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(12) Patent Application Publication (10) Pub. No.: US 2004/0266668A1 Nakajima Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0266668A1 Nakajima Et Al US 2004O266668A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0266668A1 Nakajima et al. (43) Pub. Date: Dec. 30, 2004 (54) QUINOXALINYL MACROCYCLIC HEPATITIS C SERINE PROTEASE (I) INHIBITORS (76) Inventors: Suanne Nakajima, Cambridge, MA (US); Miao Zhenwei, Medway, MA (US); Ying Sun, Waltham, MA (US); Datong Tang, Malden, MA (US); Guoyou Xu, Auburndale, MA (US); Brian Porter, Cambridge, MA (US); Yat Sun Or, Watertown, MA (US); Zhe Wang, Hockessin (DE) Correspondence Address: EDWARDS & ANGELL, LLP P.O. BOX 55874 (II) BOSTON, MA 02205 (US) (21) Appl. No.: 10/826,743 (22) Filed: Apr. 16, 2004 Related U.S. Application Data (60) Provisional application No. 60/509,071, filed on Apr. 18, 2003. Publication Classification (51) Int. Cl." ............................. A61K 38/12; CO7K 5/12 (52) U.S. Cl. ............................... 514/9; 530/317; 544/405 which inhibit Serine protease activity, particularly the activ ity of hepatitis C virus (HCV) NS3-NS4A protease. Conse quently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful (57) ABSTRACT as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforemen tioned compounds for administration to a Subject Suffering from HCV infection. The invention also relates to methods The present invention relates to compounds of Formula I or of treating an HCV infection in a Subject by administering II, or a pharmaceutically acceptable Salt, ester, or prodrug, a pharmaceutical composition comprising the compounds of thereof: the present invention. US 2004/0266668A1 Dec. 30, 2004 QUINOXALINYL MACROCYCLIC HEPATITIS C replication. Despite the huge number of Viral variants asso SERINE PROTEASE INHIBITORS ciated with HCV infection, the active site of the NS3 protease remains highly conserved thus making its inhibition CROSS-REFERENCE TO RELATED an attractive mode of intervention. Recent SucceSS in the APPLICATIONS treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle 0001. This applications claims benefit of U.S. provisional against HCV. application (conversion of U.S. Ser. No. 10/418, 759) filed Apr. 18, 2003, the entire contents of which is 0007 HCV is a flaviridae type RNA virus. The HCV herein incorporated by reference. genome is enveloped and contains a single Strand RNA molecule composed of circa 9600 base pairs. It encodes a TECHNICAL FIELD polypeptide comprised of approximately 3010 amino acids. 0002 The present invention relates to novel macrocycles 0008. The HCV polyprotein is processed by viral and having activity against the hepatitis C virus (HCV) and host peptidase into 10 discreet peptides which Serve a useful in the treatment of HCV infections. More particularly, variety of functions. There are three Structural proteins, C, the invention relates to macrocyclic compounds, composi E1 and E2. The P7 protein is of unknown function and is tions containing Such compounds and methods for using the comprised of a highly variable Sequence. There are Six Same, as well as processes for making Such compounds. non-structural proteins. NS2 is a zinc-dependent metallo proteinase that functions in conjunction with a portion of the BACKGROUND OF THE INVENTION NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at 0.003 HCV is the principal cause of non-A, non-B hepa the N-terminal end, which requires NS4A as a cofactor, and titis and is an increasingly Severe public health problem both an ATP-ase-dependent helicase function at the carboxyl in the developed and developing World. It is estimated that terminus. NS4A is a tightly associated but non-covalent the virus infects over 200 million people worldwide, Sur cofactor of the Serine protease. passing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV 0009. The NS3.4A protease is responsible for cleaving infected patients, due to the high percentage of individuals four sites on the viral polyprotein. The NS3-NS4A cleavage inflicted with chronic infections, are at an elevated risk of is autocatalytic, occurring in cis. The remaining three developing cirrhosis of the liver, Subsequent hepatocellular hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans. NS3 is a Serine protease which is struc carcinoma and terminal liver disease. HCV is the most turally classified as a chymotrypsin-like protease. While the prevalent cause of hepatocellular cancer and cause of NS Serine protease possesses proteolytic activity by itself, patients requiring liver transplantations in the western the HCV protease enzyme is not an efficient enzyme in terms world. of catalyzing polyprotein cleavage. It has been shown that a 0004. There are considerable barriers to the development central hydrophobic region of the NS4A protein is required of anti-HCV therapeutics, which include, but are not limited for this enhancement. The complex formation of the NS3 to, the persistence of the virus, the genetic diversity of the protein with NS4A Seems necessary to the processing Virus during replication in the host, the high incident rate of events, enhancing the proteolytic efficacy at all of the Sites. the Virus developing drug-resistant mutants, and the lack of reproducible infectious culture Systems and Small-animal 0010) A general strategy for the development of antiviral models for HCV replication and pathogenesis. In a majority agents is to inactivate virally encoded enzymes, including of cases, given the mild course of the infection and the NS3, that are essential for the replication of the virus. complex biology of the liver, careful consideration must be Current efforts directed toward the discovery of NS3 pro tease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, given to antiviral drugs, which are likely to have significant N. Sonenberg, Hepatitis C Therapeutics: Current Status and side effects. Emerging Strategies, Nature Rev. Drug Discov:, 1,867-881 0005. Only two approved therapies for HCV infection are (2002). Other patent disclosures describing the synthesis of currently available. The original treatment regimen gener HCV protease inhibitors are: WO 00/59929 (2000); WO ally involves a 3-12 month course of intravenous inter 99/07733 (1999); WO 00/09543 (2000), WO 99/50230 feron-C. (IFN-O.), while a new approved second-generation (1999); U.S. Pat. No. 5,861,297 (1999); and US2002/ treatment involves co-treatment with IFN-O. and the general 0037998 (2002). antiviral nucleoside mimics like ribavirin. Both of these treatments suffer from interferon related side effects as well SUMMARY OF THE INVENTION as low efficacy against HCV infections. There exists a need for the development of effective antiviral agents for treat 0011. The present invention relates to novel macrocyclic ment of HCV infection due to the poor tolerability and compounds and methods of treating a hepatitis C infection disappointing efficacy of existing therapies. in a Subject in need of Such therapy with Said macrocyclic compounds. The present invention further relates to phar 0006. In a patient population where the majority of maceutical compositions comprising the compounds of the individuals are chronically infected and asymptomatic and present invention, or pharmaceutically acceptable Salts, the prognoses are unknown, an effective drug would desir esters, or prodrugs thereof, in combination with a pharma ably possess Significantly fewer Side effects than the cur ceutically acceptable carrier or excipient. rently available treatments. The hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme required for pro 0012. In one embodiment of the present invention there cessing of the viral polyprotein and consequently viral are disclosed compounds represented by Formulas I and II, US 2004/0266668A1 Dec. 30, 2004 or pharmaceutically acceptable salts, esters, or prodrugs eroaryl, Substituted heteroaryl, heterocycloalkyl, thereof: substituted heterocycloalkyl, or -NH N=CH(R); (I) 0020 Each R is independently selected from Y. N W-Z hydrogen, C-C alkyl, Substituted C-C alkyl, n C-C alkenyl, Substituted C-C alkenyl, C-C, 2 alkynyl, Substituted C-C alkynyl, C-C2 X N Q cycloalkyl, Substituted C-C cycloalkyl, aryl, Sub stituted aryl, arylalkyl, substituted arylalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, Sub O lm O OR stituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, H N N-. G / 2-Rs ls 0021) Each R is independently selected from A a. O hydrogen, C-C alkyl, C-C alkyl, Substituted R6 C-C alkyl, C-C alkenyl, substituted C-C alk CH enyl, C-C alkynyl, Substituted C-C alkynyl, N- CH2N/ C-C2 cycloalkyl, substituted C-C2 cycloalkyl, H alkylamino, dialkylamino, arylamino, diarylamino, (II) aryl, substituted aryl, arylalkyl, Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Sub X N O stituted heterocycloalkyl; 0022. Each R is independently selected from: 0023 (i) -C-C alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally Substituted with one or more Substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or Substituted heteroaryl, 0024 (ii) -C-C alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or 0013) Wherein Substituted heteroaryl; 0014) A is independently selected from hydrogen; 0025 (iii)-C-C alkynyl containing 0, 1, 2, or 3 -(C=O)-O-R, -(C=O)-R, -C(=O)- heteroatoms selected from O, S, or N, optionally NH-R, -C(=S)-NH-R, or -S(O)-R; Substituted with one or more substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or 0015) G is independently selected from -OH, Substituted heteroaryl; 0026 Rs and R are each independently selected from hydrogen or methyl; 0016 L is independently selected from -S-, 0027 j=0, 1, 2, 3, or 4; -SCH-, -SCHCH-, -S(O)-, -S(O)CHCH-, -S(O)-, -S(O)CHCH-, 0028 m=0, 1, or 2; and -O-, -OCH-, -OCHCH-, -(C=O)- CH-, -CH(CH)CH-, -CFHCH-, or 0029) s=0, 1 or 2.
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