Pyrazole 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 stereoisomer thereof: Ra and R4 are each independently chosen from hydrogen and C1-4alkyl; n is 0, 1, 2, 3, or 4; p is 2, 3, or 4; X is independently chosen from C, N, S, and O, wherein at least one X is other than carbon; A is chosen from aryl, and heteroaryl; R2 and R3 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, wherein each of R2 and R3 are independently substituted with 0, 1, 2, 3, or 4, substituents R5a; R5a is selected from: hydrogen, 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, C2-10 alkynyl(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, C1-10 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, heteroarylC0-10alkylamino(oxy)0-1carbonylC0-10 alkyl, (C3-8)heterocycloalkylC0-10alkylamino(oxy)0-1carbonylC0-10 alkyl, C1-10 alkyl(oxy)0-1carbonylaminoC0-10 alkyl, C1-10 heteroalkyl(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, amino, (C0-10 alkyl)1-2 amino, C1-4acylamino C0-10 alkyl, hydroxy, C0-10 alkylalkoxy, cyano, C1-6alkylcyano, and C1-6haloalkyl; wherein R5a is each optionally substituted with 0, 1, 2, 3, or 4 substituents, R6, 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, C1-10 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 (C6H15) 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 alkoxy, cyano, and C1-6haloalkyl; and R6 is optionally substituted with 0, 1, 2, or 3 substituents independently chosen from hydroxy, (C1-6)alkoxy, halogen, CO2H, —(C0-6)alkylCN, —O(C═O)C1-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, —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, —SO2CF2H, —C1-10 alkylsulfinyl, —O—Si, —OSi(C6H15), —O(0-1)(C1-10)haloalkyl, and NH2.