US 9,957,264 B2 · Geminally substituted cyanoethylpyrazolo pyridones as Janus kinase inhibitors

Abstract

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.

A compound of Formula I or a pharmaceutically acceptable salt, or a stereoisimer thereof:

A is selected from phenyl, methyl, ethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, isoindolinyl, benzo[d]thiazolyl,
2,3-dihydro-1H-indenyl, quinolinyl, pyridinyl, and indolinyl;
R2 and R3 are each independently selected from hydrogen, C1-4alkyl and hydroxy, wherein R2 and R3 may optionally, join together with the carbon they are attached to form a 3 to 6 membered ring;
X1 is C;
X2, X3, and X4 are each independently selected from O, N, S, and C and provided that the formed ring system contains 0, 1, 2, or 3 atoms selected from O, N and S;
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3, or 4;
R4 is selected from:
halogen,
oxo (═O),
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,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
C0-10 alkyl(oxy)0-1(carbonyl)0-1aminoC0-10 alkyl,
C1-10 alkylamino(carbonyl)0-1C0-10alkyl,
(C1-10)heteroalkyl(oxy)0-1(carbonyl)0-1aminoC0-10alkyl,
(C1-10)heteroalkylamino(carbonyl)0-1C0-10alkyl,
C3-12 cycloalkyl C0-10 alkylaminoC0-10 alkyl,
aryl C0-10 alkylaminoC0-10 alkyl,
heteroaryl C0-10 alkylaminoC0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkylaminoC0-10 alkyl,
C1-10 alkylsulfonyl,
C1-10 heteroalkylsulfonyl,
(C3-12)cycloalkylC0-10alkylsulfonyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonyl,
heteroarylC0-10 alkylsulfonyl,
arylC0-10 alkylsulfonyl,
—SO2NH2,
—SO2NH(C1-6alkyl),
—SO2N(C1-6alkyl)2,
C0-10 alkylsulfamoyl,
C1-10 heteroalkylsulfamoyl,
(C3-12)cycloalkylC0-10 alkylsulfamoyl,
(C3-12)cycloheteroalkylC0-10 alkylsulfamoyl,
heteroarylC0-10 alkylsulfamoyl,
arylC0-10 alkylsulfamoyl,
C0-10 alkylsulfonimidoylC0-10 alkyl,
C1-10 heteroalkylsulfonimidoylC0-10 alkyl,
(C3-12)cycloalkylC0-10 alkylsulfonimidoylC0-10 alkyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonimidoylC0-10 alkyl,
heteroarylC0-10 alkylsulfonimidoylC0-10 alkyl,
arylC0-10 alkylsulfonimidoylC0-10 alkyl,
(C1-10 alkyl)1-2amino,
—CO2(C0-10 alkyl),
—(C0-10 alkyl)CO2H,
—SO2CF3,
—SO2CF2H,
—SO2CH2CF3,
C1-10 alkylsulfinyl,
C1-4acylaminoC0-10 alkyl,
hydroxy,
—(C1-10 alkyl)OH,
C1-10 alkoxyC0-10 alkyl,
cyano,
(C1-6alkyl)cyano, and
C1-6haloalkyl,
wherein two R4 together with the ring atom to which each is attached optionally may form a saturated ring;
R5 is selected from:
halogen,
oxo (═O),
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,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
C0-10 alkylaminocarbonylC0-10alkyl,
C0-10 alkyl(oxy)0-1(carbonyl)0-1 aminoC0-10 alkyl,
(C1-10)heteroalkyl(oxy)0-1(carbonyl)0-1 aminoC0-10 alkyl,
C3-12 cycloalkyl C0-10 alkylaminoC0-10 alkyl,
aryl C0-10 alkylaminoC0-10 alkyl,
heteroaryl C0-10 alkylaminoC0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkylaminoC0-10 alkyl,
(C1-10 alkyl)1-2 amino,
—SF5,
C0-10 alkylsulfonyl,
C1-10 heteroalkylsulfonyl,
(C3-12)cycloalkylC0-10alkylsulfonyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonyl,
heteroarylC0-10 alkylsulfonyl,
arylC0-10 alkylsulfonyl,
C0-10 alkylsulfamoyl,
C1-10 heteroalkylsulfamoyl,
(C3-12)cycloalkylC0-10 alkylsulfamoyl,
(C3-12)cycloheteroalkylC0-10 alkylsulfamoyl,
heteroarylC0-10 alkylsulfamoyl,
C0-10 alkylsulfonimidoylC0-10 alkyl,
C1-10 heteroalkylsulfonimidoylC0-10 alkyl,
(C3-12)cycloalkylC0-10 alkylsulfonimidoylC0-10 alkyl,
(C3-12)cycloheteroalkylC0-10alkylsulfonimidoylC0-10 alkyl,
heteroarylC0-10 alkylsulfonimidoylC0-10 alkyl,
arylC0-10 alkylsulfonimidoylC0-10 alkyl,
—SO2NH2,
—SO2NH(C1-6alkyl),
—SO2N(C1-6alkyl)2,
arylC0-10 alkylsulfamoyl,
(C0-10 alkyl)1-2 amino,
—CO2(C0-10 alkyl),
—(C0-10 alkyl)CO2H,
—SO2CF3,
—SO2CF2H,
—SO2CH2CF3,
C1-10 alkylsulfinyl,
C1-4acylaminoC0-10 alkyl,
hydroxy,
—(C1-10 alkyl)OH,
C1-10 alkoxyC0-10 alkyl,
cyano,
(C1-6alkyl)cyano, and
C1-6haloalkyl;
and
wherein R4 and R5 are 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,
C3-12 cycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
heteroaryl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1C0-10 alkyl,
C1-10 alkyl(carbonyl)0-1 oxyC0-10 alkyl,
C2-10 alkenyl(carbonyl)0-1 oxyC0-10 alkyl,
C1-10 heteroalkyl(carbonyl)0-1 oxyC0-10 alkyl,
aryl C0-10 alkyl (carbonyl)0-1 oxyC0-10 alkyl,
(C3-12)cycloalkyl C0-10 alkyl(carbonyl)0-1 oxyC0-10 alkyl,
heteroarylC0-10 alkyl(carbonyl)0-1 oxyC0-10 alkyl,
(C3-12)heterocycloalkyl C0-10 alkyl(carbonyl)0-1 oxyC0-10 alkyl,
((C0-10)alkyl)1-2aminocarbonyloxy,
aryl (C0-10)alkylaminocarbonyloxy,
—CO2(C0-10 alkyl),
—(C0-10 alkyl)CO2H,
oxo (═O),
C0-10 alkylsulfonyl,
C1-10 heteroalkylsulfonyl,
(C3-12)cycloalkylsulfonyl,
(C3-12)cycloheteroalkylsulfonyl,
heteroarylsulfonyl,
arylsulfonyl,
aminosulfonyl,
—SO2NH2,
—SO2NH(C1-6alkyl),
—SO2N(C1-6alkyl)2,
—SO2CF3,
—SO2CF2H,
C1-10 alkylsulfinyl,
amino,
(C1-10 alkyl)1-2amino,
-(oxy)0-1(carbonyl)0-1N(C0-10 alkyl)1-2
C1-4acylaminoC0-10 alkyl,
hydroxy,
(C1-10 alkyl)OH,
C1-10 alkoxyC0-10 alkyl,
(C1-10 alkyl)cyano,
cyano, and
C1-6haloalkyl;
and
R6 is optionally substituted with 1, 2, or 3 R7 substituents selected from hydrogen, hydroxy, (C1-6)alkyl, C1-10 alkoxyC0-10 alkyl, (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, oxo (O═), aminosulfonyl, —SO2C1-6alkyl, —SO2CF3, —SO2CF2H, —C1-10 alkylsulfinyl, —O(0-1)(C1-10)halo, —SO2NH2, —SO2NH(C1-6alkyl), —SO2N(C1-6alkyl)2, alkyl, amino(C1-6alkyl)0-2 and NH2.

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Geminally substituted cyanoethylpyrazolo pyridones as Janus kinase inhibitors

Life of this patent

Geminally substituted cyanoethylpyrazolo pyridones as Janus kinase inhibitors

Life of this patent

Abstract

Claims9