Inhibitors of p38
AssigneeVertex Pharmaceuticals Incorporated
InventorsGuy W. Bemis, Francesco Gerald Salituro, John Patrick Duffy, John E. Cochran, Edmund Martin Harrington, Mark A. Murko, Keith P. Wilson, Michael Su, Vincent P. Galullo
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Abstract
The present invention relates to inhibitors of p38, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Claims27
A compound of the formula:
- wherein:
- each of Q1 and Q2 is independently selected from 5-6 membered aromatic carbocyclic or heterocyclic ring systems, or 8-10 membered bicyclic ring systems consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring;
- Q1 is substituted with 1 to 4 substituents, independently selected from halo;
- C1-C3 alkyl optionally substituted with NR′2, OR′, CO2R′ or CONR′2;
- O—(C1-C3)-alkyl optionally substituted with NR′2, OR′, CO2R′ or CONR′2;
- NR′2;
- OCF3;
- CF3;
- NO2;
- CO2R′;
- CONHR′;
- SR′;
- S(O2)N(R′)2;
- SCF3;
- CN;
- N(R′)C(O)R4;
- N(R′)C(O)OR4;
- N(R′)C(O)C(O)R4;
- N(R′)S(O2)R4;
- N(R′)R4;
- N(R4)2;
- OR4;
- OC(O)R4;
- OP(O)3H2;
- or N═CH—N(R′)2;
- Q2 is optionally substituted with up to 4 substituents, independently selected from halo;
- CH═N—OH;
- CH═O;
- C1-C3 straight or branched alkyl optionally substituted with NR′2, OR′, CO2R′, S(O2)N(R′)2, N═CH—N(R′)2, R3, NH—CH3, NHCH2CH2OH, NHCH2CH(OH)CH2OH, CH2OCH2OCH3, NHCH2CH2NH2, NH-phenyl, piperazinyl, pyrrolidinyl or CONR′2;
- O—(C1-C3)-alkyl optionally substituted with NR′2, OR′, CO2R′, S(O2)N(R′)2, N═CH—N(R′)2, R3, or CONR′2;
- NR′2;
- OCF3;
- CF3;
- NO2;
- CO2R′;
- CONHR′;
- R3;
- OR3;
- NHR3;
- SR3;
- C(O)R3;
- C(O)N(R′)R3;
- C(O)OR3;
- SR′;
- S(O2)N(R′)2;
- SCF3;
- N═CH—N(R′)2;
- or CN;
- R′ is selected from hydrogen, (C1-C3)-alkyl;
- (C2-C3)-alkenyl or alkynyl;
- phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
- R3 is selected from a 5-6 membered aromatic carbocyclic or heterocyclic ring system;
- R4 is (C1-C4)-alkyl optionally substituted with N(R′)2, OR′, CO2R′, CON(R′)2, or SO2N(R2)2;
- or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′)2, OR′, CO2R′, CON(R′)2, or SO2N(R2)2;
- X is selected from —S—, —O—, —S(O2)—, —S(O)—, —S(O2)—N(R2)—, —N(R2)—S(O2)—, —N(R2)—C(O)O—, —O—C(O)—N(R2), —C(O)—, —C(O)O—, —O—C(O)—, —C(O)—N(R2)—, —N(R2)—C(O)—, —N(R2)—, —C(R2)2—, —C(OR2)2—, or —CH(OH)—;
- each R is independently selected from hydrogen, —R2, —N(R2)2, —OR2, SR2, —C(O)—N(R2)2, —S(O2)—N(R2)2, or —C(O)—OR2, wherein two adjacent R are optionally bound to one another and, together with each carbon to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring;
- R2 is selected from hydrogen, (C1-C3)-alkyl, or (C1-C3)-alkenyl;
- wherein each (C1-C3)-alkyl or (C1-C3)-alkenyl is optionally substituted with —N(R′)2, —OR′, SR′, —C(O)—N(R′)2, —S(O2)—N(R′)2, —C(O)—OR′, or R3;
- Y is C;
- A is CR′;
- and
- n is 1;
- wherein an aromatic heterocyclic ring system consists of 1-2 heteroatoms independently selected from N, O or S.
A compound of the formula
A compound of the formula
A compound of the formula
Dependencies are inferred from the claim text.