Inhibitors of c-Jun N terminal kinases (JNK) and other protein kinases

A compound having the formula:

• 118
• wherein
• A is N or CH;
• PG is hydrogen or a nitrogen protecting group;
• R1 is H, T(n)—R, or T(n)—Ar2;
• R is an aliphatic or substituted aliphatic group;
• n is zero or one;
• T is C(═O), CO2, CONH, S(O)2, S(O)2NH, COCH2 or CH2;
• and
• each R2 is independently selected from hydrogen, —R, —CH2OR, —CH2OH, —CH═O, —CH2SR, —CH2S(O)2R, —CH2(C═O)R, —CH2CO2R, —CH2CO2H, —CH2CN, —CH2NHR, —CH2N(R)2, —CH═N—OR, —CH═NNHR, —CH═NN(R)2, —CH═NNHCOR, —CH═NNHCO2R, —CH═NNHSO2R, -aryl, -substituted aryl, —CH2(aryl), —CH2(substituted aryl), —CH2NH2, —CH2NHCOR, —CH2NHCONHR, —CH2NHCON(R)2, —CH2NRCOR, —CH2NHCO2R, —CH2CONHR, —CH2CON(R)2, —CH2SO2NH2, —CH2 (heterocyclyl), —CH2(substituted heterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl).

A compound having the formula:

• 119
• wherein:
• X—Y is N—O or O—N providing an isoxazole or reverse isoxazole ring;
• A is N or CH;
• G is R, aryl or substituted aryl;
• R is aliphatic or substituted aliphatic
• R2 is selected from hydrogen, —R, —CH2OR, —CH2OH, —CH═O, —CH2SR, —CH2S(O)2R, —CH2(C═O)R, —CH2CO2R, —CH2CO2H, —CH2CN, —CH2NHR, —CH2N(R)2, —CH═N—OR, —CH═NNHR, —CH═NN(R)2, —CH═NNHCOR, —CH═NNHCO2R, —CH═NNHSO2R, -aryl, -substituted aryl, —CH2 (aryl), —CH2(substituted aryl), —CH2NH2, —CH2NHCOR, —CH2NHCONHR, —CH2NHCON(R)2, —CH2NRCOR, —CH2NHCO2R, —CH2CONHR, —CH2CON(R)2, —CH2SO2NH2, —CH2 (heterocyclyl), —CH2 (substituted heterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl);
• and
• R1 is selected from halogen, NH2, SR, or SO2R;
• provided that R1 is other than Br or Cl when A is CH.

A method for treating a disease state or condition in mammals that is alleviated by treatment with a protein kinase inhibitor, comprising administering to a mammal in need of such a treatment a therapeutically effective amount of a compound of formula I:

• 120
• wherein:
• X—Y—Z is selected from one of the following:
• 121
• R1 is H, CONH2, T(n)—R, or T(n)—Ar2;
• R is an aliphatic or substituted aliphatic group;
• n is zero or one;
• T is C(═O), CO2, CONH, S(O)2, S(O)2NH, COCH2 or CH2;
• each R2 is independently selected from hydrogen, —R, —CH2OR, —CH2OH, —CH═O, —CH2SR, —CH2S(O)2R, —CH2(C═O)R, —CH2CO2R, —CH2CO2H, —CH2CN, —CH2NHR, —CH2N(R)2, —CH═N—OR, —CH═NNHR, —CH═NN(R)2, —CH═NNHCOR, —CH═NNHCO2R, —CH═NNHSO2R, -aryl, -substituted aryl, —CH2(aryl), —CH2(substituted aryl), —CH2NH2, —CH2NHCOR, —CH2NHCONHR, —CH2NHCON(R)2, —CH2NRCOR, —CH2NHCO2R, —CH2CONHR, —CH2CON(R)2, —CH2SO2NH2, —CH2(heterocyclyl), —CH2(substituted heterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl);
• each R3 is independently selected from hydrogen, R. COR, CO2R or S(O)2R;
• G is R or Ar1;
• Ar1 is aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, or substituted heterocyclyl, wherein Ar1 is optionally fused to a partially unsaturated or fully unsaturated five to seven membered ring containing zero to three heteroatoms;
• Q—NH is
• 122
• wherein the H of Q—NH is optionally replaced by R3;
• A is N or CR3;
• U is CR3, O, S, or NR3;
• Ar2 is aryl, substituted aryl, heterocyclyl or substituted heterocyclyl, wherein Ar2 is optionally fused to a partially unsaturated or fully unsaturated five to seven membered ring containing zero to three heteroatoms;
• wherein each substitutable carbon atom in Ar2, including the fused ring when present, is optionally and independently substituted by halo, R, OR, SR, OH, NO2, CN, NH2, NHR, N(R)2, NHCOR, NHCONHR, NHCON(R)2, NRCOR, NHCO2R, CO2R, CO2H, COR, CONHR, CON(R)2, S(O)2R, SONH2, S(O)R, SO2NHR, or NHS(O)2R, and wherein each saturated carbon in the fused ring is further optionally and independently substituted by ═O, ═S, ═NNHR, ═NNR2, ═N—OR, ═NNHCOR, ═NNHCO2R, ═NNHSO2R, or ═NR;
• and
• wherein each substitutable nitrogen atom in Ar2 is optionally substituted by R, COR, S(O)2R, or CO2R.