Cyclic Ether Pyrazol-4-YL-Heterocyclyl-Carboxamide Compounds And Methods Of Use

摘要

Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.;

主权项

1. A method of treating a disease or disorder, the method comprising administering a compound to a subject with a disease or disorder mediated by Pim kinase, wherein the compound is selected from Formula 1: and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R1 is selected from H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C20 aryl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C1-C20 heteroaryl, and —(C1-C12 alkylene)-(C2-C20 heterocyclyl); R2 is selected from the structures: where the wavy line indicates the site of attachment; R3 is independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2CH(CH3)2, —CH═CH2, —CH═C(CH3)2, ═CH2, —CH2F, —CHF2, —CF3, —CH2OH, —CH2OCH3, —CH2NH2, —CH2NHCH3, —CH2CH2NH2, —CH2CHCH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CO2H, —COCH3, —COCH2NH2, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CHF2, —NHCH2CF3, —NHCH2CH2OH, —NHCOCH3, —N(CH3)COCH3, —NHC(O)OCH2CH3, —NHC(O)OCH2Cl3, —NHC(O)OC6H5, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —OCHF2, —OCH2F, —OCH2CH3, —OCH(CH3)2, —OCH2CH(CH3)2, —OC(CH3)3, —S(O)2N(CH3)2, —SCH3, —CH2OCH35 —S(O)2CH35 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, oxetan-3-ylmethylamino, (3-methyloxetan-3-yl)methylamino, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; or where two geminal R3 groups form a spiro ring selected from a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, or piperidinyl ring, where the spiro ring is optionally substituted with one or more groups independently selected from —F, —OH, ═O, —CH3, —NH2, —CH2F, —CH2OH, —CH2OCH3, —CH2NH2, and —CF3; or where two vicinal R3 groups form a five-membered or six-membered heterocyclyl fused ring, where the heterocyclyl fused ring is optionally substituted with one or more groups independently selected from —F, —OH, ═O, —CH3, —NH2, —CH2F, —CH2OH, —CH2OCH3, —CH2NH2, and —CF3; n is 0, 1, 2, 3, 4, 5, or 6; X is selected from the structures: where the wavy line indicates the site of attachment; R4 is independently H, F, —CH3, or —NH2; and R5 is selected from H, Cl, Br, C1-C12 alkyl, —O—(C1-C12 alkyl), —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C2-C8 alkenylene)-(C3-C12 carbocyclyl), —(C2-C8 alkenylene)-(C2-C20 heterocyclyl), C6-C20 aryl, —(C6-C20 arylene)-(C2-C20 heterocyclyl), —(C6-C20 arylene)-(C6-C20 arylene), —(C6-C20 arylene)-(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C6-C20 arylene)-O—(C2-C20 heterocyclyl), —(C6-C20 arylene)-O—(C1-C12 alkyl), C3-C12 carbocyclyl, C2-C20 heterocyclyl, C1-C20 heteroaryl, —(C1-C20 heteroaryl)-(C2-C20 heterocyclyl), and —(C1-C20 heteroaryl)-(C1-C12 alkyl); where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2NH2, —CH2CH2NH2, —CH2CHCH2NH2, —CH2CH(CH3)NH2, —CH2OH, —CH2CH2OH, —CH(CH2OH)2, —C(CH2OH)3, —CH(CH3)OH, —C(CH3)2OH, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CN, —CF3, —CHF2, —CH2F, —CO2H, —COCH3, −—COCH(CH3)2, −—CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —OCF3, —OCH(CH3)2, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholine; and wherein, said disease or disorder is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.