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US 2014/0228348 A1Published application
Cyanomethylpyrazole carboxamides as janus kinase inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsJason Brubaker, Matthew Lloyd Childers, Matthew Christopher, Joshua T. Close, Jason David Katz, Joon Jung, Scott Peterson, Phieng Siliphaivanh, Tony Siu, Graham Frank Smith, Luis E. Torres, Hyun Chong Woo, Jonathan R. Young, Hongjun Zhang
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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.
Claims21
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,
- C3-8cycloalkylC0-10 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,
- heteroarylC0-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,
- (C3-8)heterocycloalkylC0-10 alkylamino(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(C1-6 alkyl)1-2,
- —SO2C1-6alkyl,
- —SO2CF3,
- —SO2CF2H,
- C1-10 alkylsulfinyl,
- —Si(CH3)3,
- amino,
- (C0-10 alkyl)1-2 amino,
- C1-4 acylamino C0-10 alkyl,
- hydroxy,
- (C1-10 alkyl)OH,
- C0-10 alkylalkoxy,
- cyano,
- (C1-6 alkyl)cyano, and
- C1-6 halo alkyl;
- 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(C1-6 alkyl)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
- C1-4 acylamino C0-10 alkyl,
- hydroxy,
- (C1-10 alkyl)OH,
- C1-10 alkoxy,
- (C1-10 alkyl)cyano,
- cyano, and
- C1-6 haloalkyl;
- and
- wherein two R6 and the atoms to which they are attached may optionally form a 3-, 4-, 5-, or 6-membered saturated ring system;
- and
- R6 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, —SO2C1-6 alkyl, —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 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.
144 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.