Cyclosporin analogues for preventing or treating hepatitis C infection

摘要

The present invention relates to cyclosporin analogues having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel cyclosporin analogue compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.

主权项

1. A compound represented by the formula:or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein: X is OH or OAc;  where, R1 is selected from:
a) R11, wherein R11 is selected from:
1) Hydrogen;2) Deuterium;3) C1-C8 alkyl;4) Substituted C1-C8 alkyl;5) C2-C8 alkenyl;6) Substituted C2-C8 alkenyl;7) C2-C8 alkynyl;8) Substituted C2-C8 alkynyl;9) C3-C12 cycloalkyl;10) Substituted C3-C12 cycloalkyl;11) Aryl;12) Substituted aryl;13) Heterocycloalkyl;14) Substituted heterocycloalkyl;15) Heteroaryl; or16) Substituted heteroaryl;b) —C(O)OR11;c) —C(O)R11;d) —C(O)OCH2-T-R12, where T is —O— or —S— and R12 is selected from:
1) C1-C8 alkyl;2) Substituted C1-C8 alkyl;3) C2-C8 alkenyl;4) Substituted C2-C8 alkenyl;5) C2-C8 alkynyl;6) Substituted C2-C8 alkynyl;7) C3-C12 cycloalkyl;8) Substituted C3-C12 cycloalkyl;9) Aryl;10) Substituted aryl;11) Heterocycloalkyl;12) Substituted heterocycloalkyl;13) Heteroaryl; or14) Substituted heteroaryl;e) —C(O)N(R13)(R14), where R13 and R14 are independently selected from R11 and R11 is as previously defined or R13 and R14 combined together with the N which attached to is substituted or unsubstituted heterocycloalkyl;f) —C(O)SR11;g) —C(S)OR11;h) —C(O)OCH2OC(O)R12;i) —C(S)SR11; andj) R15, where R15 is selected from:
1) -M-R11, where M is selected from:
i. C1-C8 alkyl;ii. Substituted C1-C8 alkyl;iii. C2-C8 alkenyl;iv. Substituted C2-C8 alkenyl;v. C2-C8 alkynyl;vi. Substituted C2-C8 alkynyl;vii. C3-C12 cycloalkyl; andviii. Substituted C3-C12 cycloalkyl;2) -M-NR16R11, where R16 is R11 and R11 is as previously defined, or R16 and R11, taken together with the nitrogen atom to which they are attached is substituted or unsubstituted heterocycloalkyl;3) -M-S(O)mR11, where m=0, 1, or 2;4) -M-OR11;5) -M-C(O)R11;6) -M-OC(O)R12;7) -M-OC(O)OR12;8) -M-NR17C(O)R12, where R17 is R11;9) -MNR17C(O)OR12;10) -M-C(O)NR16R11;11) -M-C(O)N(R16)—OR11;12) -M-OC(O)NR16R11;13) -M-NR17C(O)NR16R11, where R11 and R16 are as previously defined or R16 and R11, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl;14) -M-C(S)SR11;15) -M-OC(S)SR12;16) -M-NR17C(O)SR12;17) -M-SC(O)NR16R11 where R11 and R16 are as previously defined or R16 and R11, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl;18) -M-CH═N—OR11; and19) -M-CH═N—NR16R11 where R11 and R16 are as previously defined or R16 and R11, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl; A is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; V is absent, —O— or —S(O)m—, where m=0, 1, or 2; W is —O— or —S(O)m—, where m=0, 1, or 2; R2 is R1; R3 is selected from methyl, ethyl, allyl and propyl; R4 and R5 are independently selected from: hydrogen, methyl, ethyl, allyl, propyl and isopropyl; R6 is 1) C1-C8 alkyl;
2) Substituted C1-C8 alkyl;3) C2-C8 alkenyl;5) Substituted C2-C8 alkenyl;6) C2-C8 alkynyl;7) Substituted C2-C8 alkynyl;8) C3-C12 cycloalkyl;9) Substituted C3-C12 cycloalkyl;10) Aryl;11) Substituted aryl;12) Heterocycloalkyl;13) Substituted heterocycloalkyl;14) Heteroaryl;15) Substituted heteroaryl;16) —C(O)OR11;17) —C(O)OCH2-T-R12, where T is —O— or —S— and R12 is selected from:
a) C1-C8 alkyl;b) Substituted C1-C8 alkyl;c) C2-C8 alkenyl;d) Substituted C2-C8 alkenyl;e) C2-C8 alkynyl;f) Substituted C2-C8 alkynyl;g) C3-C12 cycloalkyl;h) Substituted C3-C12 cycloalkyl;i) Aryl;j) Substituted aryl;k) Heterocycloalkyl;l) Substituted heterocycloalkyl;m) Heteroaryl; orn) Substituted heteroaryl;18) —C(O)N(R13)(R14);19) —C(O)SR11;20) —C(S)OR11;21) —C(O)OCH2OC(O)R12;22) —C(S)SR11; and23) R15, where R15 is selected from:
a) -M-R11;b) -M-NR16R11;c) -M-S(O)mR11;d) -M-OR11;e) -M-C(O)R11;f) -M-OC(O)R12;g) -M-OC(O)OR12;h) -M-NR17C(O)R12;i) -MNR17C(O)OR12;j) -M-C(O)NR16R11;k) -M-C(O)N(R16)—OR11;l) -M-OC(O)NR16R11;m) -M-NR17C(O)NR16R11;n) -M-C(S)SR11;o) -M-OC(S)SR12;p) -M-NR17C(O)SR12;q) -M-SC(O)NR16R11;r) -M-CH═N—OR11; ands) -M-CH═N—NR16R11; and n and n′ are each independently 0, 1 or 2.