发明名称 2'-CYANO SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF USEFUL FOR THE TREATMENT OF VIRAL DISEASES
摘要 The present invention relates to 2′-Cyano Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R1, R2 and R3 are as defined herein. The present invention also relates to compositions comprising at least one 2′-Cyano Substituted Nucleoside Derivative, and methods of using the 2′-Cyano Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.;
申请公布号 US2014161770(A1) 申请公布日期 2014.06.12
申请号 US201214111688 申请日期 2012.04.11
申请人 Girijavallabhan Vinay;Njoroge F. George;Bogen Stephane;Kerekes Angela;Bennett Frank;Huang Ying;Nair Latha;Pissarnitski Dmitri;Verma Vishal;Dang Qun;Davies Ian;Olsen David B.;Stamford Andrew;Vacca Joseph P. 发明人 Girijavallabhan Vinay;Njoroge F. George;Bogen Stephane;Kerekes Angela;Bennett Frank;Huang Ying;Nair Latha;Pissarnitski Dmitri;Verma Vishal;Dang Qun;Davies Ian;Olsen David B.;Stamford Andrew;Vacca Joseph P.
分类号 C07H19/16;A61K31/7076;A61K45/06;C07H19/20;C07H19/10;C07H19/06;A61K31/7056;A61K31/7068 主分类号 C07H19/16
代理机构 代理人
主权项 1. A compound having the structure: or a pharmaceutically acceptable salt thereof, wherein: X is O, S or CH2;B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups: Y is N or —C(R19)—;R1 is H, R2 is H or or 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, R5, R7 and R8 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, —OR20, —SR20 or —N(R20)2;R6, R9 and R10 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR20, —SR20, —S(O)R20, —S(O)2R20, —S(O)2N(R20)2, —NHC(O)OR20, —NHC(O)N(R20)2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R20)2, —NH(C1-C6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C1-C6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R20, —C(O)OR20, —C(O)N(R20)2 and —NHC(O)R20, wherein said C2-C6 alkenyl group and said C2-C6 alkynyl group can be optionally substituted a halo group;R12 is H or —(C1-C6 alkylene)-T-R21;R13 is H or —(C1-C6 alkylene)-T-R21, or R12 and R13 can join to form a C2-C4 alkylene group between the oxygen atoms that R12 and R13 are attached to, wherein said C2-C4 alkylene group is substituted with at least one C6-C10 aryl group;R14 is H, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, 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 R22;R15 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, —OR20, —SR20, guanidino, —N(R20)2, —C(O)OR20, —C(O)N(R20)2, —NHC(O)R20, 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 —OR20;R16 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, —OR20, —SR20, guanidino, —N(R20)2, —C(O)OR20, —C(O)N(R20)2, —NHC(O)R20, 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 —OR20;R17 is H, C1-C20 alkyl, C2-C20 alkenyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), —(C1-C3 alkylene)m-(C6-C10 aryl) or 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, —OR20, —C(O)OR20, 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(R20)2, —C(O)N(R20)2—SR20, —S(O)R20, —S(O)2R20, —S(O)2N(R20)2, —NHC(O)R20, —NHC(O)OR20 and —NHC(O)N(R20)2 and;R18 is H, C1-C6 alkyl, C3-C7 cycloalkyl, —(C1-C3 alkylene)m-C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl or: 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 up to five groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, —OR20, —SR20, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R20)2, —C(O)OR20, —C(O)N(R20)2 and —NHC(O)R20 R19 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, —OR20, —SR20, N(R20)2, C3-C7 cycloalkyl, C6-C10 aryl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl;each occurrence of R20 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 R26;each occurrence of R21 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —OR20, —O—(C1-C6 haloalkyl) or —N(R20)2, wherein said C2-C6 alkenyl group, said C2-C6 alkynyl group, said C3-C7 cycloalkyl group, said C3-C7 cycloalkenyl group, 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 up to five groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, —OR20, —SR20, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2 and —NHC(O)R20;R22 represents from one to five substituent groups, each independently selected from C1-C6 alkyl, halo, —OR20, —SR20, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R20)2, —C(O)OR20, —C(O)N(R20)2 and —NHC(O)R20, or any two R22 groups on adjacent ring carbon atoms can combine to form —O—R23—O—;R23 is —[C(R24)2]n—;each occurrence of R24 is independently H or C1-C6 alkyl;each occurrence of R25 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, —(C1-C3 alkylene)m-(C6-C10 aryl), 4 to 7-membered heterocycloalkyl, 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl, wherein said C1-C6 alkyl group, said C2-C6 alkenyl group, said C2-C6 alkynyl group, 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 R26; or two R25 groups, together with the common nitrogen atom to which they are attached, join to form a 4- to 7-membered heterocycloalkyl group;R26 represents from one to five substituent groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, —OR27, —SR27, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R27)2, —C(O)OR27, —C(O)N(R27)2 and —NHC(O)R27;each occurrence of R27 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);R28 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —OR20, —O—(C1-C6 haloalkyl) or —N(R20)2, wherein said C2-C6 alkenyl group, said C2-C6 alkynyl group, said C3-C7 cycloalkyl group, said C3-C7 cycloalkenyl group, 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 up to five groups, each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, —OR20, SR20, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —O—(C1-C6 haloalkyl), —CN, —NO2, —N(R20)2, —C(O)R20, —C(O)OR20, —C(O)N(R20)2 and —NHC(O)R20;each occurrence of R29 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), 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 R26;each occurrence of T is independently —S—, —O—, —SC(O)—, —SC(S)—, —OC(O)— and —OC(S)—;each occurrence of m is independently 0 or 1; andeach occurrence of n is independently 1 or 2.
地址 Whippany NJ US