P38 inhibitors and methods of use thereof

A method of treating a p38-mediated condition in a human or animal having said p38-mediated condition, wherein said p38-mediated condition is selected from pain, rheumatoid arthritis, osteoarthritis, stroke, endotoxemia, inflammatory bowel disease, tuberculosis, atherosclerosis, cachexia, psoriatic arthritis, gout, gouty arthritis, diabetes, sepsis, toxic shock syndrome, traumatic arthritis, rheumatid spondylitis, septic shock, endotoxic shock, gram negative sepsis, graft vs. host reaction, psoriasis, glomerulonephritis, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, bone resorption, reperfusion injury, allograft rejections, Crohn's disease ulcerative colitis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma, said method comprising administering to said human or animal, in an amount effective to treat said p38-mediated condition, a compound of the Formula

• wherein
• Ar1 is aryl or heteroaryl, each of which may be substituted or unsubstituted;
• A is H, OH, an amine protecting group, Zn—NR2R3, Zn—NR2(C═O)R2, Zn—SO2R2, Zn—SOR2, Zn—SR2, Zn—OR2, Zn—(C═O)R2, Zn—(C═O)OR2, Zn—O—(C═O)R2, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1 may be substituted or unsubstituted;
• Z is alkylene of from 1 to 4 carbons, or alkenylene or alkynylene each of from 2 to 4 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted;
• R2 and R3 are independently H, OH, an amine protecting group, an alcohol protecting group, an acid protecting group, a sulfur protecting group, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1 may be substituted or unsubstituted,
• or R2 together with R3 and N forms a saturated or partially unsaturated heterocycle ring of 1 or more heteroatoms in said ring, wherein said heterocycle may be substituted or unsubstituted and wherein said heterocycle may be fused to an aromatic ring;
• B is H, NH2, or substituted or unsubstituted methyl;
• E is Zn—NR2R3, Zn—(C═O)R4, Zn—(C═O)R5, Zn—NR5(C═O)R5, Zn—O(C═O)R5, Zn—OR5, Zn—SO2R5, Zn—SOR5, Zn—SR5, or Zn—NH(C═O)NHR5;
• R4 is NH(CHR6) (CH2)mOR5 where m is an integer from 1 to 4, or NR2R3;
• R5 is H, OH, an amine protecting group, an alcohol protecting group, an acid protecting group, a sulfur protecting group, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Zn-cycloalkyl, Zn-heterocycloalkyl, or Zn—Ar1 may be substituted or unsubstituted;
• R6 is a natural amino acid side chain, Zn—NR2R3, Zn—OR5, Zn—SO2R5, Zn—SOR5, or Zn—SR5;
• and
• n is 0 or 1, or a resolved enantiomer, diastereomer or pharmaceutically acceptable salt thereof.