Isoindolin-1-one derivatives useful as grk2 inhibitors

A compound of formula (I-P)

• wherein
• a is an integer from 0 to 3;
• R1 is selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano, phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydro-pyranyl;
• wherein the phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydro-pyranyl is optionally substituted with one or more substituents independently selected from the group halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy and NRJRK;
• wherein Rd and RK are each independently selected from the group consisting of hydrogen, methyl and ethyl;
• provided that when R1 is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydropyranyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and tetrahydropyranyl are optionally substituted, then a is 1 and the R1 group is bound at the 6-position of the isoindolin-2-one;
• R2 is selected from the group consisting of 5 to 10 membered heteroaryl and 5 to 10 membered heterocycloalkyl;
• wherein the 5 to 10 membered heteroaryl or 5 to 10 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of oxo, —NRARB and —C(O)—NRARB;
• wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl;
• R3 is selected from the group consisting of hydrogen, —C1-4alkyl, —C1-4alkoxy, —(C1-2alkyl)-OH, —(C1-2alkyl)-CO2H, —(C1-2alkyl)-O—(C1-2alkyl), —(C1-2alkyl)-O—(C1-2alkyl)-OH, —(C1-2alkyl)-O—(C1-2alkyl)-CO2H, —(C1-2alkyl)-O-phenyl, —(C1-2alkyl)-O—(C1-2alkyl)-phenyl, —(C1-2alkyl)-NRPRQ, —(C1-2alkyl)-O—(C1-2alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-2alkyl), —C(O)—NRPRQ, —C(O)-phenyl, C3-6cycloalkyl, 1,2,3,5-tetrazol-4-yl and −(C1-2alkyl)-1,2,3,5-tetrazol-4-yl;
• wherein RP and RQ are each independently selected from the group consisting of hydrogen, methyl and ethyl;
• is selected from the group consisting of
• (wherein Z is CH),
• (wherein Z is CH and R4 is H),
• (wherein Z is S),
• (wherein Z is N),
• (wherein Z is CH),
• (wherein Z is CH) and
• (wherein Z is CH);
• R4 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, —(C1-2alkyl)-NRSRT, —(C1-2alkyl)-CO2H, —(C1-2alkyl)-C(O)O—(C1-4alkyl), C1-4alkoxy, fluorinated C1-2alkoxy, —O—(C1-2alkyl)-CN, —O—(C1-2alkyl)-CO2H, —O—(C1-2alkyl)-C(O)—O—(C1-2alkyl), —O-phenyl, —O—(C1-2alkyl)-phenyl, —O—(C1-2alkyl)-(1,2,3,5-tetrazol-4-yl), —O-(oxetan-3-yl), —O-(tetrahydro-furan-3-yl), —O—C(O)—(C1-2alkyl), —O—C(O)—C3-6cycloalkyl, —O—C(O)—NRSRT, O—C(O)—(C1-2alkyl)-O—C(O)—(C1-2alkyl), —CO2H, —C(O)—O—(C1-4alkyl), —C(O)—NRSRT, —C(O)—NH-(phenyl), —C(O)—NH-(benzyl), —C(O)—NH-(pyridinyl), —C(O)—NH—(C1-2alkyl)-(pyridinyl), —C(O)—NH-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl), —C(O)—NH-((1R,2R,4R)-bicyclo[2.2.1]heptan-2-yl), —NH—SO2—(C1-2alkyl), —(C1-2alkyl)-SO2—NRSRT, and pyrazol-1-yl;
• wherein the phenyl, benzyl or pyridinyl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl and C1-4alkoxy;
• and wherein RS and RT are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• b is an integer from 0 to 4;
• each R5 is independently selected from the group consisting of halogen, C1-4alkyl and C1-4alkoxy;
• R6 and R7 are the same and are selected from the group consisting of hydrogen, C1-2alkyl and hydroxy substituted C1-2alkyl;
• alternatively, R6 is hydrogen and R7 is selected from the group consisting of —(C1-2alkyl)-CN, —(C1-2alkyl)-OH, —(C1-2alkyl)-CO2H, —(C1-2alkyl)-(1,2,3,5-tetrazol-4-yl) and −(C1-2alkyl)-(isoindolin-2-yl-1,3-dione);
• alternatively, R6 and R7 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cyclopent-1′1′-diyl, cyclohex-1′1′-diyl, cyclopent-3-en-1′1′-diyl, cyclohex-2-en-1′1′-diyl, cyclohex-3-en-1′1′-diyl, piperidin-4′,4′-diyl, tetrahydro-furan-3,3-diyl, tetrahydro-pyran-4′,4′-diyl, 2,3-dihydro-inden-1′1′-diyl, hexahydro-2H-cyclopenta[d]oxazol-4′,4′-diyl-2-one and hexahydro-2H-cyclopenta[d]oxazol-6′,6′-diyl-2-one;
• wherein the cyclopent-1′1′-diyl, cyclohex-1′1′-diyl, cyclopent-3-en-1′1′-diyl, cyclohex-2-en-1′1′-diyl, cyclohex-3-en-1′1′-diyl, piperidin-4′,4′-diyl, tetrahydro-furan-3′,3′-diyl, tetrahydro-pyran-4′,4′-diyl or 2,3-dihydro-inden-1′1′-diyl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, C1-4alkoxy, —CO2H, —C(O)—NH2, —NRXRY, —NH—CO2H and —NH—C(O)—O—(C1-2alkyl);
• wherein RX and RY are each independently selected from the group consisting of hydrogen, methyl and ethyl;
• or stereoisomer or pharmaceutically acceptable salt thereof.