US 8,629,132 B2 · Kinase inhibitors

Abstract

The present invention provides a new group of protein kinase inhibitors, pyrropyrimidine and pyrazolopyrimidine derivatives, and pharmaceutically acceptable salts and prodrugs thereof that are useful for treating 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 pyrropyrimidine and pyrazolopyrimidine derivatives.

A compound of Formula (I):

wherein:
X is CH or N;
R1 is selected from H, halo, CN, C1-C10 alkyl or halo(C1-C4)alkyl, wherein C1-C10 alkyl, or halo(C1-C4)alkyl is optionally substituted;
R2 is aryl, cycloalkyl, arylalkyl, or heterocyclyl, wherein the aryl, cycloalkyl, arylalkyl, or heterocyclyl is optionally and independently substituted at one or more carbon atoms with 1-4 R5 or R5a groups;
and wherein aryl and heterocyclyl having one or more nitrogen atoms is optionally and independently substituted at one or more nitrogen atoms with 1-4 R6 or R6a groups;
R3 is independently halo, CN, or R7;
and
R4 is selected from (CH2)nOH, (CH2)nNR11R12, C(O)NHR7, C(O)NR11R12, C(O)R7, C(O)NR7R7, C(O)NR7R8, (CH2)nNR7R7, (CH2)nNR7R8, (CH2)nCN, (CH2)nSR7, (CH2)nS(O)nR7, or (CH2)nS(O)nNR7R7, wherein each n is independently 1 or 2;
wherein:
Each R5 is independently selected from halo, CF3, SR7, OR7, OC(O)R7, O(CH2)nNR7R7, O(CH2)nNR11R12, O(CH2)nR7, O(CH2)nC(O)NR11R12, O(CH2)nC(O)NR7R7, NR7R7, NR7R8, NHC(O)NH2, C(O)OR7, NO2, CN, C(O)R7, OSO2CH3, S(O)nR7, S(O)nNR7R7, NR7C(O)NR7R7, NR7C(O)R7, NR7C(O)OR7, NR7S(O)nR7, or NR11R12, wherein each n is independently 1 or 2;
Each R5a is independently selected from amino, halo, hydroxy, C1-C10 alkyl, C2-C10alkenyl, C3-C10 alkynyl, C3-C12cycloalkyl, C5-C10cycloalkenyl, alkoxy, haloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the C1-C10 alkyl, C2-C10alkenyl, C3-C10alkynyl, C3-C12cycloalkyl, C5-C10cycloalkenyl, alkoxy, haloalkyl, aryl, heteroaryl, or heterocyclyl is optionally and independently substituted with 1 to 3 groups selected from halo, hydroxy, alkyl, R9, or R10;
Each R6 is independently R7, C(O)CH2CN, C(O)R7, C(O)OR7, CO2(C1-C6alkyl), C(O)NR7R7, SO2NR7R7, or SO2R7;
Each R6a is independently hydroxy, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl, C3-C12 cycloalkyl, C5-C10 cycloalkenyl, haloalkyl, wherein each R6a group is optionally and independently substituted with 1-3 groups selected from hydroxy, aryl, alkyl, halo, R9, or R10;
Each R7 is independently H, C1-C10alkyl, C2-C10alkenyl, C3-C10alkynyl, C3-C12 cycloalkyl, C5-C12cycloalkenyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, or heterocyclyl, wherein the C1-C10alkyl, C2-C10alkenyl, C3-C10alkynyl, C3-C12 cycloalkyl, C5-C12cycloalkenyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, or heterocyclyl is optionally and independently substituted with 1-4 groups selected from aryl, cycloalkyl, heteroaryl, heterocyclyl, alkyl, halo, amino, hydroxy, R9, or R10;
Each R8 is independently C(O)R7, C(O)OR7, C(O)NR7R7, or S(O)nR7, wherein n is 1 or 2;
Each R9 is independently CF3, SR7, OR7, NR7R7, NR11R12, C(O)NR7R7, C(O)NR11R12, S(O)nNR7R7, or S(O)nR7, wherein each n is independently 1 or 2;
Each R10 is C(O)O(C1-C6)alkyl, or halo(C1-C4)alkyl;
and
R11 and R12, taken together with the nitrogen atom to which they are bonded form:
i) a 3-8 membered saturated or partially saturated ring having no heteroatom other than the nitrogen atom to which R11 and R12 are bonded, wherein said 3-8 membered saturated or partially saturated ring is optionally and independently substituted with 1-4 groups selected from R5 or R5a at one or more substitutable carbon atoms;
ii) a 5-8 membered saturated or partially saturated ring having 1-3 heteroatoms, in addition to the nitrogen atom to which R11 and R12 are bonded, wherein said 1-3 heteroatoms are independently selected from nitrogen, oxygen, sulfur, sulfone or sulfoxide, and wherein said 5-8 membered saturated or partially saturated ring having 1-3 heteroatoms is optionally and independently substituted with 1-4 groups selected from R5 or R5a at one or more substitutable carbon atoms and at one or more substitutable nitrogen atoms with R6 or R6a;
iii) a 9-10 membered saturated or partially saturated bicyclic ring having no heteroatom other than the nitrogen atom to which R11 and R12 are bonded, wherein said 9-10 membered saturated or partially saturated bicyclic ring having no heteroatom is optionally substituted with 1-4 groups independently selected from R5 or R5a at one or more substitutable carbon atoms;
iv) a 9-10 membered saturated or partially saturated bicyclic ring having 1-5 heteroatoms, in addition to the nitrogen atom to which R11 and R12 are bonded, wherein said heteroatoms are independently selected from nitrogen, oxygen, sulfur, sulfoxide, sulfone, carboxamide or sulfoxamide;
or
v) a 6-14 membered saturated or partially saturated bridged ring having 1-3 heteroatoms in addition to the nitrogen atom to which R11 and R12 are bonded, wherein said 1-3 heteroatoms are independently selected from nitrogen, oxygen, sulfur, sulfone, or sulfoxide, and wherein said 6-14 membered saturated or partially saturated bridged ring having 1-3 heteroatoms is optionally and independently substituted with 1-4 groups selected from R5 or R5a at one or more substitutable carbon atoms and at one or more substitutable nitrogen atoms with R6 or R6a;
or a pharmaceutically acceptable salt thereof.

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Kinase inhibitors

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Kinase inhibitors

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Abstract

Claims10