Macrocyclic peptides active against the hepatitis C virus

{
  "publication_number": "US6608027B1",
  "country": "US",
  "kind": "B1",
  "title": "Macrocyclic peptides active against the hepatitis C virus",
  "abstract": "The present invention covers macrocyclic compounds of formula I active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus. wherein W, R 21, R 22, R 3, R 4, D and A are as defined herein, or a pharmaceutically acceptable salts or ester thereof.",
  "claims": [
    "1. A compound of formula (I): wherein W is CH or N, R 21 is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, hydroxy, or N(R 23) 2, wherein each R 23 is independently H, C 1-6 alkyl or C 3-6 cycloalkyl; R 22 is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 2-7 alkoxyalkyl, C 3-6 cycloalkyl, C 6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Het being substituted with R 24, wherein R 24 is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2, N(R 25) 2, NH - C(O) - R 25 or NH - C(O) - NH - R 25, wherein each R 25 is independently: H, C 1-6 alkyl or C 3-6 cycloalkyl; or R 24 is NH - C(O) - OR 26 wherein R 26 is C 1-6 alkyl or C 3-6 cycloalkyl; R 3 is hydroxy, NH 2, or a group of formula - NH - R 31, wherein R 31 is C 6 or 10 aryl, heteroaryl, - C(O) - R 32, - C(O) - NHR 32 or - C(O) - OR 32, wherein R 32 is C 1-6 alkyl or C 3-6 cycloalkyl; D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41, wherein R 41 is H, C 1-6 alkyl, C 3-6 cycloalkyl or - C(O) - R 42, wherein R 42 is C 1-6 alkyl, C 3-6 cycloalkyl or C 6 or 10 aryl; R 4 is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, halo, amino, oxo, thio and C 1-6 thioalkyl, and A is an amide of formula - C(O) - NH - R 5, wherein R 5 is selected from the group consisting of: C 1-8 alkyl, C 3-6 cycloalkyl, C 6 or 10 aryl and C 7-16 aralkyl; or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.",
    "2. A compound of formula I according to claim 1, wherein said R 1 moiety is selected from the 2 different diastereoisomers represented by structures (i) and (ii):",
    "3. The compound of formula I according to claim 2, wherein D is linked syn to A as represented by formula (ii).",
    "4. The compound of formula I according to claim 1, wherein W is N; R 21 is H, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, chloro, or N(R 23) 2, wherein R 23 is H or C 1-6 alkyl; R 22 is H, C 1-6 thioalkyl, C 1-6 alkoxy, phenyl or Het selected from the group consisting of: wherein R 24 is H, C 1-6 alkyl, NH - R 25, NH - C(O) - R 25 or NH - C(O) - NH - R 25, wherein each R 25 is independently: H, C 1-6 alkyl, or C 3-6 cycloalkyl; or NH - C(O) - OR 26, wherein R 26 is C 1-6 alkyl.",
    "5. A compound of formula I according to claim 4, wherein R 21 is H or C 1-6 alkoxy.",
    "6. The compound of formula I according to claim 4, wherein R 22 is C 1-4 alkoxy, phenyl or Het selected from the group consisting of: wherein R 24 is H, C 1-6 alkyl, NH - R 25, or NH - C(O) - R 25; wherein each R 25 is C 1-6 alkyl or C 3-6 cycloalkyl, or NH - C(O) - OR 26, wherein R 26 is as defined in claim 4.",
    "7. A compound of formula I according to claim 6, wherein R 21 is methoxy.",
    "8. The compound of formula I according to claim 7, wherein R 22 is ethoxy, or Het selected from the group consisting of: wherein R 24a is NH - R 25 or NH - C(O) - R 25, wherein R 25 is C 1-6 alkyl or C 3-6 cycloalkyl; or R 24a is NH - C(O) - OR 26, wherein R 26 is C 1-6 alkyl, and R 24b is H or C 1-6 alkyl.",
    "9. The compound of formula I according to claim 1, wherein R 3 is an amide of formula NH - C(O)R 32 or a urea of formula NH - C(O) - NH - R 32 or a carbamate of formula NH - C(O) - OR 32, wherein R 32 is C 1-6 alkyl or C 3-6 cycloalkyl.",
    "10. The compound of formula I according to claim 9, wherein R 3 is a urea or a carbamate, wherein R 32 is C 1-6 alkyl or C 4-6 cycloalkyl.",
    "11. The compound of formula I according to claim 10, wherein R 3 is a carbamate and R 32 is tert-butyl, cyclobutyl or cyclopentyl.",
    "12. The compound of formula I according to claim 1, wherein D is a 6 to 8 atom saturated or unsaturated alkylene chain optionally containing one or two heteroatoms independently selected from: O, S or N - R 41, wherein R 41 is H, C 1-6 alkyl, or C 2-7 acyl.",
    "13. The compound of formula I according to claim 12, wherein D optionally contains one heteroatom selected from: NH, or N - C 2-7 acyl.",
    "14. The compound according to claim 13, wherein said heteroatom is selected from: NH or N(Ac).",
    "15. The compound according to claim 13, wherein said D chain contains 7 atoms.",
    "16. The compound according to claim 15, wherein said heteroatom is at position 10 of said D chain.",
    "17. The compound according to claim 13, wherein said D chain is saturated.",
    "18. The compound of formula I according to claim 12, wherein D is a 6 to 8 atom saturated or unsaturated alkylene chain optionally containing one heteroatom selected from: O, or S.",
    "19. The compound according to claim 18, wherein said D chain contains 7 atoms.",
    "20. The compound according to claim 19, wherein said heteroatom is at position 9 of said D chain.",
    "21. The compound according to claim 20, wherein said D chain is substituted at position 8 with R 4, wherein R 4 is H or C 1-6 alkyl.",
    "22. The compound according to claim 21, wherein said R 4 is H or methyl.",
    "23. The compound according to claim 22, wherein said R 4 is H or 8-(S) - Me.",
    "24. The compound according to claim 23, wherein said D chain is saturated.",
    "25. The compound according to claim 19, wherein said D chain contains one double bond at position 11,12.",
    "26. The compound according to claim 25, wherein said double bond is trans.",
    "27. The compound of formula I according to claim 12, wherein D is a 6 to 8 atom, saturated or unsaturated, all carbon alkylene chain.",
    "28. The compound of formula I according to claim 27, wherein D is a 7 atom chain.",
    "29. The compound of formula I according to claim 28, wherein D is saturated.",
    "30. The compound according to claim 29, wherein said D chain is substituted with R 4, wherein R 4 is H, oxo, hydroxy, alkoxy or alkyl.",
    "31. The compound according to claim 30, wherein said R 4 is H or C 1-6 alkyl.",
    "32. The compound according to claim 31, wherein said R 4 is H or methyl.",
    "33. The compound according to claim 32, wherein said R 4 is H or 10-(S) - Me.",
    "34. The compound of formula I according to claim 28, wherein D contains one double bond.",
    "35. The compound of formula I according to claim 34, wherein said double bond is at position 13,14 of said D chain.",
    "36. The compound of formula I according to claim 35, wherein said double bond is cis.",
    "37. The compound according to claim 36, wherein said D chain is substituted with R 4, wherein R 4 is H, oxo, hydroxy, C 1-6 alkoxy or C 1-6 alkyl.",
    "38. The compound according to claim 37, wherein said R 4 is H or C 1-6 alkyl.",
    "39. The compound according to claim 38, wherein said R 4 is H or methyl.",
    "40. The compound according to claim 39, wherein said R 4 is H or 10-(S) - Me.",
    "41. The compound of formula I according to claim 1, wherein A is a carboxylic acid.",
    "42. A compound according to claim 1, wherein W is N; R 3 is a group of formula - NH - C(O) - NHR 32 or - NH - C(O) - OR 32, wherein R 32 is C 1-4 alkyl or C 4-6 cycloalkyl; D is a 6 to 8 atom saturated or unsaturated alkylene chain linked to R 1 syn to A, optionally containing one or two heteroatoms independently selected from: O, S or N - R 41, wherein R 41 is H or C 2-7 acyl; R 4 is H or from one to three substituents independently selected from hydroxy or C 1-6 alkyl; and A is a carboxylic acid, or a pharmaceutically acceptable salt or ester thereof.",
    "43. The compound of formula I according to claim 42, wherein R 21 is H or methoxy; R 22 is C 1-6 alkoxy, or Het selected from the group consisting of: wherein R 24a is H, C 1-6 alkyl, NH - R 25, NH - C(O) - R 25 or NH - C(O) - NH - R 25, wherein R 25 is: H, C 1-6 alkyl or C 3-6 cycloalkyl; or R 24a is NH - C(O) - OR 26, wherein R 26 is C 1-6 alkyl or C 3-6 cycloalkyl; and R 24b is H or C 1-6 alkyl; R 3 is urea of the formula NH - C(O) - NHR 32 or a carbamate of the formula NH - C(O) - OR 32, wherein R 32 is C 1-6 alkyl or C 3-6 cycloalkyl; D is a 7-atom alkylene chain optionally containing one double bond at position 11,12 or 13,14; said D chain optionally containing one heteroatom independently selected from: O, S, NH, N(Me), and N(Ac); and R 4 is C 1-6 alkyl.",
    "44. The compound of formula I according to claim 43, wherein R 21 is methoxy, and R 22 is ethoxy or wherein R 24a is NH - (C 1-4 alkyl); NH - (C 3-6 cycloalkyl); NH - C(O) - (C 1-4 alkyl); NH - C(O) - (O) - (C 1-4 alkyl); or NH - C(O) - NH - (C 1-4 alkyl); D is a C7 all carbon chain, saturated or containing one cis double bond at position 13,14.",
    "45. A compound of formula: comprising a single stereoisomer at R 1, wherein the optional double bond between 12 and 13, the position 13-R 1 group bond stereochemistry and R 22 are defined as follows: double bond between 12 and position 13 - R 1 bond Cpd. # 13: stereochem: R 22: 101 12,13-trans 1R, position 13 syn to phenyl; amide 102 none 1R, position 13 syn to phenyl; acid and none 1R position 13 syn to phenyl 103 amide.",
    "46. A compound of formula: comprising a single stereoisomer at R 1, wherein R 3, R 4, the optional 11, 12 or 13, 14 double bond position 14-R 1 bond stereochemistry, R 21 and R 22 are defined as follows: position 14-R 1 bond Cpd double stereo- # R 3: R 4: bond: chemistry: R 21: R 22: 202 NH-Boc H 11,12- 1R or 1S, H H; trans position 14 syn to acid 203 NH-acetyl H 11,12- 1R or 1S, H H; trans position 14 syn to acid 205 NH-Boc 11-OH none 1R or 1S, H H; 12-OH position 14 cis syn to acid 206 NH-Boc H 13,14- 1R, H H; cis position 14 syn to acid 207 NH-Boc H 13,14- 1R, OMe H; cis position 14 syn to acid 208 NH-Boc H 13,14- 1R, OMe phenyl; cis position 14 syn to acid 209 NH-C(O)- H 13,14- 1R, OMe phenyl; NH-tBu cis position 14 syn to acid 210 NH-Boc H 13,14- 1S, OMe phenyl; cis position 14 syn to acid 211 NH 2 H 13,14- 1R, OMe phenyl; cis position 14 syn to acid 213 OH (one H 13,14- 1R, OMe H; isomer) cis position 14 syn to acid 214 NH-Boc 10-oxo 13,14- 1R, OMe phenyl; cis position 14 syn to acid 215 NH-Boc H none 1R, OMe phenyl; position 14 syn to acid 217 NH-Boc 10-OH 13,14- 1R, OMe phenyl; (mixt cis position 14 dia syn to acid stereo) 218 NH-Boc 10-oxo 13,14- 1R, OMe phenyl; cis position 14 syn to amide 219 NH-Ac H none 1R, OMe phenyl; position 14 syn to acid and 220 NH-Boc H 13,14- cis 1R, position 14 syn to amide OMe",
    "47. A compound of formula: comprising a single stereoisomer at R 1, wherein R 3, D, D - R 1 bond stereochemistry, R 21 and R 22 are defined as follows: D - R 1 bond Cpd. # R 3: - D -: stereochemistry: R 21: R 22: 301 NH - Boc 1R or 1S, D syn to acid H H; 302 NH - Boc 1R, D syn to amide OMe Ph; 303 NH - Boc 1R, D syn to amide OMe Ph; 304 NH - Boc 1R, D syn to acid OMe Ph; 305 HO 1R, D syn to acid OMe Ph; 306 NH - Boc 1R, D syn to amide OMe Ph; 307 NH - Boc 1R, D syn to acid OMe and 308 NH - Ac 1R, D syn to acid OMe OEt.",
    "48. A compound of formula: wherein the position 14-R 1 bond is syn to acid, R 4, X 9, and the optional 11,12 double bond are defined as follows: 11, 12 double Cpd # R 4: X 9: bond: 401 H CH 2 trans; 402 H CH 2 cis; 403 H O trans; 404 O trans; 405 O trans; 406 H O none; 407 O none; 408 O none; 409 O cis; 410 S trans; 411 S cis; and 8-(Me) 2 9-S Cis. 412",
    "49. A compound of formula: wherein the position 14-R 1 bond is syn to acid, X 10, X 11, and X 12 are defined as follows: Cpd # X 10: X 11: X 12: 501 CH 2 O CH 2; 502 CH 2 CH 2 CH 2; 503 CH 2 CH 2 NH; 504 CH 2 CH 2 N(Me); 505 CH 2 CH 2 N(CO)Me; 506 CH 2 CH 2 N(CO)Ph; 507 NH CH 2 CH 2; and N(CO)Me CH 2 CH 2 508.",
    "50. A compound of formula: wherein the position 14-R 1 bond is syn to acid, R 21 and R 22 are defined as follows: Cpd # R 21: R 22: 601 N(Me) 2 602 OH (CF 3); and 603 OMe",
    "51. A compound of formula: wherein the position 14-R 1 bond is syn to acid, R 4, X 9, X 10, X 11, the optional 13,14 double bond and R 22 are defined as follows: X 9; X 10; 13,14 double Cpd # R 4: and X 11: bond: R 22: 701 H X 9 = CH 2 Cis phenyl; X 10 = CH 2 X 11 = O 702 H CH 2 (All) Cis 703 H CH 2 (All) None 704 H CH 2 (All) Cis 705 H CH 2 (All) Cis 707 H CH 2 (All) Cis 708 H CH 2 (All) Cis 709 H CH 2 (All) None 710 H CH 2 (All) None 711 H CH 2 (All) None 712 H CH 2 (All) Cis - OEt; 713 H CH 2 (All) None 714 H CH 2 (All) None - OEt; 715 H CH 2 (All) Cis 716 H CH 2 (All) Cis 717 H CH 2 (All) Cis 718 H CH 2 (All) Cis 719 H CH 2 (All) Cis 720 H CH 2 (All) None 721 H CH 2 (All) None 722 H CH 2 (All) Cis 723 H CH 2 (All) None 724 H CH 2 (All) None 725 H CH 2 (All) Cis 726 H CH 2 (All) Cis 727 H CH 2 (All) Cis - CH 2 - OMe; 728 H CH 2 (All) Cis Me; 729 H CH 2 (All) Cis 730 H CH 2 (All) None 731 H CH 2 (All) Cis 732 H CH 2 (All) Cis 733 H CH 2 (All) Cis 734 H CH 2 (All) Cis 735 H CH 2 (All) Cis 736 H CH 2 (All) Cis 737 H CH 2 (All) Cis 738 H CH 2 (All) Cis 739 10-(R) Me CH 2 (All) none Ph; 740 10-(S) Me CH 2 (All) none Ph; and 741 H CH 2 (All) Cis",
    "52. A compound of formula: wherein the position 14-R 1 bond is syn to acid, said 13,14 double bond is cis, R 32, R 4 and R 22 are defined as follows: Cpd # R 32: R 4: R 22: 801 H 803 n-Pr H OEt; 804 H 805 H 806 H OEt; 807 H OEt; 808 H OEt; 809 H 810 H 811 H 812 H 813 H OEt; 814 H 815 H 816 H 817 H 818 H 819 H 820 H 821 H 822 H 823 H and 824 10-(R) Me OEt.",
    "53. A compound of formula: wherein the position 14-R 1 bond is syn to acid, R 32, R 4 and R 22 are defined as follows: Cpd # R 32: R 4: R 22: 901 H OEt; 902 H 903 H 904 H 905 H 906 H 907 H 908 H 909 H 910 H 911 H 912 H 913 H 914 H 915 H and 916 10 (R) Me OEt.",
    "54. A method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I according to claim 1.",
    "55. A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "56. The pharmaceutical composition according to claim 55, further comprising an immunomodulatory agent.",
    "57. The pharmaceutical composition according to claim 56, wherein said immunomodulatory agent is selected from the group consisting of: α-, β-, and γ-interferons.",
    "58. The pharmaceutical composition according to claim 55, further comprising an antiviral agent.",
    "59. The pharmaceutical composition according to claim 58, wherein said antiviral agent is selected from the group consisting of: ribavirin and amantadine.",
    "60. The pharmaceutical composition according to claim 55, further comprising another inhibitor of HCV NS 3 protease.",
    "61. The pharmaceutical composition according to claim 55, further comprising an inhibitor of other targets in the HCV life cycle.",
    "62. A method for treating or preventing the contamination of a material by the hepatits C virus comprising contacting said material with an effective amount of a compound of formula I according to claim 1.",
    "63. A method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.",
    "64. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 55.",
    "65. The pharmaceutical composition according to claim 61, wherein said inhibitor inhibits a target selected from the group consisting of: helicase, polymerase, and metalloprotease.",
    "66. The pharmaceutical composition according to claim 57, wherein the immunomodulatory agent is α-interferon.",
    "67. The pharmaceutical composition according to claim 57, further comprising an antiviral agent.",
    "68. The pharmaceutical composition according to claim 67, wherein the antiviral agent is ribavirin.",
    "69. The pharmaceutical composition according to claim 66, further comprising an antiviral agent.",
    "70. The pharmaceutical composition according to claim 69, wherein the antiviral agent is ribavirin.",
    "71. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 57.",
    "72. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 59.",
    "73. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 60.",
    "74. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 61.",
    "75. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 66.",
    "76. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 67.",
    "77. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 68.",
    "78. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 69.",
    "79. A method of treating a hepatitis C viral infection in a human by administering thereto an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 70.",
    "80. A compound according to claim 44, wherein R 3 is - NH - C(O) - OR 32, wherein R 32 is C 1-4 alkyl or C 4-6 cycloalkyl; D is a C7 all carbon chain, saturated or containing one cis double bond at position 13,14; and R 22 is wherein R 24a is NH - (C 1-4 alkyl); NH - (C 3-6 cycloalkyl); NH - C(O) - (C 1-4 alkyl); NH - C(O) - O - (C 1-4 alkyl); or NH - C(O) - NH - (C 1-4 alkyl).",
    "81. A compound of formula: wherein said position 14-R 1 bond is syn to acid, said 13,14 double bond is cis, R 32, R 4 and R 22 are defined as follows: Cpd # R 32: R 4: R 22: 825 H 826 H 827 H and 828 H",
    "82. The compound 208 according to claim 46.",
    "83. The compound 209 according to claim 46.",
    "84. The compound 214 according to claim 46.",
    "85. The compound 217 according to claim 46.",
    "86. The compound 408 according to claim 48.",
    "87. The compound 508 according to claim 49.",
    "88. The compound 601 according to claim 50.",
    "89. The compound 603 according to claim 50.",
    "90. The compound 702 according to claim 51.",
    "91. The compound 703 according to claim 51.",
    "92. The compound 709 according to claim 51.",
    "93. The compound 714 according to claim 51.",
    "94. The compound 715 according to claim 51.",
    "95. The compound 719 according to claim 51.",
    "96. The compound 725 according to claim 51.",
    "97. The compound 736 according to claim 51.",
    "98. The compound 738 according to claim 51.",
    "99. The compound 801 according to claim 52.",
    "100. The compound 809 according to claim 52.",
    "101. The compound 810 according to claim 52.",
    "102. The compound 811 according to claim 52.",
    "103. The compound 812 according to claim 52.",
    "104. The compound 814 according to claim 52.",
    "105. The compound 818 according to claim 52.",
    "106. The compound 819 according to claim 52.",
    "107. The compound 821 according to claim 52.",
    "108. The compound 822 according to claim 52.",
    "109. The compound 823 according to claim 52.",
    "110. The compound 827 according to claim 81.",
    "111. The compound 904 according to claim 53.",
    "112. The compound 909 according to claim 53.",
    "113. The compound 914 according to claim 53.",
    "114. The compound 916 according to claim 53.",
    "115. A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I according to any one of claims 82 to 114, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.",
    "116. The pharmaceutical composition according to claim 115, further comprising an immunomodulatory agent.",
    "117. The pharmaceutical composition according to claim 116, wherein said immunomodulatory agent is selected from the group consisting of: α-, β-, and γ-interferons.",
    "118. The pharmaceutical composition according to claim 117, wherein said immunomodulatory agent is α-interferon.",
    "119. The pharmaceutical composition according to claim 115, further comprising an antiviral agent.",
    "120. The pharmaceutical composition according to claim 119, wherein said antiviral agent is ribavirin.",
    "121. The pharmaceutical composition according to claim 117, further comprising an antiviral agent.",
    "122. The pharmaceutical composition according to claim 121, wherein said antiviral agent is ribavirin.",
    "123. The pharmaceutical composition according to claim 118, further comprising an antiviral agent.",
    "124. The pharmaceutical composition according to claim 123, wherein said antiviral agent is ribavirin.",
    "125. The pharmaceutical composition according to claim 115, further comprising another inhibitor of HCV NS 3 protease.",
    "126. The pharmaceutical composition according to claim 115, further comprising an inhibitor of other targets in the HCV life cycle.",
    "127. The pharmaceutical composition according to claim 126, wherein said inhibitor inhibits a target selected from the group consisting of: a helicase, a polymerase, and a metalloprotease.",
    "128. A compound having the following formula (A): wherein X is PG or R 2; each PG is independently a protecting group; R 2 is as defined in claim 1; A′ is a protected carboxylic acid; and n is 2.",
    "129. A process for preparing a compound of formula (A) according to claim 128, said process comprising reacting a compound of formula (B) with a compound of formula (C): wherein PG, X, A′ and n are as defined in claim 128.",
    "130. A compound having the following formula (D): wherein X is PG or R 2; PG is a protecting group; R 2 is as defined in claim 1; A′ is a protected carboxylic acid; and n is 2.",
    "131. A process for preparing a compound of the formula (D) according to claim 130, said process comprising cleaving the protecting group PG on the pyrrolidine ring in the compound of formula (A): wherein X is PG or R 2; each PG is independently a protecting group; R 2, A′ and n are as defined in claim 130.",
    "132. A compound having the following formula (E): wherein X is PG or R 2; PG is a protecting group; R 2 is as defined in claim 1; A′ is a protected carboxylic acid; R 3 is as defined in claim 1; n is 0 or 2; and: (1) when n is 0, D′ is a 5-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41, or (2) when n is 2, D′ is a 3-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41; and R 41 is as defined in claim 1.",
    "133. A process for preparing a compound of formula (E) according to claim 132, said process comprising reacting a compound of formula (D) with a compound of formula (F): wherein X, A′, n, R 3, and D′ are as defined in claim 132.",
    "134. A compound having the following formula (G): wherein R 2 and R 3 are as defined in claim 1; A′ is a protected carboxylic acid; n is 0 or 2; and (1) when n is 0, D′ is a 5-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41, or (2) when n is 2, D′ is a 3-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41; and R 41 is as defined in claim 1.",
    "135. A process for preparing a compound of formula (G) according to claim 134, said process comprising causing a ring-closure of the compound of formula (E) by reacting the compound of formula (E) in the presence of a transition metal-based catalyst to obtain a compound of formula (G′): wherein X is PG or R 2; PG is a protecting group; and R 2, R 3, D′, n and A′ are as defined in claim 134; and when X is PG, the compound of formula (G′) is deprotected and further reacted with a compound R 2 - OH to obtain a compound of formula (G): wherein R 2, R 3, D′, n and A′ are as defined in claim 134.",
    "136. A compound having the following formula (H): wherein R 2 and R 3 are as defined in claim 1; A′ is a protected carboxylic acid; n is 0 or 2; and (1) when n is 0, D′ is a 5-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41, or (2) when n is 2, D′ is a 3-atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N - R 41; and R 41 is as defined in claim 1.",
    "137. A process for preparing a compound of the formula (H) according to claim 136, said process comprising subjecting the compound of formula (G) to hydrogenation: wherein R 2, R 3, D′, n, and A′ are as defined in claim 136.",
    "138. A compound having the following formula (J): wherein R 2 and R 3 are as defined in claim 1; m is 1 to 5; n is 1 to 5; A′ is a protected carboxylic acid; and Cbz is benzyloxycarbonyl.",
    "139. A compound of the following formula (K): wherein R 2 and R 3 are defined in claim 1; m is 1 to 5; n is 1 to 5; A′ is a protected carboxylic acid; and Cbz is benzyloxycarbonyl.",
    "140. A process for preparing a compound of formula (K) according to claim 139, said process comprising subjecting the compound of formula (J) to hydroboration and then oxidation: wherein R 2, R 3, m, n, A′ and Cbz are as defined in claim 139.",
    "141. A compound having the following formula (L): wherein R 2 and R 3 are as defined in claim 1; m is 1 to 5; n is 1 to 5; and A′ is a protected carboxylic acid.",
    "142. A process for preparing a compound of formula (L) according to claim 141, said process comprising subjecting the compound of formula (K) to hydrogenation in the presence of acid: wherein R 2 and R 3, m, n and A′ are as defined in claim 141; and Cbz is benzyloxycarbonyl.",
    "143. A method of preventing a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.",
    "144. A method of treating a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, and at least one additional agent selected from an immunomodulatory agent, an antiviral agent, another inhibitor of HCV NS3 protease, and an inhibitor of another target in the HCV life cycle, wherein said at least one additional agent is administered prior to, concurrently with, or following the administration of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof.",
    "145. A method of preventing a hepatitis C viral infection in a mammal comprising administering to the mammal an anti-hepatitis C virally effective amount of a combination of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof, and at least one additional agent selected from an immunomodulatory agent, an antiviral agent, another inhibitor of HCV NS3 protease, and an inhibitor of another target in the HCV life cycle, wherein said at least one additional agent is administered prior to, concurrently with, or following the administration of the compound of formula I according to claim 1, or a therapeutically acceptable salt or ester thereof."
  ],
  "cpc": [
    "C07K 5/06139",
    "A61K 38/00",
    "C07K 5/0802"
  ],
  "assignees": [
    "BOEHRINGER INGELHEIM CA LTD"
  ],
  "filing_date": "2001-01-16",
  "publication_date": "2003-08-19",
  "grant_date": "2003-08-19",
  "priority_date": "1999-04-06",
  "application_number": "US-76094601-A",
  "family_id": "27736913",
  "citations": [
    "CA2087021A1",
    "CA2222524A1",
    "EP0937459A2",
    "US3139421A",
    "US5114918A",
    "US5192746A",
    "US5633388A",
    "US5721210A",
    "US5830888A",
    "US5866684A",
    "US5869253A",
    "US6018020A",
    "US6323180B1",
    "WO0009543A2",
    "WO0009558A1",
    "WO0177113A2",
    "WO0181325A2",
    "WO0208244A2",
    "WO0208256A2",
    "WO0218369A2",
    "WO9200995A1",
    "WO9415958A2",
    "WO9533764A2",
    "WO9701579A2",
    "WO9706804A1",
    "WO9743310A1",
    "WO9817679A1",
    "WO9822496A2",
    "WO9846597A1",
    "WO9846630A1",
    "WO9853814A1",
    "WO9907733A2",
    "WO9907734A2",
    "WO9938888A2",
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    "WO9964442A1"
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}