Indole-type derivatives as inhibitors of p38 kinase

A pharmaceutical composition for treating conditions characterized by enhanced p38-α activity which composition comprises

• a therapeutically effective amount of a compound of the formula
• 241
• and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein
• 242
• represents a single or double bond;
• one Z2 is CA or CR8A and the other is CR1, CR12, NR6 or N wherein each R1, R6 and R8 is independently hydrogen or noninterfering substituent;
• A is —Wi—COXjY wherein Y is COR2 or an isostere thereof and R2 is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1;
• Z3 is NR or O;
• each R3 is independently a noninterfering substituent;
• n is 0-3;
• each of L1 and L2 is a linker;
• each R4 is independently a noninterfering substituent;
• m is 0-4;
• Z1 is CR5 or N wherein R5 is hydrogen or a noninterfering substituent;
• each of l and k is an integer from 0-2 wherein the sum of l and k is 0-3;
• Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring;
• and
• the distance between the atom of Ar linked to L2 and the center of the α ring is 4.5-24 Å.

A method to treat a condition mediated by p38-α kinase comprising administering to a subject in need of such treatment a compound of the formula:

• 243
• composition thereof, wherein
• 244
• represents a single or double bond;
• one Z2 is CA or CR8A and the other is CR1, CR12, NR6 or N wherein each R1, R6 and R8 is independently hydrogen or noninterfering substituent;
• A is —Wi—COXjY wherein Y is COR2 or an isostere thereof and R2 is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1;
• Z3 is NR7 or O;
• each R3 is independently a noninterfering substituent;
• n is 0-3;
• each of L1 and L2 is a linker;
• each R4 is independently a noninterfering substituent;
• m is 0-4;
• Z1 is CR5 or N wherein R5 is hydrogen or a noninterfering substituent;
• each of l and k is an integer from 0-2 wherein the sum of l and k is 0-3;
• Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring;
• and
• the distance between the atom of Ar linked to L2 and the center of the α ring is 4.5-24 Å.