P38 inhibitors and methods of use thereof

A compound having the formula

• or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein:
• X is O, S, SO, SO2, NR7, C═O, CR7R7a, C═NOR1, C═CHR1 or CHOR1;
• Ar1 is a 5- or 6-membered aryl or heteroaryl ring, wherein said aryl and heteroaryl are optionally substituted with one or more groups independently selected from NH2, NHMe, NMe2, CH2OH, cyclopropyl, C1-C3 alkyl, C1-C3 haloalkyl, OH, CN, F, Cl, Br I, SCH3, OCH3, and OCF3;
• A is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR16, NR16R17, NR16(C═O)R17, NR16C(═O)NR17R18, NR16C(═O)R17, OC(═O)NR16R17, CR17═NOR16, SO2R19, SOR17, SR17, SO2NR16R17, OR16, (C═O)R6, (C═O)OR16, O—(C═O)R16, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, and a 5- or 6-membered heteroaryl or aryl ring;
• B is H, NH2, NHMe, NMe2, CH3, 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;
• R1 is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl;
• R4 is
• G is a C2-C4 hydrocarbon chain, which taken together with the atoms to which it is attached, forms a 5 to 7 membered saturated or unsaturated ring that is optionally substituted with one or more R30 groups;
• R7 and R7a are independently H or C1-C12 alkyl,
• or R7 and R7a together with the carbon to which they are attached form a cyclopropyl ring;
• R8 is H or Me;
• R15 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, oxo, OH, O—(C1-C6 alkyl), S—(C1-C6 alkyl), NH—(C1-C6 alkyl), N—(C1-C6 alkyl)2, SO—(C1-C6 alkyl), and SO2—(C1-C6 alkyl),
• or R15 is a saturated, partially unsaturated, or fully unsaturated three to seven membered carbocyclic ring or heterocyclic ring having one or two heteroatoms independently selected from O, S and N, wherein said carbocyclic and heterocyclic rings are optionally attached to the nitrogen of the lactam ring through a C1-C4 alkyl, and wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, O—(C1-C6 alkyl), S—(C1-C6 alkyl), NH2, oxo, nitro, cyano, C(═O)OH, C(═O)O—(C1-C6 alkyl), NH—(C1-C6 alkyl) and N—(C1-C6 alkyl)2;
• R16, R17 and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR21, NR21R22, NR21(C═O)R22, NR21C(═O)NR22R23, CR22═NOR21SO2R24, SOR22, SR22, SO2NR21R22, OR21, (C═O)R21, (C═O)OR21, O—(C═O)R21, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, and a 5- or 6-membered heteroaryl or aryl ring,
• or R16 and R17 together with the atoms to which they are attached form a saturated or partially unsaturated 5-6 membered heterocyclic ring having one or more heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR21, NR21R22, NR21(C═O)R22, NR21C(═O)NR22R23, CR22═NOR21SO2R24, SOR22, SR22, SO2NR21R22, OR21, (C═O)R21, (C═O)OR21, O—(C═O)R21, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, and a 5- or 6-membered heteroaryl or aryl ring,
• or R17 and R18 together with the atoms to which they are attached form a saturated or partially unsaturated 5-6 membered heterocyclic ring having one or more heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O, ═NOR21, NR21R22, NR21 (C═O)R22, NR21C(═O)NR22R23, CR22═NOR21SO2R23, SOR23, SR22, SO2NR21R22, OR21, (C═O)R21, (C═O)OR21, O—(C═O)R21, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, and a 5-6 membered heteroaryl or aryl ring;
• R19 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated C3-C6 cycloalkyl, saturated or partially unsaturated C1-C6 heterocyclyl, or a 5-6 membered heteroaryl or aryl ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, ═O ═NOR21, NR21R22, NR21(C═O)R22, NR21C(═O)NR22R23, CR22═NOR21SO2R23, SOR23, SR22, SO2NR21R22, OR21, (C═O)R21, (C═O)OR21, O—(C═O)R21, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated C3-C6 cycloalkyl, saturated or partially unsaturated C1-C6 heterocyclyl, and a 5-6 membered heteroaryl or aryl ring;
• R21, R22 and R23 are independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from F, Cl, Br and I;
• R24 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from F, Cl, Br, and I;
• and
• each R30 is independently F, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a saturated or partially unsaturated 3-6 membered carbocyclic ring, a 6 membered aryl ring, or a 5-6 membered heterocyclic ring having one or two heteroatoms independently selected from O, S and N, wherein said carbocyclic, aryl, and heterocyclic rings are optionally attached to the lactam ring through a C1-C4 alkyl, and wherein said alkyl, alkenyl, alkynyl, carbocyclic ring, aryl ring, and heterocyclic ring are optionally substituted with one or more groups independently selected from oxo, OH, SH, NH2, F, Cl, Br, I, CN, C1-C6 alkyl, C2-C6 alkenyl, O—(C1-C6 alkyl), S—(C1-C6 alkyl), NH—(C1-C6 alkyl), SO—(C1-C6 alkyl), and SO2—(C1-C6 alkyl), C(═O)OH, and C(═O)O—(C1-C6)alkyl,
• or two adjacent R30 groups together with the atoms to which they are attached form a 6 membered saturated or partially unsaturated carbocyclic ring or a 6 membered aryl ring.