WO2007016441A1 - Macrocyclic peptides as hcv ns3 protease inhibitors - Google Patents
Macrocyclic peptides as hcv ns3 protease inhibitors Download PDFInfo
- Publication number
- WO2007016441A1 WO2007016441A1 PCT/US2006/029635 US2006029635W WO2007016441A1 WO 2007016441 A1 WO2007016441 A1 WO 2007016441A1 US 2006029635 W US2006029635 W US 2006029635W WO 2007016441 A1 WO2007016441 A1 WO 2007016441A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- heteroaryl
- heterocyclyl
- Prior art date
Links
- 0 C*(C)c1c[s]cn1 Chemical compound C*(C)c1c[s]cn1 0.000 description 11
- KJMHWXKOIMHKJM-IOVLZCAISA-N CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2c(cc(CCCCCO3)cc4O)c4ccn2)C1C(OC)=O)=O)NC3=O Chemical compound CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2c(cc(CCCCCO3)cc4O)c4ccn2)C1C(OC)=O)=O)NC3=O KJMHWXKOIMHKJM-IOVLZCAISA-N 0.000 description 1
- SICZIKDIJNIKAA-QBVVXRIRSA-N CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2c(cc(cc3I)/C=C/CCCO4)c3ccn2)[C@@H]1C(O)=O)=O)NC4=O Chemical compound CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2c(cc(cc3I)/C=C/CCCO4)c3ccn2)[C@@H]1C(O)=O)=O)NC4=O SICZIKDIJNIKAA-QBVVXRIRSA-N 0.000 description 1
- CXNIKLQIHMONAG-HZLLOYAISA-N CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2nc(-c3ccccc3)cc(cc3)c2cc3/C=C/CCCO2)[C@@H]1C(N[C@](C1)(C1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)NC2=O Chemical compound CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2nc(-c3ccccc3)cc(cc3)c2cc3/C=C/CCCO2)[C@@H]1C(N[C@](C1)(C1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)NC2=O CXNIKLQIHMONAG-HZLLOYAISA-N 0.000 description 1
- MJFNVVDAHSTIPR-SRZBMWHLSA-N CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2nc(Cl)cc(cc3)c2cc3/C=C/CCCO2)C1C(NC(CC1)(C1C=C)C(NC)=O)=O)=O)NC2=O Chemical compound CC(C)(C)[C@@H](C(N(C[C@@H](C1)Oc2nc(Cl)cc(cc3)c2cc3/C=C/CCCO2)C1C(NC(CC1)(C1C=C)C(NC)=O)=O)=O)NC2=O MJFNVVDAHSTIPR-SRZBMWHLSA-N 0.000 description 1
- OYZHMEGEEVZWOJ-DGMJBNSBSA-N CC(C)(C/C=C/c(ccc1ccn2)cc1c2O[C@H](C[C@H]1C(O)=O)CN1C([C@H](C1CCCC1)N1)=O)COC1=O Chemical compound CC(C)(C/C=C/c(ccc1ccn2)cc1c2O[C@H](C[C@H]1C(O)=O)CN1C([C@H](C1CCCC1)N1)=O)COC1=O OYZHMEGEEVZWOJ-DGMJBNSBSA-N 0.000 description 1
- JPZKPYPXZYSJMO-CWBIGUPCSA-N CC(C)(CCCC1=CC2C(O[C@H](C[C@H]3C(N[C@](CC4)([C@@H]4C=C)C(NS(C4CC4)(=O)=O)=O)=O)CN3C([C@H](C3CCCC3)N3)=O)=NC=CC2C=C1)COC3=O Chemical compound CC(C)(CCCC1=CC2C(O[C@H](C[C@H]3C(N[C@](CC4)([C@@H]4C=C)C(NS(C4CC4)(=O)=O)=O)=O)CN3C([C@H](C3CCCC3)N3)=O)=NC=CC2C=C1)COC3=O JPZKPYPXZYSJMO-CWBIGUPCSA-N 0.000 description 1
- GPLDBNQGYJYJJR-PHPPSXNNSA-N CC(C)[C@@H](C(N(CCC1)[C@@H]1C(OCC[Si](C)(C)C)=O)=O)NC(OCCC/C=C/c(ccc1nc(N(C)C)n2)cc1c2O)=O Chemical compound CC(C)[C@@H](C(N(CCC1)[C@@H]1C(OCC[Si](C)(C)C)=O)=O)NC(OCCC/C=C/c(ccc1nc(N(C)C)n2)cc1c2O)=O GPLDBNQGYJYJJR-PHPPSXNNSA-N 0.000 description 1
- YXVMQVUUFFAQGX-SBILIDQBSA-N CCCC[C@@H](C(N(CCC1)[C@@H]1C(NC(C1)([C@@H]1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)NC(OCCCCCc(ccc1ccn2)cc1c2O)=O Chemical compound CCCC[C@@H](C(N(CCC1)[C@@H]1C(NC(C1)([C@@H]1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)NC(OCCCCCc(ccc1ccn2)cc1c2O)=O YXVMQVUUFFAQGX-SBILIDQBSA-N 0.000 description 1
- ZLNQGUBTBAMOJO-XTDZUUPYSA-N CCCC[C@@H](C(N(C[C@@H](C1)Oc2c(cc(CCCCCO3)cc4)c4ccn2)[C@@H]1C(N[C@](C1)([C@@H]1C=C)C(O)=O)=O)=O)NC3=O Chemical compound CCCC[C@@H](C(N(C[C@@H](C1)Oc2c(cc(CCCCCO3)cc4)c4ccn2)[C@@H]1C(N[C@](C1)([C@@H]1C=C)C(O)=O)=O)=O)NC3=O ZLNQGUBTBAMOJO-XTDZUUPYSA-N 0.000 description 1
- FAIISMHJUHDVPR-RISCZKNCSA-N CCOC([C@H](C1)NC[C@@H]1Oc1c(cc(c(OC)c2)Br)c2ccn1)=O Chemical compound CCOC([C@H](C1)NC[C@@H]1Oc1c(cc(c(OC)c2)Br)c2ccn1)=O FAIISMHJUHDVPR-RISCZKNCSA-N 0.000 description 1
- DXGNZPRUMXKMLM-YFNKSVMNSA-N CCOC([C@H](C[C@H](C1)Oc2c(cc(CCCC(C)(C)COC(N[C@H]3C(C)(C)C)=O)cc4)c4ccn2)N1C3=O)=O Chemical compound CCOC([C@H](C[C@H](C1)Oc2c(cc(CCCC(C)(C)COC(N[C@H]3C(C)(C)C)=O)cc4)c4ccn2)N1C3=O)=O DXGNZPRUMXKMLM-YFNKSVMNSA-N 0.000 description 1
- MRGHPAVOLOCALL-RLZVNHAHSA-N CCOC([C@H](C[C@H](C1)Oc2c(cc(cc3OC(F)(F)F)/C=C/CCCOC(N[C@H]4C(C)(C)C)=O)c3ccn2)N1C4=O)=O Chemical compound CCOC([C@H](C[C@H](C1)Oc2c(cc(cc3OC(F)(F)F)/C=C/CCCOC(N[C@H]4C(C)(C)C)=O)c3ccn2)N1C4=O)=O MRGHPAVOLOCALL-RLZVNHAHSA-N 0.000 description 1
- SJWXXUDBCONKQY-KQZHWHMFSA-N CCOC([C@H](C[C@H](C1)Oc2nccc3c2cc(C(CCCCOC(N[C@H]2C(C)(C)C)=O)Br)cc3I)N1C2=O)=O Chemical compound CCOC([C@H](C[C@H](C1)Oc2nccc3c2cc(C(CCCCOC(N[C@H]2C(C)(C)C)=O)Br)cc3I)N1C2=O)=O SJWXXUDBCONKQY-KQZHWHMFSA-N 0.000 description 1
- IBZMTXNGZTYMNS-UUEFVBAFSA-N CC[C@H](C)C(C(NS(C1CC1)(=O)=O)=O)N Chemical compound CC[C@H](C)C(C(NS(C1CC1)(=O)=O)=O)N IBZMTXNGZTYMNS-UUEFVBAFSA-N 0.000 description 1
- GHAQJHYAZCPIGF-IAYXXWKWSA-N C[C@H](C(C(NS(C1CC1)(=O)=O)O)NC(C(C/C(/C1)=[O]/c2nccc3c2cc([C@H](CCCCOC(N[C@H]2C(C)(C)C)=O)O)cc3)N1C2=O)=O)C=C Chemical compound C[C@H](C(C(NS(C1CC1)(=O)=O)O)NC(C(C/C(/C1)=[O]/c2nccc3c2cc([C@H](CCCCOC(N[C@H]2C(C)(C)C)=O)O)cc3)N1C2=O)=O)C=C GHAQJHYAZCPIGF-IAYXXWKWSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N C[n]1cccc1 Chemical compound C[n]1cccc1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N C[n]1nccc1 Chemical compound C[n]1nccc1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- KJRRQXYWFQKJIP-UHFFFAOYSA-N Cc1c[o]cc1 Chemical compound Cc1c[o]cc1 KJRRQXYWFQKJIP-UHFFFAOYSA-N 0.000 description 1
- QENGPZGAWFQWCZ-UHFFFAOYSA-N Cc1c[s]cc1 Chemical compound Cc1c[s]cc1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N Cc1ccccn1 Chemical compound Cc1ccccn1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N Cc1ncc[nH]1 Chemical compound Cc1ncc[nH]1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- 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
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infection.
- HCV hepatitis C virus
- Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
- HTV human immunodeficiency virus
- WHO World Health Organization
- NS3 protease is located in the N-terminal domain of the NS3 protein, and is considered a prime drug target since it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions.
- the present invention relates to novel macrocyclic compounds of formula (I) and/or pharmaceutically acceptable salts and/or hydrates thereof. These compounds are useful in the inhibition of HCV (hepatitis C virus) NS3 (non-structural 3) protease, the prevention or treatment of one or more of the symptoms of HCV infection, either as compounds or their pharmaceutically acceptable salts and/or hydrates (when appropriate), or as pharmaceutical composition ingredients, whether or not in combination with other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines.
- HCV hepatitis C virus
- NS3 non-structural 3
- the present invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt and/or hydrate thereof:
- n 1 or 2;
- R 1 is CO 2 R 10 , CONR 10 SO 2 R 6 , CONR 10 SO 2 NR 8 R 9 , or tetrazolyl;
- R 2 is Ci-C ⁇ alkyl, C 2 -C 6 alkenyl or C 3 -C 8 cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;
- R 3 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 )alkyl, aryl(C r C 8 )alkyl, or Het, wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R
- Het is a 5-6 membered saturated cyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S, wherein said ring is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ;
- R 4 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(CrC 8 )alkyl, or aryl(CrC 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(Ci-C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(Cj-C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR
- R 5 is H, halo, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CN, CF 3 , SR 10 , SO 2 (Ci-C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 7 ) 2 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1 , 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cycloalky
- R 6 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 5 )alkyl 5 aryl, aryl(C r C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, or heterocyclyl(CrC 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents; and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and
- Z is C(R I0 ) 2 , O, or N(R 4 );
- M is C 1 -Ci 2 alkylene or C 2 -Ci 2 alkenylene or C 2 -Ci 2 alkynylene, wherein said alkylene or alkenylene is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of Ci-Cg alkyl, C3-C8 cycloalkyl(Ci-C 8 alkyl), and aryl(Ci-C 8 alkyl); wherein 2 substituents on adjacent carbon atoms of M are optionally taken together to form a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, O and S, or 2 substituents on the same carbon atom of M are optionally taken together to form a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;
- A is C(R 11 ) or N;
- R 11 is H, Ci-C 6 alkyl, halo, OR 10 , SR 10 , or N(R 10 ) 2 ;
- R 11 is H, C x -C 6 alkyl, halo, OH, C x -C 6 alkoxy, CN, CF 3 , SR 10 , SO 2 (Ci-C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, Ci-C 6 haloalkyl, N(R 7 ) 2 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cyclyl, cycl
- R 5 and R 11 are optionally taken together to form a 5- to 6-membered saturated, unsaturated non- aromatic, or aromatic cyclic ring having 0-2 heteroatoms selected from N, O and S; each R 7 is independently H, C 1 -C 6 alkyl, C 3 -Ce cycloalkyl, C 3 -C 6 cycloalkyl(Ci-C 5 )alkyl, aryl, aryl(Cr C 4 )alkyl, heteroaryl, heteroaryl(Ci-C 4 alkyl), heterocyclyl, or heterocycly ⁇ Q-Cs alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents; and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6- membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through
- each W is independently H, halo, OR 7 , C 1 -C 6 alkyl, CN, CF 3 , NO 2 , SR 7 , CO 2 R 7 , CON(R 7 ) 2 , C(O)R 7 , N(R 10 )C(O)R 7 , SO 2 (Ci-C 6 alkyl), S(O)(Ci-C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 7 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), halo(C r C 6 alkoxy), NR 10 SO 2 R 7 , SO 2 N(R 7 ) 2 , NHCOOR 7 , NHCONHR 7 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroary
- each W is independently halo, OR 10 , C 1 -C 6 alkyl, CN, CF 3 , NO 2 , SR 10 , CO 2 R 10 , CON(R 10 ) 2 , C(O)R 10 , N(R 10 )C(O)R 10 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), ImIo(C 1 -C 6 alkoxy), NR 10 SO 2 R 10 , SO 2 N(R 10 ) 2 , NHCOOR 10 , NHCONHR 10 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, hetero
- R 8 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 alkyl), aryl, aryl(C r C 4 alkyl), heteroaryl, heterocyclyl, heteroaryl(CrC 4 alkyl), or heterocycly ⁇ Q-Cs alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(Ci-C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(Ci-C 6 alkyl), C 1 -C 6 alkyl, C(O)R 10
- R 9 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, aryl, aryl(C !
- alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C r C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C(O)R 10 , C 1 -C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)
- R 8 and R 9 are optionally taken together, with the nitrogen atom to which they are attached, to form a 4- 8 membered monocyclic ring containing 0-2 additional heteroatoms selected from N, O and S; and
- each R 10 is independently H or C 1 -C 6 alkyl.
- the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
- the present invention further includes methods of treating or preventing one or more symptoms of HCV infection.
- the present invention includes compounds of formula I above, and pharmaceutically acceptable salts and/or hydrates thereof. These compounds and their pharmaceutically acceptable salts and/or hydrates are HCV protease inhibitors (e.g., HCV NS3 protease inhibitors).
- HCV protease inhibitors e.g., HCV NS3 protease inhibitors
- the present invention also includes compounds of formulae II, II- A, II-B, DI, HI- A and III-B wherein variables n, R 1 , R 2 , R 3 , Y, Z, M, W, A, R 5 and R 11 are as defined for formula I.
- a first embodiment of the present invention is a compound of formula I, ⁇ , II- A, II-B, HI, m-A, or III-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 is CO 2 R 10 or CONR 10 SO 2 R 6 , and all other variables are as originally defined (i.e., as defined in the Summary of the Invention).
- R 1 is CONR 10 SO 2 R 6 ; and all other variables are as defined in the first embodiment.
- R 1 is CONHSO 2 R 6 wherein R 6 is C 3 -C 8 cycloalkyl, C 1 -C 8 alkyl, aryl, aryl(C r C 4 )alkyl, wherein said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 2 W substituents; and all other variables are as defined in the first embodiment.
- R 1 is CONHSO 2 R 6 wherein R 6 is cyclopropyl; and all other variables are as defined in the first embodiment.
- R 1 is CONHSO 2 R 6 wherein R 6 is phenyl; and all other variables are as defined in the first embodiment.
- R 1 is CONHSO 2 R 6 wherein R 6 is benzyl; and all other variables are as defined in the first embodiment.
- R 1 is CONHSO 2 R 6 wherein R 6 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl; and all other variables are as defined in the first embodiment.
- R 1 is CO 2 R 10 ; and all other variables are as defined in the first embodiment.
- R 10 is CO 2 H; and all other variables are as defined in the first embodiment.
- a second embodiment of the present invention is a compound of formula I, ⁇ , II- A, II- B, in, DI-A, or ⁇ i-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 is CONHSO 2 NR 8 R 9 ; and all other variables are as originally defined.
- R 8 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 alkyl), aryl, aryl(C r C 4 alkyl), heteroaryl, or heteroaryl(Ci-C 4 alkyl); and R 9 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), Ci-C 8 alkoxy, aryl, 8TyI(C 1 -C 4 alkyl), heteroaryl, or heteroaryl(Ci-C 4 alkyl), wherein said alkyl, cycloalkyl, alkoxy, aryl, or heteroaryl in both R 8 and R 9 is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, heteroaryl, C 1 -C 6 alky
- R 8 is C r C 8 alkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), aryl, aryl(C r C 4 alkyl), heteroaryl, or heteroaryl(Ci-C 4 alkyl); and R 9 is C r C 8 alkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), C]-C 8 alkoxy, aryl, aryl(Ci-C 4 alkyl), heteroaryl, or heteroaryl(C r C 4 alkyl), wherein said alkyl, cycloalkyl, alkoxy, aryl, or heteroaryl in both R 8 and R 9 is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C r C 6
- R 8 is C 1 -C 3 alkyl, wherein said alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C(O)R 10 , Ci-C 6 haloalkyl, NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(Cj-C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R ⁇ ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , and C(O)N(R 10 ) 2 ; and R 9 is C x -C 3 alkyl, Ci-C 3 alkoxy, phenyl, or
- R 8 is methyl; and all other variables are as defined in the second embodiment.
- R 9 is methyl, methoxy, ethyl, i-propyl, phenyl, or benzyl; and all other variables are as defined in the second embodiment.
- R 8 and R 9 are taken together to form a heteocyclic ring selected from the following:
- R 8 is methyl and R 9 is methoxy; and all other variables are as defined in the second embodiment.
- a third embodiment of the present invention is a compound of formula I, ⁇ , II- A, II-B, JH, ⁇ i-A, or ⁇ i-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 2 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 2 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 2 is C 2 -C 4 alkenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 2 is vinyl; and all other variables are as defined in the second embodiment or as defined in any one of the preceding embodiments.
- R 2 is C 1 -C 4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 2 is ethyl; and all other variables are as defined in the third embodiment or as defined in any one of the preceding embodiments.
- a fourth embodiment of the present invention is a compound of formula I, H, JI-A, JI-B, JII, JH-A, or UI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is C 3 -C 8 cycloalkyl, Het, or Ci-Cg alkyl optionally substituted with 1 to 3 halo substituents; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 3 is C 5 -C 7 cycloalkyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or Ci-C 8 alkyl optionally substituted with 1 to 3 halo substituents; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments.
- R 3 is C 5 -C 6 cycloalkyl or Ci-C 8 alkyl optionally substituted with 1 to 3 halo substituents; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments.
- R 3 is propyl or butyl; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments.
- R 3 is i-propyl, n-butyl, i-butyl or t-butyl; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments.
- R 3 is cyclopentyl or cyclohexyl; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments, hi a fifth aspect of the fourth embodiment, R 3 is CH 2 CF 3 or CH 2 CHF 2 ; and all other variables are as defined in the fourth embodiment or as defined in any one of the preceding embodiments.
- a fifth embodiment of the present invention is a compound of formula I, ⁇ , II- A, JI-B, HE, HI-A, or UI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 5 is H or halo; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 5 is H, F, or Cl; and all other variables are defined in the fifth embodiment or as defined in any one of the preceding embodiments.
- R 5 is H; and all other variables are defined in the fifth embodiment or as defined in any one of the preceding embodiments.
- a sixth embodiment of the present invention is a compound of formula I, II, JI-A, H-B, IH, HI-A, or HI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 5 is aryl or heteroaryl; wherein aryl is phenyl or naphthyl and heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , N(Ci-C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, Ci-C 6 haloalkyl, halo(C r C 6 alkoxy), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloal
- R 5 is aryl wherein aryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , N(Ci-C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (Ci-C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , S(O)(C r C 6 alkyl), NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ; and all other variables are as defined
- R 12 is H, Ci-C 6 alkyl, Ci-
- R 5 is
- R 12 is H, C 1 -C 6 alkyl, Ci-C 6 alkoxy, N(R 7 ) 2 , NHCOR 13 , NHCONHR 13 or NHCOOR 13 and each R 13 is independently Q- C 6 alkyl or C 3 -C 6 cycloalkyl; and all other variables are as defined in the sixth embodiment or as defined in any one of the preceding embodiments.
- R 5 is unsubstituted phenyl; and all other variables are as defined in the sixth embodiment or as defined in any one of the preceding embodiments.
- a seventh embodiment of the present invention is a compound of formula I, II, II- A, II-
- R 5 is Ci-C 6 alkyl, C 3 -Cg cycloalkyl, Ci-C 6 haloalkyl, or heterocyclyl wherein heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said heterocyclyl, cycloalkyl, or alkyl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 ,
- N(R 7 ) 2 N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C x -C 6 alkyl, C r C 6 haloalkyl, halo(C r C 6 alkoxy), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (Ci-C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , S(O)(Ci-C 6 alkyl), NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ; wherein the 2 adjacent substituents of said cycloalkyl or heterocyclyl are optionally taken together to form a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, O and S; and all other
- R 5 is Ci-Ce alkyl; and all other variables are as defined in the seventh embodiment or as defined in any one of the preceding embodiments.
- R 5 is methyl; and all other variables are as defined in the seventh embodiment or as defined in any one of the preceding embodiments.
- R 5 is heterocyclyl wherein heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said heterocyclyl, cycloalkyl, or alkyl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 7 ) 2 , N(Ci-C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, NO 2 , CN, CF 3 , SO 2 (C r C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R
- R 5 is N-morpholinyl; and all other variables are as defined in the seventh embodiment or as defined in any one of the preceding embodiments.
- R 5 is C 1 -C 6 haloalkyl; and all other variables are as defined in the seventh embodiment or as defined in any one of the preceding embodiments.
- R 5 is CF 3 ; and all other variables are as defined in the seventh embodiment or as defined in any one of the preceding embodiments.
- An eighth embodiment of the present invention is a compound of formula I, ⁇ , II- A, II- B, HI, ⁇ i-A, or IH-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 5 is N(R 7 ) 2 ; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 5 is N(R 7 ) 2 wherein R 7 is H or Ci-C 6 alkyl; and all other variables are as defined in the eighth embodiment or as defined in any one of the preceding embodiments.
- a ninth embodiment of the present invention is a compound of formula I, II, II- A, IH, or III- A, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 11 is H, Ci-C 6 alkyl, C 1 -C 6 alkoxy, hydroxy or halo; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R 11 is Ci-C 6 alkoxy; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R 11 is methoxy; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R ⁇ is C 1 -Ce alkyl; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R 11 is methyl; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R 11 is halo or hydroxy; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R 11 is OH, Cl, or Br; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- R 11 is H; and all other variables are as defined in the ninth embodiment or as defined in any one of the preceding embodiments.
- a tenth embodiment of the present invention is a compound of formula I, ⁇ , H-A, III, or ⁇ i-A, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 5 and R 11 are taken together to form a 5- to 6-membered saturated, unsaturated non-aromatic, or aromatic cyclic ring having 1-2 oxygen atoms; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- An eleventh embodiment of the present invention is a compound of formula IV-A or IV- B, or a pharmaceutically acceptable salt or hydrate thereof, wherein R 5 is H, halo, aryl, heteroaryl, or N(R 7 ) 2 ; R 1 is CO 2 R 10 or CONHSO 2 R 6 wherein R 6 is C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, phenyl or benzyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a thirteenth embodiment of the present invention is a compound of formula I, II, II- A, ⁇ -B, HI, ⁇ i-A, or m-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is O, NH, N(Ci-Cs alkyl) or C(R 10 J 2 ; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- Z is O, NH, N(CH 3 ), or CH2; and all other variables are as defined in the thirteenth embodiment or as defined in any one of the preceding embodiments.
- a fourteenth embodiment of the present invention is a compound of formula I, II, II- A, ⁇ -B, DI, DI-A, or DI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein M is Ci-C 8 alkylene or C 2 -C 8 alkenylene, wherein said alkylene or alkenylene is optionally substituted with 1 or 2 substituents selected from Ci-C 8 alkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), or aryl(C r C 8 alkyl); and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- M is unsubstituted Ci-C 8 alkylene or unsubstituted C 2 -C 8 alkenylene; and all other variables are as defined in the fourteenth embodiment or as defined in any one of the preceding embodiments.
- M is unsubstituted C 4 alkylene or unsubstituted C 4 alkenylene; and all other variables are as defined in the fourteenth embodiment or as defined in any one of the preceding embodiments.
- M is unsubstituted C 5 alkylene or unsubstituted C 5 alkenylene; and all other variables are as defined in the fourteenth embodiment or as defined in any one of the preceding embodiments, hi a fourth aspect of the fourteenth embodiment, M is unsubstituted Ce alkylene or unsubstituted C 6 alkenylene; and all other variables are as defined in the fourteenth embodiment or as defined in any one of the preceding embodiments.
- M is unsubstituted C 7 alkylene or unsubstituted C 7 alkenylene; and all other variables are as defined in the fourteenth embodiment or as defined in any one of the preceding embodiments, hi a feature of the first aspect of the fourteenth embodiment, M is:
- a fifteenth embodiment of the present invention is a compound of formula I, D, D-A, D- B, ID, DI-A, or DI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein n is 1 ; and all other variables are as originally defined or as defined in any one of the preceding embodiments, hi one aspect of the fifteenth embodiment, W is ortho to the variable M as depicted in formulae Ia, Da, D-Aa, D-Ba, DIa, DI-Aa, DI-Ba, IV-Aa and IV-Ba.
- a sixteenth embodiment of the present invention is a compound of formula I, JI, II- A, ⁇ -B, in, IH-A, or HI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein n is 2; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- the 2 adjacent W moieties are taken together to form a 5- to 6- membered saturated, unsaturated non-aromatic, or aromatic cyclic ring having 0-2 heteroatoms selected from N, O and S.
- the 2 adjacent W moieties are taken together to form a 5-membered saturated cyclic ring having 0-2 heteroatoms selected from N, O and S.
- a seventeenth embodiment of the present invention is a compound of fo ⁇ nula I, ⁇ , II- A, ⁇ -B, DI, ⁇ i-A, or HI-B, or a pharmaceutically acceptable salt or hydrate thereof, wherein W is H, C 1 -Ce alkyl, C 1 -C 6 alkoxy, OH, halo, halo(C r C 6 alkoxy), C(O)N(R 7 ) 2 , C(O)R 7 , N(R 7 ) 2 ,or heterocyclyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- W is H; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is Ci-C 6 alkoxy; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is methoxy; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments, hi a third aspect of the seventeenth embodiment, W is C r C 6 alkyl, halo, OH, or N(R 7 ) 2 wherein R 7 is H or C r C 6 alkyl; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments. In a feature of the third aspect of the seventeenth embodiment, W is methyl; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is ImIo(C 1 -C 6 alkoxy); and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is OCF 3 , OCHF 2 , OC(CH 3 ) 3 , or OCH(CH 3 ) 2 ; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is C(O)N(R 7 ) 2 , C(O)R 7 , or heterocyclyl; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- W is C(O)N(R 7 ) 2 wherein R 7 is H or C 1 -C 6 alkyl; C(O)R 7 wherein R 7 is a 5- membered heteroaryl having 1 heteroatom O or S; or heterocyclyl wherein heterocyclyl is a 6-membered saturated ring having 1 or 2 heteroatoms selected from N, O and S; and all other variables are as defined in the seventeenth embodiment or as defined in any one of the preceding embodiments.
- An eighteenth embodiment of the present invention is a compound, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of the compounds m-i to m-38.
- a nineteenth embodiment of the present invention is a compound of formula HI, or a pharmaceutically acceptable salt or hydrate thereof, wherein Rl is CONHSO 2 R 6 , R ⁇ is C 3 -Cg cycloalkyl, Ci-C 8 alkyl, aryl, or aryl(C r C 4 )alkyl, R 2 is C 1 -C 4 alkyl or C 2 -C 4 alkenyl, R 3 is C 5 -C 6 cycloalkyl or C 1 -C 8 alkyl optionally substituted with 1 to 3 halo substituents, R 5 is H, halo, aryl, heteroaryl or N(R 7 ) 2 , and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- R5 is H, and all other variables are as defined in the nineteenth embodiment or as defined in any one of the preceding embodiments.
- R3 is C5-C6 cycloalkyl or C3-C5-alkyl, and all other variables are as defined in the nineteenth embodiment or as defined in any one of the preceding embodiments.
- R6 is C3-C5 cycloalkyl, and all other variables are as defined in the nineteenth embodiment or as defined in any one of the preceding embodiments.
- R2 is C2-C4 alkenyl
- R ⁇ is H
- R6 is C3-Cg cycloalkyl
- W is
- M is selected from the group consisting of:
- a twentieth embodiment of the present invention is a compound, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of the compounds DI-39 to ⁇ i-187.
- a twenty-first embodiment of the present invention is a compound of formula (I) and/or a pharmaceutically acceptable salt and/or hydrate thereof:
- n 1 or 2;
- R 1 is CO 2 R 10 , CONR 10 SO 2 R 6 , CONR 10 SO 2 NR 8 R 9 , or tetrazolyl;
- R 2 is C 1 -Ce alkyl, C 2 -Ce alkenyl or C 3 -C 8 cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;
- R 3 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 )alkyl, aryl(C 1 -C 8 )alkyl, or Het, wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(Ci-C 6 alkyl), C 1 -C 6 alkyl, Ci-C 6 haloalkyl, IMIO(C 1 -C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R
- Het is a 5-6 membered saturated cyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S, wherein said ring is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6 , NHCOR 6 , NHCONHR 6 , CO 2 R 10 , C(O)R 10 , and CON(R 10 ) 2 ;
- R 4 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, or aryl(CrC 8 )alkyl; wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C r C 6 alkoxy), NO 2 , CN, CF 3 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , NHCOOR 6
- R 5 is H, halo, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CN, CF 3 , SR 10 , SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 7 ) 2 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl
- Z is C(R 10 ) 2 , O, or N(R 4 );
- M is Ci-Ci 2 alkylene or C 2 -Ci 2 alkenylene, wherein said alkylene or alkenylene is optionally substituted with 1 or 2 substituents selected from the group consisting OfCi-C 8 alkyl, C 3 -C 8 cycloalkyl(Ci-C 8 alkyl), and aryl(Ci-C 8 alkyl); and the 2 substituents on adjacent carbon atoms of M are optionally taken together to fo ⁇ n a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, O and S;
- A is C(R 11 ) or N;
- R 11 is H, Ci-C 6 alkyl, halo, OR 10 , SR 10 , or N(R 10 ) 2 ;
- R 11 is H, Ci-C 6 alkyl, halo, OH, Ci-C 6 alkoxy, CN, CF 3 , SR 10 , SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, Ci-C 6 haloalkyl, N(R 7 ) 2 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl,
- each R 7 is independently H, Ci-C 6 alkyl, C 3 -C O cycloalkyl, C 3 -C 6 cycloalkyl(Ci-C 5 )alkyl, aryl, aryl(C r C ⁇ alkyl, heteroaryl, heteroaryl(C !
- each aryl is independently phenyl or naphthyl
- each heteroaryl is independently a 5- or 6- membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen
- each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen;
- each W is independently halo, OR 7 , Ci-C 6 alkyl, CN, CF 3 , NO 2 , SR 7 , CO 2 R 7 , CON(R 7 ) 2 , C(O)R 7 , N(R 10 )C(O)R 7 , SO 2 (Ci-C 6 alkyl), S(O)(Ci-C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 7 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), ImIo(C 1 -C 6 alkoxy), NR 10 SO 2 R 7 , SO 2 N(R 7 ) 2 ,
- NHCOOR 7 NHCONHR 7 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non- aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, attached through a ring carbon or nitrogen; and wherein 2 adjacent W moieties are optionally taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, unsaturated non-aromatic, or aromatic cyclic ring having 0-2 heteroatoms selected from N, O and S;
- each W is independently halo, OR 10 , C 1 -C 6 alkyl, CN, CF 3 , NO 2 , SR 10 , CO 2 R 10 , CON(R 10 ) 2 , C(O)R 10 , N(R 10 )C(O)R 10 , SO 2 (C 1 -C 6 alkyl), S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), halo(C r C 6 alkoxy), NR 10 SO 2 R 10 , SO 2 N(R 10 ) 2 , NHCOOR 10 , NHCONHR 10 , aryl, heteroaryl or heterocyclyl; wherein aryl is phenyl or naphthyl, heteroary
- R 8 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 alkyl), aryl, aryl(C r C 4 alkyl), heteroaryl, heterocyclyl, heteroaryl(Ci-C 4 alkyl), or heterocyclyl(Ci-C 8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -Cg cycloalkyl, heteroaryl, heterocyclyl, C 1 -Ce alkyl, halo(Ci-C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(C 1 -C 6 alkyl)O(C r C 6 alkyl), C 1 -C 6 alkyl, C(O)R
- R 9 is Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C r C 8 alkyl), C r C 8 alkoxy, C 3 -C 8 cycloalkoxy, aryl, aryl(Ci-C 4 alkyl), heteroaryl, heterocyclyl, heteroaryl(C r C 4 alkyl), or heterocyclyl(Ci-C 8 alkyl), wherein said alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from the group consisting of aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, Ci-C 6 alkyl, ImIo(C 1 -C 6 alkoxy), halo, OR 10 , SR 10 , N(R 10 ) 2 , N(Ci-C
- R s and R 9 are optionally taken together, with the nitrogen atom to which they are attached, to form a 4- 8 membered monocyclic ring containing 0-2 additional heteroatoms selected from N, O and S; and
- each R 10 is independently H or C r C 6 alkyl.
- a twenty-second embodiment of the present invention is a compound, or a pharmaceutically acceptable salt or hydrate thereof, which is compound ⁇ i-23 ((lR,2S)- ⁇ -( ⁇ [(2R,4S,7S)- 7-tert-Butyl-6,9-dioxo-3 ,4,6,7,8,9, 12, 13-octahydro-2H, 1 IH- 16, 18-ethanediylidene-2,5- methanopyrido [2,3 -A][1, 10,3,6] dioxadiazacyclononadecin-4-yl]carbonyl ⁇ amino)-2- vinylcyclopropanecarboxylic acid).
- Other embodiments of the present invention include the following:
- a pharmaceutical composition comprising an effective amount of a compound of formula I, ⁇ , II- A, II-B, JH, TH-A, or IE-B and a pharmaceutically acceptable carrier.
- a second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti- infective agent.
- composition of (b), wherein the HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
- HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
- a pharmaceutical combination which is (i) a compound of formula I, II, II- A,
- a second therapeutic agent selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent; wherein the compound of formula I, ⁇ , ⁇ -A, II-B, m, i ⁇ -A, or m-B and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS3 protease, or for treating or preventing infection by HCV.
- HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
- a method of inhibiting HCV NS3 protease in a subject in need thereof which comprises administering to the subject an effective amount of a compound of formula I, ⁇ , II- A, II-B, m, m-A, or m-B.
- HCV antiviral agent is an antiviral selected from the group consisting of a HCV protease inhibitor and a HCV NS5B polymerase inhibitor.
- j A method of inhibiting HCV NS3 protease in a subj ect in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
- a method of preventing or treating infection by HCV in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
- the present invention also includes a compound of the present invention (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) inhibiting HCV NS3 protease, or (b) preventing or treating infection by HCV.
- the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
- Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. Ia all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
- alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
- Ci -6 alkyl (or “C1-C6 alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- Ci_4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- haloalkyl refers to an alkyl group wherein a hydrogen has been replaced by a halogen.
- alkoxy refers to an "alkyl-O-" group.
- alkylene refers to any linear or branched chain alkylene group (or alternatively “alkanediyl”) having a number of carbon atoms in the specified range.
- -Ci-6 alkylene- refers to any of the Cl to C(, linear or branched alkylenes.
- a class of alkylenes of particular interest with respect to the invention is -(CH2)l-6- > and sub-classes of particular interest include -(CEk)I -4-, -(CEk)I -3-, -(CH2)l-2-, md -CH2-.
- alkylene -CH(CH3)- is also of interest.
- cycloalkyl refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range.
- C3_g cycloalkyl (or “C3-C8 cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- cycloalkoxy refers to a "cycloalkyl-O" group.
- halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
- halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
- all ranges cited herein are inclusive.
- a heteroaryl ring described as containing from “1 to 3 heteroatoms” means the ring can contain 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range.
- the oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
- any variable e.g., R 7 and R 10
- its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaromatic ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.
- a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).
- certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
- certain of the compounds of the present invention can exist as tautomers.
- a reference to a compound of formula I, ⁇ , H- A, II-B, HI, HI-A, or DI-B is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
- the compounds of the present inventions are useful in the inhibition of HCV protease (e.g., HCV NS3 protease) and the prevention or treatment of infection by HCV.
- HCV protease e.g., HCV NS3 protease
- the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
- the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
- the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
- the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HCV protease, e.g., by competitive inhibition.
- the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
- pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
- Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
- suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
- suitable organic ligands such as quaternary ammonium salts.
- pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
- administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment.
- administration and its variants are each understood to include concurrent and sequential provision of the compound or salt (or hydrate) and other agents.
- composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
- pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- the term "effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- the effective amount is a "therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated.
- the effective amount is a "prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
- the tenn also includes herein the amount of active compound sufficient to inhibit HCV NS3 protease and thereby elicit the response being sought (i.e., an "inhibition effective amount").
- the compounds of the present invention can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- the compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
- Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
- Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
- Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid.
- injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990.
- the compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
- mammal e.g., human
- One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
- Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
- the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly I 5 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
- the present invention also relates to a method of inhibiting HCV NS3 protease, inhibiting HCV replication, or preventing or treating HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.
- Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
- Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), pegylated interferon- ⁇ 2a (PegasysTM), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon- ⁇ 2b (PeglntronTM), a recombinant consensus interferon (such as interferon alphacon-1), and a purified interferon- ⁇ product.
- Amgen's recombinant consensus interferon has the brand name Infergen®.
- Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin.
- Viramidine represents an analog of ribavirin disclosed in WO 01/60379 (assigned to ICN Pharmaceuticals).
- the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
- the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
- HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication.
- Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, GB-2337262, WO 02/48116, WO 02/48172, and U.S. Patent No. 6,323,180.
- Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH).
- IMPDH inosine monophosphate dehydrogenase
- Ribavirin is readily phosphorylated intracellularly and the monophosphate derivative is an inhibitor of JMPDH.
- inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication.
- the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, which is disclosed in WO 97/41211 and WO 01/00622 (assigned to Vertex); another IMPDH inhibitor, such as that disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb); or mycophenolate mofetil [see A.C. Allison and E.M. Eugui, Agents Action. 44 (Suppl.): 165 (1993)].
- an inhibitor of IMPDH such as VX-497, which is disclosed in WO 97/41211 and WO 01/00622 (assigned to Vertex)
- another IMPDH inhibitor such as that disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb)
- mycophenolate mofetil see A.C. Allison and E.M. Eugui, Agents Action. 44 (Suppl.): 165 (1993)].
- the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) [for a comprehensive description of this agent, see J. Kirschbaum, Anal. Profiles Drug Subs. 12: 1-36 (1983)].
- the compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in R. E. Harry-O'kuru, et al., J. Org. Chem.. 62: 1754-1759 (1997); M. S. Wolfe, et al., Tetrahedron Lett.. 36: 7611-7614 (1995); U.S. Patent No.
- Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C- methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl-guanosine, and 9-(2-C- methyl- ⁇ -D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3 -propanediol esters of the 5 '-phosphate derivatives.
- the compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in WO 02/51425 (4 July 2002), assigned to Mitsubishi Pharma Corp.; WO 01/79246, WO 02/32920, and WO 02/48165 (20 June 2002), assigned to Pharmasset, Ltd.; WO 01/68663 (20 September 2001), assigned to ICN
- the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase.
- HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in WO 02/057287, US 6,777,395, WO 02/057425, US 2004/0067901, WO 03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512; the content of each is incorporated herein by reference in its entirety.
- HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147, assigned to Pharmasset, Ltd.).
- nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl- ⁇ -D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-amino-7-(2-C-methyl- ⁇ - D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-methylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H- pyrrolo[2,3-d]pyrimidine; 4-dimethylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3- d]pyrimidine; 4-cyclopropylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; 4- amino-7-
- the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in WO 01/77091 (18 Oct. 2001), assigned to Tularik, Inc.; WO 01/47883 (5 July 2001), assigned to Japan Tobacco, Inc.; WO 02/04425 (17 January 2002), assigned to Boehringer Ingelheim; WO 02/06246 (24 Jan. 2002), assigned to Istituto di Ricerche di Biologia Moleculare P.
- non-nucleoside inhibitors of HCV polymerase such as those disclosed in WO 01/77091 (18 Oct. 2001), assigned to Tularik, Inc.; WO 01/47883 (5 July 2001), assigned to Japan Tobacco, Inc.; WO 02/04425 (17 January 2002), assigned to Boehringer Ingelheim; WO 02/06246 (24 Jan. 2002), assigned to Istituto di Ricerche di Biologia Moleculare P.
- non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazocine-l l- carboxylic acid; 14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,l- a][2,5]benzodiazocine-l l-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8- tetrahydromdolo[2,l- ⁇ ][2,5]benzodiazocine-l 1-carboxy
- 2-Bromoindole intermediate (prepared as described in published International patent application WO2004087714) was functionalized on the indole nitrogen to introduce pre-cursor functionality W'/X' to either or both of the elements W/X of the tether.
- Pd-mediated cross-coupling methodology eg, Suzuki, Stille etc
- Functional group manipulation followed by ring closure afforded the tetracyclic system.
- Ester deprotection then yielded the target indole carboxylic acids, with the C2 aromatic tethered to the indole nitrogen.
- the C2 aromatic was introduced at the outset via Pd-mediated cross-coupling methodology (Suzuki, Stille etc).
- the tether was then built up, with cyclisation onto the indole nitrogen finally closing the ring. Ester deprotection then yielded the target indole carboxylic acids, with the C2 aromatic tethered to the indole nitrogen.
- C2-tethered indole carboxylic acids arising from Methods A-D were further derivatised through manipulation of the carboxylate functionality to give compounds bearing a carboxylate replacement or carboxamide.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- HCV NS3 protease inhibitory activity of the present compounds may be tested using assays known in the art.
- One such assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as described in Example 9.
- TRF time-resolved fluorescence
- Other examples of such assays are described in e.g., International patent publication WO2005/046712.
- Compounds useful as HCV NS3 protease inhibitors would have a Ki less than 50 ⁇ M, more preferably less than 10 ⁇ M, and even more preferably less than 100 nM.
- the present invention also includes processes for making compounds of formula I 5 ⁇ , II- A, H-B, DI 5 ⁇ i-A, or IEI-B.
- the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention. General Description of Synthesis:
- An appropriately protected 4-hydroxyproline derivative (for example, a carbamate protected nitrogen) can be reacted with potassium t-butoxide or equivalent reagent and then reacted with an appropriately substituted chloro- isoquinoline.
- the acid can then be esterified with acid in an appropriate alcohol solvent. These conditions also remove the BOC protecting group on the proline nitrogen.
- Scheme 2 describes the synthesis of the olefin containing amino acid portion.
- Preparation of the sulfonamides B can be accomplished by reaction with the appropriate sulfonyl chloride in an organic solvent (e.g., THF) with an amine base as scavenger.
- an organic solvent e.g., THF
- Urea derivatives C may be prepared by reacting the aminoester with a reagent such as carbonyldiimidazole, to form an intermediate isocyanate (Catalano et al., WO 03/062192) followed by addition of a second olefin containing amine.
- a reagent such as carbonyldiimidazole
- phosgene, diphosgene or triphosgene may be used in place of carbonyldiimidazole.
- Cyanoguanidine derivatives D can be prepared by reaction of the amino acid ester with diphenyl C-cyanocarbonimidate in an organic solvent, followed by addition of a second olefin containing amine.
- Carbamate derivatives E may be prepared by reacting an olefin containing alcohol with carbonyldiimidazole (or phosgene, triphosgene or diphosgene) in an organic solvent, followed by addition of the amino ester.
- the ester can be hydrolyzed under a range of basic conditions known to those skilled in the art (Theodora W. Greene, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, 1999). Deprotection of the carbamate protecting group on the proline portion may be carried out by a variety of methods known to persons skilled in the art (Theodora W. Greene, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, 1999). To complete the synthesis of the compounds of this invention, the amino acid derivative can be coupled to the proline derivative via a wide range of peptide coupling reagents such as DCC, EDC, BOP, TBTU etc (see Scheme 1).
- the alkenyl functionality may be introduced at this stage by palladium catalyzed reaction of a halide substituent such as bromide or iodide, or other functionality such as a triflate with an organometallic reagent such as a vinyl or allyltrialkyltin.
- a halide substituent such as bromide or iodide
- organometallic reagent such as a vinyl or allyltrialkyltin.
- Macrocyclization is then achieved by an olefin metathesis using a range of catalysts that have been described in the literature for this purpose.
- the olefinic bond produced in the ring closing metathesis may be optionally hydrogenated to give a saturated linkage or functionalized in alternative ways such as cyclopropanation.
- the proline ester is then hydrolyzed under basic conditions and coupled with the cyclopropylamino acid ester (the appropriate alkenyl or alkylcyclopropane portion of the molecule can be prepared as described previously (Llinas- Brunet et al., US 6,323,180) and subjected to an additional basic hydrolysis step to provide the final compounds.
- the proline ester can also be hydrolyzed and directly coupled to an appropriately functionalized cyclopropylamino acid acyl sulfonamide (which can be prepared according to Wang X.A. et al. WO2003/099274) to provide the final compounds.
- Molecules with 3 -substituted isoquinolines or 2-substituted quinazolines may be prepared according to Scheme 3 (wherein V is, for example, halo such as chloro).
- V is, for example, halo such as chloro.
- An appropriately substituted 3-halo isoquinoline or 2-halo quinazoline can be employed in a sequence similar to the route shown in Scheme 1.
- an R 5 group can be installed via displacement reactions or metal-mediated coupling reactions.
- Olefin metathesis catalysts include the following Ruthenium based species: F: Miller et al J. Am. Chem. Soc 1996, 118, 9606; G: Kingsbury et al J. ⁇ 7??. Chem. Soc 1999, 121, 791; H: Scholl et al Org. Lett. 1999, 1, 953; Hoveyda et al US2002/0107138; K: Furstner et al. J. Org. Chem 1999, 64, 8275.
- the utility of these catalysts in ring closing metathesis is well known in the literature (e.g. Traka and Grubbs, Ace. Chem. Res. 2001, 34, 18).
- Structure L is the Zhan ruthenium metathesis catalyst RC-303 (Zhan catalyst IB, RC-303, Zannan Pharma Ltd.)
- Step 1 tert-Butyl ((IRJZR)-I-J ⁇ ( cvclopropylsulfonv ⁇ aminoicarbonvU- ⁇ -ethylcvclopropy ⁇ carbamate
- a hydrogenaton vessel was charged with a methanol (1000 niL) slurry of tert-butyl ((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)carbamate (164 g, 0.50 mol) (Wang et al, US 6,995,174) and 5% Ru/C (dry, 7.5 wt%, 12.4 g) and set stirring.
- the vessel was placed under nitrogen (20 psig) and vented to atmospheric pressure three times to remove residual oxygen.
- the vessel was then placed under hydrogen (50 psig). After 20 hours, the vessel was vented to atmospheric pressure.
- the reaction slurry was then transferred out of the reaction and filtered through solka flok (34 grams, wetted w/ 100 mL methanol) to yield a clear, light brown solution.
- the solka flok was rinsed with methanol (200 mL x 2).
- the combined methanol solutions were concentrated under reduced pressure to yield crude product as a white solid (153 g).
- the crude product was slurried in ethyl acetate (800 mL), warmed to 40 0 C and aged 30 minutes. The solution was then seeded, aged 30 minutes, and heptane (500 mL) was added via addition funnel over 30 minutes.
- the partially crystallized solid was cooled to room temperature and aged overnight after which additional heptane (500 mL) was added. After one hour, additional heptane (250 mL) was added via addition funnel, and the white slurry aged for one hour. The solution was filtered and the solid was rinsed with heptane/EtOAc (500 mL, 4:1) and dried under reduced pressure to give tert-butyl ((lR,2R)-l- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2- ethylcyclopropyl)carbamate (125.9 g).
- Step 2 (lR,2R)-l-Amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide hydrochloride (Intermediate A3)
- Diisopropylethyl amine (9.85 g, 76.2 mmol) was added dropwise to a 0 °C solution of 4- penten-1-ol (7.22 g, 83.9 mmol) and triphosgene (11.3 g, 38.1 mmol) in 160 mL dioxane.
- the resulting white suspension was stirred for 5 min at 0 0 C, then allowed to warm to 25 0 C over 1 h.
- the suspension was cooled to 0 0 C with an ice bath and 1 N NaOH (76.2 mL) and L-tert-buXy ⁇ g ⁇ ycms (10.0 g, 76.2 mmol) were added.
- the reaction mixture was warmed to 25 0 C and stirred for 18 h.
- Step 3 N- ⁇ [(l,l-Dimethylpent-4-en-l-yl)amino]carbonyl ⁇ -L-valine (Intermediate B50)
- Step 2 N-Hept-6-enoyl-3-methyl-L-valine ( " Intermediate B53 * )
- Step 4 Ethyl (4R)-4-[(7-bromo-6-methoxyisoquinolin-l-y ⁇ oxy]-L-prolinate hydrochloride (Intermedate Cl)
- Step 3 Methyl C4i? * )-4- ⁇ [7-( ' allyloxy ' )isoquinolin-l-yl]oxy ⁇ -L-prolinate ( " Intermedate C4 ⁇ )
- Step l Ethyl r2R.4S.7SV15-bromo-7-tert-butyl-22-iodo-6.9-dioxo-3.4 ⁇ 6.7.8.9.12 ⁇ 13.14.15-decahvdro- 2H.11 H- 16.18-ethanediylidene-2,5 -methanopyrido [2.3 -k] [ 1.10.3.6] dioxadiazacyclononadecine-4- carboxylate
- Step 2 f2R.4S.7SV7-tert-butyl-22-iodo-6.9-dioxo-3.4.6.7.8.9.12.13-octahvdro-2H.l 1H-16.18- ethanediylidene-2,5-methanopyridor2.3-k1[1.10,3.6]dioxadiazacyclononadecine-4-carboxylic acid (Interniedate Dl)
- Step 1 Ethyl ⁇ R.4S.7SV15-bromo-7-tert-butyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l IH- 16.18-ethanediylidene-2.5-methanopyrido[2.3-k][1.10.3.6]dioxadiazacyclononadecine-4-carboxylate
- Step 2 (2R,4S,7S)-7-tert-Butyl-lS-methoxy- ⁇ .g-dioxo-3,4,6,7,8,9,12,13,14,15-decahvdro ⁇ H.l IH- 16.18-ethanediylidene-2,5-methanopyrido[2,3-k] [1,10,3 ,6]dioxadiazacyclononadecine-4-carboxylic acid dntermedate D2)
- Step 1 Ethyl (2R.4S.7SV 7-tert-butyl-6.9-dioxo-22-vinyl-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.1 IH- 16.18-ethanediylidene-2,5-methanopyrido[2,3-k] [1.10.3.6]dioxadiazacyclononadecine-4-carboxylate
- Step 2 Ethyl (2R.4S.7SV7-tert-butyl-22-ethyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l IH- 16.18-ethanediylidene-2.5-methanopyrido [2.3 -k] [ 1.10.3.6] dioxadiazacyclononadecine-4-carboxylate (Intermedate D7)
- Step 1 Ethyl r2R.4S.7S)-7-cvclopentyl-22-iodo-12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15- decahvdro-2H.1 IH-16.18-(ethanediylideneV2.5-methanopyridor2.3- k] [ 1 , 10,3 ,6 "
- Step 2 Ethyl (2RASJS)-l-c ⁇ c ⁇ openM-22-Gth ⁇ l-l2 ⁇ 2-dime-&wl-6.9-dioxo-3A.6J.S.9 ⁇ 2 ⁇ 3.U ⁇ 5- decahydro-2H.1 IH- 16.18-(ethanediylideneV2.5-methanopyrido[2.3- k] ⁇ 1.10.3 ,61dioxadiazacyclononadecine-4-carboxylate flntermedate OS)
- Step 1 Ethyl f2R.4SJSy7-cvclohexyl-6.9-dioxo-3 A6 J.8.9.12.13.14.15-decahvdro-2H.l 1H-16.18- ( " ethanediylideneV2,5-methanopyridor2,3-A:1 FL 10,3 ,61dioxadiazacyclononadecine-4-carboxylate
- Step 2 Ethyl r2R.4S.75)-7-cvclohexyl-22-iodo-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahydro-2H.l IH- 16.18-rethanediylidene ' )-2,5-methanopyridor2J-A:iri.l0,3.61dioxadiazacvclononadecine-4-carboxvlate
- Step 3 r2R.4S.7S)-7-Cvclohexyl-22-methoxy-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l IH- 16.18-(ethanediylideneV2.5-methanopyrido[2,3-A:][l,10,3,61dioxadiazacyclononadecine-4-carboxylic acid (Intermediate DlO)
- Step 1 Methyl r2R.4S.7SV7-tert-butyl-22-hvdroxy-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro- 2H.l lH-16J8-ethanediylidene-2.5-methanopyrido[2,3-k][l,10,3,61dioxadiazacyclononadecine-4- carboxylate
- Step 2 Methyl ⁇ R.4S.7SV7-tert-butyl-22-ethoxy-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l IH-
- Step l EthvK2R.4S.7S)-7-fe ⁇ -butyl-12.12-dimethyl-6.9-dioxo-3,4,6,7,8,9,12,13,14,15-decahvdro- 2H.llH-16.18-(ethanediylideneV2.5-methanopyrido[2,3-A:][U0.,3.6]dioxadiazacyclononadecine-4- carboxylate
- Step 2 Ethyl (2R.4S JSV7-tert-butyl-19 ⁇ odo-12.12 ⁇ limetfayl-6.9- ⁇ oxo-3,4,6,7,8,9,12,13,14,15- decahvdro-2H.llH-16J8-(ethanediylideneV2.5-methanopyridor2,3- ki r 1.10.3.61 dioxadiazacyclononadecine-4-carboxvlate
- Step 3 Ethyl ⁇ R.4S.7SV7-tert-butyl-19-ethyl-12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13,14.15- decahydro-2H.l lH-16.18-(ethanediylideneV2.5-methanopyrido[2.3- k] [ 1.10.3.6] dioxadiazacyclononadecine-4-carboxylate (Intermedate D 16) Ethyl (2R,4S,7S)-7-tert-butyl- 19-ethyl- 12, 12-dimethyl-6,9-dioxo-3 ,4,6,7,8,9, 12,13,14,15- decahydro-2H,l lH-16,18-(ethanediylidene)-2,5-methanopyrido[2,3- k][l,10,3,6]dioxadiazacyclononadecine
- Step 2 Ethyl N-[(pent-4-en-l-yloxy)carbonyl]-l-norleucyl-f4RV4-[(7-bromoisoquinolin-l-yl)oxy]-L- prolinate
- Step 3 Ethyl N-rCpent-4-en-l-yloxy)carbonyl1-L-norleucyl-(4R)-4-[( ' 7-vinylisoqumolin-l-yl)oxy1-L- prolinate
- Step 4 Ethyl (2R.4S.7SV7-bu ⁇ yl-6.9-dioxo-3.4.6.7.8.9.12.13-octahvdro-2H.l IH-16.18-ethanediylidene- 2,5-methanopyridor23-kiri,10,3.61dioxodiazacyclononadecine-4-carboxvlate
- the olefin from Step 3 (40 mg, 0.074 mmol) was dissolved in dichloroethane (10 mL) and nitrogen bubbled through the solution for 15 min.
- Dichloro(5-chloro-2-isopropoxybenzylidene)(l,3- dimesitylimidazolidin-2-ylidene)ruthenium (Zhan ruthenium metathesis catalyst RC-301, Zhan Catalyst I (as depicted as J on page 35), RC-301, Zannan Pharma Ltd.) (5 mg, 0.007 mmol) was added and the reaction mixture heated in an 80 0 C oil bath for 2 h, after which reaction was complete.
- the reaction mixture was purified directly by reverse phase ⁇ PLC to yield a white foam which was dissolved in T ⁇ F (0.25 mL) and ethanol (0.25 mL) and a solution of LiOH in water (4.5 mg in 0.25 mL) was added.
- the reaction mixture was heated to 40 0 C for 2 h, cooled to room temperature, 3M HCl (0.06 mL) and DMF (0.5 mL) were added and the reaction mixture was purified by reverse phase ⁇ PLC to give the desired product as solid.
- Step l flR ⁇ SVl ⁇ r(2R.4SJSV7-Butyl-6.9 ⁇ Uoxo-3A6J.8.9J2J3J4J5 ⁇ ecahy(faO-2Rl lH-16.18- ethanediylidene-2.5-methanopyridiner2.3-k][l,10,3.6]dioxadiazacyclononadecin-4-yl]carbonyljaminoV 2-vinylcyclopropanecarboxylic acid
- Step 2 r2R.4S.7SV7-Butyl-6.9-dioxo-N-r(lR.2S ' )-l- ⁇ r(phenylsulfonvnamino1carbonvU-2- vinylcvclopropylV3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l 1H-16.18-ethanediylidene-2.5- methanopyridine F2.3 -kl F 1.10.3.61 dioxadiazacyclononadecine-4-carboxamide
- the NS3 protease TRF assay was performed in a final volume of lOO ⁇ l in assay buffer containing 50 mM HEPES, pH 7.5, 150 inM NaCl, 15 % glycerol, 0.15 % Triton X-IOO, 10 mM DTT, and 0.1 % PEG 8000.
- the NS3 protease was pre-incubated with various concentrations of inhibitors for 10-30 minutes.
- the peptide substrate for the assay is Ac-C(Eu)-DDMEE-Abu-[COO]-XSAK(QSY7)- NH2, where Eu is an europium-labeled group, Abu is 1-aminobutanoic acid which connects an ester linkage with 2-hydroxy propanoic acid (X). Hydrolysis of the peptide by NS3 protease activity causes in separation of the fluorophore from the quencher, resulting in an increase in fluorescence. Activity of the protease was initiated by adding the TRF peptide substrate (final concentration 50-100 nM). The reaction was quenched after 1 hour at room temperature with 100 ⁇ l of 500 mM MES, pH 5.5.
- Step 1 Ethyl (4R>4-r7-bromoisoquinolin-l-vDoxy1-L-prolinate hydrochloride
- Step 2 Ethyl N-r(pent-4-en-l-yloxy)carbonyl]-l-tert-butyl-(4R)-4-[(7-bromoisoquinolin-l-yl)oxy]-L- prolinate
- Step 3 Ethyl N-[rpent-4-en-l-yloxy)carbonyl]-L-tert-butylglycine-(4RV4-[ " (7-vinylisoquinolin-l-yl)oxy1- L-prolinate
- Step 4 Ethyl ⁇ R ⁇ S.ySVy-tert-butyl- ⁇ .g-dioxo ⁇ .e.y.S.g. ⁇ .O-octahvdro ⁇ H.HH-l ⁇ .lS- ethanediylidene-2.5-methanopyridor2.3-k1 Tl , 10.3.6]dioxodiazacyclononadecine-4-carboxylate
- the olefin from Step 3 (1.0 gm, 1.86 mmol) was dissolved in dichloromethane (200 mL) and nitrogen bubbled through the solution for 30 min.
- Bis(tricyclohexylphosphine)-3-phenyl-lH-indene- lylideneruthenium dichloride (Neolyst M1 catalyst, Strem Chemicals, CAS#250220-36-1) (300 mg, 0.30 mmol) dissolved in degassed dichloromethane was added over 30 minutes and the reaction let stir 24hrs or until complete.
- Step 5 riR.2S)-l-r(rr2i?.4S.7S)-7-tert-Butyl-6.9-dioxo-3.4.6.7.8.9.12.13-octahvdro-2H.l 1H-16.18- ethanediylidene-2,5-methanopyridor2.3-/ciri.l0.3.6]dioxadiazacyclononadecin-4-yl]carbonvUaminoV2- vinylcyclopropanecarboxylic acid
- the foam was dissolved in dichloromethane (40 mL) and cyclopropanesulfonic acid (l-(R)-amino-2-(S)-vinyl-cyclopropanecarbonyl)-amide hydrochloride salt (Al)(0.419 mg, 1.58 mmol) (Llinas-Brunet et al US03/15755 and Wang et al WO 03/099274), diisopropylethylamine (0.75 mL, 4.30 mmol), dimethylaminopyridine ( 0.087 gm, 0.72 mmol) and HATU ( 0.65 gm, 1.72 mmol) was added and the reaction mixture was stirred at room temperature overnight.
- Step 1 Ethyl r2R.4S.7SV7-tert-butyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.HH-16.18- ethanediylidene-2.5-methanopyridor2,3-kiri.l0.3.61dioxadiazacvclononadecine-4-carboxylate
- Step 2 ⁇ R.4S.7SV7-tert-butyl-N-r(lR.2SVl-(rfcvclopropylsulfonyl N )amino1carbonvn-2- vmylcvclopropylV6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.11 H- 16.18-ethanediylidene-2.5- methanopyrido [2.3 -k] [ 1.10.3.6] dioxadiazacyclononadecine-4-carboxamide
- Step 1 Ethyl (2R.4S.7SV7-tert-butyl-22-iodo-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.l IH- 16,18-ethanediylidene-2.5-methanopyridor2.3-k1F1.10.3.61dioxadiazacvclononadecine-4-carboxylate
- Step 2 f2R.4S.7SV7-tert-butyl-N-fdR.2SVl-(
- Step 1 Ethyl r4R)-4-[r7-bromoisoquinolin-l-yl)oxy]-l-[(;2S)-2-cyclopentyl-2-(;([(2.2-dimethylpent-4-en- l-yl)oxy1carbonyl ⁇ amino)acetyl1-L-prolinate
- Step 2 Eihyl (4i?)-l-r(25)-2-cyclopentyl-2-( ⁇ r(2,2-dimethylpent-4-en-l-yl)oxy]carbonyl ⁇ amino)acetyl]- 4-r(7-vinylisoquinolin-l-yl ' )oxy1-L-prolinate
- Ethyl (4i?)-4-[(7-bromoisoquinolin-l-yl)oxy]-l-[(2S)-2-cyclopentyl-2-( ⁇ [(2,2- dimethylpent-4-en-l-yl)oxy]carbonyl ⁇ amino)acetyl]-L-prolinate (526 mg, 0.83 mmol) was dissolved in ethanol (10 mL) and nitrogen was bubbled through for 15 min.
- Step 3 Ethyl (2Jt4 ⁇ '.7-?J4 J g)-7-cvclopentyl-12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13-octahvdro- 2H, 1 IH- 16, 18-etheno-2, 5-methanopyrido [2,3 -k] [ 1 , 10.3 , 6] dioxadiazacyclononadecine-4-carboxylate
- Step 4 f2i?.4S.7S.14 ⁇ -7-Cvclopentyl-12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13-octahvdro-2H.l lH- 16 J 8-etheno-2.5-methanopyridor2,3- ⁇ l [1, 10.3,61dioxadiazacvclononadecine-4-carboxylic acid
- Step 5 (2RAS J S.14ff)-7-Cvclopentyl-N-f f 1R.2SV 1 - ( rfcvclopropylsulfonvnaminolcarbonyll -2- vinylcvclopropyD- ⁇ . ⁇ -dimethyl- ⁇ .g-dioxo-S ⁇ .ej ⁇ .g. ⁇ .lS-octahvdro ⁇ H.HH-l ⁇ .lS-etheno- ⁇ .S- methanopyrido[2.3-fc][lJ0,3,6]dioxadiazacyclononadecine-4 ⁇ carboxamide ( ⁇ I-39)
- Step 1 Ethyl r2R.4S.7S)-7-cvclopentyl- 12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro- 2H.l lH-16.18-etheno-2.5-methanopyridor2.3-A:iri.l0.3.61dioxadiazacvclononadecine-4-carboxylate
- Step 2 (2R.4 ⁇ 7S)-7-Cvclopentyl-N-rflR,2S)-l-[[(;cvclopropylsulfonyl)amino1carbonyU-2- vinylcvclopropylV 12.12-dimethyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.1 IH- 16.18-etheno- 2,5-methanopyrido[2,3-A:]riJ0.3,61dioxadiazacyclononadecine-4-carboxamide (DI-40)
- Step 1 l-fe7Y-Butyl 2-[2-(trimethylsilyl)ethyll (2£4S)-4-hydroxypyrrolidine-l,2-dicarboxylate
- Step 2 1-tert-Butyl 2-r2-ftrimethylsilyl)ethyl1 (2S.4S)-4-IT2-chloro-6-iodoquinazolin-4- vDoxylpyrrolidine- 1.2-dicar boxylate
- Step 3 1-tert-Butyl 2-[2-Ctrimethylsilyl)ethyl] f2S,4S)-4-[(2-chloro-6-vinylquinazolin-4- vDoxylpyrrolidine- 1 ,2-dicarboxylate
- Step 4 2-ftrimethylsilyl)ethyl N-[ ⁇ ent-4-en-l-yloxy ' )carbonyll-L-valyl-f4R)-4-([ ' 2-riH-1.2.3- benzotriazol- 1 -yloxyV6-vinylquinazolin-4-yl1 oxyl -L-prolinate
- Step 5 2-rTrimethylsilyl)ethyl (IE.15S.18£20RV2-qH- 1.2.3-benzotriazol- 1 -yloxyV 15-isopropyl- 13.16- dioxo- 10.11.13.14.15.16.19.20-octahvdro-9H 18H-4.6-C ethanediylidene)- 17,20-methanopyrimidor4.5- k] [1.10.3.61 dioxadiazacyclononadecine- 18-carboxylate
- Step 6 2-( TrimethylsilvDethyl (IE.15S.18S.20RV2-f dimethylamino V 1 S-isopropyl- 13.16-dioxo- 10.11.13.14.15.16.19.20-octahvdro-9H 18H-4.6-(ethanediylidene)- 17.20-methanopyrimido[ " 4.5- ⁇ iri.10-,3.61 dioxadiazacyclononadecine- 18-carboxvlate :
- Step 7 2-fTrimethylsilvnethyl ⁇ 5S.18S.20R)-2-(dimethylamino)-15-isopropyl-13.16-dioxo-
- Step 8 ⁇ 5SU8£20Ry2-(Dimemylaminoyi5-isopropyl43J6-dioxo-8.9.10.11.13.14.15.16.19.20- decahydro-7H,18H-4,6-(ethanediylidene)-17,20-methanopyrimido[4,5-
- Step 9 Ethyl fli?,2S)-l-r ⁇ rri5S.18S.20RV2-(dimethylaminoV15-isopropyl-13.16-dioxo-
- step 7 The oil from step 7 was dissolved in DMF (2 mL) and diisopropylamine (80 ⁇ L, 0.45 mmol), and (2R,3S)-3-vinyl-2-aminocyclopropyl carboxylic acid ethyl ester hydrochloride (Intermediate A2) (44 mg, 0.23 mmol) added, followed by TBTU (36 mg, 0.23 mmol) and the reaction mixture stirred at RT for 1 h.
- DMF diisopropylamine
- (2R,3S)-3-vinyl-2-aminocyclopropyl carboxylic acid ethyl ester hydrochloride (Intermediate A2) (44 mg, 0.23 mmol) added, followed by TBTU (36 mg, 0.23 mmol) and the reaction mixture stirred at RT for 1 h.
- Step 10 ( IR2S) ⁇ 1 -( ( IT 15S.18S.20R>2-f DimethylaminoV 15-isopropyl- 13.16-dioxo-
- Step h ⁇ R ⁇ SVl-dr ⁇ R ⁇ SJS.MEVy-tert-Butyl-e.g-dioxo-S ⁇ . ⁇ J.S.g. ⁇ .D-octahvdro- ⁇ H.UH-l ⁇ .lS- etheno-2.5-methanopyrido[2.3-k1 [1.10,3.6]dioxadiazacyclononadecin-4-yl "
- Step 2 f2R.4S.7SJ4 ⁇ -7-fe ⁇ -Butyl-N-r ⁇ R.2,y)-l-((rfdimethylamino')sulfonyllamino)carbonvn-2- vinylcvclopropyr
- step 1 To the product from step 1 (100 mg, 0.169 mmol), ⁇ , ⁇ -dimethylsulfamide (84 mg, 0.677 mmol), DIPEA (0.148 mL, 0.847 mmol), and DMAP (83 mg, 0.677 mmol) in DMF (3 mL) was added DBU (0.115 mL, 0.762 mmol) and the mixture was stirred for 5 min. ⁇ ATU (70.8 mg, 0.186 mmole) was added and mixture was stirred for 18 h. Additional ⁇ ATU (15 mg) was added and the mixture stirred for an additional 3 h. The mixture was then purified by prep ⁇ PLC to give 65 mg of the title compound as a foam.
- EXAMPLE 166 was prepared according to the procedure described for EXAMPLE 165 by using piperidine-1 -sulfonamide in Step 2.
- LRMS (ESI) m/z 737.5 [(M+ ⁇ ) + ; calcd for C 37 H 49 N 6 O 8 S: 737.3].
- EXAMPLE 167 was prepared according to the procedure described for EXAMPLE 165 by using N-benzyl-N-methylsulfamide in Step 2. LRMS (ESI) m/z 773.6 [(M+H) + ; calcd for
- Step 1 Ethyl riR.2S)-l-d[ ' (2R.4S.7S)-7-cvclohexyl-23-methoxy-12.12-dimethyl-6.9-dioxo- 3.4.6.7.8.9.12.13.14.15-decahvdro-2H.1 IH- 16.18-(ethanediylideney2.5-methanopyrido[ " 2.3- ⁇ fl Tl - 10.3.61 dioxadiazacvclononadecin-4-yllcarbonyl
- Ethyl (lR,2S)-l-( ⁇ [(2i?,4S,7S)-7-cyclohexyl-23-methoxy-12,12-dimethyl-6,9-dioxo- 3,4,6,7,8,9,12,13,14,15-decahydro-2H,l lH-16,18-(ethanediylidene)-2,5-methanopyrido[2,3- k] [ 1 , 10,3 ,6]dioxadiazacyclononadecin-4-yl] carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylate was prepared using the procedure described for EXAMPLE 15 using Intermediates A2, B23 and Cl. LRMS (M+ ⁇ ) + 705.6.
- EXAMPLE 168 was prepared according to the procedure described for EXAMPLE 165 by using ethyl (li?,2S)-l-( ⁇ [(2R,4S,7S)-7-cyclohexyl-23-methoxy-12,12-dimethyl-6,9-dioxo
- Step 1 Ethyl (2R.4S.7 ⁇ -22-bromo-7-te ⁇ -butyl-6.9-dioxo-3,4.6,7.8.9.12J3.14.15-decahvdro-2H.l IH- 16,18-f ethanediylidene)-2,5-methanopyrido[2.3 -k] [ 1 , 10.3 ,6]dioxadiazacyclononadecine-4-carboxylate rm-186) and Ethyl (2RASJS)- 17.22-dibromo-7-fert-butyl-6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro- 2H.1 IH- 16.18-(ethanediylidene)-2,5-methanopyrido[2.3-fc] [1.10,3 ,6]dioxadiazacyclononadecine-4- carboxylate
- Step 2 f2R.4S.7SV22-bromo-7-tert-butyl-N-( ' ⁇ R.2S ' )-l- ⁇ r(cvclopropylsulfonyl ' )aminolcarbonvU-2- vinylcyclopropyiy6.9-dioxo-3.4.6.7.8.9.12.13 , 14.15-decahvdro-2H.1 IH- 16.18-ethanediylidene-2.5- methanopyrido [2.3-k] [1.10.3 ,6]dioxadiazacyclononadecine-4-carboxamide ( " HI-182)
- EXAMPLE 169 was prepared from HI-186 using the procedure described for EXAMPLE 14, Steps 4 and 5.
- LRMS (ESI) m/z 774.5 [(M+H) + ; calcd for C 35 H 45 BrN 5 O 8 S: 774.2].
- EXAMPLE 170 f2R.4S.7SV 17.22-dibromo-7-tert-butyl-N-(T 1R.2S V 1 - ( rCcvclopropylsulfonvnaminolcarbonyll -2- vinylcvclopropyiy 6.9-dioxo-3.4.6.7.8.9.12.13.14.15-decahvdro-2H.1 IH- 16.18-fethanediylideneV2,5- methanopyrido
- Step 1 Ethyl (4RV4-rf7-bromo-6-methoxyisoquinolin-l-yl ' )oxyl-l-rf2SV2-cyclohexyl-2-( ⁇
- Ethyl (4R)-4-[(7-bromo-6-methoxyisoquinolin- 1 -yl)oxy]-l -[(2S)-2-cyclohexyl-2-( ⁇ [(2,2- dimethylpent-4-en-l-yl)oxy]carbonyl ⁇ amino)acetyl]-L-prolinate was prepared according to the procedure given for EXAMPLE 14, Step 1 using intermediates B23 and Cl.
- Step 3 (2R.4S.7,SV7-Cvclohexyl-N-f ( " 1R.2SV 1 - ( rCcvclopropylsulfonvDaminoicarbonyl ⁇ -2- vinylcyclopropyD-22-methoxy- 12.12.14-trimethyl-6,9-dioxo-3,4,6.7X9, 11.12.13.14-decahydro-2H- 15.17-etheno-2.5-methanopyrido[2.3-A:][1.10.3.61dioxadiazacyclooctadecine-4-carboxamide (III-184)
- Step 1 1.2-Pyrrolidinedicarboxylic acid. 4-[Y7-bromo-l-isoquinolinyl)oxy "
- Step 2 N-( ⁇ [5-( 1 - ⁇ [(3R, 5S)- 1 -(fe/t-Butoxycarbonyl)-5-(ethoxycarbonyl)pyrrolidin-3 -yl] oxy ⁇ isoquinolin- 7-yl)pent-4-yn- 1 -yl] oxy ⁇ carbonyl)-3 -methyl-L-valine
- Step 3 7-Ethyl ⁇ R.4S.7S)-7-terr-butyl-6.9-dioxo-14.15-didehvdro-3.4.6.7.8.9.12.13-octahvdro-2H.l IH- 16,18-(ethanediylidene)-2,5-methanopyrido[ " 2,3 k]
- Step 4 r2R.4S.7S)-7-fe ⁇ -Butyl-N-rrii?.2S)-l-(rrcvclopropylsulfonvnaminolcarbonyl>-2- vinylcvclopropyl)-6.9-dioxo- 14.15-didehvdro-3.4.6.7.8.9.12.13-octahvdro-2H.1 IH- 16.18-
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2008001588A MX2008001588A (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as hcv ns3 protease inhibitors. |
NZ565269A NZ565269A (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as HCV NS3 protease inhibitors |
BRPI0614205A BRPI0614205A2 (en) | 2005-08-01 | 2006-07-28 | compound, pharmaceutical composition and compound use |
US11/989,886 US8278322B2 (en) | 2005-08-01 | 2006-07-28 | HCV NS3 protease inhibitors |
EP06800513A EP1913016B1 (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as hcv ns3 protease inhibitors |
CA2615896A CA2615896C (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as hcv ns3 protease inhibitors |
AU2006275605A AU2006275605B2 (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as HCV NS3 protease inhibitors |
JP2008525069A JP4705984B2 (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as HCV NS3 protease inhibitors |
IL189166A IL189166A0 (en) | 2005-08-01 | 2008-01-31 | Macrocyclic peptides as hcv ns3 protease inhibitors |
NO20081086A NO20081086L (en) | 2005-08-01 | 2008-02-29 | Macrocyclic peptides as HCV NS3 protease inhibitors |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US70425605P | 2005-08-01 | 2005-08-01 | |
US60/704,256 | 2005-08-01 | ||
US72450905P | 2005-10-07 | 2005-10-07 | |
US60/724,509 | 2005-10-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007016441A1 true WO2007016441A1 (en) | 2007-02-08 |
Family
ID=37404447
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/029635 WO2007016441A1 (en) | 2005-08-01 | 2006-07-28 | Macrocyclic peptides as hcv ns3 protease inhibitors |
Country Status (16)
Country | Link |
---|---|
US (1) | US8278322B2 (en) |
EP (1) | EP1913016B1 (en) |
JP (1) | JP4705984B2 (en) |
KR (1) | KR20080036598A (en) |
AU (1) | AU2006275605B2 (en) |
BR (1) | BRPI0614205A2 (en) |
CA (1) | CA2615896C (en) |
CR (1) | CR9731A (en) |
EC (1) | ECSP088157A (en) |
IL (1) | IL189166A0 (en) |
MA (1) | MA29757B1 (en) |
MX (1) | MX2008001588A (en) |
NO (1) | NO20081086L (en) |
NZ (1) | NZ565269A (en) |
RU (1) | RU2008107972A (en) |
WO (1) | WO2007016441A1 (en) |
Cited By (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007148135A1 (en) * | 2006-06-23 | 2007-12-27 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
EP1905777A1 (en) * | 2005-07-04 | 2008-04-02 | Zheng-Yun Zhan | Ruthenium complex ligand, ruthenium complex, carried ruthenium complex catalyst and the preparing methods and the use thereof |
WO2008051514A2 (en) | 2006-10-24 | 2008-05-02 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
WO2008051475A2 (en) | 2006-10-24 | 2008-05-02 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
WO2008057209A1 (en) * | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
WO2009010804A1 (en) * | 2007-07-19 | 2009-01-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
WO2009076747A1 (en) | 2007-12-19 | 2009-06-25 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
JP2009537481A (en) * | 2006-05-15 | 2009-10-29 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | Macrocyclic compounds as antiviral agents |
WO2009134624A1 (en) | 2008-04-28 | 2009-11-05 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
WO2010011566A1 (en) * | 2008-07-22 | 2010-01-28 | Merck & Co., Inc. | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2010080874A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
WO2010080389A1 (en) | 2008-12-19 | 2010-07-15 | Gilead Sciences, Inc. | Hcv ns3 protease inhibitors |
US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
EP2268285A1 (en) * | 2008-02-25 | 2011-01-05 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
JP2011509242A (en) * | 2007-12-21 | 2011-03-24 | アビラ セラピューティクス, インコーポレイテッド | HCV protease inhibitors and uses thereof |
US7915291B2 (en) | 2002-05-20 | 2011-03-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7935670B2 (en) | 2006-07-11 | 2011-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2012061248A2 (en) | 2010-11-01 | 2012-05-10 | Rfs Pharma, Llc | Novel specific hcv ns3 protease inhibitors |
CN102458444A (en) * | 2009-05-13 | 2012-05-16 | 英安塔制药有限公司 | Macrocyclic compounds as hepatitis c virus inhibitors |
US8202996B2 (en) | 2007-12-21 | 2012-06-19 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
US8222203B2 (en) | 2007-12-14 | 2012-07-17 | Enanta Pharmaceuticals, Inc. | Macrocyclic oximyl hepatitis C serine protease inhibitors |
US8232246B2 (en) | 2009-06-30 | 2012-07-31 | Abbott Laboratories | Anti-viral compounds |
EP2481807A2 (en) | 2007-03-09 | 2012-08-01 | Merck Sharp & Dohme Corporation | In vivo HCV resistance to anti-viral inhibitors |
US8273709B2 (en) | 2007-12-14 | 2012-09-25 | Enanta Pharmaceuticals, Inc. | Triazole-containing macrocyclic HCV serine protease inhibitors |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8283309B2 (en) | 2007-12-20 | 2012-10-09 | Enanta Pharmaceuticals, Inc. | Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors |
US8293705B2 (en) | 2007-12-21 | 2012-10-23 | Avila Therapeutics, Inc. | HCV protease inhibitors and uses thereof |
US8304385B2 (en) | 2007-11-14 | 2012-11-06 | Enanta Pharmaceuticals, Inc. | Macrocyclic tetrazolyl hepatitis C serine protease inhibitors |
US8309685B2 (en) | 2007-12-21 | 2012-11-13 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US8324155B2 (en) | 2007-11-14 | 2012-12-04 | Enanta Pharmaceuticals, Inc. | Quinoxaline-containing compounds as hepatitis C virus inhibitors |
WO2012176149A1 (en) | 2011-06-23 | 2012-12-27 | Panmed Ltd. | Treatment of hepatitis c virus |
US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
US8372802B2 (en) | 2008-03-20 | 2013-02-12 | Enanta Pharmaceuticals, Inc. | Fluorinated macrocyclic compounds as hepatitis C virus inhibitors |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8383583B2 (en) | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
WO2013028470A1 (en) | 2011-08-19 | 2013-02-28 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
US8420596B2 (en) | 2008-09-11 | 2013-04-16 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014008285A1 (en) * | 2012-07-03 | 2014-01-09 | Gilead Sciences, Inc. | Inhibitors of hepatitis c virus |
US8648037B2 (en) | 2010-09-21 | 2014-02-11 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived HCV serine protease inhibitors |
US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8778877B2 (en) | 2007-12-21 | 2014-07-15 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US8937041B2 (en) | 2010-12-30 | 2015-01-20 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8975232B2 (en) | 2010-07-29 | 2015-03-10 | President And Fellows Of Harvard College | Macrocyclic kinase inhibitors and uses thereof |
US8987302B2 (en) | 2010-06-24 | 2015-03-24 | Panmed Ltd. | Treatment of hepatitis C virus related diseases using hydroxychloroquine or a combination of hydroxychloroquine and an anti-viral agent |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
US9120818B2 (en) | 2010-12-14 | 2015-09-01 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
US9193740B2 (en) | 2009-10-19 | 2015-11-24 | Enanta Pharmaceuticals, Inc. | Bismacrocyclic compounds as hepatitis C virus inhibitors |
US9243038B2 (en) | 2011-07-01 | 2016-01-26 | President And Fellows Of Harvard College | Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof |
US9284307B2 (en) | 2009-08-05 | 2016-03-15 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9598433B2 (en) | 2012-11-02 | 2017-03-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9617310B2 (en) | 2013-03-15 | 2017-04-11 | Gilead Sciences, Inc. | Inhibitors of hepatitis C virus |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9873707B2 (en) | 2013-10-18 | 2018-01-23 | Merck Sharp & Dohme Corp. | Methods and intermediates for preparing macrolactams |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US11040976B2 (en) | 2015-04-24 | 2021-06-22 | President And Fellows Of Harvard College | Substrate selective inhibitors of insulin-degrading enzyme (IDE) and uses thereof |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
US11674136B2 (en) | 2018-02-09 | 2023-06-13 | President And Fellows Of Harvard College | DNA-templated macrocycle library |
US12083099B2 (en) | 2020-10-28 | 2024-09-10 | Accencio LLC | Methods of treating symptoms of coronavirus infection with viral protease inhibitors |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014064534A2 (en) | 2012-10-05 | 2014-05-01 | Chrontech Pharma Ab | Injection needle, device, immunogenic compositions and method of use |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
CN109641874A (en) | 2016-05-10 | 2019-04-16 | C4医药公司 | C for target protein degradation3The glutarimide degron body of carbon connection |
CN109562107A (en) | 2016-05-10 | 2019-04-02 | C4医药公司 | Heterocycle degron body for target protein degradation |
TWI658568B (en) * | 2017-01-03 | 2019-05-01 | Leadtrend Technology Corporation | High-voltage semiconductor device and synchronous-rectification controller |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000009543A2 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
WO2003064455A2 (en) * | 2002-01-30 | 2003-08-07 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis c virus |
Family Cites Families (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3480613A (en) * | 1967-07-03 | 1969-11-25 | Merck & Co Inc | 2-c or 3-c-alkylribofuranosyl - 1-substituted compounds and the nucleosides thereof |
US6128582A (en) | 1996-04-30 | 2000-10-03 | Vertex Pharmaceuticals Incorporated | Molecules comprising an IMPDH-like binding pocket and encoded data storage medium capable of graphically displaying them |
GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
GB9707659D0 (en) | 1997-04-16 | 1997-06-04 | Peptide Therapeutics Ltd | Hepatitis C NS3 Protease inhibitors |
ATE283865T1 (en) | 1997-08-11 | 2004-12-15 | Boehringer Ingelheim Ca Ltd | PEPTIDE ANALOGUES WITH INHIBITORY EFFECT ON HEPATITIS C |
DE69829381T2 (en) | 1997-08-11 | 2006-04-13 | Boehringer Ingelheim (Canada) Ltd., Laval | HEPATITIS C INHIBITOR PEPTIDE |
IT1299134B1 (en) | 1998-02-02 | 2000-02-29 | Angeletti P Ist Richerche Bio | PROCEDURE FOR THE PRODUCTION OF PEPTIDES WITH PROTEAS INHIBITING THE NS3 PROTEASIS OF THE HCV VIRUS, PEPTIDES SO OBTAINABLE AND PEPTIDES |
MXPA00008348A (en) | 1998-02-25 | 2005-07-15 | Univ Emory | 2'-fluoronucleosides. |
GB9806815D0 (en) | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
ES2281170T3 (en) | 1998-03-31 | 2007-09-16 | Vertex Pharmaceuticals Incorporated | SERINA PROTEASES INHIBITORS, PARTICULARLY PROTEASE NS3 OF THE HEPATITIS VIRUS C. |
GB9812523D0 (en) | 1998-06-10 | 1998-08-05 | Angeletti P Ist Richerche Bio | Peptide inhibitors of hepatitis c virus ns3 protease |
DE69908376T2 (en) | 1998-08-10 | 2004-04-01 | The Hokkaido Electric Power Co., Inc., Sapporo | METHOD FOR PRODUCING NORMAL GLYCOPEPTIDES |
CA2348234A1 (en) | 1998-10-29 | 2000-05-11 | Chunjian Liu | Compounds derived from an amine nucleus that are inhibitors of impdh enzyme |
US6608027B1 (en) * | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
UA74546C2 (en) | 1999-04-06 | 2006-01-16 | Boehringer Ingelheim Ca Ltd | Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition |
ATE248835T1 (en) | 1999-06-25 | 2003-09-15 | Vertex Pharma | PRODRUGS OF IMPDH-INHIBITING CARBAMATES |
CN1623984A (en) | 1999-12-27 | 2005-06-08 | 日本烟草产业株式会社 | Fused-ring compounds and use thereof as drugs |
US6495677B1 (en) | 2000-02-15 | 2002-12-17 | Kanda S. Ramasamy | Nucleoside compounds |
US6455508B1 (en) | 2000-02-15 | 2002-09-24 | Kanda S. Ramasamy | Methods for treating diseases with tirazole and pyrrolo-pyrimidine ribofuranosyl nucleosides |
PL364995A1 (en) * | 2000-02-18 | 2004-12-27 | Shire Biochem Inc. | Method for the treatment or prevention of flavivirus |
WO2001077091A2 (en) | 2000-04-05 | 2001-10-18 | Tularik Inc. | Ns5b hcv polymerase inhibitors |
KR20030036152A (en) * | 2000-04-05 | 2003-05-09 | 쉐링 코포레이션 | Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising N-cyclic P2 moieties |
AU2001259068A1 (en) | 2000-04-13 | 2001-10-30 | Pharmasset, Ltd. | 3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
EP1294735A2 (en) | 2000-05-26 | 2003-03-26 | Novirio Pharmaceuticals Limited | Methods and compositions for treating flaviviruses and pestiviruses |
US6448281B1 (en) | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
GB0017676D0 (en) | 2000-07-19 | 2000-09-06 | Angeletti P Ist Richerche Bio | Inhibitors of viral polymerase |
WO2002014376A2 (en) * | 2000-08-10 | 2002-02-21 | Trustees Of Boston College | Recyclable metathesis catalysts |
US6955174B2 (en) * | 2000-08-18 | 2005-10-18 | Uryovascular Systems, Inc. | Cryotherapy method for detecting and treating vulnerable plaque |
US20030008841A1 (en) | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
US6809101B2 (en) | 2000-09-01 | 2004-10-26 | Shionogi & Co., Ltd. | Compounds having anti-hepatitis C virus effect |
KR101195019B1 (en) | 2000-10-18 | 2012-10-29 | 파마셋 인코포레이티드 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
CA2430458A1 (en) | 2000-12-12 | 2002-06-20 | Schering Corporation | Diaryl peptides as ns3-serine protease inhibitors of hepatits c virus |
AU2002230763A1 (en) | 2000-12-13 | 2008-01-03 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
WO2002048165A2 (en) | 2000-12-15 | 2002-06-20 | Pharmasset Ltd. | Antiviral agents for treatment of flaviviridae infections |
WO2002051425A1 (en) | 2000-12-26 | 2002-07-04 | Mitsubishi Pharma Corporation | Remedies for hepatitis c |
EP2399588B1 (en) | 2001-01-22 | 2020-04-29 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
EP1423095B1 (en) | 2001-08-14 | 2016-09-28 | Tel Aviv University Future Technology Development L.P. | Lipidated glycosaminoglycan particles and their use in drug and gene delivery for diagnosis and therapy |
US7138376B2 (en) * | 2001-09-28 | 2006-11-21 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides |
US20040006002A1 (en) | 2001-09-28 | 2004-01-08 | Jean-Pierre Sommadossi | Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside |
WO2003062192A1 (en) | 2002-01-17 | 2003-07-31 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin k inhibitors |
GB0201179D0 (en) | 2002-01-18 | 2002-03-06 | Angeletti P Ist Richerche Bio | Therapeutic agents |
AU2003209045B2 (en) | 2002-02-13 | 2006-12-14 | Isis Pharmaceuticals, Inc. | Methods of inhibiting orthopoxvirus replication with nucleoside compounds |
AU2003232071A1 (en) | 2002-05-06 | 2003-11-17 | Genelabs Technologies, Inc. | Nucleoside derivatives for treating hepatitis c virus infection |
MY140680A (en) * | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
CA2488534A1 (en) | 2002-06-21 | 2003-12-31 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
US20060234962A1 (en) | 2002-06-27 | 2006-10-19 | Olsen David B | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
JP5087211B2 (en) | 2002-06-28 | 2012-12-05 | イデニクス(ケイマン)リミテツド | 2 'and 3'-nucleoside prodrugs for the treatment of flavivirus infection |
CN100348607C (en) | 2002-06-28 | 2007-11-14 | 埃迪尼克斯(开曼)有限公司 | For the treatment of Flaviviridae viral infection in 2 'and 3'-nucleoside prodrugs |
MXPA04012802A (en) | 2002-06-28 | 2005-04-19 | Idenix Cayman Ltd | 2aCOE-C-METHYL-3aCOE-O-L-VALINE ESTER RIBOFURANOSYL CYTIDINE FOR TREATMENT OF FLAVIVIRIDAE INFECTIONS. |
WO2004007512A2 (en) | 2002-07-16 | 2004-01-22 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
KR20050037559A (en) | 2002-07-25 | 2005-04-22 | 마이크로로직스 바이오테크, 인코포레이티드 | Anti-viral 7-deaza d-nucleosides and uses thereof |
SG174624A1 (en) | 2002-08-01 | 2011-10-28 | Pharmasset Inc | Compounds with the bicyclo[4.2.1]nonane system for the treatment of flaviviridae infections |
PL376043A1 (en) | 2002-09-30 | 2005-12-12 | Genelabs Technologies, Inc. | Nucleoside derivatives for treating hepatitis c virus infection |
CA2504344A1 (en) | 2002-11-01 | 2004-05-21 | Viropharma Incorporated | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases |
US20040254159A1 (en) * | 2003-02-27 | 2004-12-16 | Hasvold Lisa A. | Heterocyclic kinase inhibitors |
WO2004101605A1 (en) * | 2003-03-05 | 2004-11-25 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibiting compounds |
NZ543250A (en) * | 2003-04-02 | 2008-12-24 | Boehringer Ingelheim Int | Pharmaceutical compositions for hepatitis C viral protease inhibitors |
GB0307891D0 (en) | 2003-04-04 | 2003-05-14 | Angeletti P Ist Richerche Bio | Chemical compounds,compositions and uses |
WO2004094452A2 (en) * | 2003-04-16 | 2004-11-04 | Bristol-Myers Squibb Company | Macrocyclic isoquinoline peptide inhibitors of hepatitis c virus |
US7176208B2 (en) * | 2003-04-18 | 2007-02-13 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
DE602004010137T2 (en) * | 2003-05-21 | 2008-09-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | COMPOUNDS AS HEPATITIS C INHIBITORS |
PT1633766T (en) | 2003-05-30 | 2019-06-04 | Gilead Pharmasset Llc | Modified fluorinated nucleoside analogues |
GB0313250D0 (en) | 2003-06-09 | 2003-07-16 | Angeletti P Ist Richerche Bio | Therapeutic agents |
MXPA05013452A (en) * | 2003-06-19 | 2006-03-09 | Hoffmann La Roche | PROCESSES FOR PREPARING 4aCOEAZIDO NUCLEOSIDE DERIVATIVES. |
TW200510425A (en) | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
GB0321003D0 (en) | 2003-09-09 | 2003-10-08 | Angeletti P Ist Richerche Bio | Compounds, compositions and uses |
GB0323845D0 (en) | 2003-10-10 | 2003-11-12 | Angeletti P Ist Richerche Bio | Chemical compounds,compositions and uses |
US7132504B2 (en) | 2003-11-12 | 2006-11-07 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
JP4682155B2 (en) | 2004-01-21 | 2011-05-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Macrocyclic peptide active against hepatitis C virus |
JP4143669B2 (en) | 2004-02-24 | 2008-09-03 | 日本たばこ産業株式会社 | Four-ring condensed heterocyclic compounds and their use as HCV polymerase inhibitors |
GB0413087D0 (en) | 2004-06-11 | 2004-07-14 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
GB0416396D0 (en) | 2004-07-22 | 2004-08-25 | Angeletti P Ist Richerche Bio | Therapeutic agents |
US7153848B2 (en) | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
JP2008510748A (en) | 2004-08-23 | 2008-04-10 | エフ.ホフマン−ラ ロシュ アーゲー | Antiviral 4'-azido-nucleoside |
GB0419850D0 (en) | 2004-09-07 | 2004-10-13 | Angeletti P Ist Richerche Bio | Therapeutic agents |
CA2585084A1 (en) | 2004-10-26 | 2006-05-04 | Immacolata Conte | Tetracyclic indole derivatives as antiviral agents |
EP1879607B1 (en) | 2005-05-02 | 2014-11-12 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
GB0509326D0 (en) | 2005-05-09 | 2005-06-15 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
US7470664B2 (en) * | 2005-07-20 | 2008-12-30 | Merck & Co., Inc. | HCV NS3 protease inhibitors |
RU2008107972A (en) | 2005-08-01 | 2009-09-10 | Мерк энд Ко., Инк. (US) | MACROCYCLIC PEPTIDES AS HCV NS3-PROTEASE INHIBITORS |
WO2007028789A1 (en) | 2005-09-07 | 2007-03-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Quinazoline derivatives as antiviral agents |
GB0518390D0 (en) | 2005-09-09 | 2005-10-19 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
GB0519797D0 (en) | 2005-09-29 | 2005-11-09 | Istituto Di Ricerche D Biolog | Therapeutic agents |
GB0609492D0 (en) | 2006-05-15 | 2006-06-21 | Angeletti P Ist Richerche Bio | Therapeutic agents |
EP2029741A4 (en) | 2006-06-08 | 2011-03-16 | Merck Sharp & Dohme | A rapid method to determine inhibitor sensitivity of ns3/4a protease sequences cloned from clinical samples |
GB0612423D0 (en) | 2006-06-23 | 2006-08-02 | Angeletti P Ist Richerche Bio | Therapeutic agents |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
CA2667266C (en) | 2006-10-24 | 2015-11-24 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
AU2007309544B2 (en) | 2006-10-24 | 2012-05-31 | Msd Italia S.R.L. | HCV NS3 protease inhibitors |
BRPI0718161A2 (en) | 2006-10-27 | 2013-11-26 | Merck & Co Inc | COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF THE COMPOUND. |
CA2667032A1 (en) | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
CA2705449C (en) | 2006-11-09 | 2017-01-10 | Twinblade Technologies Holding Sweden Ab | Hub device |
WO2008112108A1 (en) | 2007-03-09 | 2008-09-18 | Merck & Co., Inc. | In vivo hcv resistance to anti-viral inhibitors |
US7968544B2 (en) | 2007-06-29 | 2011-06-28 | Gilead Sciences, Inc. | Modulators of toll-like receptor 7 |
CA2699891C (en) | 2007-07-19 | 2013-10-22 | Nigel Liverton | Macrocyclic compounds as antiviral agents |
CN102026544A (en) | 2007-11-14 | 2011-04-20 | 益安药业 | Macrocyclic tetrazolyl hepatitis c serine protease inhibitors |
CL2008003384A1 (en) | 2007-11-14 | 2009-12-11 | Enanta Pharm Inc | Macrocyclic quinoxaline derived compounds, serine protease inhibitors; pharmaceutical composition comprising them; and its use in the treatment of hepatitis c. |
-
2006
- 2006-07-28 RU RU2008107972/04A patent/RU2008107972A/en not_active Application Discontinuation
- 2006-07-28 AU AU2006275605A patent/AU2006275605B2/en not_active Ceased
- 2006-07-28 WO PCT/US2006/029635 patent/WO2007016441A1/en active Application Filing
- 2006-07-28 BR BRPI0614205A patent/BRPI0614205A2/en not_active IP Right Cessation
- 2006-07-28 NZ NZ565269A patent/NZ565269A/en unknown
- 2006-07-28 US US11/989,886 patent/US8278322B2/en active Active
- 2006-07-28 EP EP06800513A patent/EP1913016B1/en active Active
- 2006-07-28 JP JP2008525069A patent/JP4705984B2/en not_active Expired - Fee Related
- 2006-07-28 KR KR1020087002861A patent/KR20080036598A/en not_active Application Discontinuation
- 2006-07-28 CA CA2615896A patent/CA2615896C/en not_active Expired - Fee Related
- 2006-07-28 MX MX2008001588A patent/MX2008001588A/en unknown
-
2008
- 2008-01-31 IL IL189166A patent/IL189166A0/en unknown
- 2008-01-31 EC EC2008008157A patent/ECSP088157A/en unknown
- 2008-02-14 CR CR9731A patent/CR9731A/en not_active Application Discontinuation
- 2008-02-25 MA MA30689A patent/MA29757B1/en unknown
- 2008-02-29 NO NO20081086A patent/NO20081086L/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000009543A2 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
WO2003064455A2 (en) * | 2002-01-30 | 2003-08-07 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis c virus |
Non-Patent Citations (1)
Title |
---|
POUPART ET AL, J.ORG.CHEM., vol. 66, no. 14, 2001, pages 4743 - 4751, XP002408789 * |
Cited By (158)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9636375B2 (en) | 2002-05-20 | 2017-05-02 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8889871B2 (en) | 2002-05-20 | 2014-11-18 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8299094B2 (en) | 2002-05-20 | 2012-10-30 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9227940B2 (en) | 2002-05-20 | 2016-01-05 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7915291B2 (en) | 2002-05-20 | 2011-03-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
EP1905777A1 (en) * | 2005-07-04 | 2008-04-02 | Zheng-Yun Zhan | Ruthenium complex ligand, ruthenium complex, carried ruthenium complex catalyst and the preparing methods and the use thereof |
EP1905777A4 (en) * | 2005-07-04 | 2011-03-23 | Scitech Co Ltd Zannan | Ruthenium complex ligand, ruthenium complex, carried ruthenium complex catalyst and the preparing methods and the use thereof |
EP2886549A1 (en) * | 2005-07-04 | 2015-06-24 | Zannan Scitech Co., Ltd. | Ruthenium complex ligand, ruthenium complex and the use of the complex as a catalyst in olefin metathesis reactions |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8178520B2 (en) | 2006-05-15 | 2012-05-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
JP2009537481A (en) * | 2006-05-15 | 2009-10-29 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | Macrocyclic compounds as antiviral agents |
JP2009541293A (en) * | 2006-06-23 | 2009-11-26 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | Macrocyclic compounds as antiviral agents |
WO2007148135A1 (en) * | 2006-06-23 | 2007-12-27 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
CN101501061B (en) * | 2006-06-23 | 2016-03-09 | Msd意大利有限公司 | As the macrocylc compound of antiviral |
US8314062B2 (en) | 2006-06-23 | 2012-11-20 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
US7935670B2 (en) | 2006-07-11 | 2011-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
AU2007309488B2 (en) * | 2006-10-24 | 2012-10-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2008051514A2 (en) | 2006-10-24 | 2008-05-02 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
EP2079479A2 (en) * | 2006-10-24 | 2009-07-22 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
EP2079479A4 (en) * | 2006-10-24 | 2010-12-22 | Merck Sharp & Dohme | Hcv ns3 protease inhibitors |
EP2079480A2 (en) * | 2006-10-24 | 2009-07-22 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
US8309540B2 (en) | 2006-10-24 | 2012-11-13 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8138164B2 (en) | 2006-10-24 | 2012-03-20 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2008051475A2 (en) | 2006-10-24 | 2008-05-02 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
EP2079480A4 (en) * | 2006-10-24 | 2011-06-15 | Merck Sharp & Dohme | Hcv ns3 protease inhibitors |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
KR20090075874A (en) * | 2006-10-27 | 2009-07-09 | 머크 앤드 캄파니 인코포레이티드 | HCV NS3 protease inhibitors |
US9738661B2 (en) | 2006-10-27 | 2017-08-22 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2008057209A1 (en) * | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
KR101615500B1 (en) * | 2006-10-27 | 2016-04-27 | 머크 샤프 앤드 돔 코포레이션 | HCV NS3 protease inhibitors |
US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
EP2481807A2 (en) | 2007-03-09 | 2012-08-01 | Merck Sharp & Dohme Corporation | In vivo HCV resistance to anti-viral inhibitors |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
WO2009010804A1 (en) * | 2007-07-19 | 2009-01-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
AU2008277377B2 (en) * | 2007-07-19 | 2013-08-01 | Msd Italia S.R.L. | Macrocyclic compounds as antiviral agents |
US8383583B2 (en) | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
US8304385B2 (en) | 2007-11-14 | 2012-11-06 | Enanta Pharmaceuticals, Inc. | Macrocyclic tetrazolyl hepatitis C serine protease inhibitors |
US8324155B2 (en) | 2007-11-14 | 2012-12-04 | Enanta Pharmaceuticals, Inc. | Quinoxaline-containing compounds as hepatitis C virus inhibitors |
US8951998B2 (en) | 2007-11-14 | 2015-02-10 | Enanta Pharmaceuticals, Inc. | Quinoxaline-containing compounds as hepatitis C virus inhibitors |
RU2493160C2 (en) * | 2007-11-14 | 2013-09-20 | Энанта Фармасьютикалз, Инк. | Quinoxaline-containing compounds as hepatitis c virus inhibitors |
US8222203B2 (en) | 2007-12-14 | 2012-07-17 | Enanta Pharmaceuticals, Inc. | Macrocyclic oximyl hepatitis C serine protease inhibitors |
US8273709B2 (en) | 2007-12-14 | 2012-09-25 | Enanta Pharmaceuticals, Inc. | Triazole-containing macrocyclic HCV serine protease inhibitors |
WO2009076747A1 (en) | 2007-12-19 | 2009-06-25 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8283309B2 (en) | 2007-12-20 | 2012-10-09 | Enanta Pharmaceuticals, Inc. | Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors |
US9676785B2 (en) | 2007-12-21 | 2017-06-13 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
US9694086B2 (en) | 2007-12-21 | 2017-07-04 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
US8293705B2 (en) | 2007-12-21 | 2012-10-23 | Avila Therapeutics, Inc. | HCV protease inhibitors and uses thereof |
US9163061B2 (en) | 2007-12-21 | 2015-10-20 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US8202996B2 (en) | 2007-12-21 | 2012-06-19 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
US8741837B2 (en) | 2007-12-21 | 2014-06-03 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US8309685B2 (en) | 2007-12-21 | 2012-11-13 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
JP2011509242A (en) * | 2007-12-21 | 2011-03-24 | アビラ セラピューティクス, インコーポレイテッド | HCV protease inhibitors and uses thereof |
JP2015113346A (en) * | 2007-12-21 | 2015-06-22 | セルジーン アビロミクス リサーチ, インコーポレイテッド | Hcv protease inhibitors and uses thereof |
US8338606B2 (en) | 2007-12-21 | 2012-12-25 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
US8778877B2 (en) | 2007-12-21 | 2014-07-15 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
JP2011513224A (en) * | 2008-02-25 | 2011-04-28 | メルク・シャープ・エンド・ドーム・コーポレイション | Therapeutic compounds |
EP2268285B1 (en) * | 2008-02-25 | 2018-06-27 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
US8591878B2 (en) | 2008-02-25 | 2013-11-26 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
EP2268285A1 (en) * | 2008-02-25 | 2011-01-05 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
US8372802B2 (en) | 2008-03-20 | 2013-02-12 | Enanta Pharmaceuticals, Inc. | Fluorinated macrocyclic compounds as hepatitis C virus inhibitors |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2271345A4 (en) * | 2008-04-28 | 2011-08-31 | Merck Sharp & Dohme | Hcv ns3 protease inhibitors |
WO2009134624A1 (en) | 2008-04-28 | 2009-11-05 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
EP2271345A1 (en) * | 2008-04-28 | 2011-01-12 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
US8461107B2 (en) | 2008-04-28 | 2013-06-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
JP2011528713A (en) * | 2008-07-22 | 2011-11-24 | メルク・シャープ・エンド・ドーム・コーポレイション | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
KR101313675B1 (en) | 2008-07-22 | 2013-10-02 | 이스티투토 디 리세르쉐 디 비올로지아 몰레콜라레 피. 안젤레티 에스.알.엘. | Macrocyclic quinoxaline compounds as HCV NS3 Protease inhibitors |
EP2540349A1 (en) | 2008-07-22 | 2013-01-02 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions comprising a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitor |
WO2010011566A1 (en) * | 2008-07-22 | 2010-01-28 | Merck & Co., Inc. | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
US8080654B2 (en) | 2008-07-22 | 2011-12-20 | Insituto di Ricerche di Biologia Molecolare P. Angeletti SpA | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
EA019327B1 (en) * | 2008-07-22 | 2014-02-28 | Мерк Шарп Энд Домэ Корп. | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
US7973040B2 (en) | 2008-07-22 | 2011-07-05 | Merck Sharp & Dohme Corp. | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
EP2540350A1 (en) | 2008-07-22 | 2013-01-02 | Merck Sharp & Dohme Corp. | Combinations of a macrocyclic quinoxaline compound which is an HCV NS3 protease inhibitors with other HCV agents |
US8877929B2 (en) | 2008-09-04 | 2014-11-04 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
US8357806B2 (en) | 2008-09-04 | 2013-01-22 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8642538B2 (en) | 2008-09-11 | 2014-02-04 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US9309279B2 (en) | 2008-09-11 | 2016-04-12 | Abbvie Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8420596B2 (en) | 2008-09-11 | 2013-04-16 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2010080389A1 (en) | 2008-12-19 | 2010-07-15 | Gilead Sciences, Inc. | Hcv ns3 protease inhibitors |
WO2010080874A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
CN102458444A (en) * | 2009-05-13 | 2012-05-16 | 英安塔制药有限公司 | Macrocyclic compounds as hepatitis c virus inhibitors |
US8936781B2 (en) | 2009-05-13 | 2015-01-20 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis C virus inhibitors |
US8232246B2 (en) | 2009-06-30 | 2012-07-31 | Abbott Laboratories | Anti-viral compounds |
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US9284307B2 (en) | 2009-08-05 | 2016-03-15 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors |
US9193740B2 (en) | 2009-10-19 | 2015-11-24 | Enanta Pharmaceuticals, Inc. | Bismacrocyclic compounds as hepatitis C virus inhibitors |
US8987302B2 (en) | 2010-06-24 | 2015-03-24 | Panmed Ltd. | Treatment of hepatitis C virus related diseases using hydroxychloroquine or a combination of hydroxychloroquine and an anti-viral agent |
US8975232B2 (en) | 2010-07-29 | 2015-03-10 | President And Fellows Of Harvard College | Macrocyclic kinase inhibitors and uses thereof |
US9220748B2 (en) | 2010-09-21 | 2015-12-29 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived HCV serine protease inhibitors |
US8648037B2 (en) | 2010-09-21 | 2014-02-11 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived HCV serine protease inhibitors |
WO2012061248A2 (en) | 2010-11-01 | 2012-05-10 | Rfs Pharma, Llc | Novel specific hcv ns3 protease inhibitors |
US9120818B2 (en) | 2010-12-14 | 2015-09-01 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
US8937041B2 (en) | 2010-12-30 | 2015-01-20 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
US9527885B2 (en) | 2011-05-05 | 2016-12-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2012176149A1 (en) | 2011-06-23 | 2012-12-27 | Panmed Ltd. | Treatment of hepatitis c virus |
US8912141B2 (en) | 2011-06-23 | 2014-12-16 | Panmed Ltd. | Treatment of hepatitis C virus |
US9243038B2 (en) | 2011-07-01 | 2016-01-26 | President And Fellows Of Harvard College | Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof |
US9610322B2 (en) | 2011-07-01 | 2017-04-04 | President And Fellows Of Harvard College | Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof |
WO2013028470A1 (en) | 2011-08-19 | 2013-02-28 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
US9073825B2 (en) | 2011-08-19 | 2015-07-07 | Merck Sharp & Dohme Limited | Methods and intermediates for preparing macrolactams |
US9242917B2 (en) | 2011-08-19 | 2016-01-26 | Merck Sharp & Dohme Limited | Crystal forms of a HCV protease inhibitor |
US9238604B2 (en) | 2011-08-19 | 2016-01-19 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
EP3159345A1 (en) * | 2012-07-03 | 2017-04-26 | Gilead Sciences, Inc. | Inhibitors of hepatitis c virus |
US10335409B2 (en) | 2012-07-03 | 2019-07-02 | Gilead Pharmasset Llc | Inhibitors of hepatitis C virus |
AP3903A (en) * | 2012-07-03 | 2016-11-17 | Gilead Sciences Inc | Inhibitors of hepatitis C virus |
EP3825312A1 (en) * | 2012-07-03 | 2021-05-26 | Gilead Pharmasset LLC | Intermediates for preparing inhibitors of hepatitis c virus |
AU2019222909B2 (en) * | 2012-07-03 | 2021-03-25 | Gilead Pharmasset Llc | Inhibitors of Hepatitis C virus |
US10603318B2 (en) | 2012-07-03 | 2020-03-31 | Gilead Pharmasset Llc | Inhibitors of hepatitis C virus |
KR102040023B1 (en) | 2012-07-03 | 2019-11-05 | 길리애드 파마셋 엘엘씨 | Inhibitors of hepatitis c virus |
AU2013286729B2 (en) * | 2012-07-03 | 2015-11-12 | Gilead Pharmasset Llc | Inhibitors of hepatitis C virus |
MD20140136A2 (en) * | 2012-07-03 | 2015-05-31 | Gilead Sciences, Inc. | Inhibitors of hepatitis C virus |
US9296782B2 (en) | 2012-07-03 | 2016-03-29 | Gilead Sciences, Inc. | Inhibitors of hepatitis C virus |
AU2017203984B2 (en) * | 2012-07-03 | 2019-06-06 | Gilead Pharmasset Llc | Inhibitors of Hepatitis C virus |
KR20160040743A (en) * | 2012-07-03 | 2016-04-14 | 길리애드 사이언시즈, 인코포레이티드 | Inhibitors of hepatitis c virus |
EA027390B1 (en) * | 2012-07-03 | 2017-07-31 | Джилид Сайэнс, Инк. | Inhibitors of hepatitis c virus |
KR101610575B1 (en) | 2012-07-03 | 2016-04-07 | 길리애드 사이언시즈, 인코포레이티드 | Inhibitors of hepatitis c virus |
EP3492464A1 (en) * | 2012-07-03 | 2019-06-05 | Gilead Sciences, Inc. | Intermediates for preparing inhibitors of hepatitis c virus |
PH12016502040A1 (en) * | 2012-07-03 | 2019-02-27 | Gilead Sciences Inc | Inhibitors of hepatitis c virus |
WO2014008285A1 (en) * | 2012-07-03 | 2014-01-09 | Gilead Sciences, Inc. | Inhibitors of hepatitis c virus |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9598433B2 (en) | 2012-11-02 | 2017-03-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
US9617310B2 (en) | 2013-03-15 | 2017-04-11 | Gilead Sciences, Inc. | Inhibitors of hepatitis C virus |
US9873707B2 (en) | 2013-10-18 | 2018-01-23 | Merck Sharp & Dohme Corp. | Methods and intermediates for preparing macrolactams |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US10105365B2 (en) | 2014-01-03 | 2018-10-23 | Abbvie Inc. | Solid antiviral dosage forms |
US9744170B2 (en) | 2014-01-03 | 2017-08-29 | Abbvie Inc. | Solid antiviral dosage forms |
US11040976B2 (en) | 2015-04-24 | 2021-06-22 | President And Fellows Of Harvard College | Substrate selective inhibitors of insulin-degrading enzyme (IDE) and uses thereof |
US11674136B2 (en) | 2018-02-09 | 2023-06-13 | President And Fellows Of Harvard College | DNA-templated macrocycle library |
US12083099B2 (en) | 2020-10-28 | 2024-09-10 | Accencio LLC | Methods of treating symptoms of coronavirus infection with viral protease inhibitors |
Also Published As
Publication number | Publication date |
---|---|
CA2615896A1 (en) | 2007-02-08 |
RU2008107972A (en) | 2009-09-10 |
AU2006275605A1 (en) | 2007-02-08 |
KR20080036598A (en) | 2008-04-28 |
NO20081086L (en) | 2008-04-30 |
JP4705984B2 (en) | 2011-06-22 |
MA29757B1 (en) | 2008-09-01 |
EP1913016A1 (en) | 2008-04-23 |
MX2008001588A (en) | 2008-02-19 |
US20110028494A1 (en) | 2011-02-03 |
BRPI0614205A2 (en) | 2016-11-22 |
US8278322B2 (en) | 2012-10-02 |
ECSP088157A (en) | 2008-02-20 |
IL189166A0 (en) | 2008-08-07 |
NZ565269A (en) | 2010-03-26 |
AU2006275605B2 (en) | 2011-01-06 |
EP1913016B1 (en) | 2013-01-16 |
CR9731A (en) | 2008-04-10 |
JP2009503080A (en) | 2009-01-29 |
CA2615896C (en) | 2012-11-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1913016A1 (en) | Macrocyclic peptides as hcv ns3 protease inhibitors | |
JP4621282B2 (en) | HCV NS3 protease inhibitor | |
EP2083844B1 (en) | Hcv ns3 protease inhibitors | |
US8461107B2 (en) | HCV NS3 protease inhibitors | |
EP2086982B1 (en) | Hcv ns3 protease inhibitors | |
CA2667146C (en) | Hcv ns3 protease inhibitors | |
EP1879607A2 (en) | Hcv ns3 protease inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680028188.4 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2615896 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12008500159 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 565269 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006275605 Country of ref document: AU Ref document number: DZP2008000052 Country of ref document: DZ Ref document number: 2008010176 Country of ref document: EG |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2008/001588 Country of ref document: MX Ref document number: 189166 Country of ref document: IL Ref document number: 2008525069 Country of ref document: JP Ref document number: 11989886 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08010100 Country of ref document: CO Ref document number: 1020087002861 Country of ref document: KR |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006800513 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2008-009731 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 2006275605 Country of ref document: AU Date of ref document: 20060728 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1699/DELNP/2008 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008107972 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: PI0614205 Country of ref document: BR Kind code of ref document: A2 Effective date: 20080131 |