P38 inhibitors and methods of use thereof

A compound of Formula I:

• and metabolites, solvates, tautomers, resolved enantiomers, diastereomers, and salts thereof, wherein:
• A is H, an amine protecting group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O (with the proviso that it is not substituted on an aryl or heteroaryl), ═NOR4 (with the proviso that it is not substituted on an aryl or heteroaryl), —NR4R5, —NR4(C═O)R5, —NR4C(═O)NR5R7, —CR5═NOR4—SO2R6, —SOR6, —SR5, —SO2NR4R5, —OR4, —(C═O)R4, —(C═O)OR4, —O—(C═O)R4, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• B is H, —NH2, —NHMe, —NMe2, —CH3, —CF3, —CH2OH, cyclopropyl, C1-C3 alkyl, —OH, CN, F, Cl, Br or I, wherein said alkyl is optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• W is C(═O) or SO2;
• X is O, S, SO, SO2, NH, NCH3, C(═O), CH2, CH(CH3), C(CH3)2, C═NOR4, C═CR4 or CHOR4;
• Y is —C((═O)R4—C(═O)OR4, —C(═O)NR4R5, —CR4R5OR7, —C(═O)NR4OR5 or —C(═O)NR4NR5R7;
• R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR4, —NR4R5, —NR4(C═O)R5, —NR4C(═O)NR5R7, —CR5═NOR4—SO2R6, —SOR6, —SR5, —SO2NR4R5, —OR4, —(C═O)R4, —(C═O)OR4, —O—(C═O)R4, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• R2 and R6 are independently alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O (with the proviso that it is not substituted on an aryl or heteroaryl), ═NOR4 (with the proviso that it is not substituted on an aryl or heteroaryl), —NR4R5, —NR4(C═O)R5, —NR4C(═O)NR5R7, —CR5═NOR4—SO2R6, —SOR6, —SR5, SO2NR4R5, —OR4, —(C═O)R4, —(C═O)R4, —O—(C═O)R4, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I and OH,
• or R1 and R2 together with the atom to which they are attached form a saturated or partially unsaturated 3-10 membered carbocyclic ring or a saturated or partially unsaturated 3-10 membered heterocyclic ring having 1 or more heteroatoms, wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR4, —NR4R5, —NR4(C═O)R5, —NR4C(═O)NR5R7, —CR5═NOR4—SO2R6, —SOR6, —SR5, SO2NR4R5, —OR4, —(C═O)R4, —(C═O)OR4, —O—(C═O)R4, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• R3 is H, C1-C4 alkyl, C3-C6 cycloalkyl or —OR4, wherein said alkyl and cycloalkyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, and alkyl;
• R4, R5 and R7 are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O (with the proviso that it is not substituted on an aryl or heteroaryl), ═NOR8 (with the proviso that it is not substituted on an aryl or heteroaryl), —NR8R9, —NR8(C═O)R9, —NR8C(═O)NR9R10, —CR9═NOR8—SO2R6, —SOR6, —SR9, —SO2NR8R9, —OR8, —(C═O)R8, —(C═O)OR8, —O—(C═O)R8, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I,
• or R4 and R5 together with the atom to which they are attached form a saturated or partially unsaturated 4-8 membered carbocyclic ring or a saturated or partially unsaturated 4-8 membered heterocyclic ring having 1 or more heteroatoms, wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR8, —NR8R9, —NR8(C═O)R9, —NR8C(═O)NR9R10, —CR9═NOR8—SO2R11, —SOR11, —SR9, SO2NR8R9, —OR8, —(C═O)R8, —(C═O)OR8, —O—(C═O)R8, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I, and wherein said carbocyclic and heterocyclic rings are optionally fused to an aromatic ring,
• or R5 and R7 together with the atom to which they are attached form a saturated or partially unsaturated 4-8 membered heterocyclic ring having 1 or more heteroatoms, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR8, —NR8R9, —NR8(C═O)R9, —NR8C(═O)NR9R10, —CR9═NOR8—SO2R11, —SOR11, —SR9, SO2NR8R9, —OR8, —(C═O)R8, —(C═O)OR8, —O—(C═O)R8, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I, and wherein said heterocyclic ring is optionally fused to an aromatic ring;
• R8, R9 and R10 are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• R11 is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, heteroaryl and aryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, and I;
• and
• Ar is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more groups independently selected from —NH2, —NHMe, —NMe2, —CH3, —CF3, —CH2OH, cyclopropyl, —OH, CN, F, Cl, Br, I, and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from F, Cl, Br and I.