P38 inhibitors and methods of use thereof

A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the Formula

• 34
• wherein
• X is O, S, SO, SO2, NR7, C═O, CHR7, —C═CHR1, —C═NOR1, or CHOR1;
• R1 is H, PO3H2, SO3H2, 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 having from 1 to 4 carbons, or alkenylene or alkynylene each having from 2 to 4 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted;
• R7 is H or substituted or unsubstituted methyl;
• 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;
• 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 having 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 H, Zn-NR2R3, Zn-(CO)R5, Zn-O(C═O)R5, Zn-OR5, Zn-SO2R5, Zn-SOR5, Zn-SR5, or R5;
• 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;
• and
• n is 0 or 1.

A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the Formula

• 35
• wherein
• X is O, S, SO, SO2, NR7, C═O, CHR7, —C═NOR1, —C═CHR1, or CHOR1;
• R1 is H, PO3H2, SO3H2, 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 having from 1 to 4 carbons, or alkenylene or alkynylene each having from 2 to 4 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted;
• R7 is H or substituted or unsubstituted methyl;
• 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;
• 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 having 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-(C═O)R4, Zn-NR5(CO)R5, Z-NH(C═O)NHR5;
• R4 is a substituted or unsubstituted natural or unnatural amino acid, a protected natural or unnatural amino acid, 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.

A method of treating or preventing a p38-mediated condition, comprising administering an amount of a compound effective to treat or prevent said p38-mediated condition or a pharmaceutical composition comprising said compound, to a human or animal in need thereof, wherein the compound has the Formula

• 36
• wherein
• Y is C, N;
• W is C, N, S, or O, provided that W is N, S, or O when Y is C, and W is C or N when Y is N;
• U is CH or N;
• V is C-E or N;
• X is O, S, SO, SO2, NR7, C═, CHR7, —C═NOR1, —C═CHR1, or CHOR1;
• R1 is H, PO3H2, SO3H2, 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 having from 1 to 4 carbons, or alkenylene or alkynylene each having from 2 to 4 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted;
• R7 is H or substituted or unsubstituted methyl;
• 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;
• 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 having 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 H, 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, Zn-NH(C═O)NHR5, or R5;
• R4 is a substituted or unsubstituted natural or unnatural amino acid, a protected natural or unnatural amino acid, 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,
• provided that when B is H and A is CH═CH—R8 where R8 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then X-Ar1 is a substituent where Ar1 is other than substituted or unsubstituted aryl, heteroaryl, NH-alkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH-alkoxy, or NH-dialkylamide when X is O, S, C═O, S═O, C═CH2, CO2, NH, or N(C1-C8-alkyl).