Claims for Patent: 8,648,037

Summary for Patent: 8,648,037

Title:	Macrocyclic proline derived HCV serine protease inhibitors
Abstract:	The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
Inventor(s):	Yat Sun Or, Jun Ma, Guoqiang Wang, Jiang Long, Bin Wang
Assignee:	Enanta Pharmaceuticals Inc
Application Number:	US13/237,120
Patent Claims:	1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)—or —C(═ON—CN)—; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; M1 and M2 are each independently selected from O or NR1; each R1 is independently selected at each occurrence from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from 0, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, and substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; W is absent, —O—, —S—, NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—; X and Y are taken together with the carbon atoms to which they are attached to form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocylic; X′ is N each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; R4 and R5 are each independently selected from H and R3; R and R′ are each independently selected from the group consisting of: (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, r substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen or deuterium; G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and R″ is selected from hydrogen, methyl, ethyl, and allyl. 2. The compound of claim 1, wherein the compound is of Formula II: or a pharmaceutically acceptable salt thereof, where X1-X4 are independently selected from —CR6 and N, wherein each R6 is independently selected from: (i) hydrogen; halogen; —NO2; —CN; or N3; (ii) -M-R3, wherein M is O, S, NH; (iii) NR4R5; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)—or —C(═N—CN)—; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; M1 and M2 are each independently selected from O and NR1; each R1 is independently selected at each occurrence from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) -C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; W is absent, —O—, —S—, NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—; X′ is N each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; R4 and R5 are each independently selected from H and R3; R and R′ are each independently selected from the group consisting of: (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4- C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen; deuterium; G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and R″ is selected from hydrogen, methyl, ethyl, and allyl. 3. The compound of claim 1, wherein the compound is of Formula III or IV: or a pharmaceutically acceptable salt thereof, where each Yi and Y2 are independently selected from CR6, N, and each Y3 is selected from NR6, S and O; each R6 is independently selected from: (i) hydrogen; halogen; —NO2; —CN; or N3; (ii) -M-R3, wherein M is O, S, or NH; (iii) NR4R5; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)—or —C(═N—CN)—; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; M1 and M2 are each independently selected from O and NR1; each R1 is independently selected at each occurrence from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; W is absent, O, S, NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—; X′ is N; each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; each R4 and R5 is independently selected from H and R3; R and R′are each independently selected from the group consisting of: (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen or deuterium; G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and R″ is selected from hydrogen, methyl, ethyl, and allyl. 4. The compound of claim 1, wherein the compound is of Formula VI: or a pharmaceutically acceptable salt thereof, wherein X1-X4 are independently selected from —CR6 and N, wherein each R6 is independently selected from: (i) hydrogen; halogen; —NO2; —CN; or N3; (ii) -M-R3, wherein M is O, S, or NH; (iii) NR4R5; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; M1 and M2 are each independently selected from O and NR1; each R1 is independently selected at each occurrence from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3- C12 cycloalkenyl; each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; each R4 and R5 is independently selected from H and R3; R and R′are each independently selected from the group consisting of: (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4- C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen; or deuterium; G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and R″ is selected from hydrogen, methyl, ethyl, and allyl. 5. The compound of claim 1, wherein the compound is of Formula VII: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4′ are each independently R6, or R1′ and R2′, R2′ and R3′, or R3 40 and R4′ combined together with the carbons they are attached to form aromatic or heteroaromatic or cyclic or heterocyclic ring; {circle around (B)} is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl; each R6 is independently selected from: (i) hydrogen; halogen; —NO2; —CN; or N3; (ii) -M-R3, wherein M is O, S, or NH; (iii) NR4R5; (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from 0, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2—C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted -C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl; each R4 and R5 is independently selected from H and R3, or R4 and R5 taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R and R′ are each independently selected from the group consisting of: (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl; (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (iii) heterocycloalkyl or substituted heterocycloalkyl; and (iv) hydrogen; or deuterium; and R″ is selected from hydrogen, methyl, ethyl, and allyl. 6. The compound of claim 5, wherein {circle around (B)} is selected from: 7. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient. 8. A method of treating a hepatitis C viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1. 9. A method of inhibiting the replication of hepatitis C virus, comprising contacting the hepatitis C virus with a hepatitis C virally effective NS3 protease inhibitory amount of the composition compound of claim 1. 10. The method of claim 8, further comprising administering concurrently an additional anti-hepatitis C virus agent. 11. The method of claim 10, wherein said additional anti-hepatitis C virus agent is selected from the group consisting of α-interferon, β-interferon, ribavarin, and adamantine. 12. The method of claim 10, wherein said additional anti-hepatitis C virus agent is an inhibitor of hepatitis C virus helicase, polymerase, metalloprotease, or IRES. 13. The pharmaceutical composition of claim 7, further comprising another anti-HCV agent. 14. The pharmaceutical composition of claim 7, further comprising an agent selected from interferon, ribavirin, amantadine, another HCV protease inhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, and an internal ribosome entry site inhibitor. 15. The pharmaceutical composition of claim 7, further comprising pegylated interferon. 16. The pharmaceutical composition of claim 7, further comprising another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator. 17. A compound of the formula or a pharmaceutically acceptable salt thereof 18. A pharmaceutical composition comprising the compound of claim 17 in combination with a pharmaceutically acceptable carrier. 19. A method of treating a hepatitis C viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 17. 20. A compound of the formula or a pharmaceutically acceptable salt thereof 21. A pharmaceutical composition comprising the compound of claim 20 in combination with a pharmaceutically acceptable carrier. 22. A method of treating a hepatitis C viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 20. 23. The compound of claim 1, selected from compounds of Formula VIII, and pharmaceutically acceptable salts thereof, wherein R, -L2-W-L1-, R′ and G for each compound are delineated in Table 1: TABLE 1 Compound R —L2—W—L1— R′ G 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256.