Inhibitors of P38

A compound of the formula:

• wherein each of Q1 and Q2 is independently selected from a phenyl, a 5-6 membered aromatic heterocyclic ring system, or a 8-10 membered bicyclic ring system selected from the group consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring;
• the rings that make up Q1 are substituted with 1 to 4 substituents, each of which is 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;
• the rings that make up Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo;
• C1-C3 straight or branched alkyl optionally substituted with NR′2, OR′, CO2R′, S(O2)N(R′)2, N=CH—N(R′)2, R3, 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;
• Q2′ is selected from phenyl or a 5-6 member aromatic heterocyclic ring optionally substituted with 1-3 substituents, each of which is independently selected from halogen;
• C1-C3 alkyl optionally substituted with NR′2, OR′, CO2R′, CONR′2, or O—P(O3)H2;
• O—(C2-C3)-alkyl optionally substituted with NR′2, OR′, CO2R′, CONR′2, or OP(O3)H2;
• OCF3;
• CF3;
• OR4;
• O—CO2R4;
• O—P(O3)H2;
• 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;
• provided that Q2′ is not phenyl optionally substituted 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• 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;
• or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• R3 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with R′, R4, —C(O)R′, —C(O)R4, —C(O)OR4 or -J;
• or an 8-10 membered bicyclic ring system selected from the group consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring each optionally substituted with R′, R4, —C(O)R′, —C(O)R4, —C(O)OR4 or -J;
• R4 is (C1-C4)-straight or branched 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;
• R5 is selected from hydrogen;
• (C1-C3)-alkyl optionally substituted with R3;
• (C2-C3)-alkenyl or alkynyl each optionally substituted with R3;
• phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• W is selected from hydrogen;
• N(R2)SO2—N(R2)2;
• N(R2)SO2—N(R2)(R3);
• N(R2)C(O)—OR2;
• N(R2)C(O)—N(R2)2;
• N(R2)C(O)—N(R2)(R3);
• N(R2)C(O)—R2;
• N(R2)2;
• C(O)—R2;
• CH(OH)—R2;
• C(O)—N(R2)2;
• C(O)—OR2;
• J;
• or (C1-C4) straight or branched alkyl optionally substituted with N(R′)2, OR′, CO2R′, CON(R′)2, R3, SO2N(R2)2, OC(O)R2, OC(O)R′, OC(O)N(R2)2, —N(R4)(R5), —C(O)N(R5)(R2), —C(O)R5, —N(R2)C(O)N(R2)(R5), —NC(O)OR5, —OC(O)N(R2)(R5), or -J;
• a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′)2, OR′, CO2R′, CON(R′)2, or SO2N(R2)2;
• or a 8-10 membered carbocyclic or heterocyclic ring system optionally substituted with N(R′)2, OR′, CO2R′, CON(R′)2, or SO2N(R2)2;
• provided that, unless U is W, W is not an R3 substituted C1 alkyl;
• W′ is selected from N(R2)—SO2—Q2;
• N(R2)—CO2—Q2;
• N(R2)—C(O)—Q2;
• N(R2)(Q2);
• C(O)—Q2;
• CO2—Q2;
• C(O)N(R2)(Q2);
• C(R2)2Q2;
• each R is independently selected from hydrogen, —R2, —N(R2)2, —OR2, SR2, —C(O)—N(R2)2, —S(O2)—N(R2)2, —C(O)—OR2 or —C(O)R2 wherein two adjacent R are optionally bound to one another and, together with each Y 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′, —NSO2R4, —NSO2R3, —C(O)N(R′)(R3), —NC(O)R4, —N(R′)(R3), —N(R′)(R4), —C(O)R3, —C(O)N(R′)(R4), —N(R4)2, —C(O)N═C(NH)2 or R3;
• Y is C;
• Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or C(F);
• U is selected from R or W;
• V is selected from —C(O)NH2, —P(O)(NH2)2, or —SO2NH2;
• J is a (C1-C4) straight chain or branched alkyl substituted with 1-3 substituents selected from D, —T—C(O)R′, or —OPO3H2;
• D is selected from
• T is O or NH;
• and
• G is NH2 or OH;
• provided that in compounds of formula (Ia), when W is hydrogen, Z is CU or N, and V is —C(O)NH2, then U is not hydrogen;
• and
• in compounds of formula (Ia), when W is hydrogen;
• Z is CH or N;
• V is —C(O)NH2;
• and U is —R2, —N(R2)2, —OR2, —SR2, —C(O)—N(R2)2, —S(O2)—N(R2)2, —C(O)—OR2 or —C(O)R2;
• then each of these R2 is not hydrogen, (C1-C3)-alkyl, or (C2-C3)-alkenyl, or (C1-C3)-alkyl or (C2-C3)-alkenyl substituted with —N(R′)2, —OR′, —SR′, —C(O)—N(R′)2, —S(O2)—N(R′)2, —C(O)—OR′, or an unsubstituted 5-6 membered aromatic carbocyclic or heterocyclic ring system.