EP2393359A1 - Linked dibenzimidazole derivatives - Google Patents

Linked dibenzimidazole derivatives

Info

Publication number
EP2393359A1
EP2393359A1 EP10739272A EP10739272A EP2393359A1 EP 2393359 A1 EP2393359 A1 EP 2393359A1 EP 10739272 A EP10739272 A EP 10739272A EP 10739272 A EP10739272 A EP 10739272A EP 2393359 A1 EP2393359 A1 EP 2393359A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
group
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10739272A
Other languages
German (de)
French (fr)
Other versions
EP2393359A4 (en
Inventor
Yao-Ling Qiu
Ce Wang
Lu Ying
Xiaowen Peng
Yat Sun Or
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Enanta Pharmaceuticals Inc
Original Assignee
Enanta Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enanta Pharmaceuticals Inc filed Critical Enanta Pharmaceuticals Inc
Publication of EP2393359A1 publication Critical patent/EP2393359A1/en
Publication of EP2393359A4 publication Critical patent/EP2393359A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel antiviral agents. More specifically, the present invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, methods for inhibiting HCV viral replication, methods for treating or preventing HCV infection, and processes for making the compounds.
  • HCV Hepatitis C virus
  • 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.
  • Pegylated interferon (Peg-IFN)
  • both initial and sustained response rates have improved substantially
  • combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy.
  • side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.
  • 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) 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.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA - A Publication of the RNA Society. 1(5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition,
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • NS5A is a membrane-anchored phosphoprotein that is observed in basally phosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms. While its function has not fully been elucidated, NS5A is believed to be important in viral replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 151 2-22) encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • the NS5B protein is fairly well conserved both intra- typically (-95-98% amino acid (aa) identity across Ib isolates) and inter-typically (-85% aa identity between genotype Ia and Ib isolates).
  • the essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4): 2046-2051).
  • inhibition of NS5B RdRp activity is predicted to be useful to treat HCV infection.
  • 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • HCV NS5A protein is described, for example, in Tan, S. -L., Katzel, M.G. Virology 2001, 284, 1; and in Rice, C. M. Nature 2005, 435, 374.
  • the present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds.
  • Compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention provides a compound of Formula (1-1):
  • A is independently selected from the group consisting of: aryl, heteroaryl, heterocyclic, C 3 -Cg cycloalkyl, and C 3 -Cg cycloalkenyl, all optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R 10 , -OR 11 , N(R ⁇ ) 2 , -C(O)R 11 , -CO 2 R 11 , -C(O)N(R n ) 2 and -N(R n )C(O)R n ;
  • A is preferably phenyl, 5-7-membered heteroaryl, 5-7-membered heterocyclic, C5-C7 cycloalkyl, or C 5 -C 7 cycloalkenyl, all optionally substituted with one or more substituents independently selected from halogen and R 10 ;
  • R 10 at each occurrence is independently C 1 -C 4 alkyl optionally substituted with one or more halogen atoms;
  • PAGE 4 OF 191 R 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of: halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b , preferably halogen and optionally substituted C 1 - C 4 alkyl;
  • R a and R b at each occurrence are each independently hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C 2 -Cs alkenyl; or R a and R b taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u and v at each occurrence are each independently 0, 1, 2, or 3, preferably 0 or 1;
  • R 3 and R 4 at each occurrence are each independently hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cs alkenyl or optionally substituted C 3 - Cs cycloalkyl, preferably hydrogen or optionally substituted Ci -C 4 alkyl; or alternatively, R 3 and R 4 taken together with the carbon atom to which they are attached form optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic;
  • R 5 at each occurrence is independently hydrogen, optionally substituted Ci-C 8 alkyl, or optionally substituted C 3 -Cs cycloalkyl, preferably hydrogen or optionally substituted Ci-C 4 alkyl;
  • R 6 at each occurrence is independently selected from the group consisting of: hydrogen, -C(O)-R 12 , -C(O)-C(O)-R 12 , -S(O) 2 -R 12 , and -C(S)-R 12 , preferably -C(O)-R 12 ;
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , -NR c R d , -CH(R 13 )NR a R b , and -CH(R 13 )NR c R d , preferably optionally substituted Ci-C 8 alkyl and -O-R 11 ;
  • R 13 at each occurrence is independently selected from the group consisting of: optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, and optionally
  • PAGE 5 OF 191 substituted heteroarylalkyl preferably Ci-Cs alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl);
  • R c and R d at each occurrence are each independently selected from the group consisting of: hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ) 2 ;
  • m is O, 1, or 2; preferably 1;
  • n is O, 1, 2, 3, or 4; preferably 0, 1, or 2;
  • X at each occurrence is independently selected from O, S, S(O), SO 2 , CH 2 , CHR 7 , and C(R 7 ) 2 ; preferably CH 2 or CHR 7 ; provided that when m is O, X is selected from CH 2 , CHR 7 , and C(R 7 ) 2 ; or
  • R 7 at each occurrence is independently selected from the group consisting of: halogen, cyano, -O-R 11 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C 4 alkyl, preferably methyl or halogen; or, two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached form a fused, optionally substituted -C 3 -Cg 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 form a spiro, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • the present invention provides a compound of
  • A is an optionally substituted linear aliphatic group
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted Ci-C 4 alkyl, -O-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b ; preferably hydrogen, halogen and optionally substituted Ci-C 4 alkyl;
  • R 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl
  • R a and R b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, and optionally substituted C 2 - C 8 alkenyl; or R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u and v at each occurrence are each independently 1, 2, or 3; Q and J are each independently selected from:
  • R 3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cs alkenyl, and optionally substituted C 3 -Cs cycloalkyl; preferably hydrogen or optionally substituted C1-C4 alkyl; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic; R 5 at each occurrence is independently hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C 3 -Cs cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl;
  • R 6 at each occurrence is independently selected from the group consisting of -C(O)-R 12 , -C(O)-C(O)-R 12 , -S(O) 2 -R 12 , and -C(S)-R 12 , preferably -C(O)-R 12 , more preferably an optionally substituted amino acid acyl;
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , and -NR c R d , preferably optionally substituted Ci-C 8 alkyl and -0-R 11 ;
  • 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 Ci-C 8 alkyl; more preferably Ci-C 8 alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl); and
  • R c and R d at each occurrence are each independently selected from the group consisting of hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ),; m is O, 1, or 2, preferably 1;
  • PAGE 7 OF 191 n is 1, 2, 3, or 4, preferably 1 or 2;
  • X at each occurrence is independently selected from O, S, S(O), SO 2 , and C(R 7 )2, preferably CH 2 or CHR 7 ; provided that when m is O, 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 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C1-C4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively, two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • the present invention provides a compound of Formula (3-1):
  • A is a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 - C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted;
  • D is absent or an optionally substituted aliphatic group;
  • T is absent or an optionally substituted linear aliphatic group containing zero to eight carbons
  • E is absent or independently selected from optionally substituted aryl and optionally substituted heteroaryl; wherein one or two of D, E, and T are absent;
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted Ci-C 4 alkyl, -O-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b ; preferably hydrogen, halogen and optionally substituted Ci-C 4 alkyl;
  • PAGE 8 OF 191 R 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl
  • R a and R b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 8 alkyl, and optionally substituted C 2 - Cg alkenyl; or R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u and v at each occurrence are each independently 1, 2, or 3;
  • R 3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 2 -Cg alkenyl, and optionally substituted C 3 -Cg cycloalkyl; preferably hydrogen or optionally substituted C1-C4 alkyl; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic;
  • R 5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C 3 -Cg cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl; R 6 at each occurrence is independently selected from the group consisting of
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , and -NR c R d , preferably optionally substituted Ci-C 8 alkyl and -O-R 11 ;
  • R 13 at each occurrence is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 3 -Cg cycloalkyl, C 3 -Cg cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-Cg alkyl; more preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl); and
  • R c and R d at each occurrence are each independently selected from the group consisting of hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ) 2 ;
  • m is O, 1, or 2, preferably 1;
  • n is 1, 2, 3, or 4, preferably 1 or 2;
  • X at each occurenece is independently selected from O, S, S(O), SO 2 , and C(R 7 ) 2 , preferably CH 2 or CHR 7 ; provided that when m is O, X is C(R 7 ) 2 ; and
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -0-R 11 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting the replication of a RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • this invention is directed to methods of inhibiting the replication of HCV.
  • the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt
  • this invention is directed to methods of treating or preventing infection caused by HCV.
  • Yet another aspect of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically HCV.
  • the present invention relates to compounds of Formula (1-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (1-Ia), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-Id), or a pharmaceutically acceptable salt thereof:
  • R 3 , R 4 , R 5 and R 12 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-Ie), or a pharmaceutically acceptable salt thereof:
  • R 3 , R 4 , R 5 and R 12 are as previously defined in Formula (l-I).and X 1 is CH 2 , CHF, CH(OH), or CF 2 .
  • the present invention relates to compounds of Formula (1-If), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-If), wherein R 12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl); or a pharmaceutically acceptable salt thereof.
  • R 3 , R 5 and R 12 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-IIa), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (1-1) and A 1 is independently an aryl; preferably phenyl or naphthyl ring, optionally substituted with one or more substituents independently selected from halogen and R 10 ; and R 10 is as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-IIb), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (1-1) and A 2 is independently a heteroaryl, preferably 5-7-membered heteroaryl, optionally with one or
  • the present invention relates to compounds of Formula (1-IIc), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (1-1) and A 4 is independently a C 3 -Cs cycloalkyl, preferably 5-7-membered cycloalkyl, optionally with one or more substituents independently selected from halogen and R 10 ; and R 10 is as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-IIe), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (1-1) and A 5 is independently a C 3 -Cg cycloalkenyl, preferably 5-7-membered cycloalkenyl, optionally substituted with one or more substituents independently selected from halogen and R 10 ; and R 10 is as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-IIIa), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIb), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIc), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIId), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIe), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIf), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIg), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIh), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of
  • Representative compounds of Formula (1 " -1) are those selected fr “ om compounds 1- 1 to 1-360, l-354a, l-357a, and 1-361 to 1-372 compiled in the following tables:
  • the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (2-Ia), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2- Ib), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ic), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Id), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ie), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-If), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-If), wherein R 12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl); or a pharmaceutically acceptable salt thereof.
  • the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine moiety is represented by Formulae (2-Ig-l, 2-Ig-2 and 2-Ig-3):
  • the present invention relates to compounds of Formula (2-Ih), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ii), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ij), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ik), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-11), or a pharmaceutically acceptable salt thereof:
  • a and X 1 are as previously defined in Formula (2-1) and R 13a at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl).
  • the present invention relates to compounds of Formula (2-IIa), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (2-1) and A 1 is Ci-Cs alkyl, preferably C3-C6 alkyl, each optionally substituted.
  • the present invention relates to compounds of Formula (2-IIb), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (2-1) and A 2 is C 2 -Cs alkenyl, preferably C 3 -C 6 alkenyl, each optionally substituted.
  • the present invention relates to compounds of Formula (2-IIc), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (2-1) and A 3 is C 2 -Cs alkynyl, preferably C 3 -C 6 alkynyl, each optionally substituted.
  • the present invention relates to compounds of Formula (2 -Hd), or a pharmaceutically acceptable salt thereof:
  • a 4 is a linear aliphatic group containing a group selected from C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R n )C(0)C(0)N(R ⁇ ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R n )S(O) 2 or C(0)N(R n )S(0) 2 N(R ⁇ ); and R 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-IIe), or a pharmaceutically acceptable salt thereof:
  • a 5 is a linear aliphatic group containing an olef ⁇ nic double bond and a group selected from C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R 1 ⁇ C(O)C(O)N(R 11 ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R 1 ⁇ S(O) 2 or C(0)N(R n )S(0) 2 N(R n ); and R 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2 -Hf), or a pharmaceutically acceptable salt thereof:
  • a 6 is a linear aliphatic group containing an alkynic triple bond and a group selected from C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R 1 ⁇ C(O)C(O)N(R 11 ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R 1 ⁇ S(O) 2 or
  • the present invention relates to compounds of Formula (2-Hg), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined for Formula (2-1); and A 7 is a linear aliphatic group containing one or more groups independently selected from O and N(R 11 ); and R 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-Hh), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-IIi), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (2-1); and A 9 is a linear aliphatic group containing an alkynic triple bond and one or more groups independently selected from O and N(R 11 ); and R 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-IIIa), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (2-1) and L 1 is selected from C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ),
  • R 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-IIIb), or a pharmaceutically acceptable salt thereof:
  • R , 11 is as previously defined in Formula (2-1).
  • the present invention relates to compounds of
  • Representative compounds having the Formula (2-1) are those selected from compounds 2-1 to 2-352, 2- Ia, 2-3a, and 2-353 to 2-357 compiled in the following tables:
  • the present invention relates to compounds of Formula (3- Ia), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3- Ib), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ic), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Id), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ie), or a pharmaceutically acceptable salt thereof:
  • A, D, E, T, u, v, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 12 are as previously defined in Formula (3-1) and X 1 is independently CH 2 , CHF, CH(OH), or CF 2 .
  • the present invention relates to compounds of Formula (3-If), or a pharmaceutically acceptable salt thereof:
  • A, D, E, T, u, v, X 1 , R 1 , R 2 , R 7 and R 12 are as previously defined in Formula (3-1).
  • the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine moiety is represented by Formula (3- Ig-I, 3-Ig-2 and 3-Ig-3):
  • the present invention relates to compounds of Formula (3-Ih), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ii), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ij), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ik), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of
  • the present invention relates to compounds of
  • A, D, E, T and X 1 are as previously defined in Formula (3-1) andR 1Ja at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino or O(Cl-C4 alkyl).
  • the present invention relates to compounds of Formula (3-IIa), or a pharmaceutically acceptable salt thereof:
  • the compound has the Formula (3-IIa), wherein A is a heterocyclic; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (3-IIb), or a pharmaceutically acceptable salt thereof:
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and D 2 is an optionally substituted C 2 -C 4 alkenyl.
  • the present invention relates to compounds of Formula (3-IIc), or a pharmaceutically acceptable salt thereof:
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and D 3 is an optionally substituted C 2 -C 4 alkynyl.
  • the present invention relates to compounds of Formula (3-IId), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-IIe), or a pharmaceutically acceptable salt thereof:
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and D 5 is selected from C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R n )C(0)C(0)N(R n ), N(R n )S(O) 2 N(R n ), C(O)N(R 1 ⁇ S(O) 2 and C(0)N(R n )S(0) 2 N(R n ); and R 11 is as previously defined in Formula (3-1).
  • the present invention relates to compounds of
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and D 6 is an optionally substituted C 3 -Cg cycloalkyl or optionally substituted C 3 -Cg cycloalkenyl.
  • the present invention relates to compounds of
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and E 1 is an optionally substituted aryl.
  • the present invention relates to compounds of Formula (3-IIIb), or a pharmaceutically acceptable salt thereof:
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and E 2 is an optionally substituted heteroaryl.
  • the present invention relates to compounds of Formula (3-IIIc), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-IIId), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A 2 is an optionally substituted heteroaryl.
  • the present invention relates to compounds of Formula (3-IIIe), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-IIIf), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-IIIg), or a pharmaceutically acceptable salt thereof:
  • Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A 5 is an optionally substituted C 3 -Cg cycloalkenyl.
  • the present invention relates to compounds of Formula (3-IVa), or a pharmaceutically acceptable salt thereof:
  • A, Q, J, u, v, R 1 and R 2 are as previously defined in Formula (3-1) and D 8 and T 1 are each independently linear aliphatic group containing zero to six carbons, optionally contain one or more groups selected from O, N(R 11 ), C(O), S(O) 2 , C(O)O, and C(O)N(R 11 ); and R 11 is as previously defined in Formula (3-1).
  • the present invention relates to compounds of
  • Representative com F pounds of the present invention are those selecte from compounds 3-1 to 3-334 compiled in the following tables:
  • R z may be attached to either the carbon atom in the benzimidazole ring or, alternatively, in Formula (1-1), R 2 may take the place of the hydrogen atom on the nitrogen ring to form an N- substituted benzimidazole.
  • any substituent or variable e.g., A, R 1 , R 2 , u, m, etc.
  • each of the two R 1 groups may be the same or different.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention. It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.
  • references 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 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 pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents known in the art, with a pharmaceutically acceptable carrier or excipient.
  • 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.
  • agents to be administered in combination with a compound or combination of compounds of the present invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms.
  • agents include, but not limited to, host immune modulators (for example, interferon- alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example
  • compositions of the present invention may further comprise other inhibitor(s) of targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • one embodiment of the present invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising coadministering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • 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 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.
  • RNA-containing virus is hepatitis C virus (HCV).
  • Yet another embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • a non- limiting example of the RNA-containing virus is hepatitis C virus (HCV).
  • a further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • PAGE 61 OF 191 by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T- 1249, or any combination thereof.
  • a non- limiting example of the RNA-containing virus is hepatitis C virus (HCV).
  • a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) or hepatitis B virus (HBV).
  • HAV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • 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.
  • 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-containing virus in a patient, particularly hepatitis C virus.
  • a 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.
  • said additional antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • 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.
  • combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt thereof, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • HCV Hepatitis C virus
  • such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
  • an RNA-containing virus particularly a hepatitis C virus (HCV)
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents
  • agents that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • cytochrome P450 monooxygenase inhibitor also referred to herein as a CYP inhibitor
  • the cytochrome P450 monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the compounds of this invention.
  • the CYP inhibitor is administered in an amount sufficient to increase the bioavailiablity of a compound of the invention when the bioavailability is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
  • the invention provides methods for improving the pharmacokinetics of a compound of the invention.
  • the advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, US Patent App. Nos. 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 and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2Cl 9 (“CYP2C19”), isozyme 2D6 (“CYP2D6"), isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”), or isozyme 2El (“CYP2E1”).
  • the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant compound of the invention may be
  • CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfmavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
  • Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
  • 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.
  • the pack further comprises one or more additional agents as described herein.
  • the additional agent or agents may be provided in the same pack or in separate packs.
  • kits for a patient to use in the treatment of HCV infection or in the prevention of HCV infection comprising: a single or a plurality of pharmaceutical formulations 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.
  • kits for the simultaneous or sequential administration of a compound of the invention and a CYP inhibitor (and optionally an additional agent) or derivatives thereof are prepared in a conventional manner.
  • a kit will comprise, e. g. a composition of a compound of the invention and optionally the additional agent (s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.
  • a packaged kit contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration.
  • the instructions will typically be written instructions on a package
  • 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.
  • packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
  • aryl refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl.
  • heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • Ci-C 4 alkyl refers 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.
  • Ci-Cg alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyi, neopentyl, n-hexyl, heptyl and octyl radicals.
  • C 2 -C 8 alkenyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
  • C 2 -C 8 alkynyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • C 3 -C8-cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C 8 -cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-Cycycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1 ] heptyl, and the like.
  • C 3 -Cg cycloalkenyl 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.
  • C 3 -Cs cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples Of Cs-C 7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • arylalkyl refers to an aryl-substituted alkyl group. More preferred arylalkyl groups are aryl-Ci-C ⁇ -alkyl groups.
  • heteroarylalkyl refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-Ci-C ⁇ -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.
  • 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.
  • aliphatic groups are functional groups, such as, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 ,
  • Carbon 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.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
  • a linear aliphatic group is a non-cyclic aliphatic group.
  • the linear aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group.
  • the linear 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 functional group.
  • Y is selected from the group consisting of C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R 1 ⁇ C(O)C(O)N(R 11 ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R 1 ⁇ S(O) 2 or
  • 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.
  • alicyclic denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom, and the carbon atoms may be optionally oxo-substituted.
  • Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may
  • PAGE 67 OF 191 optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted.
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described 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).
  • 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 amino, oxo, thioxo, -NH-Ci-Ci 2 -alkyl, -NH-C 2 -C 8 -alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -Ci 2 - cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci 2 -alkyl, -O-C
  • hydroxy activating group 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, /?-nitro- benzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitro-benzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 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, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group 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 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).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • 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
  • 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, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • hydrocarbons such as hexane and toluene
  • halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like
  • heterocyclic compounds such as, for example, tetrahydrofuran and N- methylpyrrolidinone
  • ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent 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.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • stable 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).
  • subject refers to an animal.
  • 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.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • 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-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • the present invention also relates to solvates of the compounds of the present invention, for example hydrates.
  • PAGE 74 OF 191 This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes A- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable carrier or excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose;
  • PAGE 75 OF 191 starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • 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.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers 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.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or
  • 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.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose,
  • binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrroli
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • PAGE 78 OF 191 Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • 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.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No.
  • 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 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.
  • viral infections, conditions are treated or prevented in a patient such as a human or 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.
  • a therapeutically effective amount of a compound of the invention is 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 mg/Kg to about 500 mg/Kg, preferably from about 1 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
  • PAGE 79 OF 191 daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • 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 dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 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 desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 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 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).
  • such preparations may contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • additional therapeutic or prophylactic agents includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antif ⁇ brotic 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.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • anti-oxidants eg N- acetylcysteine
  • cytokine agonists e.g N- acetylcysteine
  • cytokine antagonists e.g N- acetylcysteine
  • lung surfactants e.g N- acetylcysteine
  • antimicrobial and anti-viral agents eg ribavirin and amantidine.
  • Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HCV, RNA polymerase, protease, or helicase.
  • the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy.
  • combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
  • a compound of the present invention can also be administered in combination or alternation with antiviral agent.
  • antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 24 below.
  • PPh 3 for triphenyl-phosphine
  • Troc for 2,2,2-trichloroethyl carbonyl
  • Ts for tosyl or -SO 2 - C 6 H 4 CH 3
  • Ts 2 O for tolylsulfonic anhydride or tosyl-anhydride
  • TsOH for p-tolylsulfonic acid
  • TMS for trimethylsilyl
  • TMSCl trimethylsilyl chloride.
  • the compounds of the present invention may be prepared via several different synthetic routes from a variety of benzimidazole related intermediates.
  • a retro-synthesis of those title compounds include direct formation of a suitably linked dibenzimidazole core structure followed by attachment of a suitable R 6 group, plus some functional group manipulations in between and/or after.
  • PAGE 85 OF 191 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 derivative Ia-1.1 or la-la.2 and an o-phenylenediamine Ia-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 Ia-I and amino acid Ia-1.1 or Ia-1.2 in the presence of a condensation reagent such as EDC HCl, DCC or the like; or through mixed anhydride approach by reacting acid Ia-1.1 or Ia-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 Ia-I; and 2a) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.
  • the NH group in the newly formed benzimidazole ring of la-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • SEM i.e. SEM-Cl, NaH
  • Boc Boc
  • Cbz Boc
  • Teoc Teoc
  • Troc Troc
  • 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 may be obtained from the Stille reaction conditions to those skilled in the art (see reviews: A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J. 2008, 14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed. 2007, 46, 2768; V. Farina, et al, Advances in Metal-Organic Chem.
  • allylstanne such as allyltributylstanne
  • allyltributylstanne an allylstanne such as allyltributylstanne
  • a key vinyl intermediate la-3 may be prepared by Stille reaction from bromide la-2 with tributylvinylstanne.
  • Sonogashira coupling between bromide la-2 and propargyl alcohol or 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.
  • benzimidazole bromide la-2 may be converted to methyl ketone la-7 by coupling with tributyl(l-ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis. Further elaboration of the benzimidazole intermediates starts from the vinyl intermediate la-3, which may be transformed to aldehyde la-8 through ozono lysis cleavage or to alcohol la-12 by hydroboration-oxidation sequence. Alcohol la-12 may be converted to bromide Ia- 15 by the well-known bromination procedure, which can be further functionalized to amine la-20 through azide substitution followed by reduction.
  • Aldehyde la-8 can then either be reduced to alcohol Ia-11, or be converted to ⁇ , ⁇ - unsatuated acid la-10 through Homer- Wadsworth-Emmons aldehyde homologation reaction followed by saponification.
  • Alcohol Ia-I l may be similarly converted to the correponding amine intermediate Ia- 14 and bromide intermediate Ia- 13 as described previously.
  • Bromide Ia- 13 can be homologated to alkyne intermediate Ia- 19 with a metal acetylide.
  • bromide la-13 may be also tranformed to thiol la-16 through nucleophilic substitution, which can be further oxidized to sulfonic acid Ia- 17.
  • Sulfonamide Ia- 18 may then be derived from Ia- 17 through the sulfonyl chloride activation process.
  • the compounds of the present invention may also be derived from nitrobenzimidazole la-21, which can be prepared from the corresponding 4-nitro-l,2- diaminobenzene using the similar procedures described above.
  • Intermediate la-21 can be converted to amine la-22 through N ⁇ 2 -reduction (i.e. H 2 , catalytical Pd).
  • PAGE 88 OF 191 acid such as acetic acid, hydrochloric aicd, sulfuric acid, or the like, optionally in the presence of a copper or copper salt, may afford hydroxy la-23.
  • esterbenzimidazole la-24 which can be prepared from the corresponding 4-methyl-l,2-diaminobenzoate using the procedures described above, may be hydro lyzed to the corresponding carboxylic acid la-25.
  • 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.
  • the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments with a suitable cyclic linker or formation of a cyclic linker.
  • the said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, amide coupling, ester bond formation, William etherification, Buchwald etherification, alkylation, pericyclic reaction with different variations, or the like.
  • Ia a bismetallated reagent such as 1,3- benzenediboronic acid, 1 ,4-benzene-diboronic acid, 2,5-thiophenediboronic acid, 2,5- bis(trimethylstannyl)thiophene, l,4-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzene, 1 ,4-bis(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)thiophene, 1 ,4-di(l ,3,2- dioxaborinan-2-yl)benzene, 2,5-bis(methoxy-methyl)-l,4-phenylenediboronic acid, or the like, under Suzuki or Stille conditions described in Scheme 1 to provide the linked dibenzimidazole core l-4a.
  • bromobenzimidazole l-2aa may be converted to intermediate 1-5 a by selectively reacting with metallic reagent 1-2.2a under the Suzuki or Stille conditions described previously.
  • intermediate 1-5 a may be prepared by reacting 1- 2aa with dimetallic agent 1-2.3 a to afford organometallic l-6a, followed by coupling with dibromide 1-2.4a, both may be under the previously decribed Suzuki and Stille reaction conditions.
  • the bromide 1-5 a may be further converted to organometallic l-7a with dimetallic agent 1-2.3a using the conditions described above to prepare l-6a. Under the
  • bromide l-2ab may be coupled with organometallic l-7a to afford the linked dibenzimidazole core l-4a.
  • Core l-4a may then serve as a common intermediate for further derivaizations to 1- 8a 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 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.
  • a base such as potassium carbonate
  • the bromides l-2ba and l-2bb may be converted to vinylic l-4b and l-6b, or allylic l-5b and l-7b with a vinylstanne such as tributylvinylstanne 1- 2.1b or an allylstanne such as allyltributylstanne 1-2.2b using the reaction conditions described in Scheme 1.
  • the intermediates l-4b and l-5b can be crossed-linked with intermediates l-6b and l-7b using transition metal catalyzed Hoveyda-Grubbs metathesis reaction conditions which are known to those skilled in the art (see J. D. Waetzig, et al, Chemtracts 2006, 19, 157; C. L. Dwyer, Metal-Catalysis in Industrial Organic Processes
  • the compounds of the present invention may also be derived from nitrobenzimidazole 2a- 1, which can be prepared from the corresponding 4-nitro-l,2- diaminobenzene using the procedures described in Scheme 1.
  • 2a- 1 can be converted to amine 2a-2 in two-steps: 1) NH-protection (i.e. SEM-Cl, NaH); and 2) N ⁇ 2 -reduction (i.e. H 2 , catalytical Pd).
  • Alkylation of 2a-2 with a alkylating reagent such as 1 ,2-dihaloethane, ethylene tosylate, or the like, in the presence of a base such as NaHCO 3 , K 2 CO 3 , pyridine, Et 3 N, DMAP, DBU or the like, may provide the bis- ethylenylated (piperidine)-linked dibenzimidazole 2-3 through the mono-ethylenylated intermediate.
  • the latter with two secondary ethylenediamine may be used to form the 5- membered heterocycle 2a-4 by reacting with CDI, phosgene, triphosgene, or the like, optionally in the presence of a base such as pyridine, Et 3 N, DMAP, DBU or the like.
  • a base such as pyridine, Et 3 N, DMAP, DBU or the like.
  • 2a-2 was alkylated with 1 ,4-diiodobutane followed by sulfonylation with sulfuryl chloride in the presence of a base such as NaHCO 3 , K 2 CO 3 , pyridine, Et 3 N, DMAP, DBU or the like, may provide the 7-membered heterocycle 2a-5.
  • the linked dibenzimidazole 2a-3, 2a-4, or 2a-5 can be further converted to the title compound I-b using the conditions described in Scheme 1 , it is noteworthy that the SEM-group can be
  • intermediate 2a-3 may be obtained by the Buchwald-Hartwig amination process (see references by S. L. Buchwald et al, J.
  • bromobenz-imidazole 3a-l which can be prepared similarly to that of bromides la-2 and la-3 after SEM -protecting as described above, and an amine such as piperazine or the like, using a transition metal catalyst such as palladium acetate in the presence of a base such as sodium t-butoxide (see S. M. Pyke, et al, J. Org. Chem. 2008, 73, 8880; and R. Dorta, et al, JACS 2008, 130, 6848).
  • bromide 3a-l may be reacted with glycine anhydride (piperazine-2,5-dione), imidazolidin-2-one, [l,2,5]-thiazolidine- 1,1 -dioxide under the Buchwald amidation reaction conditions (see C C. Mauger, et al, Aldrichimica Acta 2006, 39, 17; S. L. Buchwald, et al, JA CS 2009, 131, 78; Accounts Chem. Res. 2008, 41, 1439; H. C. Ma, et al, Synlett 2008, 1335; J. H. M. Lange, Tetrahedron Lett. 43, 1101; S. L.
  • glycine anhydride piperazine-2,5-dione
  • imidazolidin-2-one imidazolidin-2-one
  • Buchwald amidation reaction conditions see C C. Mauger, et al
  • bromide 3a- 1 may be subjected to lithium-halogen exchange with various (n-, s-, or t- )butyl lithium and the resulting lithiate can be trapped with a dihalide such as 1 ,4- dibromocyclohexane, 1 ,4-dichlorocyclohexane, 3,6-dibromocyclohexene, 3,6- dichlorocyclohexene, to give the cycloalkyl-linked dibenzimidazoles 3a-5 and 3a-6.
  • a dihalide such as 1 ,4- dibromocyclohexane, 1 ,4-dichlorocyclohexane, 3,6-dibromocyclohexene, 3,6- dichlorocyclohexene
  • olefins 3a-6 can be saturated under hydrogenolytic conditions with a Pd catalyst to give 3a-6.
  • Intermediates 3a-2, 3a-3, 3a-4, 3a-5, and 3a-6 may be then converted to the title compound I-c using the procedures described previously.
  • the compounds of the present invention may also be derived from bromobenzimidazoles l-2a and 1-3 a using the procedures described previously.
  • the intermediates l-2a and 1-3 a have the desired acyl groups already installed as seen in amino acid derivatives 1-1.
  • Ia and 1-1.2a which can be prepared from protected amino acids 4-1.1 and 4-1.2.
  • the invention is a process of making a compound of Formula (1-1) comprising the steps of: i) preparing a compound of Formula (1-II-a):
  • A, n, u, v, R 1 , R 2 , and R 7 are as defined in claim 1; Z a and Z b are each independently an amino protecting group or -C(O)-R 12 ; R 12 is C 1 -
  • Z c is hydrogen, an amino protecting group or -C(O)-R 12 ; iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)-
  • the invention is a process of making a compound having the Formula (2-1) comprising the steps of: i) preparing a compound of Formula (2-II-a):
  • A, n, u, v, R 1 , R 2 , and R 7 are as defined in claim 18;
  • Z a and Z b are each independently an amino protecting group or -C(O)-R 12 ; R 12 is C 1 -
  • Z c is hydrogen, an amino protecting group or -C(O)-R 12 ; iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)-
  • Z d 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 (II-d) :
  • the invention is a process of making a compound having the Formula (3-1) comprising the steps of: i) preparing a compound of Formula (3 -II-a):
  • Z a and Z b are each independently an amino protecting group or -C(O)-R 1Z ; ii) when Z a or Z b is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (3-11 -b):
  • Z c is hydrogen, an amino protecting group or -C(O)-R 12 ;
  • R 12 is Ci-Cg alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C 4 alkyl); iii) capping the released amino group of a compound of Formula (II-b) with LG- C(O)-R 12 , wherein LG is a leaving group; to give the compound of Formula (3-II-c):
  • Z d 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 (3-II-d):
  • Step Ia A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 niL, 26.7 mmol) in THF (60 mL) at -20 0 C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 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).
  • Step Ib A solution of the crude compound from step Ia (10.7 g, theo. 26.7 mmol) in glacial acetic acid (100 mL) was heated at 50 0 C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step Ic A mixture of the compound from step Ib (0.500 g, 1.37 mmol), benzene-1,4- diboronic acid (0.103 g, 0.621 mmol) and Pd(PPh 3 ) 4 (35.8 mg, 31.0 ⁇ mol) in ethanol (6 mL), toluene (6 mL) and aqueous Na 2 CO 3 (2 M, 0.4 mL) was degassed and heated to reflux under N 2 overnight. 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.
  • Step 2a A solution of the compound from step Ic (79.0 mg, 0.122 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) 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 449.39 [M+H] + .
  • Step 354a-a A solution of the compound from step Ib (2.18 g, 5.95 mmol) in DMF (50 mL) was treated with NaH (60% in mineral oil, 0.273 g, 6.84 mmol) for 1 hour before a slow addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.05 mL, 5.95 mmol). The mixture was kept stirring for 3 hours before being diluted with EtOAc and quenched with saturated NH 4 Cl. The organics were washed with water and brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 354a A solution of the compound from step 354a-b (100 mg, 0.109 mmol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at 50 0 C for 2 hours. 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 457.37 [M+H] + .
  • Step 354b The title compound was synthesized from the compound from step 354a using a procedure similar to that described in Example 3.
  • ESIMS m/z 839.34 [M+H] + .
  • Step 357a A solution of the compound from Example 357a (47.9 mg, 50.7 ⁇ mol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at 50 0 C for 2 hours.
  • Step 363a A mixture of the compound from step Ib (1 g, 2.73 mmol), bis-(pinacolato)- diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4-dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80 0 C under N 2 overnight before being evaporated.
  • Step 363b A mixture of the compound from step 363a (0.400 g, 0.969 mmol), 2,6- dibromo-naphthalene (0.126 g, 0.440 mmol), NaHCO 3 (0.296 g, 3.52 mmol) and Pd(PPh 3 ) 4 (25.4 mg, 22.0 ⁇ mol) in DME (12 mL) and water (4 mL) was degassed and heated at 85 0 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.
  • examples 1-4 to 1-360 may be prepared using procedures similar to those described in examples 1-1, 1-2, 1-3, 1-20, 1-25, 1-26, 1-42, 1- 52, 1-54, 1-62, 1-67, 1-70, 1-72, 1-78, 1-83, 1-114, 1-354, l-354a, 1-357, l-357a, 1-361 to 1-372, and/or procedures described in the Synthetic Methods.
  • Table 2 Examples 1-220 to 1-229.
  • Step la-a A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0 C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 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).
  • Step la-c A mixture of the compound of step la-b (0.250 g, 0.683 mmol), allyltributyl- stannane (0.26 mL, 0.820 mmol) and Pd(PPh 3 ) 4 (39.4 mg, 34.1 ⁇ mol) in toluene (6 mL) was degassed and heated to 110 0 C under N 2 overnight. 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.
  • Step la-d A mixture of the compound of step la-c (0.100 g, 0.306 mmol) and Grubbs-1 Catalyst (12.5 mg, 15.2 ⁇ mol) in CH 2 Cl 2 (6 mL) was degassed and heated to reflux under N 2 for 3 days.
  • Step 3a-a A solution of the compound of Example la-a (8.7 mg, 13.8 ⁇ mol) 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 427.39 [M+H] + .
  • step la-b A mixture of the compound of step la-b (0.156 g, 0.427 mmol), the compound of step Ia- c (0.127 g, 0.388 mmol), triethylamine (0.56 mL, 3.88 mmol), tri-o-tolylphosphine (15.2 mg, 48.5 ⁇ mol) and Pd(OAc) 2 (4.4 mg, 19.4 ⁇ mol) in CH 3 CN (6 mL) was degassed and heated to 80 0 C under N 2 overnight. 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.
  • Step 356a A mixture of JV-Boc-L-proline (7.03 g, 32.6 mmol) and TEA (4.55 mL, 32.6 mmol) in THF (60 mL) at -20 0 C was treated with ⁇ o-butyl chloroformate (4.27 mL, 32.6
  • examples 1-352 may be prepared using procedures similar to those described in examples Ia, 3a, 310, 353-357, and/or as described in the Synthetic Methods.
  • Step 335a A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0 C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 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).
  • Step 335c A mixture of the compound from step 335b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80 0 C under N 2 overnight before being evaporated.
  • Step 335d A mixture of the compound from step 335c (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 ⁇ mol) in DME (12 mL) and water (4 mL) was degassed and heated at 85 0 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.
  • Step 335e A mixture of the compound from step Ib (2.010 g, 5.488 mmol), trimethylsilyl-acetylene (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 0 C under N 2 overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a yellow foam (1.140 g, 54%).
  • Step 335f A suspension of the compound from step 335e (1.140 g, 2.972 mmol) and K 2 CO 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 paritioned (EtOAc - H 2 O). The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Step 336a A solution of the compound from Example 335 (0.108 g, 0.161 mmol) 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.
  • Step 336b A mixture of the crude compound from step 336a (0.161 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO
  • HCV replicon cell lines (kindly provided by R. Bartenschlager) isolated from colonies as described by Lohman et. al. (Lohman et al. (1999) Science 285: 110-113, expressly incorporated by reference in its entirety) and used for all experiments.
  • the HCV replicon has the nucleic acid sequence set forth in EMBL Accession No.: AJ242651, the coding sequence of which is from nucleotides 1801 to 8406.
  • HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genes and the HCV 3'UTR.
  • HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene, (iv) the neomycin phosphotransferase gene (neo), (v) the IRES from encephalomyocarditis virus (EMCV), and (vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations (E1202G, T1280I, K1846T) and the HCV 3'UTR.
  • 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
  • EC 50 values of single agent compounds and combinations were determined by HCV RNA detection using quantitative RT-PCR, according to the manufacturer's instructions, with a TaqMan® One-Step RT-PCR Master Mix Reagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler.
  • the TaqMan primers used for detecting and quantifying were obtained from Integrated DNA
  • HCV RNA was normalized to GAPDH RNA levels in drug-treated cells, which was detected and quantified using the Human GAPDH Endogenous Control Mix (Applied Biosystems, AB 4310884E). Total cellular RNA was purified from 96-well plates using the RNAqueous 96 kit (Ambion, Cat# AMI 812). Chemical agent cytotoxicity was evaluated using an MTS assay according to the manufacturer's directions (Promega). 3. HCV Replicon Assay - Luciferase
  • HCV replicon system assessed the potential use of the compound of the present invention or in combination therapies with Interferon alpha, cyclosporine analogs and inhibitors targeting other HCV proteins.
  • the acute effects of a single or combinations of drugs are studied in the "Huh-luc/neo-ET" replicon with each chemical agent titrated in an X or Y direction in a 6 point two-fold dilution curve centered around the EC50 of each drug.
  • replicon cells are seeded at 7,000 cells per well in 90 ul DMEM (without phenol red, Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX penicillin/streptomycin and incubated overnight at 37°C, 5% CO 2 , 100% relative humidity.
  • test compounds previously solubilized and titrated in dimethyl sulfoxide (“DMSO”) from each X plate and Y plate are diluted 1 : 100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX 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).
  • DMSO dimethyl sulfoxide
  • Drug treated cells are incubated at 37°C, 5% CO 2 , 100% relative humidity for 72 hours before performing a luciferase assay using 100 ul per well BriteLite Plus (Perkin Elmer) according to the manufacturer's instructions.
  • Data analysis utilizes the method published by Prichard and Shipman (Antiviral Research, 1990. 14:181-205). Using this method, the combination data are analyzed for antagonistic, additive, or synergistic combination effects across the entire combination surface created by the diluted compounds in combination.
  • the compounds of the present invention may inhibit HCV by mechanisms in addition to or other than NS5A inhibition.
  • the compounds of the present invention inhibit HCV replicon and in another embodiment the compounds of the present invention inhibit NS5A.
  • the compounds of the present invention can be effective against the HCV Ib genotype. It should also be understood that the compounds of the present invention can inhibit multiple genotypes of HCV. In one embodiment, compound of the present invention are active against the Ia, Ib, 2a, 2b, 3a, 4a, and 5a genotypes.
  • Table 25 shows the EC50 values of representative compounds of the present invention against the HCV Ib genotype from the above described qRT-PCR or luciferase assay. EC50 ranges against HCV Ib are as follows: A >10 nM; B 1-10 nM; C ⁇ InM.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses linked dibenzimidazole derivatives, 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.

Description

LINKED DIBENZIMIDAZOLE DERIVATIVES
Inventors: Yao-Ling Qiu, Ce Wang, Lu Ying, Xiaowen Peng, and Yat Sun Or
RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No. 61/151,079 filed February 9, 2009, U.S. Provisional Application No. 61/153,224, filed February 17, 2009, U.S. Provisional Application No. 61/156,239 filed February 27, 2009, U.S. Provisional Application No. 61/153,231 filed February 17, 2009 and U.S. Provisional Application No. 61/156,110 filed February 27, 2009. The entire teachings of the above applications are incorporated herein by reference.
TECHNICAL FIELD The present invention relates to novel antiviral agents. More specifically, the present invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, methods for inhibiting HCV viral replication, methods for treating or preventing HCV infection, and processes for making the compounds.
BACKGROUND OF THE INVENTION
Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-
PAGE 1 OF 191 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 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 liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.
First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359-362), HCV is now widely accepted as the most common causative agent of post- transfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA - A Publication of the RNA Society. 1(5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2nd Edition,
PAGE 2 OF 191 p931-960; Raven Press, N.Y.). There are three structural proteins, C, El and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are several non- structural proteins. NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus. NS4A is a tightly associated but non-covalent cofactor of the serine protease. NS5A is a membrane-anchored phosphoprotein that is observed in basally phosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms. While its function has not fully been elucidated, NS5A is believed to be important in viral replication. The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 151 2-22) encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra- typically (-95-98% amino acid (aa) identity across Ib isolates) and inter-typically (-85% aa identity between genotype Ia and Ib isolates). The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al. (2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection. Following the termination codon at the end of the long ORF, there is a 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261). The 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. In particular, compounds which are effective to inhibit the function of the NS5A protein are desired. The HCV NS5A protein is described, for example, in Tan, S. -L., Katzel, M.G. Virology 2001, 284, 1; and in Rice, C. M. Nature 2005, 435, 374.
PAGE 3 OF 191 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 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 2008/021936; WO 2006/1333262; 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; WO 2008/048589, the contents of each of which are expressly incorporated by reference herein.
SUMMARY OF THE INVENTION
The present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds. Compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
In its first principal aspect, the present invention provides a compound of Formula (1-1):
or a pharmaceutically acceptable salt thereof, wherein:
A is independently selected from the group consisting of: aryl, heteroaryl, heterocyclic, C3-Cg cycloalkyl, and C3-Cg cycloalkenyl, all optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R10, -OR11, N(Rπ)2, -C(O)R11, -CO2R11, -C(O)N(Rn)2 and -N(Rn)C(O)Rn; A is preferably phenyl, 5-7-membered heteroaryl, 5-7-membered heterocyclic, C5-C7 cycloalkyl, or C5-C7 cycloalkenyl, all optionally substituted with one or more substituents independently selected from halogen and R10;
R10 at each occurrence is independently C1-C4 alkyl optionally substituted with one or more halogen atoms;
PAGE 4 OF 191 R11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl;
R1 and R2 at each occurrence are each independently selected from the group consisting of: halogen, cyano, optionally substituted C1-C4 alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11, and -C(0)NRaRb, preferably halogen and optionally substituted C1- C4 alkyl;
Ra and Rb at each occurrence are each independently hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C2-Cs alkenyl; or Ra and Rb taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u and v at each occurrence are each independently 0, 1, 2, or 3, preferably 0 or 1;
Q and J are each independently selected from:
R3 and R4 at each occurrence are each independently hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-Cs alkenyl or optionally substituted C3- Cs cycloalkyl, preferably hydrogen or optionally substituted Ci -C4 alkyl; or alternatively, R3 and R4 taken together with the carbon atom to which they are attached form optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic;
R5 at each occurrence is independently hydrogen, optionally substituted Ci-C8 alkyl, or optionally substituted C3-Cs cycloalkyl, preferably hydrogen or optionally substituted Ci-C4 alkyl;
R6 at each occurrence is independently selected from the group consisting of: hydrogen, -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12, preferably -C(O)-R12; R12 at each occurrence is independently selected from the group consisting of: -O- R11, -NRaRb, -R13, -NRcRd, -CH(R13)NRaRb, and -CH(R13)NRcRd, preferably optionally substituted Ci-C8 alkyl and -O-R11;
R13 at each occurrence is independently selected from the group consisting of: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, and optionally
PAGE 5 OF 191 substituted heteroarylalkyl; preferably Ci-Cs alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C4 alkyl);
Rc and Rd at each occurrence are each independently selected from the group consisting of: hydrogen, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13)2; m is O, 1, or 2; preferably 1; n is O, 1, 2, 3, or 4; preferably 0, 1, or 2;
X at each occurrence is independently selected from O, S, S(O), SO2, CH2, CHR7, and C(R7)2; preferably CH2 or CHR7; provided that when m is O, X is selected from CH2, CHR7, and C(R7)2; or
R7 at each occurrence is independently selected from the group consisting of: halogen, cyano, -O-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C4 alkyl, preferably methyl or halogen; or, two vicinal R7 groups are taken together with the two adjacent atoms to which they are attached form a fused, optionally substituted -C3-Cg cycloalkyl or optionally substituted heterocyclic ring; preferably, a fused, optionally substituted cyclopropyl; or alternatively, two geminal R7 groups are taken together with the carbon atom to which they are attached form a spiro, optionally substituted C3-Cg 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 (2-1):
or a pharmaceutically acceptable salt thereof, wherein:
A is an optionally substituted linear aliphatic group; R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted Ci-C4 alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11, and -C(0)NRaRb; preferably hydrogen, halogen and optionally substituted Ci-C4 alkyl;
R11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl; and
PAGE 6 OF 191 Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, and optionally substituted C2- C8 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 and v at each occurrence are each independently 1, 2, or 3; Q and J are each independently selected from:
R6 , wherein
R3 and R4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-Cs alkenyl, and optionally substituted C3-Cs cycloalkyl; preferably hydrogen or optionally substituted C1-C4 alkyl; or alternatively, R3 and R4 can be taken together with the carbon atom to which they are attached to form optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic; R5 at each occurrence is independently hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C3-Cs cycloalkyl; preferably hydrogen or optionally substituted Ci-C4 alkyl;
R6 at each occurrence is independently selected from the group consisting of -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12, preferably -C(O)-R12, more preferably an optionally substituted amino acid acyl;
R12 at each occurrence is independently selected from the group consisting of: -O- R11, -NRaRb, -R13, and -NRcRd, preferably optionally substituted Ci-C8 alkyl and -0-R11;
R13 at each occurrence is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-C8 alkyl; more preferably Ci-C8 alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C4 alkyl); and
Rc and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13),; m is O, 1, or 2, preferably 1;
PAGE 7 OF 191 n is 1, 2, 3, or 4, preferably 1 or 2;
X at each occurrence is independently selected from O, S, S(O), SO2, and C(R7)2, preferably CH2 or CHR7; provided that when m is O, X is C(R7)2; and
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -O-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C1-C4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively, two geminal R7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
In its third principal aspect, the present invention provides a compound of Formula (3-1):
or a pharmaceutically acceptable salt thereof, wherein:
A is a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C3- C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted; D is absent or an optionally substituted aliphatic group;
T is absent or an optionally substituted linear aliphatic group containing zero to eight carbons;
E is absent or independently selected from optionally substituted aryl and optionally substituted heteroaryl; wherein one or two of D, E, and T are absent;
R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted Ci-C4 alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11, and -C(0)NRaRb; preferably hydrogen, halogen and optionally substituted Ci-C4 alkyl;
PAGE 8 OF 191 R11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl;
Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C8 alkyl, and optionally substituted C2- Cg 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 and v at each occurrence are each independently 1, 2, or 3;
Q and J are each independently selected from:
R3 and R4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C2-Cg alkenyl, and optionally substituted C3-Cg cycloalkyl; preferably hydrogen or optionally substituted C1-C4 alkyl; or alternatively, R3 and R4 can be taken together with the carbon atom to which they are attached to form optionally substituted C3-Cg cycloalkyl or optionally substituted heterocyclic;
R5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C3-Cg cycloalkyl; preferably hydrogen or optionally substituted Ci-C4 alkyl; R6 at each occurrence is independently selected from the group consisting of
-C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12, preferably -C(O)-R12, more preferably an optionally substituted amino acid acyl;
R12 at each occurrence is independently selected from the group consisting of: -O- R11, -NRaRb, -R13, and -NRcRd, preferably optionally substituted Ci-C8 alkyl and -O-R11; R13 at each occurrence is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, C3-Cg cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-Cg alkyl; more preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C4 alkyl); and
PAGE 9 OF 191 Rc and Rd at each occurrence are each independently selected from the group consisting of hydrogen, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13)2; m is O, 1, or 2, preferably 1; n is 1, 2, 3, or 4, preferably 1 or 2;
X at each occurenece is independently selected from O, S, S(O), SO2, and C(R7)2, preferably CH2 or CHR7; provided that when m is O, X is C(R7)2; and
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -0-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
Each preferred group stated above can be taken in combination with one, any or all other preferred groups. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
In yet another aspect, the present invention provides a method of inhibiting the replication of a RNA-containing virus comprising contacting said virus with a 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 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
PAGE 10 OF 191 thereof. Particularly, this invention is directed to methods of treating or preventing infection caused by HCV.
Yet another aspect of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically HCV.
DETAILED DESCRIPTION OF THE INVENTION
I. Compounds having Formula (1-1)
In certain aspects, the present invention relates to compounds of Formula (1-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to compounds of Formula (1-Ia), or a pharmaceutically acceptable salt thereof:
wherein A, u, v, R1, R2, R3, R4, R5 and R6 are as previously defined in Formula (1-1). In another embodiment, the present invention relates to compounds of Formula (1-
Ib), or a pharmaceutically acceptable salt thereof:
wherein A, u, v, m, n, R1, R2, R3, R4, R5, R6, R7 and X are as previously defined in Formula (1-1). In yet another embodiment, the present invention relates to compounds of Formula
(1-Ic), or a pharmaceutically acceptable salt thereof:
PAGE 11 OF 191 wherein A, u, v, m, n, R1, R2, R6, R7 and X are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-Id), or a pharmaceutically acceptable salt thereof:
wherein A, R3, R4, R5 and R12 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-Ie), or a pharmaceutically acceptable salt thereof:
wherein A, R3, R4, R5 and R12 are as previously defined in Formula (l-I).and X1 is CH2, CHF, CH(OH), or CF2.
In still another embodiment, the present invention relates to compounds of Formula (1-If), or a pharmaceutically acceptable salt thereof:
wherein A, X1 and R12 are as previously defined in Formula (1-1).
In an additional embodiment, the present invention relates to compounds of Formula (1-If), wherein R12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl); or a pharmaceutically acceptable salt thereof.
PAGE 12 OF 191 In still another embodiment of the present invention, the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine moiety is represented by Formulae (1-Ig-l, l-Ig-2 and l-Ig-3):
wherein A, R3, R5 and R12 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIa), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1) and A1 is independently an aryl; preferably phenyl or naphthyl ring, optionally substituted with one or more substituents independently selected from halogen and R10; and R10 is as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIb), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1) and A2 is independently a heteroaryl, preferably 5-7-membered heteroaryl, optionally with one or
PAGE 13 OF 191 more substituents independently selected from halogen and R10; and R10 is as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIc), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1) and A3 is independently a heterocyclic, preferably 5-7-membered heterocyclic, optionally with one or more substituents independently selected from halogen and R10; and R10 is as previously defined in Formula (1-1). In still another embodiment, the present invention relates to compounds of
Formula (1-IId), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1) and A4 is independently a C3-Cs cycloalkyl, preferably 5-7-membered cycloalkyl, optionally with one or more substituents independently selected from halogen and R10; and R10 is as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIe), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1) and A5 is independently a C3-Cg cycloalkenyl, preferably 5-7-membered cycloalkenyl, optionally substituted with one or more substituents independently selected from halogen and R10; and R10 is as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIa), or a pharmaceutically acceptable salt thereof:
PAGE 14 OF 191 wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIb), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIc), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIId), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIe), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIf), or a pharmaceutically acceptable salt thereof:
PAGE 15 OF 191 wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIg), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of Formula (1-IIIh), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1, and R2 are as previously defined in Formula (1-1).
In still another embodiment, the present invention relates to compounds of
Formula (1-1), or a pharmaceutically acceptable salt thereof; wherein at each occurrence is independently illustrated by one of the following groups:
Representative compounds of Formula (1"-1) are those selected fr"om compounds 1- 1 to 1-360, l-354a, l-357a, and 1-361 to 1-372 compiled in the following tables:
PAGE 16 OF 191 Table 1: Compounds 1-1 to 1-219
PAGE 17 OF 191
PAGE 18 OF 191
PAGE 19 OF 191
PAGE 20 OF 191
PAGE21 OF 191 Table 2: Compounds 1-220 to 1-229
Table 3: Compounds 1-234 to 1-243
PAGE 22 OF 191
Table 4: Compounds 1-244 to 1-263
PAGE23OF 191 Table 5: Compounds 1-264 to 1-283
Table 6: Compounds 1-284 to 1-309
PAGE 24 OF 191 Table 7: Compounds 1-310 to 1-360
PAGE25OF 191 Table 8: Compounds l-354a. l-357a. and 1-361 to 1-372
PAGE 26 OF 191 II. Compounds having the Formula (2-1)
The present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
In an embodiment, the present invention relates to compounds of Formula (2-Ia), or a pharmaceutically acceptable salt thereof:
wherein A, u, v, R1, R2, R3, R4, R5 and R6 are as previously defined in Formula (2-1).
In another embodiment, the present invention relates to compounds of Formula (2- Ib), or a pharmaceutically acceptable salt thereof:
wherein A, u, v, m, n, R1, R2, R3, R4, R5, R6, R7 and X are as previously defined in Formula (2-1).
In yet another embodiment, the present invention relates to compounds of Formula (2-Ic), or a pharmaceutically acceptable salt thereof:
wherein A, u, v, m, n, R1, R2, R6, R7 and X are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Id), or a pharmaceutically acceptable salt thereof:
wherein A, R3, R4, R5 and R12 are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Ie), or a pharmaceutically acceptable salt thereof:
PAGE 27 OF 191 wherein A, R3, R4, R5 and R12 are as previously defined in Formula (2-1) and X1 is CH2, CHF, CH(OH), or CF2.
In still another embodiment, the present invention relates to compounds of Formula (2-If), or a pharmaceutically acceptable salt thereof:
wherein A, X1 and R12 are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-If), wherein R12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl); or a pharmaceutically acceptable salt thereof.
In still another embodiment of the present invention, the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine moiety is represented by Formulae (2-Ig-l, 2-Ig-2 and 2-Ig-3):
wherein A, R3, R5, and R12 are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Ih), or a pharmaceutically acceptable salt thereof:
PAGE 28 OF 191 wherein A, X1 and R11 are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Ii), or a pharmaceutically acceptable salt thereof:
wherein A, X1, Ra and Rb are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Ij), or a pharmaceutically acceptable salt thereof:
wherein A, X1, Rc and Rd are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Ik), or a pharmaceutically acceptable salt thereof:
wherein A, X1 and R13 are as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-11), or a pharmaceutically acceptable salt thereof:
wherein A and X1 are as previously defined in Formula (2-1) and R13a at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl).
In still another embodiment, the present invention relates to compounds of Formula (2-IIa), or a pharmaceutically acceptable salt thereof:
PAGE 29 OF 191
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1) and A1 is Ci-Cs alkyl, preferably C3-C6 alkyl, each optionally substituted.
In still another embodiment, the present invention relates to compounds of Formula (2-IIb), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1) and A2 is C2-Cs alkenyl, preferably C3-C6 alkenyl, each optionally substituted.
In still another embodiment, the present invention relates to compounds of Formula (2-IIc), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1) and A3 is C2-Cs alkynyl, preferably C3-C6 alkynyl, each optionally substituted.
In still another embodiment, the present invention relates to compounds of Formula (2 -Hd), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1); and A4 is a linear aliphatic group containing a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rπ), N(Rπ)S(0)2N(Rn), C(O)N(Rn)S(O)2 or C(0)N(Rn)S(0)2N(Rπ); and R11 is as previously defined in Formula (2-1).
PAGE 30 OF 191 In still another embodiment, the present invention relates to compounds of Formula (2-IIe), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1).; and A5 is a linear aliphatic group containing an olefϊnic double bond and a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(R1 ^C(O)C(O)N(R11), N(Rπ)S(0)2N(Rn), C(O)N(R1 ^S(O)2 or C(0)N(Rn)S(0)2N(Rn); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2 -Hf), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1); and A6 is a linear aliphatic group containing an alkynic triple bond and a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(R1 ^C(O)C(O)N(R11), N(Rπ)S(0)2N(Rn), C(O)N(R1 ^S(O)2 or
C(0)N(Rn)S(0)2N(Rn); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Hg), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined for Formula (2-1); and A7 is a linear aliphatic group containing one or more groups independently selected from O and N(R11); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-Hh), or a pharmaceutically acceptable salt thereof:
PAGE 31 OF 191 wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1); and A8 is a linear aliphatic group containing an olefmic double bond and one or more groups independently selected from O and N(R11); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-IIi), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1); and A9 is a linear aliphatic group containing an alkynic triple bond and one or more groups independently selected from O and N(R11); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-IIIa), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1) and L1 is selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11),
N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rn), N(Rn)S(O)2N(Rn), C(O)N(R1 ^S(O)2 or C(0)N(Rn)S(0)2N(Rn); and R11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of Formula (2-IIIb), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (2-1) and L2 is a linear aliphatic group containing one to four carbons and two groups independently selected
PAGE 32 OF 191 from O, N(R11), C(O), S(O)2, C(O)O, C(O)N(R I1h1), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(O)N(Rn), N(Rn)S(O)2N(Rπ), C(O)N(Rn)S(O)2 or C(O)N(Rn)S(O)2N(Rn); and
R , 11 is as previously defined in Formula (2-1).
In still another embodiment, the present invention relates to compounds of
Formula (2-1), or a pharmaceutically acceptable salt thereof; wherein at each occurrence is independently illustrated by one of the following groups:
Representative compounds having the Formula (2-1) are those selected from compounds 2-1 to 2-352, 2- Ia, 2-3a, and 2-353 to 2-357 compiled in the following tables:
Table 9: Compounds 2-1 to 2-219
PAGE 33 OF 191
PAGE 34 OF 191 Me
PAGE 35 OF 191
PAGE 36 OF 191
PAGE 37 OF 191
Table 10: Compounds 2-220 to 2-229
PAGE 38 OF 191 Compound 2-230
Compound 2-231
Table 11 : Compounds 2-234 to 2-243
Table 12: Compounds 2-244 to 2-263
PAGE 39 OF 191
Table 13: Compounds 2-264 to 2-283
PAGE 40 OF 191 Table 14: Compounds 2-284 to 2-309
Table 15: Compounds 2-310 to 2-352
PAGE41 OF 191
Table 16: Compounds 2- Ia. 2-3 a. and 2-353 to 2-357
III. Compounds having the Formula (3-1) The present invention relates to compounds of Formula (3-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
PAGE 42 OF 191 In another embodiment, the present invention relates to compounds of Formula (3- Ia), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, u, v, R1, R2, R3, R4, R5 and R6 are as previously defined in Formula (3-1).
In another embodiment, the present invention relates to compounds of Formula (3- Ib), or a pharmaceutically acceptable salt thereof:
(3-lb) (R2)v wherein A, D, E, T, u, v, m, n, R1, R2, R3, R4, R5, R6,R7 and X are as previously defined in Formula (3-1).
In yet another embodiment, the present invention relates to compounds of Formula (3-Ic), or a pharmaceutically acceptable salt thereof:
where ήinn AA,, DD,, EE,, TT,, uu, v, m, n, R1, R2, R6, R7 and X are as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of Formula (3-Id), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, u, v, R1, R2, R3, R4, R5 and R12 are as previously defined in Formula (3-1).
PAGE 43 OF 191 In still another embodiment, the present invention relates to compounds of Formula (3-Ie), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, u, v, R1, R2, R3, R4, R5, R7 and R12 are as previously defined in Formula (3-1) and X1 is independently CH2, CHF, CH(OH), or CF2.
In still another embodiment, the present invention relates to compounds of Formula (3-If), or a pharmaceutically acceptable salt thereof:
V -/v (3-If) V (R2), ~NH oΛRl2 wherein A, D, E, T, u, v, X1, R1, R2, R7 and R12 are as previously defined in Formula (3-1).
In still another embodiment of the present invention, the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine moiety is represented by Formula (3- Ig-I, 3-Ig-2 and 3-Ig-3):
wherein A, D, E, T, R3, R5, and R12 are as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of Formula (3-Ih), or a pharmaceutically acceptable salt thereof:
PAGE 44 OF 191 wherein A, D, E, T, X1 and R11 are as previously defined in Formula (3-1)
In still another embodiment, the present invention relates to compounds of Formula (3-Ii), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, X1, Ra and Rb are as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of Formula (3-Ij), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, X1, Rc and Rd are as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of Formula (3-Ik), or a pharmaceutically acceptable salt thereof:
wherein A, D, E, T, X1 and R13 are as previously defined in Formula (3-1)
In still another embodiment, the present invention relates to compounds of
Formula (3-Ik), wherein R13 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl); or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention relates to compounds of
Formula (3-11), or a pharmaceutically acceptable salt thereof:
PAGE 45 OF 191 wherein A, D, E, T and X1 are as previously defined in Formula (3-1) andR1Ja at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino or O(Cl-C4 alkyl).
In still another embodiment, the present invention relates to compounds of Formula (3-IIa), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D1 is an optionally substituted C1-C4 alkyl. In another embodiment, the compound has the Formula (3-IIa), wherein A is a heterocyclic; or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention relates to compounds of Formula (3-IIb), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D2 is an optionally substituted C2-C4 alkenyl.
In still another embodiment, the present invention relates to compounds of Formula (3-IIc), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D3 is an optionally substituted C2-C4 alkynyl.
In still another embodiment, the present invention relates to compounds of Formula (3-IId), or a pharmaceutically acceptable salt thereof:
PAGE 46 OF 191 wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D4 is selected from O and N(R11); and R11 is as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of Formula (3-IIe), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D5 is selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rn), N(Rn)S(O)2N(Rn), C(O)N(R1 ^S(O)2 and C(0)N(Rn)S(0)2N(Rn); and R11 is as previously defined in Formula (3-1). In still another embodiment, the present invention relates to compounds of
Formula (3-IIf), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D6 is an optionally substituted C3-Cg cycloalkyl or optionally substituted C3-Cg cycloalkenyl. In still another embodiment, the present invention relates to compounds of
Formula (3-IIg), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D7 is an optionally substituted heterocyclic. In still another embodiment, the present invention relates to compounds of
Formula (3-IIIa), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and E1 is an optionally substituted aryl.
PAGE 47 OF 191 In still another embodiment, the present invention relates to compounds of Formula (3-IIIb), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and E2 is an optionally substituted heteroaryl.
In still another embodiment, the present invention relates to compounds of Formula (3-IIIc), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1); E is present and as previously defined for Formula (3-1); and A1 is an optionally substituted aryl.
In still another embodiment, the present invention relates to compounds of Formula (3-IIId), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A2 is an optionally substituted heteroaryl.
In still another embodiment, the present invention relates to compounds of Formula (3-IIIe), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A3 is an optionally substituted heterocyclic.
In still another embodiment, the present invention relates to compounds of Formula (3-IIIf), or a pharmaceutically acceptable salt thereof:
PAGE 48 OF 191 wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A4 is an optionally substituted C3-C8 cycloalkyl.
In still another embodiment, the present invention relates to compounds of Formula (3-IIIg), or a pharmaceutically acceptable salt thereof:
wherein Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1); E is present and as previously defined in Formula (3-1); and A5 is an optionally substituted C3-Cg cycloalkenyl.
In still another embodiment, the present invention relates to compounds of Formula (3-IVa), or a pharmaceutically acceptable salt thereof:
wherein A, Q, J, u, v, R1 and R2 are as previously defined in Formula (3-1) and D8 and T1 are each independently linear aliphatic group containing zero to six carbons, optionally contain one or more groups selected from O, N(R11), C(O), S(O)2, C(O)O, and C(O)N(R11); and R11 is as previously defined in Formula (3-1).
In still another embodiment, the present invention relates to compounds of
occurence is independently illustrated by one of the following groups:
PAGE 49 OF 191
Representative comFpounds of the present invention are those selecte from compounds 3-1 to 3-334 compiled in the following tables:
Table 17: Compounds 3-1 to 3-219
PAGE 50 OF 191
PAGE51 OF 191
PAGE 52 OF 191
PAGE 53 OF 191
PAGE 54 OF 191
Table 18: Compounds 3-220 to 3-229
PAGE 55 OF 191 Compound 3-230
Compound 3-233
Table 19: Compounds 3-234 to 3-243
Table 20: Compounds 3-244 to 3-263
PAGE 56 OF 191
Table 21 : Compounds 3-264 to 3-289
PAGE 57 OF 191
Table 22: Compounds 3-290 to 3-334
PAGE 58 OF 191 Table 23: Compounds 3-335 to 3-337
Compounds of Formulae (1-1), (2-1) and (3-1)
It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a
substitutent at any given location. For example, in the structure Rz may be attached to either the carbon atom in the benzimidazole ring or, alternatively, in Formula (1-1), R2 may take the place of the hydrogen atom on the nitrogen ring to form an N- substituted benzimidazole.
It is intended that the definition of any substituent or variable (e.g., A, R1, R2, 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 R1 groups may be the same or different. It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention. It should be understood that 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 prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
PAGE 59 OF 191 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 pharmaceutically acceptable carrier or excipient. Yet a further embodiment of the present invention is a pharmaceutical composition comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents known in the art, with a pharmaceutically acceptable carrier or excipient.
It will be further appreciated that compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection. Other agents to be administered in combination with a compound or combination of compounds of the present invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These agents include, but not limited to, host immune modulators (for example, interferon- alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example, HCV P7 and the like; and any agent or combination of agents that inhibit the replication of HCV by targeting other proteins of the viral genome involved in the viral replication and/or interfere with the function of other viral targets, such as inhibitors of NS3/NS4A protease, NS3 helicase, NS5B polymerase, NS4A protein and NS5 A protein.
According to yet another embodiment, the pharmaceutical compositions of the present invention may further comprise other inhibitor(s) of targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
PAGE 60 OF 191 Accordingly, one embodiment of the present invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising coadministering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof. Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome. 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 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). Yet another embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof. An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof. A non- limiting example of the RNA-containing virus is hepatitis C virus (HCV).
A further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof. The agent that treats patients for disease caused
PAGE 61 OF 191 by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T- 1249, or any combination thereof. 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 or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) or 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.
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-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 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 therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt thereof, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition. In addition, such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
PAGE 62 OF 191 Hence, a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form. Antiviral agents contemplated for use in such combination therapy include agents
(compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
Other agents 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 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 increase the bioavailiablity of a compound of the invention when the bioavailability is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
In one embodiment, the invention provides methods for improving the pharmacokinetics of a compound of the invention. The advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, US Patent App. Nos. 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 and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2Cl 9 ("CYP2C19"), isozyme 2D6 ("CYP2D6"), isozyme 1A2 ("CYP1A2"), isozyme 2C9 ("CYP2C9"), or isozyme 2El ("CYP2E1"). In a preferred embodiment, the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant compound of the invention may be
PAGE 63 OF 191 used in a method of this invention. These CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfmavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
It will be understood that the administration of the combinations of the invention by means of a single patient pack, or patient packs of each formulation, containing within a package insert instructing the patient to the correct use of the invention is a desirable additional feature of this invention.
According to a further aspect of the invention is a pack comprising at least a compound of the invention and a CYP inhibitor and an information insert containing directions on the use of the combination of the invention. In an alternative embodiment of this invention, the pack further comprises one or more additional agents as described herein. The additional agent or agents may be provided in the same pack or in separate packs.
Another aspect of this involves a packaged kit for a patient to use in the treatment of HCV infection or in the prevention of HCV infection, comprising: a single or a plurality of pharmaceutical formulations of each pharmaceutical component; a container housing the pharmaceutical formulation (s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.
Accordingly, this invention provides kits for the simultaneous or sequential administration of a compound of the invention and a CYP inhibitor (and optionally an additional agent) or derivatives thereof are prepared in a conventional manner. Typically, such a kit will comprise, e. g. a composition of a compound of the invention and optionally the additional agent (s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.
In another embodiment, a packaged kit is provided that contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration. The instructions will typically be written instructions on a package
PAGE 64 OF 191 insert, a label, and/or on other components of the kit, and the dosage form or forms are as described herein. Each dosage form may be individually housed, as in a sheet of a metal foil- plastic laminate with each dosage form isolated from the others in individual cells or bubbles, or the dosage forms may be housed in a single container, as in a plastic bottle. The present kits will also typically include means for packaging the individual kit components, i. e., the dosage forms, the container means, and the written instructions for use. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
DEFINITIONS Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl.
The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.
In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.
The terms "Ci-C4 alkyl," "Ci-C6 alkyl," "Ci-C8 alkyl," "C2-C4 alkyl," or "C3-C6 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-Cg alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyi, neopentyl, n-hexyl, heptyl and octyl radicals. The terms "C2-C8 alkenyl," "C2-C4 alkenyl," "C3-C4 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 one carbon-carbon
PAGE 65 OF 191 double bond by the removal of a single hydrogen atom. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
The terms "C2-C8 alkynyl," "C2-C4 alkynyl," "C3-C4 alkynyl," or "C3-C6 alkynyl," as used herein, refer to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like. The term "C3-C8-cycloalkyl", or "C5-C7-cycloalkyl," as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted. Examples of C3-C8-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-Cycycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1 ] heptyl, and the like.
The term "C3-Cg cycloalkenyl", or "C5-C7 cycloalkenyl" as used herein, refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond, and the carbon atoms may be optionally oxo-substituted. Examples of C3-Cs cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples Of Cs-C7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
The term "arylalkyl", as used herein, refers to an aryl-substituted alkyl group. More preferred arylalkyl groups are aryl-Ci-Cβ-alkyl groups. The term "heteroarylalkyl", as used herein, refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-Ci-Cβ-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.
An "aliphatic" group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are functional groups, such as, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2,
PAGE 66 OF 191 C(O)NHS(O)2NH or C(O)NHS(O)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo- substituted. An aliphatic group may be straight chained, branched 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 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 a linear aliphatic group is said to "contain" or "include" or "comprise" one or more specified functional groups, the linear aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group. In some examples, the linear aliphatic group can be represented by the formula M-Y-M', where M and M' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and Y is a functional group. In some examples, Y is selected from the group consisting of C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(R1 ^C(O)C(O)N(R11), N(Rπ)S(0)2N(Rn), C(O)N(R1 ^S(O)2 or
C(0)N(Rn)S(0)2N(Rn); wherein R11 is as previously defined. In another aspect of the invention, an exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group such as described herein. The term "alicyclic," as used herein, denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom, and the carbon atoms may be optionally oxo-substituted. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted. The terms "heterocyclic" or "heterocycloalkyl" can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may
PAGE 67 OF 191 optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted.
It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent 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, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-Ci2- cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -0-C3-Ci2- cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-Ci-Ci2-alkyl, -C(O)-C2-C8- alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C i2-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)-heterocycloalkyl, -CONH2, -CONH-Ci-Ci2-alkyl, -CONH-C2-C8-alkenyl, -CONH- C2-C8-alkynyl, -CONH-C3-Ci2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH- heterocycloalkyl, -OCO2-Ci-Ci2-alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, - OCO2-C3-C 12-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2- Ci-Ci2 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-Ci2-cycloalkyl, -CO2- aryl, CO2-heteroaryl, CO2-heterocyloalkyl, -OCONH2, -0C0NH-d-Ci2-alkyl, -OCONH- C2-C8-alkenyl, -OCONH-Cz-Cs-alkynyl, -OCONH-C3-C i2-cycloalkyl, -OCONH-aryl, - OCONH-heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)H, -NHC(O)-Ci-Ci2-alkyl, - NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-Ci2-cycloalkyl, -NHC(O)- aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-Ci-Ci2-alkyl, -NHCO2- C2-C8-alkenyl, -NHCO2- C2-C8-alkynyl, -NHCO2-C3-C 12-cycloalkyl, -NHC02-aryl, -
NHCO2-heteroaryl, -NHCO2- heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-Ci-Ci2-alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12- cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-Ci-Ci2-alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-
PAGE 68 OF 191 alkynyl, -NHC(S)NH-C3-C12-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-Ci-Ci2-alkyl, - NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-Ci2- cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH- heterocycloalkyl, -NHC(NH)-Ci-Ci2-alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8- alkynyl, -NHC(NH)-C3-C i2-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, - NHC(NH)-heterocycloalkyl, -C(NH)NH-Ci-Ci2-alkyl, -C(NH)NH-C2-C8-alkenyl, - C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C i2-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH- heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-Ci-Ci2-alkyl, -S(O)-C2-C8-alkenyl, - S(O)- C2-C8-alkynyl, -S(O)-C3-Ci2-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)- heterocycloalkyl, -SO2NH2, -SO2NH-Ci-Ci2-alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH- C2- C8-alkynyl, -SO2NH-C3-C i2-cycloalkyl, -S02NH-aryl, -SO2NH-heteroaryl, -SO2NH- heterocycloalkyl, -NHSO2-Ci-Ci2-alkyl, -NHSO2-C2-C8-alkenyl, - NHSO2-C2-C8-alkynyl, -NHSO2-C3-Ci2-cycloalkyl, -NHS02-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-Ci2-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, - SH, -S-Ci-Ci2-alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-Ci2-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. The term "halogen," as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.
The term "hydrogen" includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable. The term "hydroxy activating group", as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, /?-nitro- benzoate, phosphonate and the like. 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-nitro-benzoate, phosphonate groups, for example.
The term "hydroxy protecting group," as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions
PAGE 69 OF 191 during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 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, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. The term "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 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 chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-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.
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
PAGE 70 OF 191 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, trifluoroacetoxy and the like. The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
The term "protic solvent' as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
PAGE 71 OF 191 The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefmic double bonds, other
PAGE 72 OF 191 unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate,
PAGE 73 OF 191 succinate, sulfate, tartrate, thiocyanate, /?-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).
The present invention also relates to solvates of the compounds of the present invention, for example hydrates.
PAGE 74 OF 191 This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention. For example, compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes A- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
PHARMACEUTICAL COMPOSITIONS
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients. As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose;
PAGE 75 OF 191 starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or
PAGE 76 OF 191 wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose,
PAGE 77 OF 191 mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
PAGE 78 OF 191 Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No. 5,508,269 to Smith et ah, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in U.S. Pat. No. 6,014,969, incorporated herein by reference.
ANTIVIRAL ACTIVITY
An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
According to the methods of treatment of the present invention, viral infections, conditions are treated or prevented in a patient such as a human or 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 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 mg/Kg to about 500 mg/Kg, preferably from about 1 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
PAGE 79 OF 191 daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
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 dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 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 desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 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 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 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
PAGE 80 OF 191 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 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 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 or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
The said "additional therapeutic or prophylactic agents" includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifϊbrotic 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 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 by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HCV, RNA polymerase, protease, or helicase.
Recently, it has been demonstrated that the efficacy of a drug against a viral infection, such as HIV, can be prolonged, augmented, or restored by administering the
PAGE 81 OF 191 drug in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principal drug. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
A compound of the present invention can also be administered in combination or alternation with antiviral agent. Exemplary antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 24 below.
Table 24
PAGE 82 OF 191
Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.
ABBREVIATIONS
Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for
PAGE 83 OF 191 azobisisobutyronitrile; BINAP for 2,2'-bis(diphenylphosphino)-l,r-binaphthyl; BoC2O for di-/er/-butyl-dicarbonate; Boc for /-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; Bu3SnH for tributyltin hydride; BOP for (benzotriazol-1- yloxy)tris(dimethylamino)phos-phonium Hexafluorophosphate; Brine for sodium chloride solution in water; Cbz for carbobenzyloxy; CDI for carbonyldiimidazole; CH2Cl2 for dichloromethane; CH3 for methyl; CH3CN for acetonitrile; Cs2CO3 for cesium carbonate; CuCl for copper (I) chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; dppb for diphenylphosphino butane; DBU for l,8-diazabicyclo[5.4.0]undec-7-ene; DCC for N,N'-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIBAL-H for diisobutylaluminium hydride; DIPEA or (i- Pr)2EtN for N,N-diisopropylethyl amine; Dess-Martin periodinane for 1,1,1- tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one; DMAP for A- dimethylaminopyridine; DME for 1 ,2-dimethoxy-ethane; DMF for N ,N- dimethylformamide; DMSO for dimethyl sulfoxide; DMT for methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA for diphenylphosphoryl azide; EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; EDC HCl for N-(3- dimethylamino-propyl)-N'-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et2O for diethyl ether; Fmoc for 9-fluorenylmethoxycarbonyl; Grubbs-1 catalyst for benzylidene-bis(tricyclohexylphosphine)dichlororuthenium; HATU for 0-(7- azabenzotriazol-l-yl)-N,N,N',N',-tetramethyluronium Hexafluorophosphate; HCl for hydrogen chloride; HOBT for 1-hydroxybenzotriazole; K2CO3 for potassium carbonate; n- BuLi for n-butyl lithium; /-BuLi for /-butyl lithium; /-BuLi for /-butyl lithium; PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP for lithium 2,2,6,6- tetramethylpiperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or -SO2-CH3; Ms2O for methanesulfonic anhydride or mesyl-anhydride; NaBH4 for sodium borohydride; NaBH3CN for sodium cyanoborohydride; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCO3 for sodium bicarbonate or sodium hydrogen carbonate; Na2CO3 sodium carbonate; NaOH for sodium hydroxide; Na2SO4 for sodium sulfate; NaHSO3 for sodium bisulfite or sodium hydrogen sulfite; Na2S2O3 for sodium thiosulfate; NH2NH2 for hydrazine; NH4HCO3 for ammonium bicarbonate; NH4Cl for
PAGE 84 OF 191 ammonium chloride; NMMO for N-methylmorpholine N-oxide; NaIO4 for sodium periodate; Ni for nickel; OH for hydroxyl; OsO4 for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB for p-methoxybenzyl; POPd for dihydrogen dichlorobis(di-tert- butylphosphinito-κP)palladate(II); Pd2(dba)3 for tris(dibenzylidene-acetone) dipalladium (0); Pd(PPh3)4 for tetrakis(triphenylphosphine)palladium (0); PdCl2(PPh3)2 for trans- dichlorobis(triphenyl-phosphine)palladium (II); Pt for platinum; Rh for rhodium; rt for romm temperature; Ru for ruthenium; SEM for (trimethylsilyl)ethoxymethyl; TBAF for tetrabutylammonium fluoride; TBS for tert-butyi dimethylsilyl; TEA or Et3N for triethylamine; Teoc for 2-trimethylsilyl-ethoxy-carbonyl; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA for N,N,N' ,N'-tetramethylethylenediamine; TPP or
PPh3 for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Ts for tosyl or -SO2- C6H4CH3; Ts2O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; TMS for trimethylsilyl; or TMSCl for trimethylsilyl chloride.
SYNTHETIC METHODS The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared. Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of ordinary skill in the art. It will be readily apparent to one of ordinary skill in the art that the compounds defined above can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be readily apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the variables to successfully complete the syntheses below. The variables are as defined above unless otherwise noted below.
The compounds of the present invention may be prepared via several different synthetic routes from a variety of benzimidazole related intermediates. A retro-synthesis of those title compounds include direct formation of a suitably linked dibenzimidazole core structure followed by attachment of a suitable R6 group, plus some functional group manipulations in between and/or after.
A general synthesis and further elaboration of some benzimidazole related intermediates are summarized in Scheme 1.
PAGE 85 OF 191 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 derivative Ia-1.1 or la-la.2 and an o-phenylenediamine Ia-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 Ia-I and amino acid Ia-1.1 or Ia-1.2 in the presence of a condensation reagent such as EDC HCl, DCC or the like; or through mixed anhydride approach by reacting acid Ia-1.1 or Ia-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 Ia-I; and 2a) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.
PAGE 86 OF 191
Optionally, the NH group in the newly formed benzimidazole ring of la-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), 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
PAGE 87 OF 191 la-6 as a key intermediate. Alternatively, la-6 may be obtained from the Stille reaction conditions to those skilled in the art (see reviews: A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J. 2008, 14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed. 2007, 46, 2768; V. Farina, et al, Advances in Metal-Organic Chem. 1996, 5, 1), using an allylstanne such as allyltributylstanne as the allyl donor. Analogously a key vinyl intermediate 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 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 la-7 by coupling with tributyl(l-ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis. Further elaboration of the benzimidazole intermediates starts from the vinyl intermediate la-3, which may be transformed to aldehyde la-8 through ozono lysis cleavage or to alcohol la-12 by hydroboration-oxidation sequence. Alcohol la-12 may be converted to bromide Ia- 15 by the well-known bromination procedure, which can be further functionalized to amine la-20 through azide substitution followed by reduction. Aldehyde la-8 can then either be reduced to alcohol Ia-11, or be converted to α, β- unsatuated acid la-10 through Homer- Wadsworth-Emmons aldehyde homologation reaction followed by saponification. Alcohol Ia-I l may be similarly converted to the correponding amine intermediate Ia- 14 and bromide intermediate Ia- 13 as described previously. Bromide Ia- 13 can be homologated to alkyne intermediate Ia- 19 with a metal acetylide. In addition, bromide la-13 may be also tranformed to thiol la-16 through nucleophilic substitution, which can be further oxidized to sulfonic acid Ia- 17. Sulfonamide Ia- 18 may then be derived from Ia- 17 through the sulfonyl chloride activation process.
The compounds of the present invention may also be derived from nitrobenzimidazole la-21, which can be prepared from the corresponding 4-nitro-l,2- diaminobenzene using the similar procedures described above. Intermediate la-21 can be converted to amine la-22 through Nθ2-reduction (i.e. H2, catalytical Pd). Diazotization of amine la-22 with a nitrite such as sodium nitrite, isobutyl nitrite, or the like, in an aqueous
PAGE 88 OF 191 acid such as acetic acid, hydrochloric aicd, sulfuric acid, or the like, optionally in the presence of a copper or copper salt, may afford hydroxy la-23.
Analogously, esterbenzimidazole la-24, which can be prepared from the corresponding 4-methyl-l,2-diaminobenzoate using the procedures described above, may be hydro lyzed 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.
With suitably substituted benzimidazoles in hand, such as those listed in Scheme 1 , the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments with a suitable cyclic linker or formation of a cyclic linker. The said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, amide coupling, ester bond formation, William etherification, Buchwald etherification, alkylation, pericyclic reaction with different variations, or the like.
As illustrated in Schemes Ia, Ib, 2 and 3, in which s and t at each occurrence are each independently 0, 1, 2 or 3; M, M1, and M2 at each occurrence are each independently a boron, tin, silicon, zinc, zirconium, or copper species; PG is a hydroxy or amino protection group; and R12a at each occurrence are each independently R12. The bromides 1- 2aa and l-2ab may be coupled with partner 1-2. Ia, a bismetallated reagent such as 1,3- benzenediboronic acid, 1 ,4-benzene-diboronic acid, 2,5-thiophenediboronic acid, 2,5- bis(trimethylstannyl)thiophene, l,4-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzene, 1 ,4-bis(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)thiophene, 1 ,4-di(l ,3,2- dioxaborinan-2-yl)benzene, 2,5-bis(methoxy-methyl)-l,4-phenylenediboronic acid, or the like, under Suzuki or Stille conditions described in Scheme 1 to provide the linked dibenzimidazole core l-4a.
Alternatively, bromobenzimidazole l-2aa may be converted to intermediate 1-5 a by selectively reacting with metallic reagent 1-2.2a under the Suzuki or Stille conditions described previously. Yet alternatively, intermediate 1-5 a may be prepared by reacting 1- 2aa with dimetallic agent 1-2.3 a to afford organometallic l-6a, followed by coupling with dibromide 1-2.4a, both may be under the previously decribed Suzuki and Stille reaction conditions. The bromide 1-5 a may be further converted to organometallic l-7a with dimetallic agent 1-2.3a using the conditions described above to prepare l-6a. Under the
PAGE 89 OF 191 Suzuki or Stille conditions, bromide l-2ab may be coupled with organometallic l-7a to afford the linked dibenzimidazole core l-4a.
Core l-4a may then serve as a common intermediate for further derivaizations to 1- 8a 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 acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate. Various carboxylic acids including amino acids in racemic or optical form are commercially available, and/or can be synthesized in racemic or optical form, see references cited in reviews by D. Seebach, et al, Synthesis 2009, 1; C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569; 2000, 11, 645; and 1998, 9, 3517; and experimental examples compiled in patent application WO 2008/021927A2 by C. Bachand, et al, from BMS, which is incorporated herein by reference. l-8a 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 compound I-a using the conditions described above.
PAGE 90 OF 191 Scheme 1a
As shown in Schem Ib, the bromides l-2ba and l-2bb may be converted to vinylic l-4b and l-6b, or allylic l-5b and l-7b with a vinylstanne such as tributylvinylstanne 1- 2.1b or an allylstanne such as allyltributylstanne 1-2.2b using the reaction conditions described in Scheme 1. The intermediates l-4b and l-5b can be crossed-linked with intermediates l-6b and l-7b using transition metal catalyzed Hoveyda-Grubbs metathesis reaction conditions which are known to those skilled in the art (see J. D. Waetzig, et al, Chemtracts 2006, 19, 157; C. L. Dwyer, Metal-Catalysis in Industrial Organic Processes
2006, 201; S. T. Diver, et al, Chem. Review 2004, 104, 1317; A. J. Vernall, et al, Aldrichimica Acta 2003, 36, 93; S. T. Connon, et al, Angew. Chem. Int. Ed. 2003, 42,
1900; S. E. Gibson, et al, Topics in Organometallic Chemistry 1998, l(Alkene Metathesis in Organic Synthesis), 155; Y. Schrodi, et al, Aldrichimica Acta 2007, 40, 45), giving the corresponding olefin l-8b, a core structure of a linked dibenzimidazole. Alternatively and additionally, intermediates l-4b and l-5b may be coupled with bromide l-3b under the well-known Heck reaction conditions (reviewed by M. Arisawa, Chem. Pharm. Bull.
2007, 55, 1099; P. Guiry, et al, Current Org. Chem. 2004, 8, 781; J. T. Link, Org. React. 2002, 60, 167; S. Braese, et al, Metal-Catalyzed Cross-Coupling Reactions 1998, 99) to give olefin l-9b, another core structure of a linked dibenzimidazole. The structural cores l-8b and l-9b then may be served as common intermediates for further derivatizations to
PAGE 91 OF 191 the title compounds I-ab of the present invention using the procedures similar to that described in Scheme Ia.
Sch
The compounds of the present invention may also be derived from nitrobenzimidazole 2a- 1, which can be prepared from the corresponding 4-nitro-l,2- diaminobenzene using the procedures described in Scheme 1. As shown in Scheme 2, 2a- 1 can be converted to amine 2a-2 in two-steps: 1) NH-protection (i.e. SEM-Cl, NaH); and 2) Nθ2-reduction (i.e. H2, catalytical Pd). Alkylation of 2a-2 with a alkylating reagent such as 1 ,2-dihaloethane, ethylene tosylate, or the like, in the presence of a base such as NaHCO3, K2CO3, pyridine, Et3N, DMAP, DBU or the like, may provide the bis- ethylenylated (piperidine)-linked dibenzimidazole 2-3 through the mono-ethylenylated intermediate. The latter with two secondary ethylenediamine may be used to form the 5- membered heterocycle 2a-4 by reacting with CDI, phosgene, triphosgene, or the like, optionally in the presence of a base such as pyridine, Et3N, DMAP, DBU or the like. Similarly 2a-2 was alkylated with 1 ,4-diiodobutane followed by sulfonylation with sulfuryl chloride in the presence of a base such as NaHCO3, K2CO3, pyridine, Et3N, DMAP, DBU or the like, may provide the 7-membered heterocycle 2a-5. The linked dibenzimidazole 2a-3, 2a-4, or 2a-5 can be further converted to the title compound I-b using the conditions described in Scheme 1 , it is noteworthy that the SEM-group can be
PAGE 92 OF 191 removed at the same time when deprotecting the Boc-protection in acid as described above.
Alternatively as shown Scheme 3, intermediate 2a-3 may be obtained by the Buchwald-Hartwig amination process (see references by S. L. Buchwald et al, J.
Organomet. Chem. 1999, 576, 125; J. F. Hartwig, Angew. Chem., Int. Ed. 1998, 37, 2046; V. T. Abaev et al, Russian Chem. Reviews 2008, 77, 177; and J. F. Hartwig, Modern Arene Chemistry 2002, 107-168; S. L. Buchwald, et al, Angew. Chem., Int. Ed. 2008, 47, 6338) from bromobenz-imidazole 3a-l, which can be prepared similarly to that of bromides la-2 and la-3 after SEM -protecting as described above, and an amine such as piperazine or the like, using a transition metal catalyst such as palladium acetate in the presence of a base such as sodium t-butoxide (see S. M. Pyke, et al, J. Org. Chem. 2008, 73, 8880; and R. Dorta, et al, JACS 2008, 130, 6848). Also two molecules of bromide 3a-l may be reacted with glycine anhydride (piperazine-2,5-dione), imidazolidin-2-one, [l,2,5]-thiazolidine- 1,1 -dioxide under the Buchwald amidation reaction conditions (see C C. Mauger, et al, Aldrichimica Acta 2006, 39, 17; S. L. Buchwald, et al, JA CS 2009, 131, 78; Accounts Chem. Res. 2008, 41, 1439; H. C. Ma, et al, Synlett 2008, 1335; J. H. M. Lange, Tetrahedron Lett. 43, 1101; S. L. Buchwald, et al, JACS 2002, 124, 7421), to give the diamide, urea, or sulfonamide-linked dibenzimidazole 3a-2, 3a-3, or 3a-4. Additionally, bromide 3a- 1 may be subjected to lithium-halogen exchange with various (n-, s-, or t- )butyl lithium and the resulting lithiate can be trapped with a dihalide such as 1 ,4- dibromocyclohexane, 1 ,4-dichlorocyclohexane, 3,6-dibromocyclohexene, 3,6- dichlorocyclohexene, to give the cycloalkyl-linked dibenzimidazoles 3a-5 and 3a-6. Also olefins 3a-6 can be saturated under hydrogenolytic conditions with a Pd catalyst to give 3a-6. Intermediates 3a-2, 3a-3, 3a-4, 3a-5, and 3a-6 may be then converted to the title compound I-c using the procedures described previously.
PAGE 93 OF 191
As shown in Scheme 4, the compounds of the present invention (for example I-a) may also be derived from bromobenzimidazoles l-2a and 1-3 a using the procedures described previously. The intermediates l-2a and 1-3 a have the desired acyl groups already installed as seen in amino acid derivatives 1-1. Ia and 1-1.2a, which can be prepared from protected amino acids 4-1.1 and 4-1.2.
Scheme 4
I-a
In one aspect, the invention is a process of making a compound of Formula (1-1) comprising the steps of: i) preparing a compound of Formula (1-II-a):
PAGE 94 OF 191 via a transition-metal catalyzed cross-coupling reaction; wherein:
A, n, u, v, R1, R2, and R7 are as defined in claim 1; Za and Zb are each independently an amino protecting group or -C(O)-R12; R12 is C1-
Cg alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (II-b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R12; iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)-
R12, wherein LG is a leaving group; to give the compound of Formula (II-c):
wherein Z is an amino protecting group -C(O)-R ; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (II-d):
In another apect, the invention is a process of making a compound having the Formula (2-1) comprising the steps of: i) preparing a compound of Formula (2-II-a):
via a transition-metal catalyzed cross-coupling or metathesis reaction; amide or urea formation; ester or carbamate formation; or ether formation;
PAGE 95 OF 191 wherein:
A, n, u, v, R1, R2, and R7 are as defined in claim 18;
Za and Zb are each independently an amino protecting group or -C(O)-R12; R12 is C1-
C8 alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (II-b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R12; iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)-
R , wherein LG is a leaving group; to give the compound of Formula (II-c):
wherein Zd is an amino protecting group -C(O)-R12; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (II-d) :
In yet another aspect, the invention is a process of making a compound having the Formula (3-1) comprising the steps of: i) preparing a compound of Formula (3 -II-a):
((RI 7)n via a transition-metal catalyzed cross-coupling reaction; amide or urea formation; ester or carbamate formation; or ether formation; wherein A, T, n, u, v, R1, R2, and R7 are as defined in claim 33;
PAGE 96 OF 191 Za and Zb are each independently an amino protecting group or -C(O)-R1Z; ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (3-11 -b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R12; R12 is Ci-Cg alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); iii) capping the released amino group of a compound of Formula (II-b) with LG- C(O)-R12, wherein LG is a leaving group; to give the compound of Formula (3-II-c):
wherein Zd is an amino protecting group -C(O)-R12; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (3-II-d):
It will be appreciated that, with appropriate manipulation and protection of any chemical functionality, synthesis of compounds of the present invention is accomplished by methods analogous to those above and to those described in the Experimental section. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts "Protective Groups in Organic Synthesis", 3rd Ed (1999), J Wiley and Sons.
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.
PAGE 97 OF 191 EXAMPLES
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.
Example 1-1.
Step Ia. A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 niL, 26.7 mmol) in THF (60 mL) at -20 0C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 0C 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 (Na2SO4), 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 Ib. A solution of the crude compound from step Ia (10.7 g, theo. 26.7 mmol) in glacial acetic acid (100 mL) was heated at 50 0C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H]+. 1H NMR (CDCl3) 10.96, 10.93 (2 s, IH), 7.81, 7.30 (2 s, IH), 7.53, 7.17 (2d, J= 8.5 Hz,
PAGE 98 OF 191 IH), 7.23, 7.03 (2d, J= 8.5 Hz, IH), 5.09, 5.07 (2s, IH), 3.42-3.49 (m, 2H), 2.75-2.85 (m, IH), 2.13-2.23 (m, 2H), 1.97-2.00 (m, IH), 1.48 (s, 9H).
Step Ic. A mixture of the compound from step Ib (0.500 g, 1.37 mmol), benzene-1,4- diboronic acid (0.103 g, 0.621 mmol) and Pd(PPh3)4 (35.8 mg, 31.0 μmol) in ethanol (6 mL), toluene (6 mL) and aqueous Na2CO3 (2 M, 0.4 mL) was degassed and heated to reflux under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow solid (0.158 g, 23%). ESIMS m/z = 649.50 [M+H]+.
Example 1-2.
Step 2a. A solution of the compound from step Ic (79.0 mg, 0.122 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) 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 = 449.39 [M+H]+.
Step 2b. A mixture of the crude compound from step 2a (0.122 mmol at most) and (R)- dimethylamino phenyl acetic acid (prepared according to WO 2008/021927, 54.5 mg, 0.305 mmol) in DMF (3 mL) was treated with HATU (0.102 g, 0.268 mmol) in the presence of DIPEA (0.30 mL, 2.44 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by reverse phase HPLC (C 18, H2O/CH3CN/TFA) to give the title compound as its TFA salts and as a white solid (0.116 g, 2 steps 78%). ESIMS m/z = 111. IQ [M+H]+.
Example 1-3.
A mixture of the crude compound from step 2a (0.122 mmol at most) and (R)- (methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 76.4 mg, 0.366 mmol) in DMF (3 mL) was treated with HATU (0.102 g, 0.268 mmol) in the presence of DIPEA (0.30 mL, 2.44 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography
PAGE 99 OF 191 (silica, CH2Cl2-MeOH) to give the title compound as a yellow solid (82.4 mg, 2 steps 81%). ESIMS m/z = 831.59 [M+H]+.
Example 1-20.
A mixture of the crude compound from step 2a (0.0786 mmol at most) and (i?)-α-methoxy phenyl acetic acid (32.7 mg, 0.197 mmol) in DMF (2 mL) was treated with HATU (68.7 mg, 0.181 mmol) in the presence of DIPEA (0.27 mL, 1.572 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (33.0 mg, 2 steps 56%). ESIMS m/z = 745.05 [M+H]+.
Example 1-25.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)- tetrahydrofuran-2-carboxylic acid (22mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown oil, which was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a yellow solid (40 mg, 2 steps 82%). ESIMS m/z = 645.00 [M+H]+.
Example 1-26.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (R)-tetrahydro- furan-2-carboxylic acid (22mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (16 mg, 2 steps 32%). ESIMS m/z = 645.06 [M+H]+.
PAGE 100 OF 191 Example 1-42.
MeO2CHNv >~^s.
Step 42a. A mixture of trans -4-aminocyclohexanecarboxylic acid (500 mg, 3.5 mmol) in aqueous sodium hydroxide (IM, 3.5 mL) was added sodium carbonate (371 mg, 3.5 mmol) and methyl chloro formate (0.3 mL, 3.9 mmol). The resulting solution was stirred at room temperature for 2 hours before being extracted with dichloromethane. The aqueous phase was acidified with hydrochloric acid (IM, 7 mL) and the resulting cloudy suspension was extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated to afford the crude desired product as white solid (546 mg, 78%). ESIMS m/z = 224.01 [M+Na]+.
Step 42b. A mixture of the crude compound from step 2a (0.077 mmol at most) and the compound from step 42a (39 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (41 mg, 2 steps 62%). ESIMS m/z = 815.03 [M+H]+.
Example 1-52.
A mixture of the crude compound from step 2a (0.077 mmol at most) and isonicotinic acid (24mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (39 mg, 2 steps 76%). ESIMS m/z = 658.99 [M+H]+. Example 1-54.
PAGE 101 OF 191 A mixture of the crude compound from step 2a (0.077 mmol at most) and picolinic acid (24mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (38 mg, 2 steps 74%). ESIMS m/z = 659.02 [M+H]+.
Example 1-62.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-(methoxy- carbonylamino)propanoic acid (prepared according to WO 2008/021927, 28 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2- MeOH) to give the title compound as a yellow solid (52 mg, 2 steps 96%). ESIMS m/z = 707.06 [M+H]+.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-(methoxy- carbonylamino)butanoic acid (prepared according to WO 2008/021927, 31 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2- MeOH) to give the title compound as a yellow solid (50.5 mg, 2 steps 89%). ESIMS m/z = 734.97 [M+H]+. Example 1-70.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (2S,3S)-3- hydroxy-2-(methylperoxymethylamino)butanoic acid (prepared according to WO
PAGE 102 OF 191 2008/021927, 30 mg, 0.19 mmol) in DMF (2 niL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (48 mg, 2 steps 81%). ESIMS m/z = 767.08 [M+H]+.
Example 1-72.
A mixture of the crude compound from step 2a (78.7 μmol at most) and (2S,3R)-3- methoxy-2-(methoxycarbonylamino)butanoic acid (prepared according to WO 2008/021927, 34.6 mg, 0.181 mmol) in DMF (3 mL) was treated with HATU (65.8 mg, 0.173 mmol) in the presence of DIPEA (0.20 mL, 1.57 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, CH2Cl2-MeOH) to give the title compound as a white solid (50.2 mg, 2 steps 80%). ESIMS m/z = 795.54 [M+H]+. Example 1-78.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2- cyclopropyl-2-(methoxycarbonylamino) acetic acid (prepared according to WO 2008/021927, 30 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (55 mg, 2 steps 95%). ESIMS m/z = 759.36 [M+H]+.
Example 1-83.
A mixture of the crude compound from step 2a (0.156 mmol at most) and (S)-2-(methoxy- carbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 68.2 mg,
PAGE 103 OF 191 0.386 mmol) in DMF (3 niL) was treated with HATU (0.136 g, 0.358 mmol) in the presence of DIPEA (0.39 rnL, 3.12 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, CH2Cl2-MeOH) to give the title compound as a white solid (98.3 mg, 2 steps 83%). ESIMS m/z = 763.22 [M+H]+.
Example 1-114.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-(methoxy- carbonylamino)-3-(lH-pyrazol-l-yl)propanoic acid (prepared with similar procedure as that of 42a, 41 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (40 mg, 2 steps 64%). ESIMS m/z = 838.96 [M+H]+. Example l-354a.
Step 354a-a. A solution of the compound from step Ib (2.18 g, 5.95 mmol) in DMF (50 mL) was treated with NaH (60% in mineral oil, 0.273 g, 6.84 mmol) for 1 hour before a slow addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.05 mL, 5.95 mmol). The mixture was kept stirring for 3 hours before being diluted with EtOAc and quenched with saturated NH4Cl. The organics were washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow oil (2.75 g, 94%). ESIMS m/z = 496.33, 498.33 [M+H]+. Step 354a-b. A mixture of the compound from step 354a-a (0.200 g, 0.403 mmol), piperazine (11.6 mg, 0.134 mmol), 2-diphenylphosphono-2'-(N, N- dimethylamino)biphenyl (29.6 mg, 73.2 μmol), sodium t-butoxide (39.9 mg, 0.403 mmol) and Pd2(dba)3 (24.6 mg, 26.8 μmol) in toluene (6 mL) was degassed and heated at 80 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc
PAGE 104 OF 191 - water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a brown oil (0.102 g, 81%). The regiochemistry of the SEM- group was not determined. ESIMS m/z = 917.79 [M+H]+.
Example 1-354.
Step 354a. A solution of the compound from step 354a-b (100 mg, 0.109 mmol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at 50 0C for 2 hours. 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 = 457.37 [M+H]+.
Step 354b. The title compound was synthesized from the compound from step 354a using a procedure similar to that described in Example 3. ESIMS m/z = 839.34 [M+H]+.
Example l-357a.
A mixture of the compoun from step 354a-a (0.360 g, 0.726 mmol), glycine anhydride (27.6 mg, 0.242 mmol), (lR,2R)-N1,N2-dimethylcyclohexane-l,2-diamine (15.2 μL, 96.3 μmol), potassium phosphate (0.174 g, 0.822 mmol) and CuI (9.2 mg, 48.3 μmol) in toluene (4 mL) was degassed and heated at 100 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), 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 (47.9 mg, 21%). The regiochemistry of the SEM-group was not determined. ESIMS m/z = 945.91 [M+H]+.
Example 1-357.
Ph MeO2CHN'
Step 357a. A solution of the compound from Example 357a (47.9 mg, 50.7 μmol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at 50 0C for 2 hours. The
PAGE 105 OF 191 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 = 485.44 [M+H]+. Step 357b. The title compound was synthesized from the compound from step 357a using a procedure similar to that described in Example 3. ESIMS m/z = 867.69 [M+H]+.
Example 1-361.
A mixture of the crude compound from step 2a (0.309 mmol at most) and (S)-2- (benzyloxy-carbonylamino)-3-methylbutanoic acid (0.178 g, 0.710 mmol) in DMF (3 mL) was treated with HATU (0.258 g, 0.679 mmol) in the presence of DIPEA (0.58 mL, 4.63 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, CH2Cl2-MeOH) to give the title compound as a white solid (0.257 g, 2 steps 91%). ESIMS m/z = 915.52 [M+H]+.
Example 1-362.
Step 362a. A mixture of the title compound from example 361 (0.128 g, 0.140 mmol) and Pd(OH)2 on carbon (20% wt, 64.0 mg) in ethanol (12 mL) was treated with H2 balloon overnight. The mixture was filtered through celite and the filtrate was concentrated to give the crude desired compound as a white solid (73.7 mg, 82%). ESIMS m/z = 647.47 [M+H]+. Step 362b. A mixture of the compound from step 362a (73.7 mg, 0.114 mmol), 2- bromopyrimidine (0.124 g, 0.741 mmol) and DIPEA (47 μL, 0.376 mmol) in toluene (4 mL) and DMSO (1 mL) was degassed and heated to 90 0C under N2 overnight. The volatiles were evaporated off to provide a brown sirup. It was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a white solid (29.0 mg, 32%). ESIMS m/z = 803.41 [M+H]+.
Example 1-363.
PAGE 106 OF 191 Step 363a. A mixture of the compound from step Ib (1 g, 2.73 mmol), bis-(pinacolato)- diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4-dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80 0C under N2 overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et3N in ethyl acetate) to give the desired compound as a yellow solid (680 mg, 60%). ESIMS m/z = 414.24 [M+H]+.
Step 363b. A mixture of the compound from step 363a (0.400 g, 0.969 mmol), 2,6- dibromo-naphthalene (0.126 g, 0.440 mmol), NaHCO3 (0.296 g, 3.52 mmol) and Pd(PPh3)4 (25.4 mg, 22.0 μmol) in DME (12 mL) and water (4 mL) was degassed and heated at 85 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), 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 (0.268 g, 87%). ESIMS m/z = 699.31 [M+H]+.
Example 1-364.
The title compound was synthesized from the compound of Example 363 using procedures similar to that described in step 2b and Example 83. ESIMS m/z = 813.55 [M+H]+. Example 1-365.
A mixture of the compound from step 363a (47.2 mg, 0.114 mmol), 2,6- dibromoquinazoline (15.0 mg, 52.0 μmol) and Pd(PPh3)4 (6.0 mg, 5.2 μmol) in ethanol (3 mL), toluene (3 mL) and aqueous Na2CO3 (2 M, 0.2 mL) was degassed and heated to reflux under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a yellow solid (28.3 mg, 36%). ESIMS m/z = 701.32 [M+H]+.
PAGE 107 OF 191 Example 1-366.
The title compound was synthesized from the compound from Example 365 using procedures similar to that described in step 2b and Example 83. ESIMS m/z = 815.53 [M+H]+.
Example 1-367.
A mixture of the crude compound from step 2a (0.077 mmol at most) and 2-(pyridin-2-yl)- acetic acid (33 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (14 mg, 2 steps 26%). ESIMS m/z = 686.98 [M+H]+.
Example 1-368.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-((2- methoxy-ethoxy)carbonylamino)-3-methylbutanoic acid (prepared with similar procedure as that of 42a, 42 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (45 mg, 2 steps 69%). ESIMS m/z = 851.12 [M+H]+.
Example 1-369.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2- cyclopentyl-2-(methoxycarbonylamino) acetic acid (prepared with similar procedure as that of 42a, 35 mg, 0.19 mmol) in DMF (2 mL) was treated with HATU (73 mg, 0.19
PAGE 108 OF 191 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (51 mg, 2 steps 63%). ESIMS m/z = 815.13 [M+H]+.
Example 1-370.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-(methoxy- carbonylamino)-4-methylpentanoic acid (prepared with similar procedure as that of 42a, 32 mg, 0.19 mmol) in acetonitrile (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (55 mg, 2 steps 90%). ESIMS m/z = 790.99 [M+H]+.
Example 1-371.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (2S,3S)-2- (methoxycarbonylamino)-3-methylpentanoic acid (prepared with similar procedure as that of 42a, 32 mg, 0.19 mmol) in acetonitrile (2 mL) was treated with HATU (73 mg, 0.19 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (58.5 mg, 2 steps 95%). ESIMS m/z = 790.99 [M+H]+.
Example 1-372.
A mixture of the crude compound from step 2a (0.077 mmol at most) and (S)-2-(methoxy- carbonylamino)-3,3-dimethylbutanoic acid (prepared with similar procedure as that of 42a, 32 mg, 0.19 mmol) in acetonitrile (2 mL) was treated with HATU (73 mg, 0.19
PAGE 109 OF 191 mmol) in the presence of DIPEA (0.22 mL, 1.6 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, CH2Cl2-MeOH) to give the title compound as a yellow solid (52 mg, 2 steps 85%). ESIMS m/z = 790.99 [M+H]+.
The remaining compounds of examples 1-4 to 1-360 may be prepared using procedures similar to those described in examples 1-1, 1-2, 1-3, 1-20, 1-25, 1-26, 1-42, 1- 52, 1-54, 1-62, 1-67, 1-70, 1-72, 1-78, 1-83, 1-114, 1-354, l-354a, 1-357, l-357a, 1-361 to 1-372, and/or procedures described in the Synthetic Methods.
Table Ia: Examples 1-4 to 1-219
PAGE 110 OF 191
PAGE 111 OF 191 Me
PAGE 112 OF 191
PAGE 113 OF 191
PAGE 114 OF 191
Table 2: Examples 1-220 to 1-229.
PAGE 115 OF 191 Table 3: Examples 1-230 to 1-233.
Table 4: Examples 1-234 to 1-243.
Table 5: Examples 1-244 to 1-263.
PAGE 116 OF 191
Table 6: Examples 1-264 to 1-283.
PAGE 117 OF 191 Table 7: Examples 1-284 to 1-309.
Table 8; Examples 1-310 to 1-360.
PAGE 118 OF 191
Example 2- Ia.
Step la-a. A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 0C 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 (Na2SO4), 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 la-b. A solution of the crude compound of step la-a (10.7 g, theo. 26.7 mmol) in glacial acetic acid (100 mL) was heated at 50 0C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H]+. 1H NMR (CDCl3) 10.96, 10.93 (2 s, IH), 7.81, 7.30 (2 s, IH), 7.53, 7.17 (2d, J= 8.5 Hz,
PAGE 119 OF 191 IH), 7.23, 7.03 (2d, J= 8.5 Hz, IH), 5.09, 5.07 (2s, IH), 3.42-3.49 (m, 2H), 2.75-2.85 (m, IH), 2.13-2.23 (m, 2H), 1.97-2.00 (m, IH), 1.48 (s, 9H).
Step la-c. A mixture of the compound of step la-b (0.250 g, 0.683 mmol), allyltributyl- stannane (0.26 mL, 0.820 mmol) and Pd(PPh3)4 (39.4 mg, 34.1 μmol) in toluene (6 mL) was degassed and heated to 110 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compounds as a colorless oil (0.127 g, 60%). ESIMS m/z = 328.23 [M+H]+. Step la-d. A mixture of the compound of step la-c (0.100 g, 0.306 mmol) and Grubbs-1 Catalyst (12.5 mg, 15.2 μmol) in CH2Cl2 (6 mL) was degassed and heated to reflux under N2 for 3 days. The volatiles were evaporated and the residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the title compound as a colorless oil (8.7 mg). ESIMS m/z = 627.28 [M+H]+. Example 2-3 a.
Step 3a-a. A solution of the compound of Example la-a (8.7 mg, 13.8 μmol) 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 = 427.39 [M+H]+.
Step 3a-b. A mixture of the crude compound of step 3a-a (13.8 μmol at most) and (R)- (methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 7.2 mg, 34.5 μmol) in DMF (3 mL) was treated with HATU (12.0 mg, 31.7 μmol) in the presence of DIPEA (34.4 μL, 0.276 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, CH2Cl2-MeOH) to give the title compound as a very light yellow solid (8.8 mg, 2 steps 79%). ESIMS m/z = 809.30 [M+H]+.
Example 2-310.
PAGE 120 OF 191 A mixture of the compound of example 3 a (5.8 mg, 7.1 μmol) and Pd(OH)2 on carbon (20%, 15.0 mg) in ethanol (3 mL) was treated with H2 balloon overnight. It was filtered through celite and the filtrate was concentrated. The residue was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a white solid (5.0 mg, 86%). ESIMS m/z = 811.34 [M+H]+.
Example 2-353.
A mixture of the compound of step la-b (0.156 g, 0.427 mmol), the compound of step Ia- c (0.127 g, 0.388 mmol), triethylamine (0.56 mL, 3.88 mmol), tri-o-tolylphosphine (15.2 mg, 48.5 μmol) and Pd(OAc)2 (4.4 mg, 19.4 μmol) in CH3CN (6 mL) was degassed and heated to 80 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), 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 (0.165 g, 70%). ESIMS m/z = 613.47 [M+H]+.
Example 2-354.
The title compound was synthesized from the compound from Example 353 using procedures similar to that described in Example 3a. ESIMS m/z = 795.56 [M+H]+. Example 2-355.
The title compound was synthesized from the compound from Example 354 using procedures similar to that described in Example 310. ESIMS m/z = 797.69 [M+H]+.
Example 2-356.
Step 356a. A mixture of JV-Boc-L-proline (7.03 g, 32.6 mmol) and TEA (4.55 mL, 32.6 mmol) in THF (60 mL) at -20 0C was treated with ώo-butyl chloroformate (4.27 mL, 32.6
PAGE 121 OF 191 mmol) for 30 minutes before a slow addition of 4-nitro-l,2-diaminobenzene (5.00 g, 32.6 mmol) in THF (20 mL). It was then kept at -20 0C 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 (Na2SO4), filtered and evaporated to give the crude desired compound as a dark brown foam which was directly used in the next step. ESIMS m/z = 351.23 [M+H]+. Step 356b. A mixture of the compound from step 356a (32.6 mmol at most) and Pd on carbon (10%, 500 mg) in ethanol (200 mL) was treated with H2 balloon overnight. The mixture was filtered through celite and the filtrate was concentrated to give the crude desired compound as a dark purple foam which was directly used in the next step. ESIMS m/z = 321.25 [M+H]+.
Step 356c. A solution of the crude compound from step 356b (32.6 mmol at most) in glacial acetic acid (60 mL) was heated at 40 0C for 3 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the desired compound as a purple foam (7.02 g, 3 steps 71%). ESIMS m/z = 303.28 [M+H]+. Step 356d. A mixture of the compound from step 356c (0.200 g, 0.662 mmol), CDI (53.7 mg, 0.331 mmol) and triethylamine (0.11 mL, 0.794 mmol) in THF (5 mL) was kept stirring under N2 overnight. The volatiles were evaporated and the residue was was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a light purple solid(0.115 g, 55%). ESIMS m/z = 631.54 [M+H]+.
Example 2-357.
The title compound was synthesized from the compound from Example 356 using procedures similar to that described in Example 3a. ESIMS m/z = 813.65 [M+H]+.
The remaining compounds of examples 1-352 may be prepared using procedures similar to those described in examples Ia, 3a, 310, 353-357, and/or as described in the Synthetic Methods.
PAGE 122 OF 191 Table 9: Examples 2-1 to 2-219
PAGE 123 OF 191
PAGE 124 OF 191
PAGE 125 OF 191
PAGE 126 OF 191
PAGE 127 OF 191
Example 2-230
Example 2-231
Table 11 : Examples 2-234 to 2-243
MeO2CHN
R1 R11 Ph
PAGE 128 OF 191
Table 13: Examples 2-264 to 2-283
PAGE 129 OF 191
Table 14: Examples 2-284 to 2-309
Table 15: Examples 2-310 to 2-352
PAGE 130 OF 191
Example 3-335.
Step 335a. A mixture of JV-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-l,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 0C 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 (Na2SO4), 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 335b. A solution of the crude compound from step 335a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50 0C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z = 366.17, 368.17 [M+H]+. 1H NMR (CDCl3) 10.96, 10.93 (2 s, IH), 7.81, 7.30 (2 s, IH), 7.53, 7.17 (2d, J= 8.5 Hz, IH), 7.23, 7.03 (2d, J= 8.5 Hz, IH), 5.09, 5.07 (2s, IH), 3.42-3.49 (m, 2H), 2.75-2.85 (m, IH), 2.13-2.23 (m, 2H), 1.97-2.00 (m, IH), 1.48 (s, 9H).
PAGE 131 OF 191 Step 335c. A mixture of the compound from step 335b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80 0C under N2 overnight before being evaporated. The residue was purified by chromatography (silica, hexanes- ethyl acetate with 1% Et3N in ethyl acetate) to give the desired compound as a yellow solid (680 mg, 60%). ESIMS m/z = 414.24 [M+H]+.
Step 335d. A mixture of the compound from step 335c (0.250 g, 0.605 mmol), 1-bromo- 4-iodobenzene (0.257 g, 0.908 mmol), NaHCO3 (0.203 g, 2.42 mmol) and Pd(PPh3)4 (34.9 mg, 30.2 μmol) in DME (12 mL) and water (4 mL) was degassed and heated at 85 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), 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 335e. A mixture of the compound from step Ib (2.010 g, 5.488 mmol), trimethylsilyl-acetylene (2.33 ml, 16.46 mmol), CuI (0.110 g, 0.576 mmol) and Pd(PPh3)2Cl2 (0.308 g, 0.439 mmol) in Et3N (50 mL) was degased and then heated at 80 0C under N2 overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et3N in ethyl acetate) to give the desired compound as a yellow foam (1.140 g, 54%). ESIMS m/z = 384.22 [M+H]+. Step 335f. A suspension of the compound from step 335e (1.140 g, 2.972 mmol) and K2CO3 (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 paritioned (EtOAc - H2O). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et3N in ethyl acetate) to give the desired compound as a yellow foam (0.792 g, 86%). ESIMS m/z = 312.18 [M+H]+. Step 335g. A mixture of the compound from step 335d (97.0 mg, 0.219 mmol), the compound from step 335f (75.0 mg, 0.241 mmol), CuI (1.2 mg, 6.5 μmol) and Pd(PPh3)4 (34.9 mg, 30.2 μmol) in CH3CN (4 mL) and triethylamine (4 mL) was degassed and heated at 90 0C under N2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica,
PAGE 132 OF 191 hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.108 g, 73%). ESIMS m/z = 673.18 [M+H]+.
Example 3-336.
Step 336a. A solution of the compound from Example 335 (0.108 g, 0.161 mmol) 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. Step 336b. A mixture of the crude compound from step 336a (0.161 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO
2008/021927, 59.0 mg, 0.337 mmol) in DMF (3 mL) was treated with HATU (0.122 g, 0.321 mmol) in the presence of DIPEA (0.40 mL, 3.21 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compound as a white solid (0.102 g, 2 steps 81%). ESIMS m/z = 787.26 [M+H]+.
Example 3-337.
A mixture of the title compound from example 336 (18.1 mg, 23.0 μmol) and Pd(OH)2 on carbon (20% wt, 36.0 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, CH2Cl2-MeOH) to give the title compound as a white solid (12.7 mg, 70%). ESIMS m/z = 791.34 [M+H]+.
The title compounds of examples 1-334 may be prepared using procedures similar to those described in examples 335-337, and/or as described in the Synthetic Method. Table 16: Examples 3-1 to 3-219
PAGE 133 OF 191
PAGE 134 OF 191
PAGE 135 OF 191
PAGE 136 OF 191
PAGE 137 OF 191
Table 17: Examples 3-220 to 3-229
PAGE 138 OF 191
Example 3-233
Table 18: Examples 3-234 to 3-243
PAGE 139 OF 191 Table 19: Examples 3-244 to 3-263
Table 20: Examples 3-264 to 3-289
PAGE 140 OF 191
Table 21 : Examples 3-290 to 3-334
PAGE 141 OF 191 BIOLOGICAL ACTIVITY
1. HCV Replicon Cell Lines
HCV replicon cell lines (kindly provided by R. Bartenschlager) isolated from colonies as described by Lohman et. al. (Lohman et al. (1999) Science 285: 110-113, expressly incorporated by reference in its entirety) and used for all experiments. The HCV replicon has the nucleic acid sequence set forth in EMBL Accession No.: AJ242651, the coding sequence of which is from nucleotides 1801 to 8406.
The coding sequence of the published HCV replicon was synthesized and subsequently assembled in a modified plasmid pBR322 (Promega, Madison, WI) using standard molecular biology techniques. One replicon cell line ("SGR 11-7") stably expresses HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genes and the HCV 3'UTR. Another replicon cell line ("Huh-luc/neo-ET") described by Vrolijk et. al. (Vrolijk et. al. (2003) Journal of Virological Methods 110:201-209, expressly incorporated by reference in its entirety) stably expresses HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene, (iv) the neomycin phosphotransferase gene (neo), (v) the IRES from encephalomyocarditis virus (EMCV), and (vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations (E1202G, T1280I, K1846T) and the HCV 3'UTR.
These cell lines were maintained at 37°C, 5% CO2, 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 IOOX penicillin/streptomycin (Cat# 15140-122, Invitrogen) and Geneticin (Cat# 10131-027, Invitrogen) at 0.75 mg/ml or 0.5 mg/ml for 11-7 and Huh-luc/neo-ET cells, respectively.
2. HCV Replicon Assay - qRT-PCR
EC50 values of single agent compounds and combinations were determined by HCV RNA detection using quantitative RT-PCR, according to the manufacturer's instructions, with a TaqMan® One-Step RT-PCR Master Mix Reagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler. The TaqMan primers used for detecting and quantifying were obtained from Integrated DNA
PAGE 142 OF 191 Technologies. HCV RNA was normalized to GAPDH RNA levels in drug-treated cells, which was detected and quantified using the Human GAPDH Endogenous Control Mix (Applied Biosystems, AB 4310884E). Total cellular RNA was purified from 96-well plates using the RNAqueous 96 kit (Ambion, Cat# AMI 812). Chemical agent cytotoxicity was evaluated using an MTS assay according to the manufacturer's directions (Promega). 3. HCV Replicon Assay - Luciferase
Since clinical drug resistance often develops in viral infections following single agent therapies, there is a need to assess the additive, antagonistic, or synergistic properties of combination therapies. We used the HCV replicon system to assess the potential use of the compound of the present invention or in combination therapies with Interferon alpha, cyclosporine analogs and inhibitors targeting other HCV proteins. The acute effects of a single or combinations of drugs are studied in the "Huh-luc/neo-ET" replicon with each chemical agent titrated in an X or Y direction in a 6 point two-fold dilution curve centered around the EC50 of each drug. Briefly, replicon cells are seeded at 7,000 cells per well in 90 ul DMEM (without phenol red, Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX penicillin/streptomycin and incubated overnight at 37°C, 5% CO2, 100% relative humidity. 16-2Oh after seeding cells, test compounds previously solubilized and titrated in dimethyl sulfoxide ("DMSO") from each X plate and Y plate are diluted 1 : 100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX 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% CO2, 100% relative humidity for 72 hours before performing a luciferase assay using 100 ul per well BriteLite Plus (Perkin Elmer) according to the manufacturer's instructions. Data analysis utilizes the method published by Prichard and Shipman (Antiviral Research, 1990. 14:181-205). Using this method, the combination data are analyzed for antagonistic, additive, or synergistic combination effects across the entire combination surface created by the diluted compounds in combination.
The compounds of the present invention may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment the compounds of the present invention inhibit HCV replicon and in another embodiment the compounds of the present invention inhibit NS5A.
PAGE 143 OF 191 The compounds of the present invention can be effective against the HCV Ib genotype. It should also be understood that the compounds of the present invention can inhibit multiple genotypes of HCV. In one embodiment, compound of the present invention are active against the Ia, Ib, 2a, 2b, 3a, 4a, and 5a genotypes. Table 25 shows the EC50 values of representative compounds of the present invention against the HCV Ib genotype from the above described qRT-PCR or luciferase assay. EC50 ranges against HCV Ib are as follows: A >10 nM; B 1-10 nM; C < InM.
Table 25: Genotype-lb replicon EC 50
PAGE 144 OF 191

Claims

WHAT IS CLAIMED IS:
1. A compound represented by Formula (1-1):
or a pharmaceutically acceptable salt thereof, wherein:
A is independently selected from the group consisting of: aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, all optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R10, -OR11, N(Rπ)2, -C(O)R11, -CO2R11, -C(0)N(Rn)2, and -N(Rn)C(0)Rπ; R10 at each occurrence is independently C1-C4 alkyl optionally with one or more halogen atoms;
R11 at each occurrence is independently hydrogen or optionally substituted Ci-C8 alkyl;
R1 and R2 at each occurrence are each independently selected from the group consisting of: halogen, cyano, optionally substituted Ci-C4 alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11, and -C(0)NRaRb;
Ra and Rb at each occurrence are each independently hydrogen, optionally substituted Ci-C8 alkyl, or optionally substituted C2-C8 alkenyl; or Ra and Rb taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u and v at each occurrence are each independently 0, 1, 2, or 3; Q and J at each occurrence are each independently selected from:
wherein
R3 and R4 at each occurrence are each independently hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl or optionally substituted C3- C8 cycloalkyl; or alternatively, R3 and R4 taken together with the carbon atom to which they are attached form optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic;
PAGE 145 OF 191 R5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C3-Cg cycloalkyl;
R6 at each occurrence is independently selected from the group consisting of: hydrogen, -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12; R12 at each occurrence is independently selected from the group consisting of: -O-
R11, -NRaRb, -R13, -NRcRd, -CH(R13)NRaRb and -CH(R13)NRcRd;
R13 at each occurrence is independently selected from the group consisting of: optionally substituted Ci-Cg alkyl, optionally substituted C2-Cg alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-Cg cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl;
Rc and Rd at each occurrence are each independently selected from the group consisting of: hydrogen, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13),; m is O, 1, or 2; n is O, 1, 2, 3, or 4;
X at each occurrence is independently selected from O, S, S(O), SO2, CH2, CHR7, and C(R7)2; provided that when m is O, X is selected from CH2, CHR7, and C(R7)2; and R7 at each occurrence is independently selected from the group consisting of: halogen, cyano, -0-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C1-C4 alkyl; optionally, two vicinal R7 groups taken together with the two adjacent atoms to which they are attached form a fused, optionally substituted -C3-C8 cycloalkyl or optionally substituted heterocyclic ring; or alternativelly and optionally, two geminal R7 groups taken together with the carbon atom to which they are attached form a spiro, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring.
2. A compound of claim 1, wherein A is independently an aryl, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt.
PAGE 146 OF 191
3. A compound of claim 1 , wherein A is independently a heteroaryl, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 , wherein A is independently a heterocyclic, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1, wherein A is independently a C3-Cs cycloalkyl, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , wherein A is independently a C3-Cs cycloalkenyl, optionally with substituted one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1, wherein A is independently a phenyl, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 , wherein A is independently a 5-7-membered heteroaryl, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 , wherein A is independently a 5-7-membered heterocyclic, optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1, wherein A is independently a C5-C7 cycloalkyl or C5-C7 cycloalkenyl, both optionally substituted with one or more substituents independently selected from halogen and R10; or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 , wherein u and v at each occurrence are each independently 0 or 1 ; and when present, R1 and R2 at each occurrence are each
PAGE 147 OF 191 independently halogen or optionally substituted C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1, wherein Q and J at each occurrence are each independently selected from: cr *R12, and O^R12; wherein X at each occurrence independently CH2, CF2, CHF, or CH(OH); or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 1 selected from the group of compounds 1-1 to 1- 360 compiled in the following tables: Compounds 1 - 1 to 1 -219
PAGE 148 OF 191
PAGE 149 OF 191 Me
PAGE 150 OF 191
PAGE 151 OF 191
PAGE 152 OF 191
Compounds 1-220 to 1-229
PAGE 153 OF 191
Compounds 1-234 to 1-243
Compounds 1-244 to 1-263
PAGE 154 OF 191
Compounds 1-264 to 1-283
PAGE 155 OF 191 Compounds 1-284 to 1-309
Compounds 1-310 to 1-360
PAGE 156 OF 191
14. A compound of claim 1 , represented by Formula (l-II), or a pharmaceutically acceptable salt thereof:
15. A compound of claim 14, wherein A is independently a phenyl, 6-membered heteroaryl, bicyclic aryl, or bicyclic heteroaryl; u is 0; v is 0; m is 1; n is 0, 1 or 2; X at each occurrence is independently CH2, CF2, CHF, or C(R7)2; R12 at each occurrence is independently Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl); R7 at each occurrence is independently methyl, fluoro or hydroxy; or two vicinal R7 groups taken together with the two adjacent atoms to which they are attached form a fused, optionally substituted cyclopropyl; or alternatively two geminal R7 groups taken together with the carbon atom to which they are attached form a spiro, optionally substituted cyclopropyl; or a pharmaceutically acceptable salt thereof.
PAGE 157 OF 191 (R7)n
1-χ
16. The compound of claim 1, wherein YΦ -^ is selected from the group listed below, or a pharmaceutically acceptable salt thereof:
17. A compound according to claim 1 selected from the following table:
PAGE 158 OF 191
18. A compound represented by Formula (2-1):
or a pharmaceutically acceptable salt thereof, wherein:
A is an optionally substituted linear aliphatic group;
R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C4 alkyl, -0-R11, -NRaRb, -C(O)R11, -CO2R11, and -C(0)NRaRb;
R , 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cs alkyl;
Ra and R at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, and optionally substituted C2- Cs 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 and v are each independently 1 , 2, or 3; Q and J are each independently selected from:
R3 and R4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-Cs alkenyl, and optionally substituted C3-Cs cycloalkyl; or alternatively, R3 and R4 can be
PAGE 159 OF 191 taken together with the carbon atom to which they are attached to form optionally substituted C3-Cg cycloalkyl or optionally substituted heterocyclic;
R5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C3-C8 cycloalkyl; R6 is selected from the group consisting of -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-
R12, and -C(S)-R12;
R12 at each occurrence is independently selected from the group consisting of -O- R11, -NRaRb, -R13, and -NRcRd; wherein
R13 at each occurrence is independently selected from the group consisting of: hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 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, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13),; m is O, I, or 2; n is 1, 2, 3, or 4;
X at each occurrence is independently selected from O, S, S(O), SO2, and C(R7)2; provided that when m is O, X is C(R7)2; and
R7 at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, -0-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C1-C4 alkyl; or two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring; or alternatively two geminal R7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring.
19. The compound of claim 18, wherein Q and J are each independently selected from:
pharmaceutically acceptable salt thereof.
PAGE 160 OF 191
20. The compound of claim 18, wherein Q and J are each independently O-^R12; pharmaceutically acceptable salt thereof.
21. The compound of claim 18, wherein u and v at each occurrence are each 1 ; and R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen or optionally substituted C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.
22. The compound of claim 18, wherein Q and J at each occurrence are each
independently ό^R12; and R1 and R2 are each hydrogen; or a pharmaceutically acceptable salt thereof.
23. The compound of claim 18, wherein A is selected from Ci-Cs alkyl, C2-Cs alkenyl, and C2-Cs alkynyl, each optionally substituted; or a pharmaceutically acceptable salt.
24. The compound of claim 18, wherein A is a linear aliphatic group containing a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rn)C(0)N(Rn), N(Rπ)C(0)C(0)N(Rn), N(Rn)S(O)2N(Rπ), C(O)N(Rn)S(O)2 or C(0)N(Rn)S(0)2N(Rn); or a pharmaceutically acceptable salt thereof.
25. The compound of claim 19, wherein A is a linear aliphatic group containing an olefϊnic double bond and a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rπ), N(Rπ)S(0)2N(Rn), C(O)N(Rn)S(O)2 or C(0)N(Rn)S(0)2N(Rπ); or a pharmaceutically acceptable salt thereof.
26. The compound of claim 19, wherein A is a linear aliphatic group containing an alkynic triple bond and a group selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rn)C(0)N(Rπ), N(R1 ^C(O)C(O)N(R11),
PAGE 161 OF 191 N(R1^S(O)2N(R11), C(O)N(Rn)S(O)2 or C(O)N(Rn)S(O)2N(Rπ); or a pharmaceutically acceptable salt thereof.
27. The compound of claim 18, wherein A is a linear aliphatic group containing one or two groups independently selected from O and N(R11); or a pharmaceutically acceptable salt thereof.
28. A compound of claim 18, wherein A is a group independently selected from C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(R1 ^C(O)C(O)N(R11), N(Rπ)S(0)2N(Rn), C(O)N(R1 ^S(O)2 or C(0)N(Rn)S(0)2N(Rn); or a pharmaceutically acceptable salt thereof.
29. A compound of claim 18, wherein A is a linear aliphatic group containing one to four carbons and two groups independently selected from the group consisting of O, N(R11), C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rn), N(Rn)S(O)2N(Rn), C(O)N(R1 ^S(O)2 and C(0)N(Rn)S(0)2N(Rn); or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 18 selected from the group of compounds 2-1 to 2-393 compiled in the following tables:
Compounds 2-1 to 2-219
PAGE 162 OF 191
PAGE 163 OF 191 Me
PAGE 164 OF 191
PAGE 165 OF 191
PAGE 166 OF 191
Compounds 2-220 to 2-229
PAGE 167 OF 191 Compound 2-230
Compound 2-231
Compounds 2-234 to 2-243
Compounds 2-244 to 2-263
PAGE 168 OF 191
Compounds 2-264 to 2-283
Compounds 2-284 to 2-309
PAGE 169 OF 191
Compounds 2-310 to 2-352
PAGE 170 OF 191
31. A compound of claim 18, wherein A is independently optionally substituted C2-C8 alkenyl or optionally substituted C2-C8 alkynyl; R1 and R2 are each hydrogen; Q and J are each independently R12 ^*" ; wherein n is 1 or 2; X at each occurrence independently CH2, CF2, CHF, or C(R7)2; R12 at each occurrence is independently Ci-C8 alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C4 alkyl); R7 at each occurrence is independently hydrogen, methyl, fluoro or hydroxy; or optionally, two vicinal R7 groups taken together with the two adjacent atoms to which they are attached form a fused, optionally substituted cyclopropyl; or alternatively, two geminal R7 groups taken together with the carbon atom to which they are attached form a spiro, optionally substituted cyclopropyl; or a pharmaceutically acceptable salt thereof.
32. A compound according to claim 18 selected from the group of compounds 2- Ia, 2- 3a, and 2-353 to 2-357 compiled in the following table:
PAGE 171 OF 191
33. A compound represented by Formula (3-1):
or a pharmaceutically acceptable salt thereof, wherein: A is a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C3-
Cs cycloalkyl, and C3-Cs cycloalkenyl, each optionally substituted;
D is absent or an optionally substituted aliphatic group;
T is absent or an optionally substituted linear aliphatic group containing zero to eight carbons; E is absent or independently selected from optionally substituted aryl and optionally substituted heteroaryl;
Wherein one or two of D, E, and T are absent;
R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted Ci-C4 alkyl, -O-R11, -NRaRb, -C(O)R1 * , -CO2R1 * , and -C(0)NRaRb;
R11 at each occurrence is independently hydrogen or optionally substituted Ci-C8 alkyl;
Ra and Rb at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C2- Cg 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 and v are each independently 1 , 2, or 3;
Q and J are each independently selected from:
PAGE 172 OF 191
R3 and R4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-Cs alkenyl, and optionally substituted C3-Cs cycloalkyl; or alternatively, R3 and R4 can be taken together with the carbon atom to which they are attached to form optionally substituted C3-Cs cycloalkyl or optionally substituted heterocyclic;
R5 at each occurrence is independently hydrogen, optionally substituted Ci-Cs alkyl, or optionally substituted C3-C8 cycloalkyl;
R6 is selected from the group consisting of -C(O)-R12, -C(O)-C(O)-R12, -S(O)2- R12, and -C(S)-R12;
R12 at each occurrence is independently selected from the group consisting of: -O- R11, -NRaRb, -R13, and -NRcRd; wherein
R13 at each occurrence is independently selected from the group consisting of: hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 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, -R13, -C(O)-R13, -C(O)-OR13, -S(O)2-R13, -C(O)N(R13)2, and -S(O)2N(R13),; m is O, 1, or 2; n is 1, 2, 3, or 4;
X at each occurrence is independently selected from O, S, S(O), SO2, and C(R7)2; provided that when m is O, X is C(R7)2; and
R7 at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, -0-R11, -NRaRb, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -C1-C4 alkyl; or two vicinal R7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring; or alternatively two germinal R7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring.
PAGE 173 OF 191
34. The compound of claim 33, wherein Q and J are each independently selected from:
pharmaceutically acceptable salt thereof.
35. The compound of claim 33, wherein Q and J are each independently O-^R12; and R1 and R2 are each hydrogen; or a pharmaceutically acceptable salt thereof.
36. The compound of claim 33, wherein T and E are each absent and D is independently optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl; or a pharmaceutically acceptable salt thereof.
37. The compound of claim 33, wherein T and E are each absent and D is selected from O, N(R11), C(O), S(O)2, C(O)O, C(O)N(R11), OC(O)O, OC(O)N(R11), S(O)2N(R11), N(Rπ)C(0)N(Rn), N(Rn)C(0)C(0)N(Rn), N(Rn)S(O)2N(Rn), C(O)N(R1 ^S(O)2 or C(0)N(Rn)S(0)2N(Rn); or a pharmaceutically acceptable salt thereof.
38. The compound of claim 33, wherein T and E are each absent and D is independently optionally substituted C3-Cs cycloalkyl or optionally substituted C3-Cs cycloalkenyl; or a pharmaceutically acceptable salt thereof.
39. The compound of claim 33, wherein T and E are each absent and D is independently optionally substituted heterocyclic; or a pharmaceutically acceptable salt thereof.
40. The compound of claim 33, wherein D and T are each absent and E is independently optionally substituted aryl or optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
PAGE 174 OF 191
41. The compound of claim 33, wherein D and T are each absent and E is present; A is independently optionally substituted aryl or optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
42. The compound of claim 33, wherein D and T are each absent, E is present; and A is independently optionally substituted C3-Cs cycloalkyl or optionally substituted C3-Cs cycloalkenyl; or a pharmaceutically acceptable salt thereof.
43. The compound of claim 33, wherein D and T are each absent; E is present and A is independently optionally substituted heterocyclic; or a pharmaceutically acceptable salt thereof.
44. The compound of claim 33, wherein E is absent, D and T are each independently a linear aliphatic group containing zero to six carbons, optionally comprising one or more groups selected from O, N(R11), C(O), S(O)2, C(O)O, and C(O)N(R11); or a pharmaceutically acceptable salt thereof.
45. The compound of claim 36, wherein A is heterocyclyl; or a pharmaceutically acceptable salt thereof.
46. The compound of claim 36, wherein A is independently optionally substituted aryl or optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
47. The compound of claim 36, wherein A is independently optionally substituted C3- Cs cycloalkyl or optionally substituted C3-Cs cycloalkenyl; or a pharmaceutically acceptable salt thereof.
48. The compound according to claim 33 selected from the group of compounds 3-1 to 3-334 compiled in the following tables: Compounds 3- 1 to 3-219
PAGE 175 OF 191
PAGE 176 OF 191
PAGE 177 OF 191
PAGE 178 OF 191
PAGE 179 OF 191
PAGE 180 OF 191 Compounds 3-220 to 3-229
Compound 3-230
Compound 3-233
Compounds 3-234 to 3-243
PAGE 181 OF 191
Compounds 3-244 to 3-263
PAGE 182 OF 191 Compounds 3-264 to 3-289
Compounds 3-290 to 3-334
PAGE 183 OF 191
49. A compound of claim 33, represented by Formula (3-II), or a pharmaceutically acceptable salt thereof:
50. A compound of claim 49, wherein m is 1 ; n is 1 or 2; u is 1 or 2; A is optionally substituted phenyl or optionally substituted monocyclic heteroaryl; T is optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl; R1 at each occurrence is independently hydrogen or halogen; X at each occurrence is each independently CH2, CHF, CH(OH), CHMe, CF2, or C(R7)2; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R7 groups are taken together with the carbon to which they are attached to form a spiro C3-Cs 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 C3-Cs cycloalkyl; and R12 at each occurrence is independently optionally substituted Ci-Cs alkyl; or a pharmaceutically acceptable salt thereof.
51. A compound of claim 33 represented by Formula (3-III-a) or (3-III-b):
PAGE 184 OF 191 wherein n is 1 or 2; X at each occurrence is independently CH2, CHF, CH(OH), CHMe, CF2, or C(R7)2; wherein R7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R7 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 R12 at each occurrence is independently Ci-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); or a pharmaceutically acceptable salt thereof.
(R7)n
52. The compound of claim 33, wherein «!«<• is selected from the group listed below, or a pharmaceutically acceptable salt thereof: xQ J». vθ «UΛ γθ 1^Q «UΛ XQ J~ * XQ7 &>
53. A compound according to claim 33 selected from the group of compounds 3-335 to 3-337 compiled in the following tables:
PAGE 185 OF 191
54. A process of making a compound according to claim 1 comprising the steps of: i) preparing a compound of Formula (1-II-a):
via a transition-metal catalyzed cross-coupling reaction; wherein:
A, n, u, v, R1, R2, and R7 are as defined in claim 1;
Za and Zb are each independently an amino protecting group or -C(O)-R12; R12 is C1- C8 alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (II-b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R12; iii) capping the released amino group of a compound of Formula (II-b) with LG-C(O)-R12, wherein LG is a leaving group; to give the compound of Formula (II-c):
wherein Z is an amino protecting group -C(O)-R ; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (II-d):
55. A process of making a compound according to claim 18 comprising the steps of:
PAGE 186 OF 191 i) preparing a compound of Formula (2-II-a):
via a transition-metal catalyzed cross-coupling or metathesis reaction; amide or urea formation; ester or carbamate formation; or ether formation; wherein:
A, n, u, v, R1, R2, and R7 are as defined in claim 18;
Za and Zb are each independently an amino protecting group or -C(O)-R12; R12 is C1- Cs alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (II-b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R12; iii) capping the released amino group of a compound of Formula (II-b) with
LG-C(O)-R12, wherein LG is a leaving group; to give the compound of Formula (II-c):
wherein Z is an amino protecting group -C(O)-R ; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (II-d):
56. A process of making a compound according to claim 33 comprising the steps of: i) preparing a compound of Formula (3 -II-a):
PAGE 187 OF 191 ((RI 7)n via a transition-metal catalyzed cross-coupling reaction; amide or urea formation; ester or carbamate formation; or ether formation; wherein:
A, T, n, u, v, R1, R2, and R7 are as defined in claim 33; Za and Zb are each independently an amino protecting group or -C(O)-R12; ii) when Za or Zb is an amino protecting group, fully or selectively deprotecting a compound of Formula (II-a) to give the corresponding amine of Formula (3-II-b):
wherein Zc is hydrogen, an amino protecting group or -C(O)-R 12 ;. T Ri 12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C4 alkyl); iii) capping the released amino group of a compound of Formula (II -b) with
LG-C(O)-R12, wherein LG is a leaving group; to give the compound of Formula (3-II-c):
wherein Zd is an amino protecting group -C(O)-R12; and iv) repeated reaction sequence of deprotecting and capping (step ii-iii) to give the compound of Formula (3-II-d):
57. A pharmaceutical composition comprising a compound or a combination of compounds according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
PAGE 188 OF 191
58. A method of inhibiting the replication of an RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.
59. A method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of any one claims 1 to 53, or a pharmaceutically acceptable salt thereof.
60. The method of claim 59, wherein the RNA-containing virus is hepatitis C virus.
61. The method of claim 59, 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.
62. The method of claim 61 , 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.
63. The method of claim 61 , wherein the antiviral agent inhibit replication of HCV by inhibiting host cellular functions associated with viral replication.
64. The method of claim 61 , wherein the antiviral agent inhibits the replication of HCV by targeting proteins of the viral genome.
65. The method of claim 61 , wherein said antiviral agent is an inhibitor of a HCV viral protein, a replication process or a combination thereof, wherein said targeting protein or replication process is selected from the group consisting of helicase, protease, polymerase, metalloprotease, NS4A, NS4B, NS5A, assembly, entry, and IRES.
66. The method of claim 59, further comprising the step of co-administering an agent or combination of agents that treat or alleviate symptoms of HCV infection selected from cirrhosis, inflammation of the liver and a combination thereof.
PAGE 189 OF 191
67. The method of claim 59, further comprising the step of co-administering one or more agents that treat patients for disease caused by hepatitis B (HBV) infection.
68. The method of claim 59, further comprising the step of co-administering one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection.
69. The pharmaceutical composition of claim 57, 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.
70. The composition of claim 57, further comprising a cytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptable salt thereof.
71. The composition of claim 70, wherein the cytochrome P450 mooxygenase inhibitor is ritonavir.
72. A method of treating hepatitis C viral 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 53 or a pharmaceutically acceptable salt thereof.
PAGE 190 OF 191
EP20100739272 2009-02-09 2010-02-09 Linked dibenzimidazole derivatives Withdrawn EP2393359A4 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US15107909P 2009-02-09 2009-02-09
US15323109P 2009-02-17 2009-02-17
US15322409P 2009-02-17 2009-02-17
US15623909P 2009-02-27 2009-02-27
US15611009P 2009-02-27 2009-02-27
PCT/US2010/023645 WO2010091413A1 (en) 2009-02-09 2010-02-09 Linked dibenzimidazole derivatives

Publications (2)

Publication Number Publication Date
EP2393359A1 true EP2393359A1 (en) 2011-12-14
EP2393359A4 EP2393359A4 (en) 2012-10-03

Family

ID=42542427

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20100739272 Withdrawn EP2393359A4 (en) 2009-02-09 2010-02-09 Linked dibenzimidazole derivatives

Country Status (2)

Country Link
EP (1) EP2393359A4 (en)
WO (1) WO2010091413A1 (en)

Families Citing this family (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2750577A1 (en) 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
WO2010065674A1 (en) * 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
US8546405B2 (en) 2008-12-23 2013-10-01 Abbott Laboratories Anti-viral compounds
SG172352A1 (en) 2008-12-23 2011-07-28 Abbott Lab Anti-viral compounds
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TW201038559A (en) 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9278922B2 (en) 2009-04-15 2016-03-08 Abbvie Inc. Anti-viral compounds
HUE030465T2 (en) 2009-05-13 2017-05-29 Antiviral compounds
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2012528195A (en) * 2009-05-29 2012-11-12 メルク・シャープ・アンド・ドーム・コーポレーション Antibacterial compounds composed of three linked aryl moieties for treating diseases such as hepatitis C
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2435421A1 (en) * 2009-05-29 2012-04-04 Schering Corporation Antiviral compounds composed of three aligned aryl moieties to treat diseases such as hepatitis c
EA020031B1 (en) 2009-06-11 2014-08-29 Эббви Бахамаз Лтд. Anti-viral compounds
US8716454B2 (en) 2009-06-11 2014-05-06 Abbvie Inc. Solid compositions
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
US9394279B2 (en) 2009-06-11 2016-07-19 Abbvie Inc. Anti-viral compounds
AU2010274001A1 (en) 2009-07-16 2012-02-23 Vertex Pharmaceuticals Incorporated Benzimidazole analogues for the treatment or prevention of Flavivirus infections
WO2011015658A1 (en) * 2009-08-07 2011-02-10 Tibotec Pharmaceuticals Bis-benzimidazole derivatives as hepatitis c virus inhibitors
AU2010291215A1 (en) 2009-09-03 2012-02-23 Janssen Sciences Ireland Uc Bis-benzimidazole derivatives
CN102480971B (en) 2009-09-04 2014-11-26 杨森制药公司 Chemical compounds
UA108211C2 (en) * 2009-11-04 2015-04-10 Янссен Рід Айрленд Benzimidazole imidazole derivatives
US20110274648A1 (en) * 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US8653070B2 (en) 2009-12-14 2014-02-18 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
MX2012006877A (en) 2009-12-18 2012-08-31 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors.
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CN102858157A (en) * 2010-03-04 2013-01-02 埃南塔制药公司 Combination pharmaceutical agents as inhibitors of hcv replication
TW201139438A (en) * 2010-03-24 2011-11-16 Vertex Pharma Analogues for the treatment or prevention of flavivirus infections
CN102869657A (en) 2010-03-24 2013-01-09 沃泰克斯药物股份有限公司 Analogues for the treatment or prevention of flavivirus infections
US20130296311A1 (en) * 2010-05-28 2013-11-07 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
NZ605440A (en) 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
EP2585447A2 (en) 2010-06-28 2013-05-01 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006060A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
EP2606041A2 (en) 2010-08-17 2013-06-26 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
AU2014203655B2 (en) * 2010-10-13 2016-07-07 Abbvie Ireland Unlimited Company Anti-viral compounds
EP2651925A4 (en) * 2010-12-15 2014-06-18 Abbvie Inc Anti-viral compounds
EP2651923A4 (en) * 2010-12-15 2014-06-18 Abbvie Inc Anti-viral compounds
US20150232455A1 (en) * 2010-12-15 2015-08-20 Allan C. Krueger Anti-viral compounds
JP5906253B2 (en) * 2010-12-16 2016-04-20 アッヴィ・インコーポレイテッド Antiviral compounds
WO2012087976A2 (en) * 2010-12-21 2012-06-28 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) * 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
JP6198721B2 (en) * 2011-05-27 2017-09-20 アキリオン ファーマシューティカルズ，インコーポレーテッド Substituted aliphane, cyclophane, heteraphan, heterophane, hetero-heteraphane and metallocenes useful for treating HCV infection
WO2013016499A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Methods for preparation of thiophene compounds
AU2012286853A1 (en) 2011-07-26 2013-05-02 Vertex Pharmaceuticals Incorporated Thiophene compounds
EP2709613B2 (en) 2011-09-16 2020-08-12 Gilead Pharmasset LLC Methods for treating hcv
GB201116559D0 (en) * 2011-09-26 2011-11-09 Univ Leuven Kath Novel viral replication inhibitors
MX340033B (en) 2011-12-28 2016-06-21 Janssen Sciences Ireland Uc Hetero-bicyclic derivatives as hcv inhibitors.
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2013142157A1 (en) 2012-03-22 2013-09-26 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
TWI610916B (en) * 2012-08-03 2018-01-11 廣東東陽光藥業有限公司 Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceuticals applications thereof
EP2950786B1 (en) 2013-01-31 2019-11-27 Gilead Pharmasset LLC Combination formulation of two antiviral compounds
WO2014134251A1 (en) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
US20150023913A1 (en) 2013-07-02 2015-01-22 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
PT3038601T (en) 2013-08-27 2020-06-30 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
WO2015103490A1 (en) 2014-01-03 2015-07-09 Abbvie, Inc. Solid antiviral dosage forms
CN105272972B (en) * 2014-05-30 2018-12-11 上海唐润医药科技有限公司 Benzheterocycle hexadiene derivative with antiviral activity
JOP20160086B1 (en) 2015-05-08 2021-08-17 2 Katholieke Univ Leuven Ku Leuven Research And Development Mono- or di-substituted indole derivatives as dengue viral replication inhibitors
WO2017023631A1 (en) 2015-08-06 2017-02-09 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
BR112018068676A2 (en) * 2016-03-31 2019-01-15 Janssen Pharmaceuticals Inc substituted indole derivatives as dengue viral replication inhibitors
BR112018069601A2 (en) 2016-03-31 2019-01-29 Janssen Pharmaceuticals Inc substituted indoline derivatives as dengue viral replication inhibitors
JOP20170069B1 (en) 2016-04-01 2021-08-17 1 Janssen Pharmaceuticals Inc Substituted indoline derivatives as dengue viral replication inhibitors
JOP20180025B1 (en) 2017-03-31 2021-08-17 Janssen Pharmaceuticals Inc Substituted indoline derivatives as dengue viral replication inhibitors
JOP20180026A1 (en) 2017-03-31 2019-01-30 Univ Leuven Kath Indolein derivatives substituted as viral reproductive inhibitors of Fennec fever
BR102018007822A2 (en) 2017-04-20 2018-11-06 Gilead Sciences, Inc. compound, methods for inhibiting pd-1, pd-11 and / or interaction of pd-1 / pd-11 and for cancer treatment, pharmaceutical composition, and kit for treating or preventing cancer or a disease or condition
EP3630723B1 (en) 2017-05-22 2022-08-24 Janssen Pharmaceuticals, Inc. Substituted indoline derivatives as dengue viral replication inhibitors
UA125970C2 (en) 2017-05-22 2022-07-20 Янссен Фармасьютікалз, Інк. SUBSTITUTED INDOLINE DERIVATIVES AS DENGE VIRUS REPLICATION INHIBITORS
CR20200347A (en) 2018-02-13 2020-09-23 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
TWI712412B (en) 2018-04-19 2020-12-11 美商基利科學股份有限公司 Pd-1/pd-l1 inhibitors
SG11202012425QA (en) 2018-07-13 2021-01-28 Gilead Sciences Inc Pd-1/pd-l1 inhibitors
WO2020086556A1 (en) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US12037340B2 (en) 2021-05-21 2024-07-16 Gilead Sciences, Inc. Pentacyclic derivatives as Zika virus inhibitors
US12497408B2 (en) 2021-05-21 2025-12-16 Gilead Sciences, Inc. Tetracyclic compounds and methods for the treatment of Zika virus infection

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935982A (en) * 1997-02-28 1999-08-10 The University Of North Carolina At Chapel Hill Methods of treating retroviral infection and compounds useful therefor
EP2335700A1 (en) * 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Hepatitis C virus polymerase inhibitors with a heterobicylic structure
GB0229518D0 (en) * 2002-12-19 2003-01-22 Astrazeneca Ab Chemical compounds
JP2007509950A (en) * 2003-10-27 2007-04-19 バーテックス　ファーマシューティカルズ　インコーポレイテッド HCV treatment combination
US7772271B2 (en) * 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8143288B2 (en) * 2005-06-06 2012-03-27 Bristol-Myers Squibb Company Inhibitors of HCV replication
US8329159B2 (en) * 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7906655B2 (en) * 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

Also Published As

Publication number Publication date
EP2393359A4 (en) 2012-10-03
WO2010091413A1 (en) 2010-08-12

Similar Documents

Publication Publication Date Title
WO2010091413A1 (en) Linked dibenzimidazole derivatives
KR101411889B1 (en) Hepatitis c virus inhibitors
US8242156B2 (en) Linked dibenzimidazole derivatives
US9000020B2 (en) Linked dibenzimidazole antivirals
US8188132B2 (en) Linked dibenzimidazole derivatives
US8507522B2 (en) Hepatitis C virus inhibitors
WO2010096462A1 (en) Linked diimidazole derivatives
WO2011031934A1 (en) Hepatitis c virus inhibitors
WO2010148006A1 (en) Hepatitis c virus inhibitors
EP2575819A1 (en) Hepatitis c virus inhibitors
KR20120107529A (en) Hepatitis c virus inhibitors
WO2011031904A1 (en) Hepatitis c virus inhibitors
WO2011127350A1 (en) Hepatitis c virus inhibitors
CN104024249A (en) Hepatitis c virus inhibitors
WO2012021704A1 (en) Hepatitis c virus inhibitors
WO2013052362A1 (en) Hepatitis c virus inhibitors
AU2013204195B2 (en) Hepatitis C virus inhibitors
HK1164644B (en) Hepatitis c virus inhibitors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110908

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20120904

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 31/12 20060101ALI20120829BHEP

Ipc: A01N 43/50 20060101AFI20120829BHEP

Ipc: C07D 405/14 20060101ALI20120829BHEP

Ipc: C07D 417/14 20060101ALI20120829BHEP

Ipc: C07D 403/14 20060101ALI20120829BHEP

Ipc: C07D 409/14 20060101ALI20120829BHEP

Ipc: C07D 413/14 20060101ALI20120829BHEP

Ipc: A61K 31/4184 20060101ALI20120829BHEP

Ipc: C07D 401/14 20060101ALI20120829BHEP

17Q First examination report despatched

Effective date: 20150324

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20150804