Cyanomethylpyrazole carboxamides as janus kinase inhibitors

摘要

The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.

主权项

1. A compound of formula I or a pharmaceutically acceptable salt, or a stereoisomer thereof: Ra and R4 are each independently selected from hydrogen and C1-4alkyl; A is selected from aryl, and heteroaryl; n is independently 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X is independently selected from C, N, O and S; R3 and R7 are each independently selected from hydrogen, halogen,
C1-10 alkyl,C2-10 alkenyl,C1-10 heteroalkyl,aryl C0-10 alkylC0-10 alkyl,C3-8 cycloalkylC0-10 alkyl,heteroaryl C0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl,and wherein each of R3 and R7 are independently substituted with 0, 1, 2, 3, or 4 R5a substituents; R5a is selected from:
halogen,C1-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C1-10 heteroalkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C2-10 alkenyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C2-10 alkynyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C3-8 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C1-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,C1-10 heteroalkyl(carbonyl)0-1oxyC0-10 alkyl,C2-10 alkenyl(carbonyl)0-1oxyC0-10 alkyl,C1-10 heteroalkyl(carbonyl)0-1oxyC0-10 alkyl,aryl C0-10 alkyl (carbonyl)0-1oxyC0-10 alkyl,(C3-8)cycloalkyl C0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,heteroarylC0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,((C0-10)alkyl)1-2aminocarbonyloxy,(C0-10)heteroalkylaminocarbonyloxy,aryl (C0-10)alkylaminocarbonyloxy,(C3-8)cycloalkyl(C0-10)alkylaminocarbonyloxy,heteroaryl(C0-10)alkylaminocarbonyloxy,(C3-8)heterocycloalkyl(C0-10)alkylaminocarbonyloxy,C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,(C0-10)heteroalkylamino(oxy)0-1carbonylC0-10 alkyl,C3-8 cycloalkyl C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,aryl C0-10alkylamino(oxy)0-1carbonylC0-10 alkyl,heteroarylC0-1 alkylamino(oxy)0-1carbonylC0-10 alkyl,(C3-8)heterocycloalkylC0-10alkylamino(oxy)0-1carbonylC0-10 alkyl,C1-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,C1-10 heteroalkyl (oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,C3-8 cycloalkyl C0-10 alkyl (oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,aryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,—CO2(C0-10 alkyl),—(C0-10 alkyl)CO2H,Oxo (═O);C1-10 alkylsulfonyl,C1-10 heteroalkylsulfonyl,(C3-8) cycloalkylsulfonyl,(C3-8) cycloheteroalkylsulfonyl,heteroarylsulfonyl,arylsulfonyl,aminosulfonyl,—SO2N(C1-6alkyl)1-2,—SO2C1-6alkyl,—SO2CF3,—SO2CF2H,C1-10 alkylsulfinyl,—Si(CH3)3,amino,(C0-10 alkyl)1-2 amino,C1-4acylamino C0-10 alkyl,hydroxy,(C1-10 alkyl)OH,C0-10 alkylalkoxy,cyano,(C1-6alkyl)cyano, andC1-6haloalkyl;wherein two R5a and the atom to which they are attached may optionally form a −4, −5, or −6 member saturated ring system;wherein R5a is each optionally substituted with 1, 2, 3, or 4 R6 substituents, and R6 is independently selected from:halogen,C1-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C1-10 heteroalkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C2-10 alkenyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,aryl C2-10 alkynyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C3-8 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,C1-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,C2-10 alkenyl(carbonyl)0-1oxyC0-10 alkyl,C1-10 heteroalkyl(carbonyl)0-1oxyC0-10 alkyl,aryl C0-10 alkyl (carbonyl)0-1oxyC0-10 alkyl,(C3-8)cycloalkyl C0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,heteroarylC0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,((C0-10)alkyl)1-2aminocarbonyloxy,aryl (C0-10)alkylaminocarbonyloxy,(C3-8)cycloalkyl(C0-10)alkylaminocarbonyloxy,heteroaryl(C0-10)alkylaminocarbonyloxy,(C3-8)heterocycloalkyl(C0-10)alkylaminocarbonyloxy,C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,C3-8 cycloalkyl C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,aryl C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,heteroaryl C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,C1-10 alkyl (oxy)0-1carbonylaminoC0-10 alkyl,C3-8 cycloalkyl C0-10 alkyl (oxy)0-1carbonylaminoC0-10 alkyl,aryl C0-10 alkyl(oxy)0-1carbonylaminoC0-10 alkyl,heteroaryl C0-10 alkyl(oxy)0-1carbonylaminoC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1carbonylaminoC0-10 alkyl,—CO2(C0-10 alkyl),—(C0-10 alkyl)CO2H,Oxo (═O),C1-10 alkylsulfonyl,C1-10 heteroalkylsulfonyl,(C3-8) cycloalkylsulfonyl,(C3-8) cycloheteroalkylsulfonyl,heteroarylsulfonyl,arylsulfonyl,aminosulfonyl,—SO2N(C1-6alkyl)1-2,—SO2C1-6alkyl,—SO2CF3,—SO2CF2H,C1-10 alkylsulfinyl,—OSi(C1-10alkyl)3,—Si(CH3)3,amino,(C0-10 alkyl)1-2 amino,-(oxy)0-1(carbonyl)0-1N(C0-10 alkyl)1-2 C1-4acylamino C0-10 alkyl,hydroxy,(C1-10 alkyl)OH,C1-10 alkoxy,(C1-10 alkyl)cyano,cyano, andC1-6haloalkyl; andwherein two R6 and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system; andR6 is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C1-6)alkyl, (C1-6)alkoxy, (C1-10 alkyl)OH, halogen, CO2H, —(C0-6)alkylCN, —O(C═O)C1-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C0-6)alkyl, C1-10 alkylsulfonyl, C1-10 heteroalkylsulfonyl, oxo (O═), (C3-8) cycloalkylsulfonyl, (C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO2N(C1-6alkyl)1-2, —SO2C1-6alkyl, —SO2CF3, —Si(CH3)3, —SO2CF2H, —C1-10 alkylsulfinyl, —OSi(C1-10alkyl)3, —O(0-1)(C1-10)haloalkyl, amino(C1-6alkyl)0-2 and NH2; with the proviso that the compound of formula I is other than: 1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-3-({4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenyl}amino)-1H-pyrazole-4-carboxamide; and 1-[3-(cyanomethyl)-1-(naphthalene-2-ylsulfonyl)azetidin-3-yl]-3-(phenylamino)-1H-pyrazole-4-carboxamide.