WO2010099527A1 - Hepatitis c virus inhibitors - Google Patents
Hepatitis c virus inhibitors Download PDFInfo
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- WO2010099527A1 WO2010099527A1 PCT/US2010/025741 US2010025741W WO2010099527A1 WO 2010099527 A1 WO2010099527 A1 WO 2010099527A1 US 2010025741 W US2010025741 W US 2010025741W WO 2010099527 A1 WO2010099527 A1 WO 2010099527A1
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- 0 C*CCN(C(*)(C*)c1nc2cc(**c3cnc(C(*)(C*)N(*C)C(*)=O)[n]3)ccc2[n]1)C(*)=O Chemical compound C*CCN(C(*)(C*)c1nc2cc(**c3cnc(C(*)(C*)N(*C)C(*)=O)[n]3)ccc2[n]1)C(*)=O 0.000 description 37
- YFLIRVHBHMZZQT-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)C1c1nc(-c(cc2)cc(cc3)c2cc3-c(cc(c([nH]2)c3)nc2S(CCC2)N2C(OC(C)(C)C)=O)c3Cl)c[nH]1)=O Chemical compound CC(C)(C)OC(N(CCC1)C1c1nc(-c(cc2)cc(cc3)c2cc3-c(cc(c([nH]2)c3)nc2S(CCC2)N2C(OC(C)(C)C)=O)c3Cl)c[nH]1)=O YFLIRVHBHMZZQT-UHFFFAOYSA-N 0.000 description 1
- MKFYNQAKTJFISL-SECBINFHSA-N CC(C)(C)OC(N(CCC1)[C@@H]1C#C)=O Chemical compound CC(C)(C)OC(N(CCC1)[C@@H]1C#C)=O MKFYNQAKTJFISL-SECBINFHSA-N 0.000 description 1
- QOROSXYTKAMFAC-AWEZNQCLSA-N CC(C)(C)OC(N(CCC1)[C@@H]1C#Cc1cc(Br)ccc1N)=O Chemical compound CC(C)(C)OC(N(CCC1)[C@@H]1C#Cc1cc(Br)ccc1N)=O QOROSXYTKAMFAC-AWEZNQCLSA-N 0.000 description 1
- AEFBBYWAKYQXOD-UHFFFAOYSA-N CC(C)(C)OC(NCc1nc(-c(cc2)ccc2C#Cc2ccc3[nH]c(S(CCC4)N4C(OC(C)(C)C)=O)nc3c2)c[nH]1)=O Chemical compound CC(C)(C)OC(NCc1nc(-c(cc2)ccc2C#Cc2ccc3[nH]c(S(CCC4)N4C(OC(C)(C)C)=O)nc3c2)c[nH]1)=O AEFBBYWAKYQXOD-UHFFFAOYSA-N 0.000 description 1
- OXGJDXGEZZCILM-UHFFFAOYSA-N CC(C)c1c(ccc([IH]I)c2)c2n[nH]1 Chemical compound CC(C)c1c(ccc([IH]I)c2)c2n[nH]1 OXGJDXGEZZCILM-UHFFFAOYSA-N 0.000 description 1
- MGOJKSXCOAWKEN-UHFFFAOYSA-N CC(C)c1cnc(cc(C(C)=C)[nH]2)c2n1 Chemical compound CC(C)c1cnc(cc(C(C)=C)[nH]2)c2n1 MGOJKSXCOAWKEN-UHFFFAOYSA-N 0.000 description 1
- QKCGGLWTKGWEHT-UHFFFAOYSA-N CC(CC1C2CC2)CN1NC Chemical compound CC(CC1C2CC2)CN1NC QKCGGLWTKGWEHT-UHFFFAOYSA-N 0.000 description 1
- KHPJVGCOIIRKRJ-UHFFFAOYSA-N CC(NC1=CC(C)=C2)=CN1C2=O Chemical compound CC(NC1=CC(C)=C2)=CN1C2=O KHPJVGCOIIRKRJ-UHFFFAOYSA-N 0.000 description 1
- LJNSPAJJBTXQEN-UHFFFAOYSA-N Cc1cc(ncc(C)c2)c2[nH]1 Chemical compound Cc1cc(ncc(C)c2)c2[nH]1 LJNSPAJJBTXQEN-UHFFFAOYSA-N 0.000 description 1
- HHTYEQWCHQEJNV-UHFFFAOYSA-N Nc(c(I)c1)ccc1Br Chemical compound Nc(c(I)c1)ccc1Br HHTYEQWCHQEJNV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- 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
-
- 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
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.
- 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
- PAGE 2 OF 222 proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931-960; Raven Press, N.Y.).
- C structural proteins
- El structural proteins
- the P7 protein is of unknown function and is comprised of a highly variable sequence.
- 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 Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication.
- compounds which are effective to inhibit the function of the NS5A protein are desired.
- PAGE 3 OF 222 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.
- HCV NS5A virally encoded proteins
- the relevant patent disclosures describing the synthesis of HCV NS5 A 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 2006/133326; WO 2004/014852; WO 2008/070447; WO 2009/034390; WO 2006/079833; WO 2007/031791; WO 2007/070556; WO 2007/070600; WO 2008/064218; WO 2008/154601; WO 2007/082554; and
- 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)
- D and Z are are each independently absent or optionally substituted linear aliphatic group containing zero to eight carbon atoms;
- a and E are each independently absent or a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted;
- PAGE 4 OF 222 T is absent or an optionally substituted aliphatic group
- Ring B is a five-membered heteroaryl wherein said heteroaryl is optionally substituted; preferably, a five-membered heteroaryl containing one or more nitrogen atoms; more preferably, imidazolyl that is C-attached to group J and one of groups Z, E, T, A and D;
- R 1 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1 -C 4 alkyl, -O-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b ; preferably, hydrogen, halogen and optionally substituted C 1 -C 4 alkyl;
- R 11 at each occurrence is independently hydrogen or optionally substituted C i-C 8 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 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group; u at each occurrence is independently 1, 2, or 3;
- 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 - Cg alkenyl, and optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 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 C3-C8 cycloalkyl or optionally substituted heterocyclic;
- R 5 at each occurrence is independently hydrogen, optionally substituted Ci- Cg alkyl, or optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl; R 6 at each occurrence is independently selected from the group consisting of
- PAGE 5 OF 222 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 -C8 alkenyl, C 2 -C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-Cs alkyl; more preferably Ci-Cs 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,
- 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 are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring; preferably, a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
- the present invention provides a compound of Formula (2-1)
- D and Z are are each independently absent or optionally substituted linear aliphatic group containing zero to eight carbon atoms;
- PAGE 6 OF 222 A and E are are each independently absent or a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted;
- T is absent or an optionally substituted aliphatic group; Wherein one to four of A, D, E, T and Z is absent;
- Ring B is a five-membered heteroaryl or a 5/6-membered fused heteroaryl, wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups Z, E, T, A and D, and the 5-membered ring of said 5/6 membered fused heteroaryl is attached to group J and contains one or more nitrogen atoms; wherein said five-membered heteroaryl or 5/6-membered fused heteroaryl is optionally substituted; preferably imidazolyl or benzimidazolyl, wherein said imidazolyl or benzimidazolyl are C-attached to group J and one of groups Z, E, T, A and D;
- Ring G is a 5/6-membered fused heteroaryl other than benzimidazolyl, wherein the 6-membered ring of said 5/6-membered fused heteroaryl is attached to one of groups D, A, T, E and Z, and the 5-membered ring of said 5/6-membered fused heteroaryl is attached to group Q and contains one or more nitrogen atoms; and wherein said 5/6-membered fused heteroaryl is optionally substituted;
- 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 -
- R 5 at each occurrence is independently hydrogen, optionally substituted Ci-
- C 8 alkyl or optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl; R 6 at each occurrence is independently selected from the group consisting of
- PAGE 7 OF 222 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 11 at each occurrence is independently hydrogen or optionally substituted C 1 -C 8 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 -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;
- R 13 at each occurrence is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, C 2 -C8 alkenyl, C 2 -C8 alkynyl, C3-C8 cycloalkyl, C3-C8 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 ) 2 ;
- m is O, 1 , or 2, preferably 1 ;
- 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 -C 1 -C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C3-Q cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
- the present invention provides a pharmaceutical composition
- 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 thereof.
- 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.
- RNA-containing virus including, for example, HCV.
- Other compounds useful for inhibiting the replication of RNA-containing viruses and/or for the treatment or prophylaxis of HCV infection have been described in copending U.S. Application Serial No. 12/702,673 filed February 9, 2010 entitled “Linked Dibenzimidazole Antivirals”; U.S. Application Serial No. 12/702,692 filed February 9, 2010 entitled “Linked Dibenzimidazole Derivatives"; U.S. Application Serial No. 12/702,802 filed February 9, 2010 entitled “Linked Dibenzimidazole Derivatives"; U.S. Application Serial No. 12/707,190 filed February 17, 2010 entitled "Linked
- the present invention relates to compounds of Formula (1- I) 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:
- Ring B 1 is a f ⁇ ve-membered heteroaryl that is C-attached to J and to one of Z, E, T, A and D.
- the present invention relates to compounds of
- Ring B 2 is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B 2 is C-attached to J and to one of Z, E, T, A and D.
- the present invention relates to compounds of Formulae (1-Ic-l to l-Ic-4), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formulae (1-Id-l to l-Id-4), or a pharmaceutically acceptable salt thereof:
- A, D, E, T, Z, Ring B, R 3 , R 4 , R 5 , and R 12 are as previously defined in Formula (1-1) and X 1 is independently CH 2 , CHF, CH(OH), or CF 2 .
- the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine or five- membered heteroarylmethylamine moiety is represented by Formulae (1-Ie-l to 1- Ie-4):
- 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-Ih), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formula (1-Ii), or a pharmaceutically acceptable salt thereof:
- A, D, E, T, Z, Ring B are as previously defined in Formula (1-1) andR 13a at each occurrence is independently an optionally substituted Ci-C 8 alkyl; preferably Ci-C 8 alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl).
- the present invention relates to compounds of Formula (1-IIa), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formula (1-IIb), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formula (1-IIc), or a pharmaceutically acceptable salt thereof:
- T 1 is a linear aliphatic group, optionally containing one or more of an olef ⁇ nic double bond and an alkynic triple bond and further, optionally comprising one or more groups selected from the group consisting of O, N(R 1 !
- the present invention relates to compounds of Formula (1-IId), or a pharmaceutically acceptable salt thereof:
- T 2 is an aliphatic group comprising a C3-C8 cycloalkyl or C3-C8 cycloalkenyl and optionally contains one or more of an olefimc double bond and an alkynic triple bond and further, optionally comprises one or more groups selected from the group consisting of O, N(R 11 ), 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 n )C(0)N(R n ), N(R 11 JS(O) 2 N(R 11 ), N(R 1 ⁇ C(O)C(O)N(R 11 ), C(O)N(R n )S(O) 2 and C(0)N(R n )S(0) 2 N(R n ).
- the present invention relates to compounds of Formulae (1-IIIa-l and l-IIIa-2), or a pharmaceutically acceptable salt thereof:
- n is 1 or 2; T is absent or optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; X at each occurrence is independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl; or yet alternatively, two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C3-C8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted Ci-Cg alkyl.
- the invention is a compound of Formula (l-IIIa-3) wherein R 12 at each occurrence is independently Ci-C 8 alkyl substituted with -NHCO 2 (Ci-C 4 alkyl) or 0(Ci-C 4 alkyl).
- R 12 at each occurrence is independently Ci-C 8 alkyl substituted with -NHCO 2 (Ci-C 4 alkyl) or 0(Ci-C 4 alkyl).
- the present invention relates to compounds of
- the present invention relates to compounds of
- Formula (l-IIIa-3), or a pharmaceutically acceptable salt thereof wherein two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R 12 at each occurrence is independently Ci-C 8 alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C 4 alkyl).
- the present invention relates to compounds of Formulae (1-III-a) to (1-III-d), or a pharmaceutically acceptable salt thereof:
- n is 1 or 2;
- X at each occurrence is each independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, the two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R 7 groups are taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R 12 at each occurrence is independently Ci-Cg alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C 4 alkyl).
- the present invention relates to compounds of Formulae (1-III-a) to (1-III-d); wherein R 12 at each occurrence is independently C 1 - C 8 alkyl substituted with -NHCO 2 (Ci-C 4 alkyl) or O(C r C 4 alkyl); 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 Formulae (1-IVa-l and l-IVa-2), or a pharmaceutically acceptable salt thereof:
- Ring B 1 , Q, J, u, and R 1 are as previously defined in Formula (1-1); in Formula (1-IVa-l), A, D, and T are each present and as previously defined in Formula (1-1); and in Formula (l-IVa-2), E, T, and Z are each present and as previously defined in Formula (1-1).
- the present invention relates to compounds of Formula (1-IVb), or a pharmaceutically acceptable salt thereof:
- Ring B 1 , Q, J, u, and R 1 are as previously defined in Formula (1-1); A, E, and T are each present and as previously defined in Formula (1-1).
- the present invention relates to compounds of Formulae (1-Va-l and l-Va-2), or a pharmaceutically acceptable salt thereof:
- Ring B 1 , Q, J, u, and R 1 are as previously defined in Formula (1-1); in Formula (1-Va-l), D, A, T and E are each present and as previously defined in Formula (1-1); in Formula (l-Va-2), A, E, T, and Z are each present and as previously defined in Formula (1-1).
- the present invention relates to compounds of
- Representative compounds of the present invention are those selected from compounds 1-1-1, 1-2-1, and 1-2-2 (shown below), and compounds 1-1 to 1-545 compiled in Tables 1-9:
- Table 1 Compounds 1-1 to 1-219.
- Table 2 Compounds 1-220 to 1-229.
- Table 4 Compounds 1-244 to 1-263.
- Table 7 Compounds 1-300 to 1-434.
- the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to compounds of Formula (2-1)
- Ring B 1 is an optionally substituted f ⁇ ve-membered heteroaryl; and Ring B 1 is C-attached to J and one of Z, E, T, A and D.
- Ring B 1 is an optionally substituted f ⁇ ve-membered heteroaryl that contains one or more nitrogen atoms.
- the present invention relates to compounds of Formula (2-Iaa), or a pharmaceutically acceptable salt thereof:
- Ring B 2 is selected from imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiazolyl, and isoxazolyl; and Ring B 2 is C-attached to each of J and one of Z, E, T, A and D.
- the present invention relates to compounds of Formula (2-Ib), or a pharmaceutically acceptable salt thereof:
- Ring B 3 is an optionally substituted 5/6 fused heteroaryl, wherein the 6- membered ring of said 5/6-fused heteroaryl is C-attached to one of groups Z, E, T, A and D, and the 5-membered ring is C-attached to group J and containing one or more nitrogen atoms.
- the present invention relates to compounds of Formula (2-Ibb), or a pharmaceutically acceptable salt thereof:
- Ring B 4 is selected from the group consisting of:
- the present invention relates to compounds of Formula (2-Ic), or a pharmaceutically acceptable salt thereof:
- Ring B, D, E, T, Z, Q, and J are as previously defined in Formula (2-1) and Ring G 1 is an optionally substituted 5/6 fused heteroaryl other than benzimidazolyl, with the 6-membered ring C-attached to one of groups D, A, T, E and Z and the 5-membered ring C-attached to group J and containing one or more nitrogen atoms.
- the present invention relates to compounds of Formula (2-Icc), or a pharmaceutically acceptable salt thereof:
- Ring G is selected from the group consisting of:
- the present invention relates to compounds of Formulae (2-Id-l to 2-Id-4), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formulae (2-Ie-l to 2-Ie-4), or a pharmaceutically acceptable salt thereof:
- A, Ring B, D, E, Ring G, T, Z, R 3 , R 4 , R 5 , and R 12 are as previously defined in Formula (2-1) and X 1 is independently CH 2 , CHF, CH(OH), or CF 2 .
- the absolute stereochemistry of the pyrrolidine and 2-benzimidazolylmethylamine or f ⁇ ve- membered heteroarylmethylamine moiety is represented by Formulae (2-If-l to 2- If-4):
- the present invention relates to compounds of Formula (2-Ig), or a pharmaceutically acceptable salt thereof: wherein A, D, E, T, Z, Ring B, Ring G and R 11 are as previously defined in Formula (2-1).
- 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: wherein A, Ring B, D, E, Ring G, T, Z, and R 13 are as previously defined in Formula (2-1).
- the present invention relates to compounds of Formula (2-Ik), or a pharmaceutically acceptable salt thereof: wherein A, Ring B, D, E, Ring G, T, and Z are as previously defined in Formula (2- I) andR 13a at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cs 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: (2-iia) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-1) and T is present and as previously defined in Formula (2-1).
- the present invention relates to compounds of Formula (2-IIb), or a pharmaceutically acceptable salt thereof: (2-llb) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-1) and A is present and as previously defined in Formula (2-1).
- the present invention relates to compounds of Formula (2-IIc), or a pharmaceutically acceptable salt thereof: (2-llc) wherein Q, J, Ring B, and Ring G are as previously defined in Formula (2-1) and T 1 is a linear aliphatic group, optionally comprising one or more of an olefinic double bond, an alkynic triple bond, O, N(R 11 ), 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 n )C(0)N(R n ), N(R 1 ⁇ C(O)C(O)N(R 1 J ), N(R 1 ⁇ S(O) 2 N(R 11 ), C(O)N(R n )S(O) 2 and C(O)N(R 1 ⁇ S(O) 2 N(R 11 ).
- the present invention relates to compounds of Formula (2-IId), or a pharmaceutically acceptable salt thereof:
- T 2 is an aliphatic group comprising a C3-C8 cycloalkyl or C3-C8 cycloalkenyl and optionally comprising one or more of an olefinic double bond, an alkynic triple bond, O, N(R 11 ), 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 n )C(0)N(R n ), N(R n )S(0) 2 N(R n ), N(R 1 ⁇ C(O)C(O)N(R 11 ), C(O)N(R n )S(O) 2 and C(O)N(R n )S(O) 2 N(R n ).
- the present invention relates to compounds of Formulae (2-IIIa-l and 2-IIIa-2), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formula (2-IIIa-3), or a pharmaceutically acceptable salt thereof:
- Ring G is as previously defined in Formula (2-1); n is 1 or 2; T is absent or optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; E is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; X at each occurrence is independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro, optionally substituted C3-C8 cycloalkyl; or yet alternatively, 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 C3-C8 cycloalkyl; and R 12 at each occurrence is independently optionally substituted Ci-C
- the present invention relates to compounds of
- the present invention relates to compounds of Formulae (2-III-a) to (2-III-d), or a pharmaceutically acceptable salt thereof:
- Ring G is imidazolpyridyl; n is 1 or 2; X at each occurrence is each independently CH 2 , CHF, CH(OH), CHMe, CF 2 , or C(R 7 ) 2 ; wherein R 7 at each occurrence is independently hydrogen or methyl; alternatively, two geminal R 7 groups are taken together with the carbon to which they are attached to form a spiro cyclopropyl; or yet alternatively, two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused cyclopropyl; and R 12 at each occurrence is independently Ci-C 8 alkyl optionally substituted with amino, hydroxy, protected amino, or O(Ci-C 4 alkyl).
- the present invention relates to compounds of
- R 12 at each occurrence is independently C 1 - C 8 alkyl substituted with -NHCO 2 (Ci-C 4 alkyl) or O(C r C 4 alkyl); or a pharmaceutically acceptable salt thereof.
- the present invention relates to compounds of Formula (2-IIIb), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of Formulae (2-IVa- 1 and 2-IVa-2), or a pharmaceutically acceptable salt thereof:
- the present invention relates to compounds of
- Representative compounds of the present invention are those selected from compounds 2-1 to 2-516 compiled in Tables 10-20:
- Table 13 Compounds 2-244 to 2-263.
- Table 15 Compounds 2-274 to 2-291.
- Table 16 Compounds 2-292 to 2-426.
- Table 17 Compounds 2-427 to 2-477.
- any substituent or variable e.g., R 1 , R 2 , X, 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.
- Yet a further embodiment of the present invention is a pharmaceutical composition
- 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 are not limited to, host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleo-tides and the like); 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,
- 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 co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
- 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.
- PAGE 57 OF 222 are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
- 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 coadministering 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 coadministering 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).
- Another further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising coadministering 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
- the agent that treats patients for disease caused by human immuno-def ⁇ ciency 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,
- 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) and hepatitis B virus (HBV).
- HAV human immunodeficiency virus
- HAV hepatitis A virus
- HBV hepatitis B virus
- combination therapy to treat such co-infections by coadministering 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 (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.
- 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 improve one or more pharmacokinetic (PK) feautures including, but not limited to, plasma concentration, bioavailiablity, area under the plasma concentration time curve (AUC), elimination half-life, and systemic clearance, of a compound of the invention when one or more of its PK feautures of said compound is improved in comparison to that in the absence of the CYP inhibitor.
- PK pharmacokinetic
- the invention provides methods for improving the pharmaco-kinetics of compounds of the invention.
- the advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, US Patent
- 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
- the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant compound of the invention may be used in a method of this invention.
- CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, ⁇ oleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelf ⁇ navir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, ditiazem, erythromycin, VX-944, and VX-497.
- Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
- 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 of additional agent 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 formulation of each pharmaceutical component; a container housing the pharmaceutical formulation(s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.
- 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
- PAGE 61 OF 222 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 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.
- aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl.
- a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
- Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
- 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.
- a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
- aromatic groups can be substituted or unsubstituted.
- bicyclic aryl or "bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
- 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, «-butyl, tert-butyl, 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 double bond by the removal of a single hydrogen atom.
- Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten- 1 -yl, heptenyl, octenyl, and the like.
- 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 -C 8 -cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted.
- C3-C8-cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-C ⁇ -cycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like.
- C 3 -C 8 cycloalkenyl or “C5-C7 cycloalkenyl” as used herein, refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon- carbon double bond, and the carbon atoms may be optionally oxo-substituted.
- Examples Of C 3 -C 8 cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the
- Cs-C 7 cycloalkenyl examples 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 6 -alkyl groups.
- heteroarylalkyl refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-Ci-C ⁇ -alkyl groups.
- 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, C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
- functional groups such as, O, OH, NH, NH 2 , C(O), S(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, for example, 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 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
- 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 n )C(O)N(R n ), N(R n )C(O)C(O)N(R n ), N(R 1 ⁇ S(O) 2 N(R 11 ), C(O)N(R 1 ⁇ S(O) 2 or C(O)N(R n )S(O) 2 N(R ⁇ ); wherein R 11 is as previously defined.
- 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 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. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).
- 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
- 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, />nitrobenzoate, 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-nitrobenzoate, 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 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).
- hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,
- 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 nucleophilic substitution reaction.
- 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,
- PAGE 68 OF 222 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.
- 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. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
- 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).
- 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.
- 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.
- PAGE 70 OF 222 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.
- 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, pa
- 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. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer,
- the present invention also relates to solvates of the compounds of the invention, for example, hydrates.
- PAGE 72 OF 222 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 co valently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
- the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
- Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
- Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
- 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
- PAGE 73 OF 222 material or formulation auxiliary of any type Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as
- 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, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- 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.
- inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- the 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
- 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, 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 g
- 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.
- 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. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of which are incorporated herein by reference).
- a discussion of pulmonary delivery of antibiotics is also found in U.S. Pat. No. 6,014,969, incorporated herein by reference.
- 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
- PAGE 77 OF 222 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 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
- PAGE 78 OF 222 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). Alternatively, 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. 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.
- 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
- additional therapeutic or prophylactic agents includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g.
- compositions according to the invention may also be used in combination with gene replacement therapy.
- 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.
- a compound of the present invention can also be administered in combination or alternation with antiviral agent.
- Examplary antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 21 below.
- the compounds of the present invention may be prepared via several different synthetic routes from a variety of 5/6-membered fused heteroaryl, 5- membered heteroaryl, and related intermediates.
- a retro-synthesis of those title compounds include direct formation of a suitably linked 5/6-membered fused heteroaryl with a 5/6-membered fused heteroaryl or 5-membered heteroaryl core structure followed by attachment of a suitable R 6 group, plus some functional group manipulations in between and/or after.
- Various 5/6-membered fused heteroaryl or 5- membered heteroaryl intermediates are known to those skilled in the art, for example see the encyclopedic volumns edited by A. R. Katrizky, et al, "Comprehensive
- 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 Ia- 1.2 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 2) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.
- 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 as a key intermediate.
- la-6 may
- PAGE 86 OF 222 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
- a key vinyl intermediates 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 Horner-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 la-19 with a metal acetylide.
- bromide la-13 may be also tranformed to thiol Ia- 16 through nucleophilic substitution, which can be further oxidized to sulfonic acid la-17.
- Sulfonamide la-18 may then be derived from la-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- 1 ,2-diaminobenzene using the similar procedures described above.
- Intermediate Ia- 21 can be converted to amine la-22 through N ⁇ 2 -reduction (i.e. H 2 , catalytical Pd).
- PAGE 87 OF 222 the like, optionally in the presence of a copper or copper salt, may afford hydroxy la-23.
- benzimidazolecarboxylate la-24 which can be prepared from the corresponding 4-methyl-l,2-diaminobenzoate using the procedures described above, may be hydrolyzed 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.
- bromo-imidazole 2a-4 can be synthesized in a three-step sequence: 1) condensation between amino acid derived aldehyde 2a- 1.1 or 2a- 1.2 and glyoxal 2a- 1.3 in the presence of methanolic ammonia to generate imidazole 2a-2; 2) bromination of 2a-2 with excess amount of bromination reagent such as 2,4,4, 6-tetrabromo-2,5-cyclohexadienone, NBS, etc. to afford dibromide 2a-3; 3) selective reduction of the dibromide 2a-3 by heating in aq. Na 2 SO 3 or aq. NaHSO 3 . 2a-4 then may be served as a universal intermediate further elaborable to many other imidazole derivatives using the chemistry discussed in Scheme 1, some of which are listed in the table below.
- the NH group of imidazole related intermediates listed above may be protected with an amino protecting group (shown in Scheme 2 as PG), such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
- the protected imidazole 2a-5 may be deprotonated with a strong base such as LDA, BuLi, etc to generate a carbon anion, which may either undergo a nucleophilic substitution with an activated halide such as 2a-5.2 to afford aryl or heteroaryl substituted imidazole 2a-6 or couple with an aryl or heteroaryl halide 2a-5.1 in the presence appropriate transition metal salt to generate bicyclic heteroaryl 2a-7.
- the protected bromo imidazole 2a-8 may be subjected to lithium-halogen exchange with various ( «-, S-, or t-) butyl lithium, the resulting lithiate may undergo similar reactions to afford 2a-6 and 2a-7.
- 2a-8 is treated with metalated aryl or heteroaryl 2a-8.1, in which M at each occurrence is independently a boron, tin, silicon, zinc, zirconium, or copper species, under Suzuki or Stille conditions to those skilled in the art (see reviews: A. Suzuki, Pure Applied Chem. 1991, 63, 419; A. Suzuki,
- 2a-9 may be brominated under conditions to those skilled in the art to afford bromide 2a- 10, which may be either converted to the corresponding amine 2a-l 1, or coupled with protected amino acid 2a- 10.1 or 2a- 10.2 in the presence of a base such as Et 3 N and DIPEA to afford ketoester 2a-12.
- amine 2a- 11 may be converted to the corresponding keto-amide 2a- 13 via condensation with appropriate amino acid under standard amide formation conditions.
- 2a-12 and 2a- 13 may be tranformed to key intermediate 2a- 14 via heating with (NH 4 )OAc under thermal or microwave conditions.
- the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments, optionally with a suitable cyclic or acyclic linker or formation of a cyclic or acyclic linker.
- the said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, amide coupling, ester bond formation, William etherification, Buchwald etherif ⁇ cation, alkylation, pericyclic reaction with different variations, or the like.
- Compound 3a-4 may then serve as a common intermediate for further derivatizations to 3a-5 in two steps: 1) mono-deprotection of the linear or cyclic amine moiety may be accomplished, for example, treatment to hydrogenolytic conditions under Pd catalyst in the presence of a base such as potassium carbonate to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate.
- Various carboxylic acids including amino acids in racemic or optical form are
- PAGE 90 OF 222 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.
- 3a-5 may be further deprotected under hydrolytic conditions in the presence of an acid such as TFA or hydrogen chloride to remove the Boc protection group and the released amine functionality can be further derivatized to the title compounds Ia-I using the conditions described above.
- linkers that can be used to construct the title compounds of the present invention are compiled in the table below, in which PG and PG' at each occurrence are each independently amino or alcohol protecting group, such as Boc, Cbz, Troc, Teoc, PMB, TMS etc. These linkers are either commercially available or may be synthesized in several steps through strategies which are known to those skilled in the art.
- the compounds of the present invention may also be derived from bromobenzimidazoles 4a- 1 and imidazole 4a-2 using the procedures described previously.
- the intermediates 4a- 1 and 4a-2 have the desired acyl groups already installed as seen in amino acid derivatives 2a-10.1b and 2a-10.2b, which can be prepared from protected amino acids 2a-10.1a and 2a-10.2a through the sequences shown in Scheme 1 and 2.
- PG is carboxylic acid protecting group
- R 2 is independently R1
- the compounds of the present invention containing benzimidazole linked with other f ⁇ ve-membered heteroaryl other than imidazole may be prepared using similar procedures described above in Schemes 1-4.
- some intermediates containing a desired, suitably substituted five-membered heteroaryl have been published in US 2008/0311075A1 by C. Bachand, et al from BMS, which is incorporated by reference. Theses intermediates are compiled in the following table.
- the commercially available bromoiodoaniline 5b- 1 may be coupled to the commercially available acetylene 5b- 1.1 under the Sonogashira conditions to give phenylacetylene 5b-2.
- the latter may be cyclized to indole 5b-3 under heat or microwave condition in the presence of a copper catalyst.
- 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 93 OF 222 E is optionally substituted aryl or optionally substituted heteroaryl; T, X, n, u, R 1 , 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 Ci-C 8 alkyl optionally substituted with amino, hydroxy, protected amino, or 0(Ci-C 4 alkyl); ii)
- Z a or Z b is an amino protecting group, fully or selectively deprotecting a compound of Formula (1-II-a) to give the corresponding amine of Formula (1 -II- b):
- Z c is hydrogen, an amino protecting group or -C(O)-R 12 ; iii) Capping the released amino group of a compound of Formula (1-II-b) with LG-C(O)-R 12 , wherein LG is a leaving group; to give the compound of Formula (1-
- the invention is a process of making a compound of Formula (2-1) comprising the steps of: i. Preparing a compound of Formula (2-II-a):
- Z a and Z b are each independently an amino protecting group or -C(O)-R 12 ;
- R 12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, protected amino, or (XC 1 -C 4 alkyl); ii.
- Z a or Z is an amino protecting group, fully or selectively deprotecting a compound of Formula (2-II-a) to give the corresponding amine of Formula (2-II- b):
- Z c is hydrogen, an amino protecting group or -C(O)-R 12 ; iii. Capping the released amino group of a compound of Formula (2-II-b) with LG-C(O)-R 12 , wherein LG is a leaving group; to give the compound of Formula (2- II-c):
- Step 1-la A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 0 C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo- 1 ,2- diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 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 1-lb A solution of the crude compound from step 1-la (10.7 g, 26.7 mmol at most) 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 - aqueous NaHCOs). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step 1-ld A solution of the compound from step 1-lc (6.73 g, 16.3 mmol) in toluene (100 mL) was treated with ammonium acetate (25.1 g, 0.327 mol) at 100 0 C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SOz I ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
- Step l-2a A solution of the compound of example 1-1 (20.0 mg, 33.4 ⁇ mol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
- ESIMS m/z 399.35 [M+H] + .
- Step 1-1-la A mixture of the compound from step 1-ld (0.559 g, 1.425 mmol), trimethylsilyl-acetylene (0.60 ml, 4.275 mmol), CuI (28.5 mg, 0.150 mmol) and
- Step 1-1-lc A mixture of the compound from step 1-1-lb (80.0 mg, 0.2371 mmol), the compound from step 1-lb (86.8 mg, 0.2371 mmol), CuI (2.2 mg, 0.01185 mmol) and Pd(PPh 3 ) 2 Cl 2 (16.6 mg, 0.02371 mmol) in Et 3 N (0.3 mL) and CH 3 CN (2 mL) was heated at 85 0 C under H 2 /N 2 mixed gas for 2 hours before being evaporated.
- Step 1-2-la A solution of the compound of example 1-1-1 (48.3 mg, 0.0776 mmol) in 1,4-dioxane (1.5 mL) was treated with HCl in 1,4-dioxane (4 M, 6 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step. Step 1-2-lb.
- Table Ia Examples 1-3 to 1-219.
- Step l-357a A solution of the compound of example 1-491 (0.122 g, 0.196 mmol) in 1,4-dioxane (2 mL) was treated with HCl in 1,4-dioxane (4 M, 8 mL) at rt for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step. Step l-357b.
- Step l-442a A solution of the compound of Example 1-441 (90.0 mg, 0.144 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
- ESIMS m/z 424.11 [M+H] + .
- Step l-442b A solution of the compound of Example 1-441 (90.0 mg, 0.144 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.
- ESIMS m/z 424.11 [M+H] + .
- Step l-447a A mixture of the compound of step 1-lb (0.250 g, 0.683 mmol), allyltributyl-stannane (0.26 mL, 0.820 mmol) and Pd(PPh 3 ) 4 (39.4 mg, 34.1 ⁇ mol) in toluene (6 mL) was degassed and heated at 110 0 C under N2 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 l-447b A mixture of the compound of step 1-ld (0.180 g, 0.459 mmol), the compound of step l-447a (0.150 g, 0.459 mmol), triethylamine (0.64 mL, 4.59 mmol), tri-o-tolylphosphine (18.0 mg, 57.3 ⁇ mol) and Pd(OAc) 2 (5.1 mg, 22.9 ⁇ mol) in CH 3 CN (8 mL) was degassed and heated to 90 0 C under N 2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCOs).
- Step l-448a A solution of the compound of Example 1-447 (0.104 g, 0.163 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
- ESIMS m/z 439.24 [M+H] + .
- Step l-448b A solution of the compound of Example 1-447 (0.104 g, 0.163 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.
- ESIMS m/z 439.24 [M+H] + .
- Step 1-45Ob The mixture of (S)-I -(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5 g, 23.2 mmol) in acetonitrile (40 mL) was added 1 , 1 '-carbonyldiimidazole (3.95 g, 24.5 mmol). The resulting mixture was stirred at room temperature for 20 min before being added methyl 3,4-diaminobenzoate (3.86g, 23.2 mmol). The solution was stirred at room temperature for another 3 hours before being partitioned between water and EtOAc.
- Step 1-45Of The solution of compound from step 1-45Oe (2.Og, 4.3 mmol) in THF (45 mL) was added triethylamine (1.85 mL, 12.9 mmol) and ethyl chloroformate (1.05 mL, 10.8 mmol) at 0 0 C. The resulting mixture stirred at 0 0 C for 20 minutes before all volatiles were removed by rotavap. The residue was dissolved in THF (70 mL) before being added sodium borohydride (Ig, 26.4 mmol). The mixture was stirred at 0 0 C for another 2 hours before being partitioned between water and EtOAc.
- Step l-452a A mixture of 2-bromo-l-(5-bromothiophen-2-yl)ethanone (1.00 g, 3.52 mmol) and N-Boc-L-proline (0.758 g, 3.52 mmol) in CH 3 CN (12 mL) was added TEA (1.06 mL, 7.40 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SOzI), filtered and evaporated.
- Step l-452b A solution of the compound of step l-452a (1.47 g, 3.52 mmol) in toluene (22 mL) was added ammonium acetate (5.42 g, 70.3 mmol) and the resultant mixture was heated at 100 0 C for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step l-452c A mixture of the compound of step l-452b (0.150 g, 0.377 mmol), the compound from step l-491a (0.118 g, 0.377 mmol), triethylamine (0.52 mL, 3.77 mmol), tri-o-tolyl-phosphine (14.8 mg, 47.1 ⁇ mol) and Pd(OAc) 2 (4.2 mg, 18.8 ⁇ mol) in CH 3 CN (6 mL) was degassed and heated to 110 0 C in sealed tube for 36 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SOzI),
- Step l-458a 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et 2 O, 8.09 mL, 24.3 mmol) slowly at O 0 C for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH 4 CI. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).
- Step l-458b The compound from step l-458a (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na2SO4), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g). Step l-458c.
- Step l-458d A solution of the compound from step l-458c (at most 11.6 mmol) in toluene (60 mL) was added ammonium acetate (13.4 g, 0.174 mol) and the resultant mixture was heated up at 100 0 C for 14 hours.
- Step l-458e A mixture of the compound from step 1-lb (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 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 l-461a The desired compound was prepared from 4-bromo-l,2- diaminobenzene and N-Cbz-L-proline using procedures similar to that described in steps 1-la and 1-lb.
- ESIMS m/z 400.11, 402.11 [M+H] + .
- Step l-461b A mixture of the compound from step l-461a (1.00 g, 2.50 mmol), bis(pinacolato)diboron (1.27 g, 5.00 mmol) and potassium acetate (0.613 g, 6.25 mmol) in 1,4-dioxane (25 mL) was added Pd(PPh 3 ) 4 (0.144 g, 0.125 mmol).
- Step l-463a A mixture of the compound from example 1-462 (0.314 g, 0.416 mmol) and Pd(OH) 2 (20wt % on carbon, 150 mg) in methanol (6 mL) was adjusted pH to 3 with aqueous 6N HCl and then treated with hydrogen (60 psi) for 24 hours.
- Step l-463b The title compound was synthesized from the compound from step 1-
- Step l-467a (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (prepared according to WO 2008/021927, 0.500 g, 1.58 mmol) in CH 2 Cl 2 (16 mL) was treated with triethyl amine (0.66 mL, 4.75 mmol), di-tert-butyl dicarbonate (0.518 g, 0.237 mmol) and DMAP (38.7 mg, 0.316 mmol) for 1 hours before being evaporated to dryness. The residue was purified by flash column chromatography
- Step l-467b A mixture of the compound from step l-467a (0.650 g, 1.56 mmol), ethynyl-trimethylsilane (2.16 mL, 15.6 mmol), CuI (8.9 mg, 46.8 ⁇ mol) and Pd(PPh 3 ) 4 (90.3 mg, 78.1 ⁇ mol) in CH 3 CN (5 mL) and triethylamine (10 mL) was degassed and heated at 80 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 S0zt), filtered and evaporated.
- Step 1-467C The compound from step l-467b (0.560 g, 1.29 mmol) in MeOH (30 mL) was treated with potassium carbonate (0.535 g, 3.88 mmol) for 30 minutes before being evaporated to dryness. The residue was partitioned (EtOAc - water), and the organics were washed with brine, dried (Na 2 SOz I ), filtered and evaporated.
- Step l-467d A mixture of the compound from step l-467c (0.103 g, 0.395 mmol), 1,4-diiodo-benzene (62.0 mg, 0.188 mmol), CuI (2.1 mg, 11.2 ⁇ mol) and Pd(PPh 3 ) 4 (21.6 mg, 18.7 ⁇ mol) in CH 3 CN (1 mL) and triethylamine (4 mL) was degassed and heated to 60 0 C under N 2 for 4 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step l-467e A mixture of the compound from step l-467d (20.0 mg, 43.1 ⁇ mol), the compound from step l-458e (17.8 mg, 43.1 ⁇ mol), Pd(PPh 3 ) 4 , (9.9 mg, 8.6 ⁇ mol) and NaHCO 3 (14.5 mg, 0.172 mmol) in DME (3 mL) and H 2 O (1 mL) was degassed and heated at 90 0 C under N 2 for 14 hours.
- Step 1-47Oa A mixture of the compound of step l-467c (0.150 g, 0.575 mmol), 2,6-dibromo-naphthalene (98.6 mg, 0.345 mmol), CuI (3.3 mg, 17.2 ⁇ mol) and Pd(PPh 3 ) 4 (33.2 mg, 28.7 ⁇ mol) in CH 3 CN (1 mL) and triethylamine (4 mL) was degassed and heated to 90 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 1-47Ob A mixture of the compound from step 1-47Oa (67.6 mg, 0.145 mmol), the compound from step l-458e (59.9 mg, 0.145 mmol), Pd(PPh 3 ) 4 , (16.8 mg, 14.5 ⁇ mol) and NaHCO 3 (48.7 mg, 0.580 mmol) in DME (6 mL) and H 2 O (2 mL) was degassed and heated at 90 0 C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 O). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step l-474a A mixture of the compound from step l-515d (0.200 g, 0.643 mmol), 2,6-dibromonaphthalene (0.368 g, 1.29 mmol), CuI (3.6 mg, 19.2 ⁇ mol) and Pd(PPh 3 ) 4 (37.1 mg, 32.1 ⁇ mol) in CH 3 CN (6 mL) and triethylamine (6 mL) was degassed and heated at 90 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 SOz I ), filtered and evaporated.
- Step l-474b A mixture of the compound from step l-474a (0.214 g, 0.415 mmol), bis-(pinacolato) diboron (0.211 g, 0.829 mmol) and potassium acetate (0.102 g, 1.04 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh 3 ) 4 (23.9 mg, 20.7 ⁇ mol). The resultant mixture were degassed and heated up at 85 0 C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SOZt), filtered and evaporated.
- Step l-478a A mixture of 2,4'-dibromoacetophenone (1.59 g, 5.71 mmol) and N- Boc-glycine (1.00 g, 5.71 mmol) in CH 3 CN (20 mL) was added DIPEA (1.42 mL, 11.4 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned
- Step l-478b A solution of the compound from step l-478a (2.02 g, 5.43 mmol) in toluene (30 mL) was added ammonium acetate (8.35 g, 0.108 mol) and the resultant mixture was heated up at 100 0 C for 20 hours.
- Step 1-48Oa A solution of the compound of example 1-500 (10.0 mg, 14.7 ⁇ 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 580.55 [M+H] + .
- Step l-482a A mixture of N-Boc-L-proline (0.210 g, 0.976 mmol) and TEA (0.14 mL, 0.976 mmol) in THF (10 mL) at -20 0 C was treated with ⁇ o -butyl chloroformate (0.13 mL, 0.976 mmol) for 30 minutes before a slow addition of 5- bromo-3-fluorobenzene-l,2-diamine (0.200 g, 0.976 mmol) in THF (2 mL). It was then kept at -20 0 C for 1 hour and then slowly warmed up to rt and stirred at rt overnight.
- Step l-484a A mixture of 4-bromo-5-chlorobenzene-l,2-diamine (0.3 g, 1.19 mmol) and tin(II) chloride dihydrate (1.08 g, 4.77 mmol) in DMF (10 mL) was heated at 80 0 C for 2 hours. The reaction was cooled and then neutralized by the addition of aqueous 2N NaOH. The resultant mixture were partitioned (EtOAc - water) and the organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step l-484b The compound from step l-484a (0.250 g, 1.13 mmol) in DMF (10 mL) was treated with N-Boc-L-proline (0.243 g, 1.13 mmol), EDC-HCl (0.281 g, 1.47 mmol) and DMAP (27.6 mg, 0.226 mmol) for 12 hours before being partitioned (EtOAc - water).
- Step l-484c A solution of the crude compound from step l-484b (1.13 mmol at most) in glacial acetic acid (10 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 l-484d A mixture of the compound from step l-484c (55.0 mg, 0.140 mmol), the compound from step 1-1-lb (56.5 mg, 0.168 mmol), CuI (0.8 mg, 4.1 ⁇ mol) and Pd(PPh 3 ) 4 (8.0 mg, 6.9 ⁇ mol) in triethylamine (3 mL) and CH 3 CN (3 mL) was degassed and heated to 95 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. The residue was purified by flash column
- Step l-487a A solution of 4'-bromoacetophenone-d7 (0.500 g, 2.43 mmol) in
- Step l-487b A mixture of the compound from step l-487a (0.670 g, 2.38 mmol) and N-Boc-L-proline (0.511 g, 2.38 mmol) in CH 3 CN (20 mL) was added DIPEA
- Step l-487d A mixture of the compound from step l-487c (200 mg, 0.505 mmol), the compound from step l-515d (0.188 g, 0.606 mmol), CuI (2.9 mg, 15.1 ⁇ mol) and Pd(PPh 3 ) 4 (29.1 mg, 25.2 ⁇ mol) in triethylamine (5 mL) and CH 3 CN (5 mL) was degassed and heated at 95 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 l-489a A mixture of the compound from step l-458d (0.200 g, 0.452 mmol), bis(pinaco-lato)diboron (0.144 g, 0.565 mmol), PdCl 2 (dppf) 2 (36.9 mg, 0.0452
- Step l-491a A mixture of the compound of step 1-lb (1.600 g, 4.369 mmol), tributyl(vinyl)-tm (1.53 ml, 5.242 mmol) and Pd(PPh 3 ) 4 (5 mol%, 0.250 g, 0.218 mmol) in toluene (20 mL) was degassed and then refluxed under N 2 for 18 h before being allowed to cool to rt. The mixture was directly purified by flash column chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a pink foam (0.912 g, 67%).
- Step l-491b A mixture of the compound from step l-491a (1.251 g, 3.191 mmol), the compound of step 1-ld (1.000 g, 3.191 mmol), Pd(OAc) 2 (5 mol%, 35.8 mg, 0.160 mmol) and P(o-tolyl) 3 (0.121 g, 0.399 mmol) in Et 3 N (4.45 mL) and CH 3 CN
- Step l-497a A solution of the compound of example 1-496 (0.106 g, 0.118 mmol) in 1,4-dioxane (2 mL) was treated with HCl in 1,4-dioxane (4 M, 12 mL) at 50 0 C for 4 hour. The volatiles were evaporated off to give the crude desired compounds as a yellow solid which was used directly in the next step.
- Step l-497b A mixture of the crude compound from step l-497a (0.118 mmol at most) and (,S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (41.3 mg, 0.236 mmol) in DMF (3 mL) was treated with HATU (85.2 mg, 0.224 mmol) in the presence of DIPEA (0.41 mL, 2.360 mmol) for 1 hours at rt and the volatiles were
- Step 1-50Oc A mixture of compound from step 1-50Ob (0.800 g, 1.612 mmol), the compound from step l-515d (0.501 g, 1.612 mmol), Pd(PPh 3 ) 4 , (5 mol%, 93.1 mg, 80.6 ⁇ mol) and CuI (3 mol%, 9.2 mg, 48.3 ⁇ mol) in Et 3 N (4 mL) and THF (12 mL) was degassed and stirred at 40 0 C under N 2 for 18 hours. The volatiles were evaporated.
- Step 1-51Oa A solution of the compound fromthe compound from step l-515d (Ig, 3.21 mmol) in dichloromethane (20 mL) was treated with HCl in 1,4-dioxane (4 M, 12 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
- Step 1-51Ob The mixture of compounds from step 1-51Oa (3.21 mml at most) and the compound from step 1-515g (562 mg, 3.21 mmol) in DMF (12 mL) was added diisopropylethylamine (4.56 mL, 32 mmol) and HATU (1.22g, 3.21 mmol). The resulting solution was stirred at room temperature for 1 hour before all volatiles were removed to provide a brown slurry, which was partitioned between EtOAc and
- Step l-515b The mixture of compound from step l-515a (6.Og, 12.5 mmol) and ammonium acetate (15. Ig, 196 mmol) in toluene (80 mL) was stirred at 80 0 C for 3 hours before being partitioned between water and aqueous NaHC ⁇ 3. The organic phase was separated, dried (Na 2 SO 4 ) and concentrated to afford a deep red oil.
- Step l-515c A mixture of the compound from step 1-lb (2.010 g, 5.488 mmol), trimethyl-silylacetylene (2.33 ml, 16.46 mmol), CuI (0.110 g, 0.576 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.308 g, 0.439 mmol) in Et 3 N (50 mL) was degased and then heated at 80 0 C under N 2 overnight before being evaporated.
- Step l-515d A suspension of the compound from step l-515c (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 patitioned (EtOAc - H 2 O). The organic layer was washed with brine, dried (Na 2 SOz(), filtered and concentrated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a yellow foam (0.792 g, 86%).
- Step l-515e The mixture of compounds from step 1-515b (9.1g, 20.7 mmol) and step 1-515d (6.45g, 20.7 mmol) in THF (200 mL), triethylamine (60 mL) and acetonitrile (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.15g, I mmol) and copper(I) iodide (119 mg, 0.62 mmol). The resulting mixture was purged with nitrogen before being stirred at room temperature for 12 hours, at 50 0 C for 2 hours and at 60 0 C for 1 hour. After addition of aqueous NaOH (IM, 100 mL), the
- Step l-515f A solution of the compound from step l-515e (3g, 4.58 mmol) in dichloromethane (50 mL) and MeOH (5 mL) was treated with HCl in 1,4-dioxane (4 M, 40 mL) at rt for 2 hours.
- Step l-515g The mixture of L-valine (5Og, 0.427 mol) in 1 ,4-dioxane (140 mL) was added water (630 mL), NaOH (54.7g, 1.4 mol) and methyl chloroformate (65.7 mL, 0.85 mol). The resulting solution was stirred at 60 0 C for 22 hours before being added dichloromethane (400 mL).
- step l-515f (4.58 mml at most) and step l-515g (1.6Ig, 9.16 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (5.21 mL, 39 mmol) and HATU (3.31g, 8.7 mmol). The resulting solution was stirred at room temperature for 35 minutes before being partitioned between EtOAc (500 mL) and aqueous NaOH (0.5M, 50 mL).
- the title compound was prepared from 2,4'-dibromoacetophenone, the compound from step 1-515d and (6S)-5-[(tert-butoxy)carbonyl]-5-azaspiro[2.4]heptane-6- carboxylic acid (prepared according to WO 2009/102325) using procedures similar to that described in examples 1-1 and 1-515.
- ESIMS m/z 649.35 [M+H] + .
- the title compound was prepared from 2,4'-dibromoacetophenone, 4-bromo-l,2- diamino-benzene and (65)-5-[(?ert-butoxy)carbonyl]-5-azaspiro[2.4]heptane-6- carboxylic acid (prepared according to WO 2009/102325) using procedures similar to that described in examples 1-1 and 1-515.
- ESIMS m/z 675.35 [M+H] + .
- Step l-533a A mixture of (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2- yl)pyrrolidine-l-carboxylate (prepared according to US2008/311075A1, 47.5 mg, 0.12 mmol) and the compound from step l-515d (38 mg, 0.12 mg) in triethylamine (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting mixture was purged with nitrogen before being stirred at 100 0 C for 12 hours.
- Step l-533c The title compound was prepared from the compound of step l-533b using procedures similar to that described in step 1-2-lb.
- ESIMS m/z 805.92 [M+H] + .
- Step l-535a The desired product was prepared from (2S,4R)-l-(tert- butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid using procedures similar to that described in step l-515a.
- ESIMS m/z 476.14 [M+H] + .
- Step l-535b The desired product was prepared from the compound of step l-535a using procedures similar to that described in step l-515b.
- ESIMS m/z 455.99
- Step l-535c The desired product was prepared from the compound of step l-535b and the compound of step 1 -515 d using procedures similar to that described in step
- Step l-535d The desired product was prepared from the compound of step l-535c using procedures similar to that described in step l-515f.
- ESIMS m/z 439.26
- Step l-535e The title compound was prepared from the compound of step l-535d and the compound of step l-515g using procedures similar to that described in step
- Step l-536a The mixture of (R)-2-benzyl-l-(tert-butoxycarbonyl)pyrrolidine-2- carboxylic acid (200 mg, 0.66 mmol) and 4-bromo- 1 ,2-diaminobenzene (135 mg, 0.73 mmol) in acetonitrile (2 mL) was added EDC (138 mg, 0.73 mmol) and 4- dimethylaminopyridine (40 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 1 hour before being partitioned between water and EtOAc.
- Step l-536b The desired product was prepared from the compound of step l-536a using procedures similar to that described in step 1-lb.
- ESIMS m/z 456.17 [M+H] + .
- Step l-536c The desired product was prepared from the compound of step l-536b and the compound from step 1-1 -Ib using procedures similar to that described in step 1-1-lc.
- ESIMS m/z 713.46 [M+H] + .
- Step l-536d The desired product was prepared from the compound of step l-536c using procedures similar to that described in step 1 -515 f .
- ESIMS m/z 513.30 [M+H] + .
- Step l-536e The title compound was prepared from the compound of step l-536d and the compound from step 1-515g using procedures similar to that described in step 1-515h.
- ESIMS m/z 827.49 [M+H] + .
- Step l-537e The title compound was prepared from the compound from step 1- 537d and the compound from step 1-515g using procedures similar to that described in step l-515h.
- ESIMS m/z 829.35 [M+H] + .
- Step 1-54Oa The desired product was prepared from (2S,4R)-l-(tert- butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid using procedures similar to that described in step l-536a.
- ESIMS m/z 402.07 [M+H] + .
- Step 1-54Ob The desired product was prepared from the compound from step 1-
- Step 1-54Oc The desired product was prepared from the compound from step 1-
- Step 1-54Od The desired product was prepared from the compound from step 1-
- Step 1-54Oe The title compound was prepared from the compound from step 1-
- Step l-541a The desired product was prepared from (lR,3S,5R)-2-(tert- butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (prepared according to WO2009/102325) using procedures similar to that described in step l-536a.
- Step l-541b The desired product was prepared from compound l-541a using procedures similar to that described in step Ib.
- ESIMS m/z 378.11 [M+H] + .
- Step l-541c The desired product was prepared from the compound from step 1- 541b and the compound from step 1-1-lb using procedures similar to that described in step 1-1-lc.
- ESIMS m/z 635.43 [M+H] + .
- Step l-541d The desired product was prepared from the compound from step 1-
- Step l-542c The desired product was prepared from the compound from step 1- 542b and the compound from step 1-1-lb using procedures similar to that described in step 1-1-lc.
- ESIMS m/z 637.39 [M+H] + .
- Step l-542e The title compound was prepared from the compound from step 1- 542d and the compound from step 1-515g using procedures similar to that described in step l-515h.
- ESIMS m/z 751.44 [M+H] + .
- Step l-544a The desired product was prepared from (S)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid and 4-bromo-5 -methoxybenzene- 1 ,2- diamine (prepared according to Journal of Medicinal Chemistry 1997, 40, 730) using procedures similar procedures similar to that described in step l-536a.
- ESIMS m/z 414.10 [M+H] + .
- Step l-544b The desired product was prepared from the compound from step 1- 544a using procedures similar procedures similar to that described in step 1-lb.
- Step l-544c The desired product was prepared from the compound from step 1-
- Step l-544d The desired product was prepared from the compound from step 1-
- Step l-544e The title compound was prepared from the compound from step 1-
- Step l-545a The desired product was prepared from (lS,2S,5R)-3-(t ⁇ t- butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (prepared according to J. Org. Chem, 1999, 64, 547) using procedures similar to that described in step 1-
- Step l-545b The desired product was prepared from the compound from step 1-
- Step l-545c The desired product was prepared from the compound from step 1-
- Step l-545d The desired product was prepared from the compound from step 1-
- Step l-545e The title compound was prepared from the compound from step 1-
- Step 2-la A mixture of 7V-Boc-L-proline (2.289 g, 10.6 mmol) and 5-bromo-2,3- diamino-benzene (2.00 g, 10.6 mmol) in DMF (40 mL) were treated with EDC HCl (2.651 g, 13.8 mmol) and DMAP (0.13O g, 1.06 mmol) at rt for 12 hours and then at 60 0 C for another 12 hours. The resultant dark mixture was partitioned (EtOAc - water). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give the crude desired compound as a dark brown foam which was directed used in the next step.
- Step 2-lb A solution of the crude compound from step 2-la (theo. 10.6 mmol) in glacial acetic acid (100 mL) was heated at 50 0 C for 24 hours. The volatiles were evaporated and the resultant dark mixture was partitioned between EtOAc and
- examples 2-3 to 2-508 may be prepared using procedures similar to that described in examples 2-1, 2-2, and 2-509 to 2-516, and/or as described in the Synthetic Methods.
- Table IQa Examples 2-3 to 2-219.
- Table 17 Examples 2-427 to 2-477.
- Step 2-509a A mixture of N-Boc-L-proline (0.229 g, 1.06 mmol) and TEA (0.15 mL, 1.06 mmol) in THF (10 mL) at -20 0 C was treated with ⁇ o-butyl chloroformate (0.14 mL, 1.06 mmol) for 30 minutes before a slow addition of 6-bromopyridine- 2,3-diamine (prepared according to WO 2004/002986 and WO 2008/021851, 0.200 g, 1.06 mmol) in THF (2 mL). It was then kept at -20 0 C for 1 hour and then slowly warmed up to rt and stirred at rt overnight.
- Step 2-509b A solution of the crude compound from step 2-509a (1.06 mmol at most) in glacial acetic acid (12 mL) was heated at 80 0 C for 3 days. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica,
- Step 2-509c A mixture of 2,4'-dibromoacetophenone (5.0O g, 18.0 mmol), N-Boc- L-proline (3.87 g, 18.0 mmol) and in CH 3 CN (60 mL) was treated with TEA (5.40 mL, 37.8 mmol) at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step 2-509d A solution of the compound from step 2-509c (6.73 g, 16.3 mmol) in toluene (100 mL) was treated with ammonium acetate (25.1 g, 0.327 mol) at 100 0 C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
- Step 2-509e A mixture of the compound from step 2-509d (0.559 g, 1.425 mmol), trimethyl-silylacetylene (0.60 ml, 4.275 mmol), CuI (28.5 mg, 0.150 mmol) and Pd(PPh 3 ) 2 Cl 2 (80.0 mg, 0.114 mmol) in Et 3 N (15 mL) was heated at 80 0 C under N 2 for 6 hours before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% Et 3 N in ethyl acetate) to give the desired compound as a yellow foam (0.484 g, 83%).
- Step 2-509g A mixture of the compound from step 2-509b (23.0 mg, 62.6 ⁇ mol), the compound from step 2-509f (23.2 mg, 68.8 ⁇ mol), CuI (0.3 mg, 1.8 ⁇ mol) and
- Step 2-51Oa A solution of the compound of Example 2-509 (38.0 mg, 60.9 ⁇ 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 424.33 [M+H] + .
- Step 2-511 a 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736, 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3M in Et 2 O, 8.09 mL, 24.3 mmol) slowly at 0 0 C for 1 hour. The solution was warmed up to rt for 2 hours before being quenched with aqueous NH 4 Cl. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).
- Step 2-511b The compound from step 2-51 Ia (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCOs). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g). Step 2-511c.
- Step 2-511e A mixture of the compound from step 2-51 Id (0.200 g, 0.452 mmol), bis(pinacolato)diboron (0.144 g, 0.565 mmol), PdCl 2 (dppf) 2 (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80 0 C under N 2 for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
- Step 2-511f A mixture of the compound from step 2-509b (30.0 mg, 81.7 ⁇ mol), the compound from step 2-51 Ie (43.9 mg, 89.8 ⁇ mol), Pd(PPh 3 ) 4 , (4.6 mg, 4.0 ⁇ mol) and NaHCO 3 (27.5 mg, 0.327 mmol) in DME (6 mL) and H 2 O (2 mL) was degassed and heated at 95 0 C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 O). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by
- Step 2-513a A mixture of N-Boc-L-proline (0.450 g, 2.09 mmol) and TEA (0.29 mL, 2.09 mmol) in THF (20 mL) at -20 0 C was treated with ⁇ o-butyl chloroformate (0.27 mL, 2.09 mmol) for 30 minutes before a slow addition of 6-chloro-3,4- pyridinediamine (0.300 g, 2.09 mmol) in THF (6 mL). It was then kept at -20 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 2-513b A solution of the crude compound from step 2-513a (0.658 g, 1.93 mmol) in glacial acetic acid (12 mL) was heated at 120 0 C for 24 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - saturated aqueous NaHCOs).
- Step 2-513c The crude compound from step 2-513b (1.93 mmol at most) in aqueous 2N HCl (20 mL) was heated at 100 0 C for 2 hours before being evaporated to dryness. The residue was co-evaporated with methanol twice and then CH 2 Cl 2 twice to give the crude desired compound as a light yellow oil which was directly used in the next step.
- ESIMS m/z 223.12 [M+H] + .
- Step 2-515a A mixture of 4-bromo-2-iodoaniline (0.839 g, 2.817 mmol), tert-butyl (2S)-2-ethynylpyrrolidine-l-carboxylate (0.500 g, 2.561 mmol), CuI (14.6 mg, 0.0768 mmol) and Pd(PPh 3 ) 2 Cl 2 (90.0 mg, 0.128 mmol) in Et 3 N (15 mL) was degassed and stirred at rt under N 2 for 3.5 hours before being evaporated.
- Step 2-515b A mixture of the compound from step 2-515a (0.621 g, 1.700 mmol) and Cu(OAc) 2 (61.8 mg, 0.340 mmol) in 1 ,2-dichloroethane (10 ml) was heated at
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CN201080018566.7A CN102427731B (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
MX2011008982A MX2011008982A (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors. |
EP10746967.8A EP2400846B1 (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
RU2011135605/04A RU2544010C2 (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
CA2753382A CA2753382C (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
AU2010217797A AU2010217797B2 (en) | 2009-02-27 | 2010-03-01 | Hepatitis C virus inhibitors |
NZ595280A NZ595280A (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
KR1020137028995A KR20130130875A (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
KR1020117022672A KR101411889B1 (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
SG2011060779A SG174146A1 (en) | 2009-02-27 | 2010-03-01 | Hepatitis c virus inhibitors |
JP2011552218A JP5628841B2 (en) | 2009-02-27 | 2010-03-01 | Hepatitis C virus inhibitor |
BRPI1007836-3A BRPI1007836A2 (en) | 2009-02-27 | 2010-03-01 | Hepatitis C Virus Inhibitors |
ES10746967.8T ES2606717T3 (en) | 2009-02-27 | 2010-03-01 | Hepatitis C virus inhibitors |
IL214775A IL214775A (en) | 2009-02-27 | 2011-08-22 | Hepatitis c virus inhibitor compounds, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for the treatment of hepatitis c virus infection |
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WO2012083170A1 (en) * | 2010-12-16 | 2012-06-21 | Abbott Laboratories | Anti-viral compounds |
WO2012087976A2 (en) * | 2010-12-21 | 2012-06-28 | Intermune, Inc. | Novel inhibitors of hepatitis c virus replication |
US8211928B2 (en) | 2009-05-29 | 2012-07-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8344155B2 (en) | 2009-09-04 | 2013-01-01 | Glaxosmith Kline Llc | Chemical compounds |
WO2012158861A3 (en) * | 2011-05-18 | 2013-01-10 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives |
WO2012068234A3 (en) * | 2010-11-17 | 2013-01-17 | 12Gilead Sciences, Inc. | Antiviral compounds |
US8362020B2 (en) | 2009-12-30 | 2013-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2013016491A1 (en) | 2011-07-26 | 2013-01-31 | Vertex Pharmaceuticals Incorporated | Thiophene compounds |
WO2013016499A1 (en) | 2011-07-26 | 2013-01-31 | Vertex Pharmaceuticals Incorporated | Methods for preparation of thiophene compounds |
WO2013021344A1 (en) | 2011-08-08 | 2013-02-14 | Lupin Limited | Imidazole derivatives as antiviral agents |
US8377980B2 (en) | 2009-12-16 | 2013-02-19 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8394968B2 (en) | 2009-02-17 | 2013-03-12 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2012072713A3 (en) * | 2010-11-30 | 2013-04-04 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors such as cyclylcyclopropanamine derivatives for use in the treatment of diseases and disorders associated with flaviviridae |
EP2575475A1 (en) * | 2010-05-28 | 2013-04-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
EP2575866A1 (en) * | 2010-05-24 | 2013-04-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
US8486938B2 (en) | 2010-06-24 | 2013-07-16 | Gilead Sciences, Inc. | Pyrazolo[1,5-a]pyrimidines for antiviral treatment |
US8524717B2 (en) | 2008-10-17 | 2013-09-03 | Oryzon Genomics, S.A. | Oxidase inhibitors and their use |
US8541424B2 (en) | 2008-12-23 | 2013-09-24 | Abbott Laboratories | Anti-viral compounds |
US8546405B2 (en) | 2008-12-23 | 2013-10-01 | Abbott Laboratories | Anti-viral compounds |
US8552047B2 (en) | 2011-02-07 | 2013-10-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8575135B2 (en) | 2011-11-16 | 2013-11-05 | Gilead Sciences, Inc. | Antiviral compounds |
US8618151B2 (en) | 2008-12-03 | 2013-12-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of HCV NS5A |
US8618153B2 (en) | 2009-11-12 | 2013-12-31 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014019344A1 (en) | 2012-08-03 | 2014-02-06 | Sunshine Lake Pharma Co., Ltd. | Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof |
US8686026B2 (en) | 2010-06-10 | 2014-04-01 | Abbvie Inc. | Solid compositions |
US8691938B2 (en) | 2009-06-11 | 2014-04-08 | Abbvie Inc. | Anti-viral compounds |
US8716454B2 (en) | 2009-06-11 | 2014-05-06 | Abbvie Inc. | Solid compositions |
US8722743B2 (en) | 2010-04-19 | 2014-05-13 | Oryzon Genomics S.A. | Lysine specific demethylase-1 inhibitors and their use |
JP2014513690A (en) * | 2011-05-12 | 2014-06-05 | ブリストル−マイヤーズ スクイブ カンパニー | Hepatitis C virus inhibitor |
EP2746278A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
EP2746262A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds for combating phytopathogenic fungi |
EP2746274A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole compounds |
EP2746277A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Fungicidal imidazolyl and triazolyl compounds |
EP2745691A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted imidazole compounds and their use as fungicides |
EP2746263A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Alpha-substituted triazoles and imidazoles |
WO2014095548A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
WO2014095547A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
WO2014095672A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
US8765731B2 (en) | 2009-07-16 | 2014-07-01 | Vertex Pharmaceuticals Incorporated | Benzimidazole analogues for the treatment or prevention of flavivirus infections |
US8796466B2 (en) | 2009-03-30 | 2014-08-05 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014134251A1 (en) | 2013-02-28 | 2014-09-04 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions |
US8859555B2 (en) | 2009-09-25 | 2014-10-14 | Oryzon Genomics S.A. | Lysine Specific Demethylase-1 inhibitors and their use |
US8865912B2 (en) | 2010-10-06 | 2014-10-21 | Glaxosmithkline Llc | Benzimidazole derivatives as PI3 kinase inhibitors |
US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
EP2435424B1 (en) * | 2009-05-29 | 2015-01-21 | Merck Sharp & Dohme Corp. | Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c |
US8946296B2 (en) | 2009-10-09 | 2015-02-03 | Oryzon Genomics S.A. | Substituted heteroaryl- and aryl-cyclopropylamine acetamides and their use |
US8946238B2 (en) | 2011-12-22 | 2015-02-03 | Gilead Sciences, Inc. | Pyrazolo[1,5-A]pyrimidines as antiviral agents |
JPWO2013011932A1 (en) * | 2011-07-15 | 2015-02-23 | 塩野義製薬株式会社 | Azabenzimidazole derivatives having AMPK activation action |
JP2015506987A (en) * | 2012-02-13 | 2015-03-05 | プレシディオ ファーマシューティカルズ インコーポレイテッド | Solids containing NS5A inhibitors of HCV, compositions thereof, and uses thereof |
US8975416B2 (en) | 2008-12-02 | 2015-03-10 | Summit Corporation Plc | Antibacterial compounds |
US8980878B2 (en) | 2012-04-17 | 2015-03-17 | Gilead Sciences, Inc. | Compounds and methods for antiviral treatment |
US8987308B2 (en) | 2010-06-01 | 2015-03-24 | Summit Corporation Plc | Compounds for the treatment of Clostridium difficile-associated disease |
US8993808B2 (en) | 2009-01-21 | 2015-03-31 | Oryzon Genomics, S.A. | Phenylcyclopropylamine derivatives and their medical use |
US9006449B2 (en) | 2010-07-29 | 2015-04-14 | Oryzon Genomics, S.A. | Cyclopropylamine derivatives useful as LSD1 inhibitors |
US9006455B2 (en) | 2009-11-11 | 2015-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9012427B2 (en) | 2012-03-22 | 2015-04-21 | Alios Biopharma, Inc. | Pharmaceutical combinations comprising a thionucleotide analog |
US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
US9061966B2 (en) | 2010-10-08 | 2015-06-23 | Oryzon Genomics S.A. | Cyclopropylamine inhibitors of oxidases |
US9126986B2 (en) | 2011-12-28 | 2015-09-08 | Janssen Sciences Ireland Uc | Hetero-bicyclic derivatives as HCV inhibitors |
US9181198B2 (en) | 2010-07-29 | 2015-11-10 | Oryzon Genomics S.A. | Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use |
US9186337B2 (en) | 2010-02-24 | 2015-11-17 | Oryzon Genomics S.A. | Lysine demethylase inhibitors for diseases and disorders associated with Hepadnaviridae |
US9187496B2 (en) | 2009-12-18 | 2015-11-17 | Idenix Pharmaceuticals Llc | 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors |
WO2016004413A3 (en) * | 2014-07-03 | 2016-03-03 | Board Of Regents, University Of Texas System | Gls1 inhibitors for treating disease |
US9278922B2 (en) | 2009-04-15 | 2016-03-08 | Abbvie Inc. | Anti-viral compounds |
US9326973B2 (en) | 2012-01-13 | 2016-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
WO2016089814A1 (en) | 2014-12-02 | 2016-06-09 | Concert Pharmaceuticals, Inc. | Deuterated analogues of daclatasvir |
AU2014203655B2 (en) * | 2010-10-13 | 2016-07-07 | Abbvie Ireland Unlimited Company | Anti-viral compounds |
US9393256B2 (en) | 2011-09-16 | 2016-07-19 | Gilead Pharmasset Llc | Methods for treating HCV |
US9394279B2 (en) | 2009-06-11 | 2016-07-19 | Abbvie Inc. | Anti-viral compounds |
US9422274B2 (en) | 2013-11-15 | 2016-08-23 | Korea Institute Of Science And Technology | Oxazolidinone derivatives and composition for preventing or treating hepatitis C containing the same |
US9469597B2 (en) | 2011-10-20 | 2016-10-18 | Oryzon Genomics S.A. | (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
US9487512B2 (en) | 2011-10-20 | 2016-11-08 | Oryzon Genomics S.A. | (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
US9616058B2 (en) | 2010-02-24 | 2017-04-11 | Oryzon Genomics, S.A. | Potent selective LSD1 inhibitors and dual LSD1/MAO-B inhibitors for antiviral use |
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 |
US9770439B2 (en) | 2013-07-02 | 2017-09-26 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9775831B2 (en) | 2013-07-17 | 2017-10-03 | Bristol-Myers Squibb Company | Combinations comprising biphenyl derivatives for use in the treatment of HCV |
US9809588B2 (en) | 2014-07-03 | 2017-11-07 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US9908859B2 (en) | 2011-02-08 | 2018-03-06 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for myeloproliferative disorders |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10086011B2 (en) | 2013-08-27 | 2018-10-02 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10125128B2 (en) | 2015-06-30 | 2018-11-13 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US10150753B2 (en) | 2015-12-22 | 2018-12-11 | Board Of Regents, The University Of Texas System | Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10618895B2 (en) | 2013-12-20 | 2020-04-14 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US10710986B2 (en) | 2018-02-13 | 2020-07-14 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10722487B2 (en) | 2017-10-18 | 2020-07-28 | Board Of Regents, The University Of Texas System | Glutaminase inhibitor therapy |
US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10800789B2 (en) | 2012-05-16 | 2020-10-13 | Gilead Pharmasset Llc | Antiviral compounds |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US11203599B2 (en) | 2014-06-11 | 2021-12-21 | Gilead Pharmasset Llc | Solid forms of an antiviral compound |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
US11866428B2 (en) | 2011-04-21 | 2024-01-09 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US12037340B2 (en) | 2022-05-19 | 2024-07-16 | Gilead Sciences, Inc. | Pentacyclic derivatives as Zika virus inhibitors |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI438200B (en) * | 2009-02-17 | 2014-05-21 | 必治妥美雅史谷比公司 | Hepatitis c virus inhibitors |
CN108794454B (en) * | 2017-04-27 | 2023-08-15 | 广东东阳光药业股份有限公司 | Preparation method of imidazole ring compound |
CN114835691A (en) * | 2021-02-01 | 2022-08-02 | 江苏天士力帝益药业有限公司 | Benzimidazole derivative and application thereof |
Citations (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994014436A1 (en) | 1992-12-29 | 1994-07-07 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5508269A (en) | 1994-10-19 | 1996-04-16 | Pathogenesis Corporation | Aminoglycoside formulation for aerosolization |
US5767068A (en) | 1997-02-13 | 1998-06-16 | Pathogenesis Corporation | Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections |
WO1998043650A1 (en) | 1997-04-02 | 1998-10-08 | Pathogenesis Corporation | A method and a tobramycin aerosol formulation for treatment, prevention and containment of tuberculosis |
US6014969A (en) | 1993-05-21 | 2000-01-18 | Aradigm Corporation | Disposable package for use in aerosolized delivery of antibiotics |
WO2004002986A2 (en) | 2002-06-28 | 2004-01-08 | Banyu Pharmaceutical Co., Ltd. | Novel benzimidazole derivatives |
WO2004014852A2 (en) | 2002-08-12 | 2004-02-19 | Bristol-Myers Squibb Company | Iminothiazolidinones as inhibitors of hcv replication |
US20040091527A1 (en) | 2000-02-23 | 2004-05-13 | Pfizer Inc | Method of increasing the bioavailability and tissue penetration of azithromycin |
US20040152625A1 (en) | 2002-12-16 | 2004-08-05 | Boehringer Ingelheim International Gmbh | Method for improving the pharmacokinetics of an NNRTI |
WO2006079833A1 (en) | 2005-01-31 | 2006-08-03 | Arrow Therapeutics Limited | Quinazoline derivatives as antiviral agents |
WO2006133326A1 (en) | 2005-06-06 | 2006-12-14 | Bristol-Myers Squibb Company | Inhibitors of hcv replication |
WO2007031791A1 (en) | 2005-09-16 | 2007-03-22 | Arrow Therapeutics Limited | Biphenyl derivatives and their use in treating hepatitis c |
WO2007070600A2 (en) | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | N-(5-membered heteroaromatic ring)-amido anti-viral compounds |
WO2007070556A2 (en) | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | N-(6-membered aromatic ring)-amido anti-viral compounds |
WO2007082554A1 (en) | 2006-01-23 | 2007-07-26 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Modulators of hcv replication |
US20070244148A1 (en) * | 2003-12-22 | 2007-10-18 | Bondy Steven S | Imidazo 4,5-C Pyridine Compounds and Methods of Antiviral Treatment |
WO2007128086A2 (en) * | 2006-05-05 | 2007-11-15 | Katholieke Universiteit Leuven | Novel viral replication inhibitor |
US20080044379A1 (en) * | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2008021851A2 (en) | 2006-08-09 | 2008-02-21 | Smithkline Beecham Corporation | Novel compounds as antagonists or inverse agonists for opioid receptors |
WO2008021936A2 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008021927A2 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008048589A2 (en) | 2006-10-13 | 2008-04-24 | Xtl Biopharmaceuticals Ltd | Compounds and methods for treatment of hcv |
WO2008064218A2 (en) | 2006-11-21 | 2008-05-29 | Smithkline Beecham Corporation | Amido anti-viral compounds |
WO2008070447A2 (en) | 2006-11-21 | 2008-06-12 | Smithkline Beecham Corporation | Anti-viral compounds |
WO2008144380A1 (en) | 2007-05-17 | 2008-11-27 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008154601A1 (en) | 2007-06-12 | 2008-12-18 | Genelabs Technologies, Inc. | Anti-viral inhibitors and methods of use |
US20090004140A1 (en) * | 2007-06-26 | 2009-01-01 | Yao-Ling Qiu | 4-substituted pyrrolidine as anti-infectives |
WO2009020825A1 (en) | 2007-08-08 | 2009-02-12 | Bristol-Myers Squibb Company | Process for synthesizing compounds useful for treating hepatitis c |
WO2009020828A1 (en) | 2007-08-08 | 2009-02-12 | Bristol-Myers Squibb Company | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
WO2009034390A1 (en) | 2007-09-14 | 2009-03-19 | Arrow Therapeutics Limited | Heterocyclic derivatives and their use in treating hepatitis c |
US20090202483A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20090202478A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2009102318A1 (en) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2009102325A1 (en) | 2008-02-13 | 2009-08-20 | Bristol-Myers Squibb Company | Imidazolyl biphenyl imidazoles as hepatitis c virus inhibitors |
WO2009102694A1 (en) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | Heterocyclic derivatives as hepatitis c virus inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10237722A1 (en) * | 2002-08-17 | 2004-08-19 | Aventis Pharma Deutschland Gmbh | Indole or benzimidazole derivatives for the modulation of IKappaB kinase |
CN104163816A (en) * | 2008-12-03 | 2014-11-26 | 普雷西迪奥制药公司 | Inhibitors of HCV NS5A |
CA2750577A1 (en) * | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
TWI438200B (en) * | 2009-02-17 | 2014-05-21 | 必治妥美雅史谷比公司 | Hepatitis c virus inhibitors |
UA108211C2 (en) | 2009-11-04 | 2015-04-10 | Янссен Рід Айрленд | Benzimidazole imidazole derivatives |
-
2010
- 2010-03-01 MY MYPI2011004045A patent/MY160130A/en unknown
- 2010-03-01 RU RU2011135605/04A patent/RU2544010C2/en not_active IP Right Cessation
- 2010-03-01 CN CN201080018566.7A patent/CN102427731B/en not_active Expired - Fee Related
- 2010-03-01 ES ES10746967.8T patent/ES2606717T3/en active Active
- 2010-03-01 SG SG10201400235PA patent/SG10201400235PA/en unknown
- 2010-03-01 KR KR1020117022672A patent/KR101411889B1/en active IP Right Grant
- 2010-03-01 NZ NZ595280A patent/NZ595280A/en not_active IP Right Cessation
- 2010-03-01 CA CA2753382A patent/CA2753382C/en not_active Expired - Fee Related
- 2010-03-01 EP EP10746967.8A patent/EP2400846B1/en not_active Not-in-force
- 2010-03-01 AU AU2010217797A patent/AU2010217797B2/en not_active Ceased
- 2010-03-01 WO PCT/US2010/025741 patent/WO2010099527A1/en active Application Filing
- 2010-03-01 SG SG2011060779A patent/SG174146A1/en unknown
- 2010-03-01 MX MX2011008982A patent/MX2011008982A/en active IP Right Grant
- 2010-03-01 BR BRPI1007836-3A patent/BRPI1007836A2/en not_active Application Discontinuation
- 2010-03-01 KR KR1020137028995A patent/KR20130130875A/en not_active Application Discontinuation
- 2010-03-01 JP JP2011552218A patent/JP5628841B2/en not_active Expired - Fee Related
-
2011
- 2011-08-22 IL IL214775A patent/IL214775A/en not_active IP Right Cessation
- 2011-09-09 ZA ZA2011/06629A patent/ZA201106629B/en unknown
-
2014
- 2014-06-12 JP JP2014121521A patent/JP2014205694A/en not_active Withdrawn
Patent Citations (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994014436A1 (en) | 1992-12-29 | 1994-07-07 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US6014969A (en) | 1993-05-21 | 2000-01-18 | Aradigm Corporation | Disposable package for use in aerosolized delivery of antibiotics |
US5508269A (en) | 1994-10-19 | 1996-04-16 | Pathogenesis Corporation | Aminoglycoside formulation for aerosolization |
US5767068A (en) | 1997-02-13 | 1998-06-16 | Pathogenesis Corporation | Pure biologically active colistin, its components and a colistin formulation for treatment of pulmonary infections |
WO1998043650A1 (en) | 1997-04-02 | 1998-10-08 | Pathogenesis Corporation | A method and a tobramycin aerosol formulation for treatment, prevention and containment of tuberculosis |
US20040091527A1 (en) | 2000-02-23 | 2004-05-13 | Pfizer Inc | Method of increasing the bioavailability and tissue penetration of azithromycin |
WO2004002986A2 (en) | 2002-06-28 | 2004-01-08 | Banyu Pharmaceutical Co., Ltd. | Novel benzimidazole derivatives |
WO2004014852A2 (en) | 2002-08-12 | 2004-02-19 | Bristol-Myers Squibb Company | Iminothiazolidinones as inhibitors of hcv replication |
US20040152625A1 (en) | 2002-12-16 | 2004-08-05 | Boehringer Ingelheim International Gmbh | Method for improving the pharmacokinetics of an NNRTI |
US20070244148A1 (en) * | 2003-12-22 | 2007-10-18 | Bondy Steven S | Imidazo 4,5-C Pyridine Compounds and Methods of Antiviral Treatment |
WO2006079833A1 (en) | 2005-01-31 | 2006-08-03 | Arrow Therapeutics Limited | Quinazoline derivatives as antiviral agents |
WO2006133326A1 (en) | 2005-06-06 | 2006-12-14 | Bristol-Myers Squibb Company | Inhibitors of hcv replication |
WO2007031791A1 (en) | 2005-09-16 | 2007-03-22 | Arrow Therapeutics Limited | Biphenyl derivatives and their use in treating hepatitis c |
WO2007070600A2 (en) | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | N-(5-membered heteroaromatic ring)-amido anti-viral compounds |
WO2007070556A2 (en) | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | N-(6-membered aromatic ring)-amido anti-viral compounds |
WO2007082554A1 (en) | 2006-01-23 | 2007-07-26 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Modulators of hcv replication |
WO2007128086A2 (en) * | 2006-05-05 | 2007-11-15 | Katholieke Universiteit Leuven | Novel viral replication inhibitor |
WO2008021851A2 (en) | 2006-08-09 | 2008-02-21 | Smithkline Beecham Corporation | Novel compounds as antagonists or inverse agonists for opioid receptors |
WO2008021936A2 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008021928A2 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008021927A2 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US20080044379A1 (en) * | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2008048589A2 (en) | 2006-10-13 | 2008-04-24 | Xtl Biopharmaceuticals Ltd | Compounds and methods for treatment of hcv |
WO2008064218A2 (en) | 2006-11-21 | 2008-05-29 | Smithkline Beecham Corporation | Amido anti-viral compounds |
WO2008070447A2 (en) | 2006-11-21 | 2008-06-12 | Smithkline Beecham Corporation | Anti-viral compounds |
US20080311075A1 (en) | 2007-05-17 | 2008-12-18 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2008144380A1 (en) | 2007-05-17 | 2008-11-27 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2008154601A1 (en) | 2007-06-12 | 2008-12-18 | Genelabs Technologies, Inc. | Anti-viral inhibitors and methods of use |
US20090004140A1 (en) * | 2007-06-26 | 2009-01-01 | Yao-Ling Qiu | 4-substituted pyrrolidine as anti-infectives |
WO2009020825A1 (en) | 2007-08-08 | 2009-02-12 | Bristol-Myers Squibb Company | Process for synthesizing compounds useful for treating hepatitis c |
WO2009020828A1 (en) | 2007-08-08 | 2009-02-12 | Bristol-Myers Squibb Company | Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt |
WO2009034390A1 (en) | 2007-09-14 | 2009-03-19 | Arrow Therapeutics Limited | Heterocyclic derivatives and their use in treating hepatitis c |
WO2009102318A1 (en) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2009102694A1 (en) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | Heterocyclic derivatives as hepatitis c virus inhibitors |
US20090202483A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20090202478A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2009102325A1 (en) | 2008-02-13 | 2009-08-20 | Bristol-Myers Squibb Company | Imidazolyl biphenyl imidazoles as hepatitis c virus inhibitors |
Non-Patent Citations (46)
Title |
---|
"Comprehensive Heterocyclic Chemistry II", COMPREHENSIVE HETEROCYCLIC CHEMISTRY III, 2008 |
"Comprehensive Heterocyclic Chemistry", 1984 |
"Encyclopedia of Reagents for Organic Synthesis,", 1995, JOHN WILEY AND SONS |
"Techniques of Chemistry Series", vol. II, 1986, JOHN WILEY & SONS, article "Organic Solvents Physical Properties and Methods of Purification" |
"the Techniques of Chemistry Series", vol. II, 1986, JOHN WILEY & SONS, article "Organic Solvents Physical Properties and Methods of Purification" |
A. A. KOLYKHALOV ET AL., JOURNAL OF VIROLOGY, vol. 74, no. 4, 2000, pages 2046 - 2051 |
A. ANASTASIA ET AL.: "Handbook of Organopalladium Chemistry for Organic Synthesis", vol. 1, 2002, pages: 311 |
A. SUZUKI: "Handbook of Organopalladium Chemistry for Organic Synthesis", vol. 1, 2002, pages: 249 |
A. T. LINDHARDT ET AL., CHEM. - A EUROPEAN J., vol. 14, 2008, pages 8756 |
BEHRENS, S.E. ET AL., EMBO J., vol. 151, 1996, pages 2 - 22 |
C. CATIVIELA; M. D. DIAZ-DE-VILLEGAS, TETRAHEDRON: ASYMMETRY, vol. 18, 2007, pages 569 |
CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 33, 1985, pages 3922 - 3928 |
CHOO, Q-L ET AL., SCIENCE, vol. 244, 1989, pages 359 - 362 |
D. SEEBACH ET AL., SYNTHESIS, 2009, pages 1 |
E. A. B. KANTCHEV ET AL., ANGEW. CHEM. INT. ED., vol. 46, 2007, pages 2768 |
F. BELLINA ET AL., SYNTHESIS, 2004, pages 2419 |
J. MED. CHEM., vol. 49, 2006, pages 4721 - 4736 |
J. ORG. CHEM, vol. 64, 1999, pages 547 |
JACQUES ET AL.: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY & SONS |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, 1997, pages 730 |
KOLYKHALOV, A. ET AL., J. VIROLOGY, vol. 70, 1996, pages 3363 - 3371 |
KUO, G ET AL., SCIENCE, vol. 244, 1989, pages 362 - 364 |
L. FIESER; M. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS |
LOHMAN ET AL., SCIENCE, vol. 285, 1999, pages 110 - 113 |
M. G. ORGAN ET AL., SYNTHESIS, 2008, pages 2776 |
MILLER, R.H.; R.H. PURCELL, PROC. NATL. ACAD. SCI. USA, vol. 87, 1990, pages 2057 - 2061 |
PRICHARD; SHIPMAN, ANTIVIRAL RESEARCH, vol. 14, 1990, pages 181 - 205 |
R. LAROCK: "Comprehensive Organic Transformations", 1999, WILEY-VCH |
RICE, C. M., NATURE, vol. 435, 2005, pages 374 |
RICE, C.M.: "Virology", 1996, RAVEN PRESS, pages: 931 - 960 |
S. M. BERGE ET AL.: "pharmaceutically acceptable salts in detail", J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19 |
See also references of EP2400846A1 |
SUZUKI, PURE APPLIED CHEM., vol. 63, 1991, pages 419 |
T W GREENE; P G M WUTS: "Protective Groups in Organic Synthesis", 1999, J WILEY AND SONS |
T.H. GREENE; P.G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS |
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS |
TAN, S.-L.; KATZEL, M.G., VIROLOGY, vol. 284, 2001, pages 1 |
TANAKA, T. ET AL., BIOCHEM BIOPHYS. RES. COMMUN., vol. 215, 1995, pages 744 - 749 |
TANAKA, T. ET AL., J. VIROLOGY, vol. 70, 1996, pages 3307 - 3312 |
TELLINGHUISEN ET AL.: "Structure of the zinc-binding domain of an essentiel component of the hepatitis C virus replicase", NATURE LETTERS, vol. 435, May 2005 (2005-05-01), pages 374 - 479, XP003000242 * |
TETRAHEDRON: ASYMMETRY, vol. 11, 2000, pages 645 |
TETRAHEDRON: ASYMMETRY, vol. 9, 1998, pages 3517 |
V. FARINA ET AL., ADVANCES IN METAL-ORGANIC CHEM., vol. 5, 1996, pages 1 |
VROLIJK, JOURNAL OF VIROLOGICAL METHODS, vol. 110, 2003, pages 201 - 209 |
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., vol. 1, no. 5, July 1995 (1995-07-01), pages 526 - 537, XP009110985 |
YAMADA, N. ET AL., VIROLOGY, vol. 223, 1996, pages 255 - 261 |
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US9790196B2 (en) | 2010-11-30 | 2017-10-17 | Oryzon Genomics S.A. | Lysine demethylase inhibitors for diseases and disorders associated with Flaviviridae |
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JPWO2013011932A1 (en) * | 2011-07-15 | 2015-02-23 | 塩野義製薬株式会社 | Azabenzimidazole derivatives having AMPK activation action |
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US9670136B2 (en) | 2011-10-20 | 2017-06-06 | Oryzon Genomics S.A. | (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
US9469597B2 (en) | 2011-10-20 | 2016-10-18 | Oryzon Genomics S.A. | (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
US9487512B2 (en) | 2011-10-20 | 2016-11-08 | Oryzon Genomics S.A. | (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors |
US9809600B2 (en) | 2011-11-16 | 2017-11-07 | Gilead Pharmasset Llc | Antiviral compounds |
US10807990B2 (en) | 2011-11-16 | 2020-10-20 | Gilead Pharmasset Llc | Antiviral compounds |
US9221833B2 (en) | 2011-11-16 | 2015-12-29 | Gilead Pharmasset Llc | Antiviral compounds |
US8940718B2 (en) | 2011-11-16 | 2015-01-27 | Gilead Pharmasset Llc | Antiviral compounds |
US8921341B2 (en) | 2011-11-16 | 2014-12-30 | Gilead Pharmasset Llc | Antiviral compounds |
US9051340B2 (en) | 2011-11-16 | 2015-06-09 | Gilead Pharmasset Llc | Antiviral compounds |
US8575135B2 (en) | 2011-11-16 | 2013-11-05 | Gilead Sciences, Inc. | Antiviral compounds |
US9868745B2 (en) | 2011-11-16 | 2018-01-16 | Gilead Pharmasset Llc | Antiviral compounds |
US9278975B2 (en) | 2011-12-22 | 2016-03-08 | Gilead Sciences, Inc. | Pyrazolo[1,5-A]pyrimidines as antiviral agents |
US8946238B2 (en) | 2011-12-22 | 2015-02-03 | Gilead Sciences, Inc. | Pyrazolo[1,5-A]pyrimidines as antiviral agents |
US9126986B2 (en) | 2011-12-28 | 2015-09-08 | 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 |
JP2015506987A (en) * | 2012-02-13 | 2015-03-05 | プレシディオ ファーマシューティカルズ インコーポレイテッド | Solids containing NS5A inhibitors of HCV, compositions thereof, and uses thereof |
US9012427B2 (en) | 2012-03-22 | 2015-04-21 | Alios Biopharma, Inc. | Pharmaceutical combinations comprising a thionucleotide analog |
US9504689B2 (en) | 2012-04-17 | 2016-11-29 | Gilead Sciences, Inc. | Compounds and methods for antiviral treatment |
US10174038B2 (en) | 2012-04-17 | 2019-01-08 | Gilead Sciences, Inc. | Compounds and methods for antiviral treatment |
US8980878B2 (en) | 2012-04-17 | 2015-03-17 | Gilead Sciences, Inc. | Compounds and methods for antiviral treatment |
US10800789B2 (en) | 2012-05-16 | 2020-10-13 | Gilead Pharmasset Llc | Antiviral compounds |
EP2880030A4 (en) * | 2012-08-03 | 2016-01-13 | Sunshine Lake Pharma Co Ltd | Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof |
EP2880030A1 (en) * | 2012-08-03 | 2015-06-10 | Sunshine Lake Pharma Co., Ltd. | Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof |
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 |
WO2014019344A1 (en) | 2012-08-03 | 2014-02-06 | Sunshine Lake Pharma Co., Ltd. | Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof |
JP2015529652A (en) * | 2012-08-03 | 2015-10-08 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | Cross-linked ring compounds that are hepatitis C inhibitors and their application to pharmaceuticals |
EP2746278A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
EP2746277A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Fungicidal imidazolyl and triazolyl compounds |
WO2014095548A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
WO2014095547A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
EP2745691A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted imidazole compounds and their use as fungicides |
EP3173406A1 (en) | 2012-12-19 | 2017-05-31 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
WO2014095672A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
EP2746263A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Alpha-substituted triazoles and imidazoles |
EP2746262A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds for combating phytopathogenic fungi |
EP2746274A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole compounds |
EP3181558A1 (en) | 2012-12-19 | 2017-06-21 | Basf Se | Substituted [1,2,4]triazole compounds and their use as fungicides |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | 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 |
US9770439B2 (en) | 2013-07-02 | 2017-09-26 | 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 |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10086011B2 (en) | 2013-08-27 | 2018-10-02 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US11707479B2 (en) | 2013-08-27 | 2023-07-25 | Gilead Sciences, Inc. | Combination formulation of two antiviral compounds |
US9422274B2 (en) | 2013-11-15 | 2016-08-23 | Korea Institute Of Science And Technology | Oxazolidinone derivatives and composition for preventing or treating hepatitis C containing the same |
US11225476B2 (en) | 2013-12-20 | 2022-01-18 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US10618895B2 (en) | 2013-12-20 | 2020-04-14 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US11643410B2 (en) | 2013-12-20 | 2023-05-09 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US10105365B2 (en) | 2014-01-03 | 2018-10-23 | Abbvie Inc. | Solid antiviral dosage forms |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US9744170B2 (en) | 2014-01-03 | 2017-08-29 | Abbvie Inc. | Solid antiviral dosage forms |
US11203599B2 (en) | 2014-06-11 | 2021-12-21 | Gilead Pharmasset Llc | Solid forms of an antiviral compound |
US11958849B2 (en) | 2014-07-03 | 2024-04-16 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US10766892B2 (en) | 2014-07-03 | 2020-09-08 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
WO2016004413A3 (en) * | 2014-07-03 | 2016-03-03 | Board Of Regents, University Of Texas System | Gls1 inhibitors for treating disease |
US10344025B2 (en) | 2014-07-03 | 2019-07-09 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US9809588B2 (en) | 2014-07-03 | 2017-11-07 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US11370786B2 (en) | 2014-07-03 | 2022-06-28 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
WO2016089814A1 (en) | 2014-12-02 | 2016-06-09 | Concert Pharmaceuticals, Inc. | Deuterated analogues of daclatasvir |
US10738043B2 (en) | 2015-06-30 | 2020-08-11 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US10125128B2 (en) | 2015-06-30 | 2018-11-13 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US11713313B2 (en) | 2015-06-30 | 2023-08-01 | Board Of Regents, The University Of Texas System | GLS1 inhibitors for treating disease |
US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10150753B2 (en) | 2015-12-22 | 2018-12-11 | Board Of Regents, The University Of Texas System | Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyrdin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide |
US11603365B2 (en) | 2015-12-22 | 2023-03-14 | Board Of Regents, The University Of Texas System | Salt forms and polymorphs of (r)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido) pyridazin-3-yl)-2-fluorobutyl)-n-methyl-1H-1,2,3-triazole-4-carboxamide |
US10899740B2 (en) | 2015-12-22 | 2021-01-26 | Board Of Regents, The University Of Texas System | Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide |
US10722487B2 (en) | 2017-10-18 | 2020-07-28 | Board Of Regents, The University Of Texas System | Glutaminase inhibitor therapy |
US11045443B2 (en) | 2017-10-18 | 2021-06-29 | Board Of Regents, The University Of Texas System | Glutaminase inhibitor therapy |
US11786500B2 (en) | 2017-10-18 | 2023-10-17 | Board Of Regents, The University Of Texas System | Glutaminase inhibitor therapy |
US11555029B2 (en) | 2018-02-13 | 2023-01-17 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10710986B2 (en) | 2018-02-13 | 2020-07-14 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US12037340B2 (en) | 2022-05-19 | 2024-07-16 | Gilead Sciences, Inc. | Pentacyclic derivatives as Zika virus inhibitors |
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EP2400846A4 (en) | 2012-10-03 |
CA2753382A1 (en) | 2010-09-02 |
KR20130130875A (en) | 2013-12-02 |
SG10201400235PA (en) | 2014-07-30 |
SG174146A1 (en) | 2011-10-28 |
CN102427731A (en) | 2012-04-25 |
JP2014205694A (en) | 2014-10-30 |
MY160130A (en) | 2017-02-28 |
MX2011008982A (en) | 2011-09-15 |
BRPI1007836A2 (en) | 2015-09-01 |
CA2753382C (en) | 2014-12-23 |
ZA201106629B (en) | 2015-06-24 |
EP2400846B1 (en) | 2016-10-05 |
IL214775A0 (en) | 2011-11-30 |
IL214775A (en) | 2014-09-30 |
NZ595280A (en) | 2013-11-29 |
JP5628841B2 (en) | 2014-11-19 |
KR20110120976A (en) | 2011-11-04 |
KR101411889B1 (en) | 2014-06-27 |
CN102427731B (en) | 2015-05-13 |
ES2606717T3 (en) | 2017-03-27 |
AU2010217797A1 (en) | 2011-10-06 |
RU2544010C2 (en) | 2015-03-10 |
RU2011135605A (en) | 2013-04-10 |
AU2010217797B2 (en) | 2014-02-20 |
EP2400846A1 (en) | 2012-01-04 |
JP2012519185A (en) | 2012-08-23 |
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