Piperidine/piperazine-type inhibitors of p38 kinase

A compound of the formula:

• or the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein:
• Ar1 is an aryl group substituted with 0-5 non-interfering substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, R3Si, and NO2, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of said optional substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members;
• L1 is CO, CHOH or CH2;
• L is alkylene (1-4C) or alkenylene (1-4C) optionally substituted with a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, R3Si, and NO2, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two substituents on L can be joined to form a non-aromatic saturated or unsaturated ring that includes 0-3 heteroatoms which are O, S and/or N and which contains 3 to 8 members or said two substituents can be joined to form a carbonyl moiety or an oxime, oximeether, oximeester or ketal of said carbonyl moiety;
• each R1 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, R3Si, and NO2, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof and two of R4 on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or R4 is ═O or an oxime, oximeether, oximeester or ketal thereof;
• m is 0-4;
• Ar2 comprises an optionally substituted monocyclic or polycyclic aromatic nucleus, wherein said aromatic nucleus consists of carbocyclic or heterocyclic ring selected from (i) a five-membered heterocyclic or carbocyclic ring;
• (ii) a six-membered carbocyclic or heterocyclic ring;
• (iii) a five-membered carbocyclic or heterocyclic ring fused to another five-membered carbocyclic or heterocyclic ring;
• (iv) a six-membered carbocyclic or heterocyclic ring fused to another six-membered carbocyclic or heterocyclic ring;
• and (v) a five-membered heterocyclic or carbocyclic ring fused to a six-membered carbocyclic or heterocyclic ring;
• Z is COXjCOR3, wherein j is 0 or 1;
• and
• wherein R3 is H, or is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, heteroalkyl, SR, SOR, SO2R, SO2NR2, OR, NR2, OCOR, NRCOR, NRCONR2, NRSO2R, NRSO2NR2, OCONR2, CN, COOR, CONR2, COR, or R3Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof, or wherein R3 is OR, NR2, SR, NRCONR2, OCONR2, or NRSO2NR2, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof, and wherein two R attached to the same atom may form a 3-8 member carbocyclic or heterocyclic ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR2, OCOR, NRCOR, NRCONR2, NRSO2R, NRSO2NR2, OCONR2, or R3Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroatom-containing forms thereof wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined;
• and
• X, if present, is CR2 where R is as defined above;
• with the proviso that the portion of the compound represented by Ar2-Z is not
• 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 2-6 Å, 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.