US 8,404,677 B2 · Kinase inhibitors

Abstract

The present invention provides a new group of protein kinase inhibitors, pyrido[4,3,-d]pyrimidin-5-one derivatives, and pharmaceutically acceptable salts thereof that are useful for intreating cell proliferative disease and disorder such as cancer, autoimmune diseases, infection, cardiovascular disease and neurodegenerative disease and disorder. The present invention provides methods for synthesizing and administering the protein kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor. The invention also provides useful intermediates generated during the syntheses of the pyrido[4,3,-d]pyrimidin-5-one derivatives.

A compound of Formula (I):

wherein:(a) when R1 is H and X is NR2R3 or NR4R5, then
Y is NHR6 and Z is selected from H, halogen, C1-C3 alkyl, C2-C4 alkynyl, aryl, heteroaryl, or C3-C8 cycloalkyl, wherein the alkyl, cycloalkyl, aryl, alkynyl or heteroaryl is optionally substituted with halo, alkyl, or cyano;
wherein:
R2 and R3, taken together with the nitrogen atom to which they are bonded form:
i) a 3-8 membered saturated or partially saturated monocyclic group having no heteroatom other than the nitrogen atom to which R2 and R3 are bonded, wherein said 3-8 membered saturated or partially saturated monocyclic group is independently substituted at one or more carbon atoms with 1-2 R7 and optionally substituted at one or more carbon atoms with 0-4 R8, wherein R7 is hydroxy, heterocycloalkyl, or NR9R9 and R8 is hydroxy(C1-C6)alkyl, aryl, COOR9, (CH2)nNR9R9, or (CH2)nNR9R10, wherein each n is independently 1, 2, or 3 and the aryl is optionally substituted with halo;
or
ii) an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, sulfoxide, or sulfone;
each R9 is independently selected from H, C1-C6 alkyl, C3-C6 alkynyl, C2-C6 alkyl cyano, C2-C6 alkyl sulfone, C3-C6 cycloalkyl sulfone, C2-C6 sulfonamide, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, aryl, aryl(C1-C6)alkyl, or heteroaryl, wherein the alkyl, alkynyl, alkylcyano, alkylsulfone, sulfonamide, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, or heteroaryl is optionally substituted with R25;
R10 is C(O)R9, COOR9, C(O)NR9R9, or S(O)nR9, wherein n is 1 or 2;
R4 is selected from H, C1-C6 alkyl, or hydroxy(C1-C6)alkyl;
R5 is aryl(C1-C3)alkyl, wherein the aryl group is independently substituted at one or more carbon atoms with 1-3 R11, wherein R11 is independently selected from OR9, NR9R9, NR9COR9, or NR9S(O)nR9, wherein n is 1 or 2;
R6 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl(C1-C6)alkyl, or heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted, wherein the heterocycloalkyl, aryl, or heteroaryl of R6 is optionally substituted with an aryl selected from the group consisting of:
i) a 5-6 membered monocyclic aryl group;
ii) an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, sulfoxide, or sulfone;
iii) an 8-10 membered unsaturated or partially unsaturated bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, sulfoxide, or sulfone;
and
iv) an 8-10 membered unsaturated or partially unsaturated bicyclic aryl group having a carbonyl, carboxamide, or sulfoxamide;
or
the heterocycloalkyl, aryl, or heteroaryl of R6 is optionally substituted at one or more carbon atoms with R12, wherein each R12 is independently selected from C1-C6 alkyl, CF3, OCF3, S(O)n(C1-C4)alkyl, halo(C1-C4)alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl (C1-C6)alkyl, heteroaryl, halo, haloalkyl, SR13, OR13, OC(O)R13, NR13R13, NR13R14, COOR13, NO2, CN, C(O)R13, C(O)C(O)R13, C(O)NR13R13, S(O)nR13, S(O)nNR13R13, or NR15R16, wherein each n is independently 1 or 2 and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, or heteroaryl is optionally substituted with R25, wherein the aryl and heteroaryl of R12 is independently selected from:
i) a 5-6 membered monocyclic aryl group;
ii) an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, sulfoxide or sulfone;
iii) an 8-10 membered unsaturated or partially unsaturated bicyclic aryl group having 0-5 heteroatoms independently nitrogen, oxygen, sulfur, sulfoxide or sulfone;
or
iv) an 8-10 membered unsaturated or partially unsaturated bicyclic aryl group having a carbonyl, carboxamide, or sulfoxamide;
each R13 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkyl cyano, C2-C6 alkyl sulfone, C2-C6 sulfonamide, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl(C1-C6)alkyl, haloalkyl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkyl cyano, alkyl sulfone, alkyl sulfonamide, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, or heteroaryl is optionally substituted with R25;
R14 is C(O)R13, COOR13, C(O)NR13R13, SO2NR13R13, or S(O)nR13, wherein n is 1 or 2;
R15 and R16, taken together with the nitrogen atom to which they are bonded, form:
i) a 3-8 membered saturated or partially saturated monocyclic group, wherein the 3-8 membered saturated or partially saturated monocyclic group is optionally substituted with R25;
ii) an 8-12 membered saturated or partially saturated bicyclic group, wherein the 8-12 membered saturated or partially saturated bicyclic group is optionally substituted with R25;
iii) a 3-8 membered saturated or partially saturated monocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, sulfone or sulfoxide, wherein the 3-8 membered saturated or partially saturated monocyclic group having 1-2 heteroatoms is optionally substituted with R13 or R14;
or
iv) a 8-12 membered saturated or partially saturated bicyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, sulfone, sulfoxide, wherein the 8-12 membered saturated or partially saturated bicyclic group having 1-3 heteroatoms is optionally substituted with R13 or R14;
(b) when R1 is H and Y is NHR17 or R17, then X is OR18, NHR18, NR15R16, NR18R19, or NR19R20;
and
Z is H, halogen, C1-C3 alkyl, C2-C4 alkynyl, aryl, heteroaryl, or C3-C8 cycloalkyl, wherein the alkyl, alkynyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with halo, alkyl, or cyano, wherein:
R17 is selected from aryl(C1-C6)alkyl, aryl, or heteroaryl, wherein the aryl, or the heteroaryl is substituted at one or more carbon atoms with at least one R21 and 0-2 R22 and the aryl group of said aryl(C1-C6)alkyl is optionally substituted with halo;
R21 is independently selected from OH, CF3, OCF3, O-aryl, or NR15R16;
R22 is independently H, C1-C6 alkyl, CF3, OCF3, S(O)n(C1-C4)alkyl, halo(C1-C4)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl(C1-C6)alkyl, heteroaryl, halo, SR13, OR13, OC(O)R13, NR13R13, NR13R14, COOR13, NO2, CN, C(O)R13, C(O)C(O)R13, C(O)NR13R13, S(O)nR13, S(O)nNR13R13, NR13C(O)NR13R13, NR13C(O)R13, NR13(COOR13), NR13S(O)nR13, or NR15R16, wherein each n is independently 1 or 2 and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, or heteroaryl is optionally substituted with R25;
R18 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl(C1-C6)alkyl, hydroxy(C2-C6)alkyl, amino(C2-C6)alkyl, haloalkyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, or heteroaryl is optionally substituted with R25;
each R19 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, hydroxy(C2-C6)alkyl, amino(C2-C6)alkyl, C2-C6 alkyl cyano, C2-C6 alkyl sulfone, C2-C6 sulfonamide, C3-C6 cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl, aryl(C1-C6)alkyl, haloalkyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkyl cyano, alkylsulfone, sulfonamide, cycloalkyl, heterocycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, or heteroaryl is optionally substituted with R25;
R20 is C(O)R19COOR19, C(O)NR19R19 or S(O)nR19, wherein n is 1 or 2;
each R25 is independently selected from hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, C3-C6cycloalkyl, C3-C8 heterocycloalkyl, C4-C6 cycloalkenyl, aryl(C1-C6)alkyl, aryl, halo, haloalkyl, oxo, oxime, CF3, SR13, OCF3, OR13, OC(O)CH2R13, NR13R13, NR13R14, NHC(O)R13, (CH2)nNR13R13, COOR13, CN, C(O)R13, C(O)CF3, CONR15R16, CONH2, S(O)nR13, S(O)nNR13R13, or NR15R16, wherein each n is independently 1 or 2 and the heterocycloalkyl is optionally substituted with C1-C3 alkyl;
and
(c) when R1 is CH3, then
X is NH2 or NHR6,
Y is NHR6 or R6, and
Z is H, halogen, C1-C3 alkyl, C2-C4 alkynyl, aryl, heteroaryl, or C3-C8 cycloalkyl, wherein the alkyl, cycloalkyl, aryl, alkynyl, or heteroaryl is optionally substituted with halo, alkyl, or cyano, or
a pharmaceutically acceptable salt thereof;
wherein each heterocycloalkyl is independently a 3 to 8 membered ring haying 1 to 3 heteroatoms in the ring selected from N, O, S, sulfone or sulfoxide.

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Kinase inhibitors

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Kinase inhibitors

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Abstract

Claims63