P38 inhibitors and methods of use thereof

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

wherein

Y is C, N;

W is C or N, provided that W is N, when Y is C, and W is C when Y is N;

U is CH;

V is C-E;

X is O, S, SO, SO 2 , or NR 7 ;

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;

R 7 is H or substituted or unsubstituted methyl;

Ar 1 is aryl which may be substituted or unsubstituted;

A is H, alkyl, allyl, alkenyl, or alkynyl, wherein said alkyl, allyl, alkenyl, and alkynyl, may be substituted or unsubstituted;

R 2 and R 3 are independently H, OH, an amine protecting group, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, or Z n -Ar 1 may be substituted or unsubstituted,

B is H, NH 2 , or substituted or unsubstituted methyl;

E is Z n -(C═O)R 4 ;

R 4 is NR 2 R 3 ; and

n is 0 or 1,

provided that when B is H and A is CH═CH—R 8 where R 8 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then X is not O, S, SO NH, or N(C 1 -alkyl).

2. The compound of claim 1 , wherein Ar 1 is phenyl.

3. The compound of claim 2 , wherein Ar 1 is 4-chlorophenyl, 4-fluorophenyl, 3-methylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-(MeS)-phenyl sulfide, 3-(MeSO 2 )-phenyl, or 3-methyl-4-flurophenyl.

4. The compound of claim 1 , wherein A is H, 4-MeO-Ph-(CH 2 ), CH 2 CH═CH 2 , CH 2 CH(OH)CH 2 OH, CH 2 C(═O)H, CH 2 -isoxazole, (CH 2 )NH 2 , (CH 2 )NHBoc, CH═CHPh, CH 2 OH, CH 2 OCH 3 , methyl, ethyl, isopropyl, or CH 2 CF 3 .

5. The compound of claim 1 , wherein Y is N.

6. The compound of claim 1 , wherein Y is C.

7. The compound of claim 1 , which is selected from:

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid amide;

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-benzylaminoethyl)-amide;

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-piperidin-yl-ethyl)-amide;

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide;

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (3-morpholin-4-yl-propyl)-amide; and

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (3-dimethylaminopropyl)-amide.

8. The compound of claim 1 , which is selected from:

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid methyl-(1-methylpiperidin-4-yl)-amide;

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid [3-(methylphenylamino)-propyl]-amide;

5-(4-fluorophenoxy)-1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)amide;

5-(4-fluorophenoxy)-1-methyl-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)amide; and

5-(4-fluorophenoxy)-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)amide.

9. The compound of claim 1 , which is selected from:

4-amino-2-{[5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}butyric acid methyl ester;

4-amino-2-{[5-(4-fluorophenoxy)-1-(2,2,2-trifluoroethyl)-1H-indazole-6-carbonyl]-amino}butyric acid methyl ester; and

4-amino-2-{[5-(4-fluorophenoxy)-1-methyl-1H-indazole-6-carbonyl]-amino}butyric acid methyl ester.

10. The compound of claim 1 , which is (S)-N-(4-amino-1-hydroxybutan-2-yl)-5-(4-fluorophenoxy)-1-isobutyl-1H-indaziole-6-carboxamide.

11. The compound of claim 1 , wherein n is 0.

12. The compound of claim 11 , wherein A is alkyl, wherein said alkyl may be substituted or unsubstituted.

13. The compound of claim 11 , wherein NR 2 R 3 is NH 2 ,

14. The compound of claim 1 , wherein X is O.

15. The compound of claim 5 , wherein X is O.

16. The compound of claim 6 , wherein X is O.