Inhibitors of p38

A compound of the formula:

• wherein each of Q1 and Q2 are independently selected from a phenyl or 5-6 membered aromatic heterocyclic ring system, or an 8-14 membered saturated, partially unsaturated, or aromatic bicyclic or tricyclic ring system containing 0-4 heteroatoms;
• the rings that make up Q1 are substituted with 1 to 4 substituents, each of which is independently selected from halo;
• C1-C3 aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′ or CON(R′)2;
• O—(C1-C3)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′ or CON(R′)2;
• R′;
• N(R′)2;
• OCF3;
• CF3;
• NO2;
• CO2R′;
• CON(R′)2;
• 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;
• N═CR′—N(R′)2;
• SO2R′;
• or C(O)R′;
• the rings that make UP Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo;
• C1-C3 aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, S(O2)N(R′)2, N═CR′—N(R′)2, R3, O—P(O3)H2, or CON(R′)2;
• O—(C1-C3)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, S(O2)N(R′)2, N═CR′—N(R′)2, R3, OP(O3)H2, or CON(R′)2;
• R′;
• N(R′)2;
• OCF3;
• CF3;
• NO2;
• CO2R′;
• CON(R′)2;
• R3;
• OR3;
• N(R3)2;
• SR3;
• C(O)R3;
• C(O)N(R′)R3;
• C(O)OR3;
• SR′;
• S(O2)N(R′)2;
• SCF3;
• N═CR′—N(R′)2;
• R4;
• O—CO2R4;
• 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 CN;
• each R′ is independently selected from hydrogen;
• (C1-C3)-aliphatic;
• phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• or a 5-8 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
• each R3 is independently selected from a 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring system each optionally substituted with halo, R′, R4, —C(O)R′, —C(O)R4, —C(O)OR4, —J or —K;
• or an 8-10 membered saturated, partially unsaturated, or aromatic bicyclic ring system containing 0-4 heteroatoms, said ring system optionally substituted with halo, R′, R4, —C(O)R′, —C(O)R4, —C(O)OR4, —J or —K;
• each R4 is independently selected from —N(R′)2;
• —NR′C(O)—(C1-C4)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R5)2, —J or —K;
• —NR′—(C1-C4)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R5)2, —J or —K;
• —OC(O)—N(R′)2;
• a (C1-C4)-aliphatic, wherein up to two saturated carbon atoms of the aliphatic chain are each optionally and independently replaced by —C(O)—, —C(O)NR′—, —C(O)NR′NR′—, —CO2—, —NR′C(O)NR′—, —OC(O)—, C(O)C(O)—, —OC(O)NR′—, —NR′NR′—, —NR′CO—, —NR′O—, —O—, —S—, —SO—, —SO2—, —NR′—, —SO2NR′—, —NR′—SO2—, and wherein the aliphatic chain is optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R5)2, —J or —K;
• a (C1-C7)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R5)2, —J or —K;
• —J;
• —K;
• or a 5-6 membered aromatic or non-aromatic carbocyclic or heterocyclic ring system optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, C(O)N(R′)2, SO2N(R′)2 SO2N(R5)2, —J or —K;
• R5 is selected from hydrogen;
• or a (C1-C3)-aliphatic optionally substituted with halo, —R′, —N(R′)2, —OR′, SR′, —C(O)N(R′)2, —S(O)2N(R′)2, —C(O)OR′, —N(R′)S(O)2(R′), —N(R′)SO2R6, —C(O)N(R′)(R6), —N(R′)C(O)R′, —N(R′)(R6), —C(O)R6, —C(O)N═C(NHR′)2 or R6;
• R6 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with halo, R′, —C(O)R′ or —C(O)OR′;
• or an 8-10 membered saturated, partially unsaturated, or aromatic ring system containing 0-4 heteroatoms, said ring system optionally substituted with halo, R′, —C(O)R′ or C(O)OR′;
• Z is N, CH, C(OCH3), C(CH3), C(NH2), C(OH) or C(F);
• W is CH, C(OCH3), C(CH3), C(NH2), C(OH) or C(F);
• J is T or is a (C1-C4) aliphatic substituted with T;
• T is V, O(V) or NH(V);
• V is C(O)N═C(R)(N(R)2) wherein the two geminal R on the nitrogen are optionally taken together with the nitrogen to form a 4-8 membered heterocyclic ring;
• 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 C or N to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring;
• R2 is selected from hydrogen;
• or a (C1-C3)-aliphatic optionally substituted with halo, —R′, —N(R′)2, —OR′, SR′, —C(O)N(R′)2, —S(O2)N(R′)2, —C(O)OR′, —N(R′)SO2R8, —N(R′)SO2R7, —C(O)N(R′)(R7), —N(R′)C(O)R8, —N(R′)(R7), —N(R′)(R8), —C(O)R7, —C(O)N(R′)(R8), —N(R8)2, —C(O)N═C(NHR′)2 or R7;
• R7 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with halo, R′, R8, —C(O)R′, —C(O)R8, —C(O)OR8;
• or an 8-10 membered saturated, partially unsaturated, or aromatic bicyclic ring system containing 0-4 heteroatoms, said ring system optionally substituted with halo, R′, R8, —C(O)R′, —C(O)R8, or —C(O)OR8;
• R8 is selected from (C1-C4)-aliphatic, wherein up to two saturated carbon atoms of the aliphatic chain are each optionally and independently replaced by —C(O)—, —C(O)NR′—, —C(O)NR′NR′—, —CO2—, —NR′C(O)NR′—, —OC(O)—, —C(O)C(O)—, —OC(O)NR′—, —NR′NR′—, —NR′CO—, —NR′O—, —O—, —S—, —SO—, —SO2—, —NR′—, —SO2NR′—, —NR′SO2—, and wherein the aliphatic chain is optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R′)2;
• a (C1-C7)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, SO2N(R′)2, SO2N(R5)2;
• or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, C(O)N(R′)2, SO2N(R′)2, or SO2N(R′)2;
• K is —C(O)—D, a (C1-C4) aliphatic substituted with D or —OP(O)(OH)2;
• D is
• M is either O or NH;
• G is selected from NH2, OH, or H;
• R9 is H;
• OH;
• C(O)OH;
• (C1-C7)-aliphatic optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, CON(R′)2, or SO2N(R′)2;
• or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with halo, R′, N(R′)2, OR′, CO2R′, C(O)N(R′)2, or SO2N(R′)2;
• or G and R9 taken together with the intervening carbon may form a ring.