Acyclic cyanoethylpyrazoles 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 selected from hydrogen and C1-4alkyl; R5 is selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzimidazolyl, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[1,2-c]pyridinyl, imidazo[1,2-a]pyrimidinyl, 5,6-dihydropyrrolo[1,2-b]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyrrolyl, furopyridinyl, thienopyridinyl, benzotriazolyl, indazolyl, indolinyl, isoindolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl, imidazo(2,1-b)(1,3)thiazole, benzo-1,3-dioxolyl, phenyl, indenyl, and naphthyl, wherein R5 is substituted with 0, 1, 2, 3, or 4, substituents, R5a; R1, R2, and R3 are each independently selected from
hydrogen,C1-10 alkyl,aryl C0-10 alkylC0-10 alkyl,(C3-8)heterocycloalkyl C0-10 alkyl,C3-8 cycloalkylC0-10 alkyl, wherein each of R1, R2, and R3 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)heteroalkylaminocarbonyl oxy,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,heteroarylC0-10 alkylamino(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(C0-10alkyl),—(C0-10 alkyl)CO2H,Oxo (═O),C1-10 alkyl sulfonyl,C1-10 heteroalkylsulfonyl,(C3-8)cycloalkylsulfonyl,(C3-8)cycloheteroalkylsulfonyl,heteroarylsulfonyl,arylsulfonyl,aminosulfonyl,—SO2N(C1-6 alkyl)1-2,—SO2C1-6 alkyl,—SO2CF3,—SO2CF2H,C1-10 alkylsulfinyl,amino,(C0-10 alkyl)1-2 amino,C1-4 acylamino C0-10 alkyl,hydroxy,C0-10 alkylalkoxy,cyano,C1-6 alkylcyano, andC1-6 haloalkyl;wherein R5a is each optionally substituted with 0, 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)0-1aminocarbonyloxy,aryl(C0-10)alkylamninocarbonyloxy,(C3-8)cycloalkyl(C0-10)alkylamninocarbonyloxy,heteroaryl(C0-10)alkylaminocarbonyloxy,(C3-8)heterocycloalkyl(C0-10)alkylamninocarbonyloxy,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(C1-6 alkyl)1-2,—SO2C1-6 alkyl,—SO2CF3,—SO2CF2H,C1-10 alkylsulfinyl,—OSi(C1-10alkyl)3,amino,(C0-10 alkyl)1-2 amino,-(oxy)0-1(carbonyl)0-1N(C0-10 alkyl)1-2 C1-4 acylamino C0-10 alkyl,hydroxy,C1-10 alkoxy,cyano, andC1-6 haloalkyl; andwherein R6 is optionally substituted with 0, 1, 2, or 3 substituents independently selected 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 alkyl sulfonyl, C1-10 heteroalkylsulfonyl, oxo (O═), (C3-8)cycloalkylsulfonyl, (C3-8)cycloheteroalkylsulfonyl, heteroarylsulfonyl, aryl sulfonyl, aminosulfonyl, —SO2N(C1-6 alkyl)1-2, —SO2C1-6alkyl, —SO2CF3, —SO2CF2H, —C1-10 alkylsulfinyl, —OSi(C1-10alkyl)3, —O(0-1)(C1-10)haloalkyl, and NH2; with the proviso that the compound of formula I is other than:
2-(dimethylamino)ethyl 4-(1-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-2-cyanoethyl)piperidine-1-carboxylate; and1-[(1S or 1R)-2-cyano-1-cyclopropylethyl]-3-(phenylamino)-1H-pyrazole-4-carboxamide.