发明名称 Heterocyclyl Pyrimidine Analogues As JAK Inhibitors
摘要 The present invention relates to compounds of formula (I);;wherein X1 to X5, Z1 to Z3, Y0, RY1, RY2 and R have the meaning as cited in the description and the claims. Said compounds are useful as JAK inhibitors for the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders, and immunologically-mediated diseases. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.
申请公布号 US2014179664(A1) 申请公布日期 2014.06.26
申请号 US201214234662 申请日期 2012.07.24
申请人 Freeman Jay;Reader Valerie;Addison Glynn;Ramsden Nigel;Scanlon Jane Elizabeth;Harrison Richard John 发明人 Freeman Jay;Reader Valerie;Addison Glynn;Ramsden Nigel;Scanlon Jane Elizabeth;Harrison Richard John
分类号 C07D491/107;C07D403/14;C07D413/14;C07D403/12 主分类号 C07D491/107
代理机构 代理人
主权项 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is H; F; Cl; Sr; CN; CH3; CF3 or C(O)NH2; Ring A is a 5 membered aromatic heterocycle in which Z1, Z2, and Z3 are independently selected from the group consisting of C(R1); N; and N(R1), provided that at least one of Z1, Z2, Z3 is N or N(R1); Each R1 is independently H, halogen; CN; C(O)OR2; OR2; C(O)R2; C(O)N(R2R2a); S(O)2N(R2R2a); S(O)N(R2R2a); S(O)2R2; S(O)R2; N(R2)S(O)2N(R2aR2b); N(R2)S(O)N(R2aR2b); SR2; N(R2R2a); NO2; OC(O)R2; N(R2)C(O)R2a; N(R2)S(C)2R2a; N(R2)S(O)R2a; N(R2)C(O)N(R2aRb2); N(R2)C(O)OR2a; OC(O)N(R2R2a); T1; C1-6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein C1-6 alkyl: C2-6 alkenyl; and C2-6alkynyl are optionally substituted with one or more R3, which are the same or different; R2, R2a, R2b are independently selected from the group consisting of H; T1; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R3, which are the same or different; R3 is halogen; CN; C(O)OR4; OR4; C(O)R4; C(O)N(R4R4a); S(O)2N(R4R4a); S(O)N(R4R4a); S(O)2R4; S(O)R4; N(R4)S(O)2N(R4aR4b); N(R4)S(O)N(R4aR4b); SR4; N(R4R4a); NO2; OC(O)R4; N(R4)C(O)R4a; N(R4)S(O)2R4a; N(R4)S(O)R4a; N(R4)C(O)N(R4aR4b); N(R4)C(O)OR4a; OC(O)N(R4R4a); or T1; R4, R4a, R4b are independently selected from the group consisting of H; T1; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R5, which are the same or different; R5 is halogen; CN; C(O)OR5a; OR5a; C(O)R5a; C(O)R5a; C(O)N(R5aR5b); S(O)2N(R5aR5b); S(O)N(R5aR5b); S(O)2R5a; S(O)R5a; N(R5a)S(O)2N(R5bR5c); N(R5a)S(O)N(R5bR5c); SR5a; N(R5aR5b); NO2; OC(O)R5a; N(R5a)C(O)R5a; N(R5a)S(O)2R5b; N(R5a)S(O)R5b; N(R5a)C(O)N(R5bR5c); N(R5a)C(O)OR5b; or OC(O)N(R5aR5b); R5a, R5b, R5c are independently selected from the group consisting of H; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen; which are the same or different; T1 is C3-7 cycloalkyl; saturated 4 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T1 is optionally substituted with one or more R10, which are the same or different; Y0 is (CRY3RY4)n; n is 0; or 1; One of RY1; RY2; RY3; RY4 is RY0 and the others are selected from the group consisting of H; CH3; and CF3; RY0 is unsubstituted C1-4 alkyl; CH2CH2ORY5; CH2CH2C(O)TY1; CH2CH2C(O)ORY5; CH2CH2OC(O)RY5; CH2CH2N(RY5R5a); CH2CH2N(RY5)C(O)RY5a; CH2CH2C(O)N(RY5RY5a); CH2ORY5; CH2C(O)TY1; CH2C(O)ORY5; CH2OC(O)RY5; CH2N(RY5RY58); CH2N(RY5)C(O)RY5a; CH2C(O)N(RY5RY5a); C(O)TY1; C(O)ORY5; or C(O)N(RY5RY5a); RY5, RY5a are independently selected from the group consisting of H; TY1; and C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more RY6, which are the same or different; RY6 is halogen; ORY7; C(O)TY1; C(O)ORY7; OC(O)RY7; N(RY7RY7a); or N(RY7)C(O)RY7a; RY7; RY7a are independently selected from the group consisting of H, C1-4 alkyl; or TY1, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different; TY1 is unsubstituted C3-7 cycloalkyl; unsubstituted saturated 4 to 7 membered heterocyclyl; or saturated 7 to 11 membered heterobicyclyl; X1 is C(R6a) or N; X2 is C(R6b) or N; X3 is CH, CF, COH or N; X4 is CR6c) or N; X5 is C(R6d) or N, provided that at most two of X1, X2. X4, X5 are N; R6a, R6b, R6c, R6d are independently selected from the group consisting of H; halogen; CN; C(O)OR7; OR7; C(O)R7; C(O)N(R7R7a); S(O)2N(R7R7a); S(O)N(R7R7a); S(O)2R7; S(O)R7; N(R7)S(O)2N(R7aR7b); N(R7)S(O)N(R7aR7b); SR7; N(R7R7a); NO2; OC(O)R7; N(R7)C(O)R7a; N(R7)S(O)2R7a; N(R7)S(O)R7a, N(R7)C(O)N(R7aR7b); N(R7)C(O)OR7a; OC(O)N(R7R7a); T2; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R11, which are the same or different; Optionally the pair R6a/R6b is joined to form a ring T3; R7, R7a, R7b are independently selected from the group consisting of H; CN; T2; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R8, which are the same or different; R8 is halogen; CM; C(O)OR9; OR9; C(O)R9; C(O)N(R9R9a); S(O)2N(R9R9a); S(O)N(R9R9a); S(O)2R9; S(O)R9; N(R9)S(O)2N(R9aR9b); N(R9)S(O)N(R9aR9b); SR9; N(R9R9a); NO2; OC(O)R9; N(R9)C(O)R9a; N(R9)S(O)2R9a; N(R9)S(O)R9a; N(R9)C(O)N(R9aR9b); N(R9)C(O)OR9a; OC(O)N(R9R9a); or T2; R9; R9a, R9b are independently selected from the group consisting of H; T2; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R12, which are the same or different; R10 is halogen; CN; C(O)OR13; OR13; oxo (═O), where the ring is at least partially saturated; C(O)R13; C(O)N(R13R13a); S(O)2N(R13R13a); S(O)N(R13R13a); S(O)2R13; S(O)R13; N(R13)S(O)2N(R13aR13b); N(R13)S(O)N(R13aR13b); SR13; N(R13R13a); NO2; OC(O)R13; N(R13)C(O)R13a; N(R13)S(O)2R13a; N(R13)S(O)R13a; N(R13)C(O)N(R13aR13b); N(R13)C(O)OR13a; OC(O)N(R13R13a); C1-6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R14, which are the same or different; R13, R13a, R13b are independently selected from the group consisting of H; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R14, which are the same or different; R11, R12 are independently selected from the group consisting of halogen; CN; C(O)OR15; OR15; C(O)R15; C(O)N(R15R15a); S(O)2N(R15R15a); S(O)N(R15R15a); S(O)2R15; S(O)R15; N(R15)S(O)2N(R15aR15b); N(R15)S(O)N(R15aR15b); SR15; N(R15R15a); NO2, OC(O)R15; N(R15)C(O)R15a; N(R15)S(O)2R15a; N(R15)S(O)R15a; N(R15)C(O)N(R15aR15b); N(R15)C(O)OR15a; OC(O)N(R15R15a); or T2; R15, R15a, R15b are independently selected from the group consisting of H; T2; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R14 is halogen; CN; C(O)OR16; OR16; C(O)R16; C(O)N(R16R16a); S(O)2N(R16R16a); S(O)N(R16R16a); S(O)2R16; C(O)R16; N(R16)S(O)2N(R16aR16b); N(R16)S(O)N(R16aR16b); SR16; N(R16R16a); NO2; OC(O)R16; N(R16)C(O)R16a; N(R16)S(O)2R16a; N(R16)S(O)R16a; N(R16)C(O)N(R16aR16b); N(R16)C(O)OR16a; or OC(O)N(R16R16a); R16, R16a, R16b are independently selected from the group consisting of H; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; T2 is phenyl; naphthyl; indenyl; indanyl; C3-7 cycloalkyl; 4 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T2 optionally substituted with one or more R17, which are the same or different; T3 is phenyl; C3-7 cycloalkyl; or 4 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T3 is optionally substituted with one or more R18, which are the same or different; R17, R18 are independently selected from the group consisting of halogen; ON; C(O)OR19; OR19; oxo (═O), where the ring is at least partially saturated; C(O)R19; C(O)N(R19R19a); S(O)2N(R19R19a); S(O)N(R19R19a); S(O)2R19; S(O)R19; N(R19)S(O)2N(R19aR19b); N(R19)S(O)N(R19aR19b); SR19; N(R19R19a); NO2; OC(O)R19; N(R19)C(O)R19a; N(R19)S(O)2R19a; N(R19)S(O)R19a; N(R19)C(O)N(R19aR19b), N(R19)C(O)OR19a; OC(O)N(R19R19a); C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R20, which are the same or different; R19, R19a, R19b are independently selected from the group consisting of H; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R20, which are the same or different; R20 is halogen; ON; C(O)OR21; OR21; C(O)R21; C(O)N(R21R21a); S(O)2N(R21R21a); S(O)N(R21R21a); S(O)2R21; S(O)R21; N(R21)S(O)2N(R21aR21b); N(R21)S(O)N(R21aR21b); SR21; N(R21R21a); NO2; OC(O)R21; N(R21)C(O)R21a; N(R21)S(O)2R21a; N(R21)S(O)R21a; N(R21)C(O)N(R2laR21b); N(R21)C(O)OR21a; or OC(O)N(R21R21a); R21, R21a, R21b are independently selected from the group consisting of H; C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein C1-6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different, provided that the following compounds are excluded;
地址 Norwich GB