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US 2014/0228358 A1Published application
Acyclic cyanoethylpyrazoles as janus kinase inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsJason Brubaker, Joshua T. Close, Joon Jung, Michelle Martinez, Catherine White, Kevin Wilson, Jonathan R. Young, Hongjun Zhang
Life of this patent
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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.
Claims22
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 aryl and heteroaryl, wherein R5 is substituted with 0, 1, 2, 3, or 4, substituents, R5a;
- R1, R2, and R3 are each independently selected from hydrogen,
- halogen,
- C1-10 alkyl,
- C2-10 alkenyl,
- C1-10 hetero alkyl,
- aryl C0-10 alkylC0-10 alkyl,
- C3-8 cycloalkylC0-10 alkyl,
- heteroaryl C0-10 alkyl,
- (C3-8)heterocycloalkyl C0-10 alkyl,
- wherein each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4, substituents R5a;
- 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)0-1 oxyC0-10 alkyl,
- C1-10 heteroalkyl(carbonyl)0-1 oxyC0-10 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)0-1 oxyC0-10 alkyl,
- (C3-8)heterocycloalkyl C0-10 alkyl(carbonyl)0-1oxyC0-10 alkyl,
- ((C0-10)alkyl)1-2-aminocarbonyloxy,
- (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,
- C1-4 acylamino C0-10 alkyl,
- hydroxy,
- C0-10 alkylalkoxy,
- cyano,
- C1-6alkylcyano, and
- C1-6halo alkyl;
- 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)0-1 C0-10 alkyl,
- C1-10 heteroalkyl(oxy)0-1(carbonyl)0-1 C0-10 alkyl,
- C2-10 alkenyl(oxy)0-1(carbonyl)0-1 C0-10 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 cyclo alkyl C0-10 alkyl(oxy)0-1(carbonyl)0-1 C0-10 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)0-1 oxyC0-10 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)1-2-aminocarbonyloxy,
- 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(C1-10alkyl)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 alkoxy,
- cyano, and
- C1-6haloalkyl;
- and
- wherein 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 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, —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;
- and
- 1-[(1S or 1R)-2-cyano-1-cyclopropylethyl]-3-(phenylamino)-1H-pyrazole-4-carboxamide.
132 more elements
A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2 and JAK 3 which condition is selected from, arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim for a pharmaceutically acceptable salt or a stereoisomer thereof.
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Dependencies are inferred from the claim text.