPEA (0.15 mL, 1.22 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH 2
CI
2 -MeOH) to give the title compound as a light yellow solid (30.4 mg, 2 steps 68%). ESIMS m/z= 738.54 20 [M+H]*. Example 2-511. Step 2-51 1a. 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 25 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 CI. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 30 96%). PAGE 168 OF 222 WO 2010/099527 PCT/US2010/025741 Step 2-511b. The compound from step 2-51 la (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 NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered 5 and evaporated to give the crude desired compound as a light yellow solid (3.898 g). Step 2-511c. A mixture of the compound from step 2-51 lb (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 10 partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a yellow-white foam (4.762 g). ESIMS n/z = 462.03, 464.02 [M+H]*. Step 2-511d. A solution of the compound from step 2-511 c (at most 11.6 imol) in toluene (60 mL) was added ammonium acetate (13.4 g, 0.174 mol) and the resultant 15 mixture was heated up at 100 'C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
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 powder (3.14 g, 4 steps, 61%). ESIMS n/z= 442.02, 444.02 20 [M+H]-. Step 2-511e. A mixture of the compound from step 2-511d (0.200 g, 0.452 mmol), bis(pinacolato)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 25 allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na 2
SO
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 n/z= 490.12 [M+H]*. Step 2-511f. A mixture of the compound from step 2-509b (30.0 mg, 81.7 Imol), 30 the compound from step 2-511 e (43.9 mg, 89.8 Imol), Pd(PPh 3
)
4 , (4.6 mg, 4.0 gmol) and NaHCO 3 (27.5 mg, 0.327 mmol) in DME (6 mL) and H 2 0 (2 mL) was degassed and heated at 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
SO
4 ), filtered and evaporated. The residue was purified by PAGE 169 OF 222 WO 2010/099527 PCT/US2010/025741 chromatography (silica, hexanes-ethyl acetate) to give the title compound as a white solid (36.6 mg, 69%). ESIMS n/z = 650.45 [M+H]*. Example 2-512. Me0zCHM NHCO2Me 5 The title compound was synthesized from the compound from Example 2-511 using procedures similar to that described in Example 2-510. ESIMS n/z = 764.67 [M+H]'. Example 2-513. NO 10 Step 2-513a. A mixture of N-Boc-L-proline (0.450 g, 2.09 mmol) and TEA (0.29 mL, 2.09 mmol) in THF (20 mL) at -20 'C was treated with iso-butyl chloroformate (0.27 mL, 2.09 mmol) for 30 minutes before a slow addition of 6-chloro-3,4 pyridinediamine (0.300 g, 2.09 mmol) in THF (6 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 15 were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a yellow brown foam (0.658 g, 93%). ESIMS n/z= 341.21, 343.21 [M+H]. Step 2-513b. A solution of the crude compound from step 2-513a (0.658 g, 1.93 20 mmol) in glacial acetic acid (12 mL) was heated at 120 0 C for 24 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated to give the crude desired compound as a light yellow oil which was directly used in the next step. ESIMS n/z = 265.16 [M+H]*. 25 Step 2-513c. The crude compound from step 2-513b (1.93 mmol at most) in aqueous 2N HCI (20 mL) was heated at 100 *C for 2 hours before being evaporated to dryness. The residue was co-evaporated with methanol twice and then CH 2
CI
2 twice to give the crude desired compound as a light yellow oil which was directly used in the next step. ESIMS n/z = 223.12 [M+H]+. PAGE 170 OF 222 WO 2010/099527 PCT/US2010/025741 Step 2-513d. The crude compound from step 2-513c (1.93 mmol at most) in
CH
2 Cl 2 (16 mL) was treated with triethyl amine (2.70 mL, 19.3 mmol), di-tert-butyl dicarbonate (1.09 g, 5.02 nmol) and DMAP (23.6 mg, 0. 193 mmol) for 14 hours before being evaporated to dryness. The residue was purified by flash column 5 chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (0.510 g, 3 steps 63%). ESIMS n/z= 423.24 [M+H]+. Step 2-513e. A mixture of the compound from step 2-513d (94.0 mg, 0.222 mmol), the compound from step 2-51 le (0.119 g, 0.245 mmol), Pd(PPh) 4 , (25.7 mg, 22.2 Amol) and NaHCO 3 (74.7 mg, 0.889 mmol) in DME (6 mL) and H20 (2 mL) was 10 degassed and heated at 95 'C under N 2 for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H20). The organics were washed with brine, dried (Na 2
SO
4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a brown solid (52.1 mg, 36%). ESIMS n/z= 650.40 [M+H]*. 15 Example 2-514. MeO2CHi
NHC
2 Me The title compound was synthesized from the compound from Example 2-513 using procedures similar to that described in Example 2-5 10. ESIMS n/z= 764.57 [M+H]+. 20 Example 2-515. N N S N O NH Step 2-515a. A mixture of 4-bromo-2-iodoaniline (0.839 g, 2.817 mmol), tert-butyl (2S)-2-ethynylpyrrolidine-1-carboxylate (0.500 g, 2.561 mmol), Cul (14.6 mg, 0.0768 mmol) and Pd(PPh 3
)
2 Cl 2 (90.0 mg, 0.128 mmol) in Et 3 N (15 mL) was 25 degassed and stirred at rt under N 2 for 3.5 hours 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 light brown foam (0.741 g, 79%). ESIMS n/z = 365.09, 367.09 [M+H]*. Step 2-515b. A mixture of the compound from step 2-515a (0.621 g, 1.700 mmol) 30 and Cu(OAc) 2 (61.8 mg, 0.340 mmol) in 1,2-dichloroethane (10 ml) was heated at PAGE 171 OF 222 WO 2010/099527 PCT/US2010/025741 150 "C with a microwave for 30 minutes. The mixtrue was combined with another batch (0.120 g of the compound from step la) and directly purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a yellow foam (0.625 g, 84%). ESIMS n/z = 365.09, 5 367.09 [M+H]*. Step 2-515c. A mixture of the compound from step 2-515b (60.0 mg, 0.164 mmol), the compound from step 2-509f (61.0 mg, 0.181 mmol), CuI (1.6 mg, 8.21 gmol) and Pd(PPh 3
)
2
C
2 (11.5 mg, 0.0164 mmol) in Et 3 N (3 mL) was degassed and heated at 85 *C under N 2 overnight before being evaporated. The residue was purified by 10 chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the title compound as a yellow solid (5.5 mg, 5.4%). ESIMS n/z= 622.17 [M+H]'. Example 2-516. MeO2CHN
NHCO
2 Me Step 2-516a. A solution of the compound of example 2-515 (5.5 mg, 8.46 gmol) in 15 1,4-dioxane (0.5 mL) was treated with HCl in 1,4-dioxane (4 M, 2 mL) at rt 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 2-516b. A mixture of the crude compound from step 2-516a (8.46 gmol at most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to 20 WO 2008/021927, 4.6 mg, 0.0221 mmol) in DMF (0.5 mL) was treated with HATU (7.7 mg, 0.0204 mmol) in the presence of DIPEA (0.03 mL, 0.177 mmol) for 2 hours at rt and the volatiles were evaporated off. It was purified by chromatography (silica, CH 2 Cl 2 -MeOH) to give the title compound as a yellow solid (2.6 mg, 2 steps 37%). ESIMS m/z= 804.10 [M+H]*. 25 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. 30 The HCV replicon has the nucleic acid sequence set forth in EMBL Accession No.: AJ24265 1, the coding sequence of which is from nucleotides 1801 to 8406. PAGE 172 OF 222 WO 2010/099527 PCT/US2010/025741 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 5 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 10 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, T12801, KI 846T) and the HCV 15 3'
U
TR. 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 1OX penicillin/streptomycin (Cat# 15140-122, Invitrogen) and 20 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
EC
50 values of single agent compounds and combinations were determined by HCV RNA detection using quantitative RT-PCR, according to the manufacturer's 25 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 is detected and quantified using the Human GAPDH 30 Endogenous Control Mix (Applied Biosystems, AB 4310884E). Total cellular RNA is purified from 96-well plates using the RNAqueous 96 kit (Ambion, Cat# AM1812). Chemical agent cytotoxicity is evaluated using an MTS assay according to the manufacturer's directions (Promega). 3. HCV Replicon Assay - Luciferase PAGE 173 OF 222 WO 2010/099527 PCT/US2010/025741 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 used the HCV replicon system to assess the potential use of the compound of the present invention or in 5 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 10 (without phenol red, Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non essential amino acids, 1% of Glutamax and 1% of 1 00X penicillin/streptomycin and incubated overnight at 37'C, 5% CO 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 15 phenol red, Invitrogen Cat.# 31053-036) with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 1 OOX 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 20 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 25 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. 30 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, compounds of the present invention are active against the la, lb, 2a, 2b, 3a, 4a, and 5a genotypes. Table 22 shows the EC 50 values of representative compounds of the present PAGE 174 OF 222 WO 2010/099527 PCT/US2010/025741 invention against the HCV lb genotype from the above described qRT-PCR or luciferase assay. EC 5 0 ranges against HCV lb are as follows: A >10 nM; B 1-10 nM; C<lnM. Table 22: Genotype-lb replicon EC 0 Example Range Example Range Example Range 1-2 C 1-2-1 C 1-2-2 C 1-357 C 1-442 C 1-443 C 1-445 C 1-446 C 1-448 C 1-449 C 1-451 C 1-453 C 1-454 C 1-456 C 1-457 C 1-459 C 1-460 C 1-463 C 1-464 C 1-465 C 1-466 C 1-468 C 1-469 C 1-471 C 1-472 C 1-473 C 1-475 C 1-477 C 1-479 C 1-480 C 1-481 C 1-483 C 1-485 C 1-486 C 1-488 C 1-490 C 1-492 C 1-493 C 1-494 C 1-497-a C 1-497-b C 1-499 C 1-500 B 1-501 C 1-502 C 1-503 C 1-504 C 1-505 C 1-506 C 1-507 C 1-508 C 1-509 C 1-510 C 1-511 C 1-512 C 1-513 C 1-514 C 1-515 C 1-517 C 1-519 C 1-521 C 1-523 C 1-525 C 1-526 C 1-527 C 1-528 C 1-529 C 1-530 C 1-531 C 1-532 C 1-533 C 1-534 C 1-535 C 1-536 C 1-537 C 1-538 C 1-539 C 1-540 C 1-541 C 1-542 C 2-2 C 2-510 C 2-512 C 2-516 C PAGE 175 OF 222

权利要求:
Claims (61)
[1] 1. A compound represented by Formula (1-I): (RI). D-A-T-E-Z &J 5 or a pharmaceutically acceptable salt thereof, wherein: D and Z are are each independently absent or optionally substituted linear aliphatic group comprising zero to eight carbons; A and E are are each independently absent or a cyclic group; wherein said each cyclic group is independently selected from the group consisting of aryl, 10 heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; T is absent or an optionally substituted aliphatic group; Wherein one to four of A, D, E, T and Z is absent; Ring B is a five-membered heteroaryl, wherein said heteroaryl is optionally 15 substituted; R1 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O-R 1 , -NRaR, -C(O)R 11 , -CO 2 R 1 , and -C(O)NRaRb; R" at each occurrence is independently hydrogen or optionally substituted 20 C 1 -C 8 alkyl; Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted CI-C 8 alkyl, and optionally substituted C 2 -C 8 alkenyl; or Ra and Rb can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally 25 substituted heteroaryl group; u is independently 1, 2, or 3; Q and J are each independently selected from: RR') ' R r 4 R i R6 ,and R ; PAGE 176 OF 222 WO 2010/099527 PCT/US2010/025741 R 3 and R 4 at each occurrence 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; or alternatively, R3 and R 4 can be taken together with the carbon atom to which they are attached to form 5 optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic; R5 at each occurrence is independently hydrogen, optionally substituted Ci C 8 alkyl, or optionally substituted C 3 -C 8 cycloalkyl; R is selected from the group consisting of -C(O)-R , -C(O)-C(O)-R, -S(O) 2 -R1 2 , and -C(S)-R' 2 ; 10 R at each occurrence is independently selected from the group consisting of -O-R", -NRaR , -R , and -NR'Rd; wherein R at each occurrence is independently selected from the group consisting of: hydrogen, C1-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; and 15 R' and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R1 3 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(0) 2 N(R 13 ) 2 ; m is 0, 1, or 2; n is 1, 2, 3, or 4; 20 X at each occurrence is independently selected from 0, S, S(O), SO 2 , and C(R 7 ) 2 ; provided that when m is 0, X is C(R 7 ) 2 ; and R7 at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, -O-R 11 , -NRaR, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C 1 -C 4 alkyl; or two vicinal R7 25 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring; or alternatively two geminal RC groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring. 30 PAGE 177 OF 222 WO 2010/099527 PCT/US2010/025741
[2] 2. The compound of claim 1, wherein Q and J are each independently selected from: o' 'R"2, and o'R"12; wherein X is independently CH 2 , CF2, CHF, or CH(OH); or a pharmaceutically acceptable salt thereof 5
[3] 3. The compound of claim 1, wherein Ring B is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B is C-attached to J and C-attached to one of Z, E, T, A and D; or a pharmaceutically acceptable salt. 10
[4] 4. The compound of claim 1, wherein Q and J are each independently O- R"; R' is each independently hydrogen; Ring B is selected from imidazolyl, pyrazolyl, 1,3,4-triazolyl, and 1,3,4-oxadiazolyl; and Ring B is C-attached to J and C-attached to one of Z, E, T, A and D; or a pharmaceutically acceptable salt thereof. 15
[5] 5. The compound of claim 1, wherein each of D, A, E, and Z are absent and T is present; or a pharmaceutically acceptable salt thereof.
[6] 6. The compound of claim 1, wherein each of D, E, T, and Z are absent, and A is present; or a pharmaceutically acceptable salt thereof. 20
[7] 7. The compound of claim 1, wherein each of D, E, and Z are absent and each of A and T are present; or a pharmaceutically acceptable salt thereof.
[8] 8. The compound of claim 1, wherein each of D, A, and Z are absent and each 25 of T and E are present; or a pharmaceutically acceptable salt thereof.
[9] 9. The compound of claim 1, wherein each of D, T, and Z are absent and A and E are each present; or a pharmaceutically acceptable salt thereof. 30
[10] 10. The compound of claim 1, wherein each of E and Z are absent and D, A, and T are each present; or a pharmaceutically acceptable salt thereof. PAGE 178 OF 222 WO 2010/099527 PCT/US2010/025741
[11] 11. The compound of claim 1, wherein each of D and A are absent and T, E, and Z are present or a pharmaceutically acceptable salt thereof. 5
[12] 12. The compound of claim 1, wherein each of D and Z are absent and A, T, and E are present; or a pharmaceutically acceptable salt thereof.
[13] 13. The compound of claim 1, wherein D is absent and A, T, E, and Z are are each present; or a pharmaceutically acceptable salt thereof. 10
[14] 14. The compound of claim 1, wherein Z is absent and D, A, T, and E are each present; or a pharmaceutically acceptable salt thereof.
[15] 15. The compound of claim 1, wherein each of D, A, E, and Z are absent and T 15 is an aliphatic group comprising one or more of an olefinic double bond, an alkynic triple bond, 0, N(R 1 ), C(O), S(0) 2 , C(O)O, C(O)N(R'"), OC(O)O, OC(O)N(R 1 ), S(0) 2 N(R"), N(R' 1 )C(O)N(R1), N(R")C(O)N(R"), N(R")S(O) 2 N(R), C(O)N(Ru 1 )S(O) 2 and C(O)N(R 1 u)S(O) 2 N(R 11 ); or a pharmaceutically acceptable salt thereof. 20
[16] 16. The compound according to claim 1 selected from the group of compounds 1-1-1, 1-2-1, 1-2-2, and 1-1 to 1-440 shown below, or a pharmaceutically acceptable salt thereof: 'Nj compound 1-1-1 MeO2CHN compound 1-2-1 NHCO 2 Me PhPN MeO2CN 0N O NHC 2 Me compound 1-2-2 25 PAGE 179 OF 222 WO 2010/099527 PCT/US2010/025741 Compounds 1-1 to 1-219. R Entry 1- R Entry 1- R Entry 1- RA 0 H 0 1 0 1 oo 0 N r2 3 Ny)i 00 Ph0 4 5 6 OH OH 0o 0 7 o-J,, 8 Y4. 9 --A 10 11 )lJk 12 N 0 OH 0 o 0 0 13 14 15 16 Ph-A 17 Ph 18 0 0 0 19 Ph 20 PhAU 21 Ph -A H me OH 22 23 24 Ph- Ui O O OH 0 0 0 25 26 27 0 28 29 30 r 0 31 Boc N 32 Boc()JI N3 Bo NO H H 34 N35 36 IN A 37 3 8 N7L N9 0 0 40 9 -41 42 N N N N H PAGE 180 OF 222 WO 2010/099527 PCT/US2010/025741 43 N .44 45 4 4 N N S50 52 N 5 N54 ~ J~ ,-H0 9 55 P)J 56 574.48L< OMG MeO CF 3 Ph 58 'Z1N(Ji59 60O 61 *62 * -- 634 64 65 YNH66 67 - ~ 68 69 70 71 A NI 72 iji 0 7 75 O H 0 H 76 * N 1 77 N78O N 79 80 81 OHC0 2 Bn CONH 2 0 82 83 84-'NYN e^ - 0, 8586 87..~N NH ~O NHON 0 0 88 89 90 6- N3kt 0~ 0 0~ NOTBS OTBS PAGE 181 OF 222 WO 2010/099527 PCT/US2010/025741 91 92 93 0yNH Oy NH 94 - N 95 oyN 96 A rN 97 /oyNy j 98 99 O Ph CI NHCO 2 Me 100 101 102 H N NH Me 2 N NH .- N yNH 103 H 104 MC 105 N N I NH Boc l 106 Me 107 2 108 N ' 2 Me 109 Me 110 N 1 NH 1NH NHCO 2 Me NHCO2Me 112 0 113 114 MeO2CHN MeO2C HNNHCOOMe N=N 115 116 117 NHCO2Me NHCO 2 Me NHCMe Meo ~O O O 118 119 120 o NH O NH 0 0 NHCOMe OBn Fmoc N 121 122 123 K NHC02Me NHCO 2 Me NHCO Me 0 H H HIL 124 125 126 O 127 NH 0 X 0 dNH 0 NOA 1 NH 0 127 128 129 PAGE 182 OF 222 WO 2010/099527 PCT/US2010/025741 0 130 131 132 HN HN 135 H MeO H O MeO NH 0 ~O NH 0 136 137 138 139 N 140 1 41 NN O 142 143 N 144 145 146 147 F 148 N 149 HON 1 HO PhP 151 0-N 152 Ny 153 N0 154 Nn~~J) 155 156 FC~yi CFA N N 160 Ci)Jyj 161 162 c N4CI ON __1___N __7_N_ 163 164 165 F .N CI N N 166 N167 I~ltTu, 168 F F NF N NN 172 173 174 N N N PAGE 183 OF 222 WO 2010/099527 PCT/US2010/025741 175 176 177 N 178 Ph 179- 180 N 0 PhN N N 181 182 183 18N8 18 0 N 1874 ~ r' 188 186 190 191 192 199 200N N2 1 H 193 194 195 a0 2059 H 200 N N, H O 202 HN N -oN 20 HH 208 F 2015jf~ 210 0 0 211 212 213 H2N 214 HN)% 215 N Y 216 N a HF F 217 218 18 OF 219 21PAG 18 21F 22221 WO 2010/099527 PCT/US2010/025741 Compounds 1-220 to 1-229. O$R. 07f NHCO 2 Me Entry 1- R R' R" X Entry 1- R R' R" X 220 Me H H CH 2 221 H H H CF 2 HH2 222 Me H H S 223 H H H F 224 Me H H O 225 H H H ;:H H 226 H Ph H CH 2 227 H H H OH 0H 228 H H Ph CH2 229 H H H H NHCO 2 Me NH CO 2 M' Ph A- /, N~Ph Compound 1-230 ()Compound 1-231 (s) H Ph O 2 Ph Me 2 C HNW J%)/%_ NN N, MeAH R Compound 1-232 Compound 1-233 5 Compounds 1-234 to 1-243. MeOCHNO hNHCO2Me Entry R R' R" Entry RR' " 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Et Me H 242 Me CHMe 2 H 243 Me Et H PAGE 185 OF 222 WO 2010/099527 PCT/US2010/025741 Compounds 1-244 to 1-263. 0O N: R' Entry 1- R R' Entry 1- R R' MeO2CHN MeO 2 CHN 245 Ph Ph Ph 246 MeO2CHN MO 2 CHN..X 248 N O2HNT 2497 e 2 Hy Ph PhP 248 MeO2CHN H MO 2 CHN MeO2CHN Ph Ph 2 5 0_ _ _ 0 NP21he O C H 252 N253 N Oy. MeO 2 CHN MO 2 CHN 24 MeO 2 CHN~ 5 OH~ H______ 256 4 -CNy 255 CC1 HN 0_ _ _ _0 P Ph N MeH 2 CHN H H H 258 259 ON N N 20 MeO 2 CHN~ MeO 2 CHN 21 MeO 2 CHNA MeO 2 CHN 260~r 2613 0Me MeO 2 CHN Me 2 CHN 2MeO 2 CHN A 263 N Compounds 1-264 to 1-273. R R' Me 2 CH NfjA H R"NN N 5 M Ph Entry 1- R R' R" R"' Entry 1-- R R' R" R"' 264 F H H H 265 F F H H 266 Me H H H 267 Me Me H H 268 H H MeMe 269 H H Et Et 270 CF 3 H H H 271 CF 3 H CF 3 H 272 C H H H 273 C1 H C1 H PAGE 186 OF 222 WO 2010/099527 PCTIUS2010/025741 Compounds 1-274 to 1-299. R' R" R M2CPhORN Me2HN-- ORR/ MGO 2 CHN Ph Entry 1- R R' R" R" Entry I- R R' R" R'" 274 Me H H H 275 H CO 2 H H H 276 H F H H 277 H H CO 2 H H 278 H H F H 279 H H H CO 2 H 280 H H H F 281 H CO 2 Me H H 282 H Cl H H 283 H H CO 2 Me H 284 H H Cl H 285 H H H CO 2 Me 286 H H H Cl 287 H CONH 2 H H 288 H Me H H 289 H H CONH 2 H 290 H H Me H 291 H H H CONH 2 292 H H H Me 293 H OMe H H 294 H CF 3 H H 295 H H OMe H 296 H H CF 3 H 297 H H H OMe 298 H H H CF 3 299 CO 2 Me H H H 5 Compounds 1-300 to 1-434. PhN MeO 2 CHN HA MeO 2 CHN Ph Entry Aa Entry Aa Entry Aa 1- 1- 1 300 301 302 303 304 305 306 307 308 N 309 310 311 312 313 314 315 316 N N 317 N N PAGE 187 OF 222 WO 2010/099527 PCT/US2010/025741 318 319 320 321 322 323 324 /o, 325 326 327 /vou-kA 328 /,o 329 330 v o 331 * 332 0 o y 0 0 H 333 YNH 334 0 '9-NH 335 [a0 I-NH 10 336 N 337 - N- 338 339 _ 340 341 N 342 N 343 /-N' 344 N 345 N346 N347 348 349 t-N O- 350 351 352 353 0I 0-N 354 -N 355 356 -N DN4 357 358 359 HN- HN 360 361 362 HN 363 Po( 364 365 HN 0 /A HN 366 s-N I67 368 0-1 I-NH A__0___ 369 /oN%%^/ 370 371 372 iy* <,k 4 .J 373 374 N N 375 o 376 N 377 378 0 379 0N -cf 380 381 - */ 382 N 383N N 384 o-v v/ 385 v7o-- %oy 386 oA 387 [-N i 388 389 PAGE 188 OF 222 WO 2010/099527 PCT/US2010/025741 390 - 391 o 392 HNA HN- HN-1 393 394 o 395 ~ o 396 397 - 398 399 400 401 402 403 N 405 _N 46N -y 407 408 409 410 N N 411 412 413N 414 415 416 N N 417 jN N419 420 % o 421 N 422 N 423 'o CN-&I 424 425 NCN - 427 FN N 428 N 429 430 -O- oA 431 N 432 0 O 433 N 434 PAGE 189 OF 222 WO 2010/099527 PCT/US2010/025741 Compounds 1-435 to 1-440. Ph N Od>PB MO 2 CHN Entry Bb Entry Bb Entry Bb 1- 1- 1 435 436 /- y) 437 N-NH N-N N-N 438 439 440
[17] 17. A compound of claim 1, represented by Formula (1-II), or a 5 pharmaceutically acceptable salt thereof: R a o H T - E R7 7) H N~ N R( (R()
[18] 18. A compound of claim 17, wherein m is 1; n is 1 or 2; u is 1 or 2; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally 10 substituted; T is absent or optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; R 1 at each occurrence is independently hydrogen or halogen; X at each occurrence is each independently CH2, CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R7 groups are taken together with the carbon to which 15 they are attached to form a spiro, optionally substituted C 3 -C 8 cycloalkyl; or yet alternatively, two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted C 1 -C 8 alkyl; or a pharmaceutically acceptable salt thereof. 20
[19] 19. A compound of claim 1, represented by one of Formulae (1-III-a) to (1-III d): PAGE 190 OF 222 WO 2010/099527 PCT/US2010/025741 (R-Iln-a R R2 O1N (R R O (R(R) (R 7 ); w X x R 12.f HN NH0 R 12 R2 o HN // NH 0 12 CHe C 2 o (R 7 );whri Ri atecRcurnc sidpnenl yrgno methyl; alternatively, two geminal R 7 groups are taken together with the carbon to 5 which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal Ri groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R' 2 at each occurrence is independently C 1 -Cs alkyl optionally sub stituited with amino, hydroxy, protected amino, or O(C 1 -C 4 alkyl); or a pharmaceutically acceptable salt thereof. 10
[20] 20. The compound of claim 1, wherein AwL is selected from the group listed below, or a pharmaceutically acceptable salt thereof: F MMOH -, x n 15
[21] 21. A compound according to claim 1 selected from the group of compounds 1 441 to 1-545 shown below, or a pharmaceutically acceptable salt thereof: PAGE 191 OF 222 WO 2010/099527 PCT/US2010/025741 1-441 1-4424P - NMPH Ph N 1-442 Me2HPNN Ph 1-444 2CH NHCO2Me 1-445 7 Phh N4rN CO2MeNandor 1-448 H N MeO 2 C CHO 2 MeN 1-449 P N MeMe0 2 C(s) 1-450 1-451 N 1-452 B BN N PAGE 192 OF 222 WO 2010/099527 PCTIUS2010/025741 1-453N )H S M J NIIC 2 Me NHC0 2 MO 1-454 N IHC0 2 Me NH-C0 2 Me NN andlor 1-455 r-o.Oo C HNNH an0 o N N N H NH 146NHCO 2 Me NHCO 2 MO NHC 2 Me NHC 2 Me 1-4587 'Co2M( AHCO 2 Me S) 0 ~ HN 1-469 Meo 2 CHN' ~) MeO2C HMeO 1-461 H-462EHCO2.. 0 S 1-464 W42C.N r~~COM NHC2M 1-PAGE 193 OF 2223 WO 2010/099527 PCTJUS2O1O/025741 OH 1-465 MeO2CH Y 0 N.C2. M 0 MeO 1-46 ~(HN QQNf>) [468 ~~~MeOCH/ H Q( 5 r CO M 1-466N ~N 'NH ,3,NC 2 Me 1-46 N~t 4 ~..0 S) 1-47N O 1-471 <oCHN~ 'H NHMe 0 N) MeO 2 CHNT N/ 1-472 ~ H NHCOMe 0 1, N' 0 (s 1-7 (OfOHN N 1 1-4705 MeO 2 CHN N~.'~r'. ~HOM 1-478 PN ,NC2 1-479 ," PAGE194 F 22 WO 20 10/099527 PCTUS2O1O/025741 1-480 W) 4 o HNN HCO2Me 0 N H-8 N NHC02MG 1-482 I 1-484 0 H-4 Il)o NN ac 0 Is deMtiN 1-488 M02'.~'H-4 H0M A h 0 sduti 1-484 NH V-490 N 1-48591N;4 1-486NI92NH0M PAGE195 F 22 WO 2010/099527 PCT/US2010/025741 1-493 Me2C NM M60 2 CHN 0 -N AHCOMe 1-494 MN VN MeO 2 CHN 0 NH0 2 M NHCO2Me SEM SEM 1-495 N 1-496 Sn tentative 1-498 1: / N SMeN 2 CH 0 NHCO 2 Me 1-49 MeO 2 CHN 0CN 1-4991 NHC 2 Me 1-500 MNt2CH NHC 2 Me 1-501 NHCO 2 Me MeO 2 CHN 1-504 NHC 2 Me 0H 0 MeO 2 CHN 1-54 0 H 1-505 AHC0 2 Me PAGE 196 OF 222 WO 2010/099527 PCT/US2010/025741 AcHN 1-506 eHNHI N NHCOzMe Ph) 1-507 NH NHCO 2 M 1-508 Me HC2MO MoO 2 CHN 1-509 M NHCO2Me MeO 2 CH 1-510 MeO2CHN 1-5101) H , NH_ 0 MeO 2 CHN D 1-512 MeO 2 CH I 1-513 __ NHCO 2 Mo MeO 2 CHN 1-514 NHC 2 Me 1-515 F N 0 N MeO 2 CHN 1-519 F F NHC0 2 Me .N 222 M90 2 CHN 1-519 NS _________________A3__ F NIHC0 2 MG PAGE 197 OF 222 WO 2010/099527 PCT/US2010/025741 1-520 N MeO 2 CHN 1-521 N0 & NHCO 2 Me 1-522 N & N MeO 2 CH) 1-523 N NCO 2 Me ONN J( 1-524 ON' MeO2CH N 00 1-525 M o2MeN 1-526 ,... N CO 2 Me NHCO 2 Me 1-52 8 MeO 1-5 27 N C 2 Me MeO 2 CHN MeO 2 CHN 1-52 CO2Me MeO 2 CHNHCO2Me H NHCO 2 Me 1-532 MO h 1-533 MeO 2 PhNHOM PAG-193OF22 0 L NHC 2 MO 1-533 PAG28 19 1i 2 WO 2010/099527 PCTJUS2010/025741 1-534 Ph ivNZI 0N I H0M N N1 Hq .,R) 1-535 W MeO 2 l 1-536 NHCO 2 Me 1-5367N MeO 2 CHN b-P 1-538NHC0 2 Me 1-53791 Me0 2 CHN -P 1-54 1 ~NHC02MG H N I 1-5482N 1-543I NHC-1 Me0 2 CHN NP NHC0 2 MG 1-539 1-545NHCO 2 Me Me 2 CHN
[22] 22.~~~ ANoponHrpesnedb2FrulM2-) Q sY' 1-5412.6) PAG 19NF 2 WO 2010/099527 PCT/US2010/025741 or a pharmaceutically acceptable salt thereof, wherein: D and Z are are each independently absent or optionally substituted linear aliphatic group containing zero to eight carbons; A and E are are each independently absent or a cyclic group independently 5 selected from aryl, heteroaryl, heterocyclic, C 3 -Cs cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; T is absent or an optionally substituted aliphatic group; Wherein one to four of A, D, E, T and Z is absent; Ring B is a five-membered heteroaryl or a 5/6-membered fused heteroaryl, 10 wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups Z, E, T, A and D, and the 5-membered ring of said 5/6 membered fused heteroaryl is attached to group J and contains one or more nitrogen atoms; and wherein said heteroaryl is optionally substituted; Ring G is a 5/6-membered fused heteroaryl other than benzimidazolyl, 15 wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups D, A, T, E and Z, and wherein the 5-membered ring of said 5/6 membered fused heteroaryl is attached to group Q and contains one or more nitrogen atoms; and wherein said 5/6-membered fused heteroaryl is optionally substituted; Q and J are each independently selected from: (RT) R 3 R 4 7 -X XNR5 N ) 20 X<, and R ; R 3 and R 4 at each occurrence 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; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form 25 optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic; R 5 at each occurrence is independently hydrogen, optionally substituted C1 Cs alkyl, or optionally substituted C 3 -Cs cycloalkyl; R at each occurrence is independently selected from the group consisting of -C(O)-R 12 , -C(O)-C(O)-R 1 2 -S(0) 2 -R 12 , and -C(S)-R 12 ; 30 R at each occurrence is independently selected from the group consisting of -O-R", -NRaRb, -R", and -NR'R; PAGE 200 OF 222 WO 2010/099527 PCT/US2010/025741 R 1 1 at each occurrence is independently hydrogen or optionally substituted C 1 -Cs alkyl; and Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, and optionally substituted 5 C 2 -C 8 alkenyl; or Ra and Rb 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 at each occurrence is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -Cs alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 10 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; and Rc and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R", -C(O)-R 13 , -C(O)-OR, -S(0) 2 -R1 3 , -C(O)N(R 3 ) 2 , and -S(0) 2 N(R") 2 ; m is 0, 1, or 2; 15 n is 1, 2, 3, or 4; X at each occurrence is independently selected from 0, S, S(0), SO 2 , and C(R7) 2 ; provided that when m is 0, X is C(RT) 2 ; and R at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, -O-R 1 1, -NRa R, optionally substituted aryl, optionally 20 substituted heteroaryl, and optionally substituted -C 1 -C 4 alkyl; or two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring; or alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -C 8 25 cycloalkyl or optionally substituted heterocyclic ring.
[23] 23. The compound of claim 22, wherein Q and J are each independently 0 R12; or a pharmaceutically acceptable salt thereof 30
[24] 24. The compound of claim 22, wherein Ring B is selected fiom imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B is C-attached PAGE 201 OF 222 WO 2010/099527 PCT/US2010/025741 to J and C-attached to one of Z, E, T, A and D; or a pharmaceutically acceptable salt.
[25] 25. The compound of claim 22, wherein Ring B is selected from the group 5 consisting of ;N N N H N 0 HH HN~ H$ Q NH N N' H or a pharmaceutically acceptable salt thereof
[26] 26. The compound of claim 22, wherein Ring G is selected from the group 10 consisting of: /y- ~ k y/ :MN H QNHN4Nj /> N N H; 0 N M t - A N N auuN~ N or a pharmaceutically acceptable salt thereof. 15
[27] 27. The compound of claim 22, wherein each of D, A, E, and Z are absent and T is present; or a pharmaceutically acceptable salt thereof
[28] 28. The compound of claim 22, wherein each of D, E, T, and Z are absent, and A 20 is present; or a pharmaceutically acceptable salt thereof
[29] 29. The compound of claim 22, wherein each of D, E, and Z are absent and each of A and T are present; or a pharmaceutically acceptable salt thereof. PAGE 202 OF 222 WO 2010/099527 PCT/US2010/025741
[30] 30. The compound of claim 22, wherein each of D, A, and Z are absent and each of T and E are present; or a pharmaceutically acceptable salt thereof.
[31] 31. The compound of claim 22, wherein each of D, T, and Z are absent and A 5 and E are each present; or a pharmaceutically acceptable salt thereof.
[32] 32. The compound of claim 22, wherein each of E and Z are absent and D, A, and T are each present; or a pharmaceutically acceptable salt thereof. 10
[33] 33. The compound of claim 22, wherein each of D and A are absent and T, E, and Z are present; or a pharmaceutically acceptable salt thereof.
[34] 34. The compound of claim 22, wherein each of D and Z are absent and A, T, and E are present; or a pharmaceutically acceptable salt thereof. 15
[35] 35. The compound of claim 22, wherein D is absent and A, T, E, and Z are are each present and as previously defined; or a pharmaceutically acceptable salt thereof. 20
[36] 36. The compound of claim 22, wherein Z is absent and D, A, T, and E are each present; or a pharmaceutically acceptable salt thereof.
[37] 37. The compound of claim 22, wherein each of D, A, E, and Z are absent and T is an aliphatic group comprising one or more of an olefinic double bond, an alkynic 25 triple bond, 0, N(R"), C(O), S(0) 2 , C(0)O, C(O)N(R"), OC(0)O, OC(O)N(R"), S(0) 2 N(R"), N(R")C(O)N(R"), N(R")C(O)N(R"), N(R")S(0) 2 N(R"), C(O)N(R")S(0) 2 and C(O)N(R")S(0) 2 N(R 1 ); or a pharmaceutically acceptable salt thereof. 30
[38] 38. The compound according to claim 22 selected from the group of compounds 2-1 to 2-508 shown below, or a pharmaceutically acceptable salt thereof: Compounds 2-1 to 2-219. R R PAGE 203 OF 222 WO 2010/099527 PCT/US2010/025741 0 00 Entry 2- Entry 2- Entry 2- R j 0 0O > 2 'oYNy 3 ,Ny 4 5 6 OH OH O0 7 o'A . 8 9 10 11 12 0 OH 0 13 14 15 16 Ph 17 Ph 18 0 0 0 19 Ph, 20 Ph 21Ph OH OMe 6H 0 0 22 23 24 PhN) 1 1 6H 0 0 0 25 26 27 28 Nr' 1 29 30 31 Boc Boc N 34 35 0 36 (-N 37 38 39 _ 0 40 4 1 N42 N N O H 43 N44 Cy 45 0 46 47 HN 48 PAGE 204 OF 222 WO 2010/099527 PCT/US2010/025741 ,N-NH 0 F 0 .1 uJ 49 N1 50 51 52 N53 N-)J -(5 52 54 *I 000 55 Ph 56 57 Ph OMe Me0 Ph 58 59 1 .0 60 Ph2ij 61 *_____ _ 62 0 63 4 0 0 64 Y 65 66 0 NH 0 NH 0 67 -%f~c 68 .~~jN~169 0 6 M 70 71 72 0 00 H OH NH 76 * 078 H 00 0y7871 0%fN 72 jL1 79)"O 0 N, H 780 81 HCO 2 Bn 0 NH 2 82 N~%~1 8 O N8O4 85 86 8 0NH ONH H 00 88 89 90 0 _______N______ _ ____OTBS _ ____OTBS 79 92 93O ,. 1O H, H H NH o 94 5 83 4 96 O 0 0 222 PAG 200F 2 WO 2010/099527 PCT/US2010/025741 97 -- 98 99 O Ph CI NHCO 2 Me NH 100 101 102 H N NH M02N yNH ,,N NH 0 0 0 103 104 105 Boc 0 0 106 107 108 N 2 Me 109 rNY NHCO 2 Me 110 N NH NHCO 2 Me S NHCO 2 Me SS N 0 112 113 0 114 MeO 2 CHN MeO2CHN QNHCO 2 M NN N N N~N 115 HN N117 NHCO 2 Me NHCO 2 Me NHCM MeO 0 118 119 120 0 NH 1O NH 0 NHCOgMe OBn Fo 121 122 0 123 NHCO 2 Me NHCO 2 Me NHCO 2 Me 0 H 0. 124 P 4 125 126 O 0-I.0 0 0 O ANH 0 OXNH 0 ANH ON 127 128 0 129 0 0 0 0 OAH 130 0--f 131 - | 132 PAGE 206 OF 222 WO 2010/099527 PCT/US2010/025741 OF 133 H134 HN ~1 135 H MeO NHO MeO t|H 0 136 137 138 139 N 140 N 141 142Ph 144Ph N O Ph 145 146 147 FN Ph Ph Ph 148 Ph.N 149 HN 150 HO Ph ph Ph HN2 O 4 144 O 4b 4bPh 15 ON Bn46 O155 N 156 F-N 0 PhPh Ph 1548 Bni N4 OO 155 156 F sC HN C a N N 157 NK KrJ h 158 159 N 163 164 BnJ 165 C F .N% C1 N 166 167 168 169 170 171 172 173 174 175 176 177 NAE N N PAGjE 207 OF 222 WO 2010/099527 PCT/US2010/025741 178 Ph..leNkg 179 1 j 180 N 181 N 182 183 .,N.(M 0a 184 185 186 187 -N188 189 N 190 191 192 'yN -A N N a0 193 N 194 195 0 196 P NY . 197 N9 N NH2 199 200 201 H HrN H0 202 N N 20' 204 C YIN )r-N C H 2 N H 0o 217 218 N219 Compounds 2-220 to 2-229. HP' 2 MO 2 CH' H 5 . 7 % NHCo 2 Me PAGE 208 OF 222 WO 2010/099527 PCT/US2010/025741 Entry 2- R R' R" X Entry 2- R R' R" X 220 Me H H CH 2 221 H H H CF 2 222 Me H H S 223 H H H F 224 Me H H 0 225 H H H H 226 H Ph H CH 2 227 H H H OH OH 228 H H Ph CH 2 229 H H H H NHCO 2 Me NHCOzM. MeO 2 CHN Ph MeOCHN N P h Compound 2-230 (R) Compound 2-231 (S Y HCO 2 Me NHCO2M MeO 2 CHPh M2CHNPh 5 Compound 2-232 Compound 2-233 5 Compounds 2-234 to 2-243. Ph R " MNO2CH NHO_ NHCO2Me Entry 2- R R' R" Entry 2- R R' R" 234 Me Me H 235 H Me H 236 Me H Me 237 cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 Et Me H 242 Me CHMe 2 H 243 Me Et H Compounds 2-244 to 2-263. R R N 01i) Entry 2- R R' Entry 2- R R' 244 MeO 2 CHNyr MeO 2 CHN - 245 -N N Ph Ph PAGE 209 OF 222 WO 2010/099527 PCT/US2010/025741 246 N A MeO 2 CHN 247 MeOCHNy o Ph Ph 248 MeO2CHN MeO 2 CHN 249 MeO 2 CHN MBO 2 CHN Ph Ph 250 1.: 251 MeO 2 CHN O N SPh PhPh 252 253 CNr -o Y Me0 2 CHNA MeO 2 CHN Me0 2 CHN 254 255 cI N _____ ____O Ph MeO2CHN Me0 2 CHN H 256 257 O- N_ Ph0 Ph 258 Y 259 Mo 2 CHN ML 2 CHN, MeO 2 CHN-,A Me0 2 CHN. A 260 A I0Me 261 Me0 2 CHNA MeO 2 CHNA H 262 Me0 2 CHN- J 263 2 N Compounds 2-264 to 2-273. Ph R R' N NI MeO2CHN;-f Ph R' R"' NHC0 2 Me Entry 2- R R! R" R"' Entry 2- R R' R" R'" 264 F H H H 265 F F H H 266 Me H H H 267 Me Me H H 268 H H Me Me 269 H H Et Et 270 CF 3 H H H 271 CF 3 H CF 3 H 272 Cl H H H 273 Cl H Cl H 5 Compounds 2-274 to 2-291. MeO2C hNH CO2Me Entry 2- R R' R" Entry 2- R R' R" 274 Me H H 275 H CO 2 H H 276 H F H 277 H H CO 2 H 278 H H F 279 H CO 2 Me H PAGE 210 OF 222 WO 2010/099527 PCT/US2010/025741 280 H Cl H 281 H H CO 2 Me 282 H H Cl 283 H CONH 2 H 284 H Me H 285 H H CONH 2 286 H H Me 287 H OMe H 288 H CF3 H 289 H H OMe 290 H H CF 3 291 CO 2 Me H H Compounds 2-292 to 2-426. Pt NNH LNHCO2Me c0 Ph Entry Aa Entry Aa Entry Aa 2- 2- 2 292 293 294 295 296 297 298 299 300 N 301 302 303 304 305 306 307308 N 309 310 Y 311 /,o kA 312 Y oA H H 313 Y 314 315 ^,, 0 0 "00 316 /o 317 31 / Kmo 319 320 321 322 323 * 324 --* o / 325 -NH 326 0s-N 327 NNH32 328 329 0N 330N 331 332 333 334 335 U N 336 337 l' 338 339 NN(3NX PAGE 211 OF 222 WO 2010/099527 PCT/US2010/025741 340 P 341 N O 342 343 'N ANy 344 345 346 -N i 347 348 349 350 351 HN- -HN O 352 353 354 HN 0ONi HN HN 355 O- 356 357 358 359-N 359 36 361 362 363 364 V* o 365 366 N N 367 368 o N 369 .o 370 o 371 372 O 373 o7 374 N 375 N N 376 AwO.N*y 377 Of 378 379 I-N>-- 380 381 382 383 384 o-Z8 HNi HNj HN 385 86 386 387 - o __ -%oj 1-o 388 389 I-N4-1 390 0 0_________ 391 392 393 394 N 395 396 N 397 N398 399 PAGE 212 OF 222 WO 2010/099527 PCT/US2010/025741 400 401 402 N ,Im.I N N 403 404 405 'NI 0 406 N1 407 408 409 N- 410 O 411 N 412 -o 413 y'- YNh 414 N 415 40 <N 416 417 0N /N0 N0 418 9 419 -N N 421 422 -,- oA 423 N 424 o o 425 N 426 Compounds 2-427 to 2-477. MeO 2 CHN N NHCMe Entry 2- Aa Entry 2- Aa Entry 2- Aa 427 428 429 430 431 432 433 434 435 436 437 438 A 439 440 441 N 442 443 444 PAGE 213 OF 222 WO 2010/099527 PCT/US2010/025741 445 446 447 448 449 450 451 f(NA 452 N 453 454 455 456 457 458 459 460 461 -- 462 463 464 465 466 -NP )7 -N X 469 1 --- 1 470 J-N 471 I-N'- NA 472 -- 473 -N 474 N -N 475 |-N 476 I-No- 477 Compounds 2-478 to 2-497. MeO 2 CHN//e - N N- .NHCO2Me Ph Entry B Entry B Entry Bb 2- 2- 2 H 478 479 / ,N 480 N-NH li-LI N-N 481 482 Il)A 4 83 - /ypA H ~ HH 484 4 485 486 487 488 489 490 491 492 N1 'N HIN H 493 494 495 222 PAGE 214 OF 222 WO 2010/099527 PCT/US2010/025741 496 497 N'NH NI Compounds 2-498 to 2-508. Ph MeO2CHN 0 C NHCO2Me Entry G9 Entry Entry G9 2- 2- 2 498 499 500 501 502 503 N __N___ 504 505 506 507 508 5
[39] 39. A compound of claim 22, represented by Formula (2-II), or a pharmaceutically acceptable salt thereof: (R 7 ) -1 GT-E 7 R7. N R 7 H /IX
[40] 40. A compound of claim 39, wherein Ring G is imidazolpyridyl; m is 1; n is 1 10 or 2; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; T is absent, optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; X at each occurrence is each independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R 7 groups are taken together 15 with the carbon to which they are attached to form a spiro, optionally substituted C 3 Cs cycloalkyl; or yet alternatively, two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted C 1 -C 8 alkyl; or a pharmaceutically acceptable salt thereof. PAGE 215 OF 222 WO 2010/099527 PCT/US2010/025741
[41] 41. A compound of claim 22, represented by one of Formulae (2-HI-a) to (2-HI d): (R) .NH O R12 R12 2 N N R12 2-II- b X (R ) R)H x P G- NN ;-R 12 R1 2 2-Ill-cX (RN) ( R(RO R7 N R1224Ilkc R T 7 7) R 0 x -N //=l NH 1 5 wherein Ring G is imidazolpyridyl; n is 1 or 2; X at each occurrence is independently CH 2 , CIF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein RI at each occurrence is independently hydrogen or methyl; alternatively, the two geminal RC groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R 7 groups are taken together with the 10 two adjacent atoms to which they are attached to form a fused cyclopropyl; and R at each occurrence is independently C 1 -Cs alkyl optionally substituted with amino, hydroxy, protected amino, or O(C 1 -C 4 alkyl); or a pharmaceutically acceptable salt thereof. (R). N m) 15
[42] 42. The compound of claim 22, wherein - is selected from the group listed below, or a pharmaceutically acceptable salt thereof: M MMee F F Me Me OH PG 26F PAGE 216 OF 222 WO 2010/099527 PCTUS2010/025741
[43] 43. A compound according to claim 22 selected from the group of compounds 2 509 to 2-516 shown below, or a pharmaceutically acceptable salt thereof: 2-509 2-510 MeO2CH HCO2MG 2-511 2-5 12 M CO2Me 2-513 _ 2-514 M s HCO2Me O ( 2-515 Me0zCH H k 2-516N -N NHOM 5
[44] 44. A pharmaceutical composition comprising a compound or a combination of compounds according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
[45] 45. A method of inhibiting the replication of an RNA-containing virus 10 comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof.
[46] 46. A method of treating or preventing infection caused by an RNA-containing 15 virus comprising administering to a patient in need of such treatment a PAGE 217 OF 222 WO 2010/099527 PCT/US2010/025741 therapeutically effective amount of a compound or combination of compounds of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof.
[47] 47. The method of claim 46, wherein the RNA-containing virus is hepatitis C 5 virus.
[48] 48. The method of claim 46, further comprising the step of co-administering one or more agents selected from the group consisting of a host immune modulator and an antiviral agent, or a combination thereof 10
[49] 49. The method of claim 48, wherein the host immune modulator is selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon beta, interferon-gamma, consensus interferon, a cytokine, and a vaccine. 15
[50] 50. The method of claim 48, wherein the antiviral agents inhibit replication of HCV by inhibiting host cellular functions associated with viral replication.
[51] 51. The method of claim 48, wherein the antiviral agents inhibit the replication of HCV by targeting proteins of the viral genome. 20
[52] 52. The method of claim 48, wherein said antiviral agent is an inhibitor of a HCV viral protein, a replication process or a combination thereof, wherein said targeting protein or replication process is selected from the group consisting of helicase, protease, polymerase, metalloprotease, NS4A, NS4B, NS5A, assembly, 25 entry, and IRES.
[53] 53. The method of claim 46, further comprising the step of co-administering an agent or combination of agents that treat or alleviate symptoms of HCV infection selected from cirrhosis and inflammation of the liver. 30
[54] 54. The method of claim 46, further comprising the step of co-administering one or more agents that treat patients for disease caused by hepatitis B (HBV) infection. PAGE 218 OF 222 WO 2010/099527 PCT/US2010/025741
[55] 55. The method of claim 46, further comprising the step of co-administering one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection. 5
[56] 56. The pharmaceutical composition of claim 44, further comprising an agent selected from interferon, pegylated interferon, ribavirin, amantadine, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internal ribosome entry site inhibitor. 10
[57] 57. The composition of claim 44, further comprising a cytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptable salt thereof
[58] 58. The composition of claim 57, wherein the cytochrome P450 mooxygenase inhibitor is ritonavir. 15
[59] 59. A method of treating hepatitis C infection in a subject in need thereof comprising co-administering to said subject a cytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptable salt thereof, and a compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof. 20
[60] 60. A process of making a compound of claim I comprising the steps of: i) Preparing a compound of Formula (1-11-a): za HN )T-E.-(fI R (R _1n-n ) (Rn via a transition-metal catalyzed cross-coupling reaction; 25 wherein: E is optionally substituted aryl or optionally substituted heteroaryl; T, X, n, u, R', and R 7 are as defined in claim 1; Za and Zb are each independently an amino protecting group or -C(O)-R 1 2 ; R 2 is C 1 -C 8 atkyl optionally substituted with amino, hydroxy, protected amino, or 30 O(C-C 4 alkyl); PAGE 219 OF 222 WO 2010/099527 PCT/US2010/025741 ii) When Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (1-IT-a) to give the corresponding amine of Formula (1 I-b): z 0 HN T (RI)n (1I-b ,NXR 5 wherein Z" is hydrogen, an amino protecting group or -C(0)-R1; iii) Capping the released amino group of a compound of Formula (1-I-b) with LG-C(O)-R, wherein LG is a leaving group; to give the compound of Formula (1-TI-c): Zd HN T-E4fI R In O N R~ 10 wherein Zd is an amino protecting group -C(O)-R 12 ; and iv) Repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (1-IT-d): R12.O HN T-E R1 (RI~~n RI (1-Il-d) O(R) 15
[61] 61. A process of making a compound of claim 22 comprising the steps of: i) Preparing a compound of Formula (2-II-a): I T-'Ex (2-Il-a) ZbN (R')n. via a transition-metal catalyzed cross-coupling reaction; wherein: 20 E, G, T, X, n, u, v, R , and R7 are as defined in claim 22; Za and Zb are each independently an amino protecting group or -C(O)-R 2 ; R1 2 is C1-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or O(C 1 -C 4 alkyl); ii) When Za or Z is an amino protecting group, fully or selectively 25 deprotecting a compound of Formula (2-I-a) to give the corresponding amine of Formula (2-II-b): PAGE 220 OF 222 WO 2010/099527 PCT/US2010/025741 (RI) T'-E Z. (2-11-b) HN--(R%~ wherein Z' is hydrogen, an amino protecting group or -C(O)-R12 iii) Capping the released amino group of a compound of Formula (2-II b) with LG-C(O)-R1 2 , wherein LG is a leaving group; to give the 5 compound of Formula (2-II-c): (2-H-.c) Ns ( k wherein Zd is an amino protecting group -C(O)-R 2 ; and iv) Repeated reaction sequence of deprotecting and capping (step v-vii) to give the compound of Formula (2-II-d): (InT-E R 12 0 (2-Il-dl) o N ( 10 R1 , PAGE 221 OF 222

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PE20120124A1|2008-12-03|2012-03-17|Presidio Pharmaceuticals Inc|2-PYRROLIDIN-3-IL-1H-IMIDAZOLE DERIVATIVES, AS INHIBITORS OF THE NON-STRUCTURAL PROTEIN 5A OF THE HEPTITIS C VIRUS|

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TWI438200B|2009-02-17|2014-05-21|Squibb Bristol Myers Co|Hepatitis c virus inhibitors|

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法律状态:
2014-01-23| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE NAME OF THE INVENTOR TO READ QIU, YAO-LING; WANG, CE; PENG, XIAOWEN; YING, LU AND OR, YAT SUN |

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2017-01-19| FGA| Letters patent sealed or granted (standard patent)|

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2020-10-01| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US61/156,131||2009-02-27||

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US61/158,071||2009-03-06||

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AU2010217797A|AU2010217797B2|2009-02-27|2010-03-01|Hepatitis C virus inhibitors|

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AU2013204195A|AU2013204195B2|2009-02-27|2013-04-12|Hepatitis C virus inhibitors|AU2013204195A| AU2013204195B2|2009-02-27|2013-04-12|Hepatitis C virus inhibitors|