2′-cyano substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases

摘要

Compounds of Formula (I) are disclosed, wherein R1, R2, R3, R4, R5, and R18 are defined herein. The compounds encompassed by Formula (I) include compounds which are HCV NS5B inhibitors and other compounds which can be metabolized in vivo to HCV NS5B inhibitors. The compounds and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of infection by HCV and the prophylaxis, treatment, or delay in the onset of disease caused by HCV. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.;

主权项

1. A compound having the structure:or a pharmaceutically acceptable salt,wherein:
X is O, N, S or CH2; Y is N or —C(R6)—; R1 is H, R2 is H, —C(O)—(C1-C6 alkyl) oror R1 and R2 join to form a group having the formula: R3 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C7 cycloalkyl; R4 and R5 are each independently selected from H, —OR12, —NHC(O)OR12, —NHC(O)N(R12)2, —N(R12)2 and —NHC(O)R12; R6 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, —OR12, —SR12, —N(R12)2, C3-C7 cycloalkyl, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl; R7 is H, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, or —(C1-C3 alkylene)-C(O)O—(C1-C6 alkyl), wherein said C6-C10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R13, R8 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C1-C6 alkyl can be optionally substituted with a group selected from halo, —OR12, —SR12, guanidino, —N(R12)2, —C(O)OR12, —C(O)N(R12)2, —NHC(O)R12, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C1-C6 alkyl, halo and —OR12; R9 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C1-C6 alkyl can be optionally substituted with a group selected from halo, —OR12, —SR12, guanidino, —N(R12)2, —C(O)OR12, —C(O)N(R12)2, —NHC(O)R12, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C1-C6 alkyl, halo and —OR12; R10 is H, C1-C20 alkyl, C2-C20 alkenyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), —(C1-C3 alkylene)m-(C6-C10 aryl) or —(C1-C3 alkylene)m-adamantyl, wherein said C1-C20 alkyl group, said C2-C20 alkenyl group, said C6-C10 aryl group and said adamantyl group can be optionally substituted with up to three groups, each independently selected from halo, —OR12, —C(O)OR12, CN, NO2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —N(R12)2, —C(O)N(R12)2—SR12, —S(O)R12, —S(O)2R12, —S(O)2N(R12)2, —NHC(O)R12, —NHC(O)OR12 and —NHC(O)N(R12)2; R11 is H, C1-C20 alkyl, C2-C20 alkenyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), C3-C7 cycloalkyl, —(C1-C3 alkylene)m-C6-C10 aryl or —(C1-C3 alkylene)m-adamantyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, wherein said C1-C20 alkyl group, said C2-C20 alkenyl group, said C6-C10 aryl group, said adamantyl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR12, —SR12, —S(O)R12, —S(O)2R12, —S(O)2N(R12)2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R12)2, —C(O)OR12, —C(O)N(R12)2 and —NHC(O)R12, —NHC(O)OR12 and —NHC(O)N(R12)2; each occurrence of R12 is independently H, C1-C10 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), —(C1-C3 alkylene)m-(C6-C10 aryl), —(C1-C3 alkylene)m-(4 to 7-membered heterocycloalkyl), —(C1-C3 alkylene)m-(5- or 6-membered monocyclic heteroaryl) or —(C1-C3 alkylene)m-(9- or 10-membered bicyclic heteroaryl), wherein said C3-C7 cycloalkyl group, said C6-C10 aryl group, said 4 to 7-membered heterocycloalkyl group, said -5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with R16; R13 represents from one to five substituent groups, each independently selected from C1-C6 alkyl, halo, —OR12, —SR12, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R12)2, —C(O)OR12, —C(O)N(R12)2 and —NHC(O)R12, or any two R13 groups on adjacent ring carbon atoms can combine to form —O—R14—O—; R14 is —[C(R15)2]n—; each occurrence of R15 is independently H or C1-C6 alkyl; R16 represents from one to five substituent groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, —OR17, —SR17, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R17)2, —C(O)OR17, —C(O)N(R17)2 and —NHC(O)R17; each occurrence of R17 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), —(C1-C3 alkylene)m-(C6-C10 aryl), —(C1-C3 alkylene)m-(4 to 7-membered heterocycloalkyl), —(C1-C3 alkylene)m-(5- or 6-membered monocyclic heteroaryl) or —(C1-C3 alkylene)m-(9- or 10-membered bicyclic heteroaryl); R18 is H, C1-C6 alkyl, —O(C1-C6 alkyl), C1-C6 alkynyl, C1-C6 alkenyl, or CN; and each occurrence of m is independently 0 or 1, and each occurrence of n is independently 1, 2, or 3.