Piperidine/piperazine-type 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
• 62
• and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein:
• Ar1 is an aryl group substituted with 0-5 non-interfering substituents, wherein two adjacent noninterfering substituents can form a fused aromatic or nonaromatic ring;
• L1and L2 are linkers;
• each R1 is independently a noninterfering substituent;
• Z1 is CR2 or N wherein R2 is hydrogen or a noninterfering substituent;
• m is 0-4;
• each of n and p is an integer from 0-2 wherein the sum of n and p is 0-3;
• Ar2 is a substantially planar, monocyclic or polycyclic aromatic moiety having one or more optional ring heteroatoms, said moiety being optionally substituted with one or more non-interfering substituents, two or more of which may form a fused ring;
• Z is —Wi—COXjY wherein Y is COR3 or an isostere thereof;
• R3 is 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;
• wherein the smallest number of covalent bonds in the compound separating the atom of Ar1 bonded to L2 to the atom of Ar2 bonded to L1is at least 6, where each of said bonds has a bond length of 1.2 to 2.0 angstroms;
• and/or wherein the distance in space between the atom of Ar1 bonded to L2 and the atom of Ar2 bonded to L1is 4.5-24 angstroms;
• with the proviso that the portion of the compound represented by Ar2—Z is not
• 63
• wherein represents a single or double bond;
• n is 0-3;
• one Z2 is CA or CRA and the other is CR, CR2, NR or N;
• A is —Wi—COXjY wherein Y is COR or an isostere thereof, each of W and X is a spacer of 2-6Å, and each of i and j is independently 0 or 1;
• Z3 is NR or O;
• and each R is independently hydrogen or a noninterfering substituent.

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:

• 64
• and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein
• Ar1 is an aryl group substituted with 0-5 non-interfering substituents, wherein two adjacent noninterfering substituents can form a fused aromatic or nonaromatic ring;
• L1and L2 are linkers;
• each R1 is independently a noninterfering substituent;
• Z1 is CR2 or N wherein R2 is hydrogen or a noninterfering substituent;
• m is 0-4;
• each of n and p is an integer from 0-2 wherein the sum of n and p is 0-3;
• Ar2 is a substantially planar, monocyclic or polycyclic aromatic moiety having one or more optional ring heteroatoms, said moiety being optionally substituted with one or more non-interfering substituents, two or more of which may form a fused ring;
• Z is —Wi—COXjY wherein Y is COR3 or an isostere thereof;
• R3 is 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;
• wherein the smallest number of covalent bonds in the compound separating the atom of Ar1 bonded to L2 to the atom of Ar2 bonded to L1is at least 6, where each of said bonds has a bond length of 1.2 to 2.0 angstroms;
• and/or wherein the distance in space between the atom of Ar1 bonded to L2 and the atom of Ar2 bonded to L1 is 4.5-24 angstroms;
• with the proviso that the portion of the compound represented by Ar2—Z is not
• 65
• wherein represents a single or double bond;
• n is 0-3;
• one Z2 is CA or CRA and the other is CR, CR2, NR or N;
• A is —Wi—COXjY wherein Y is COR or an isostere thereof, each of W and X is a spacer of 2-6Å, and each of i and j is independently 0 or 1;
• Z3 is NR or 0;
• and each R is independently hydrogen or a noninterfering substituent.