P38 inhibitors and methods of use thereof

1. A compound of the Formula

wherein

Ar 1 is aryl or heteroaryl, each of which may be substituted or unsubstituted;

A is H, OH, an amine protecting group, Z n -NR 2 R 3 , Z n -NR 2 (C═O)R 2 , Z n -SO 2 R 2 , Z n -SOR 2 , Z n -SR 2 , Z n -OR 2 , Z n -(C═O)R 2 , Z n -(C═O)OR 2 , Z n -O—(C═O)R 2 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalky, or Z n -Ar 1 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;

R 2 and R 3 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, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 may be substituted or unsubstituted,

or R 2 together with R 3 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, NH 2 , or substituted or unsubstituted methyl;

E is Z n -NR 2 R 3 , Z n -(C═O)R 4 , Z n -(C═O)R 5 , Z n -NR 5 (C═O)R 5 , Z n -O(C═O)R 5 , Z n -OR 5 , Z n -SO 2 R 5 , Z n -SOR 5 , Z n -SR 5 , or Z n -NH(C═O)NHR 5 ;

R 4 is NH(CHR 6 )(CH 2 ) m OR 5 where m is an integer from 1 to 4, or NR 2 R 3 ;

R 5 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, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 may be substituted or unsubstituted;

R 6 is a natural amino acid side chain, Z n -NR 2 R 3 , Z n -OR 5 , Z n -SO 2 R 5 , Z n -SOR 5 , or Z n -SR 5 ; and

n is 0 or 1, or a resolved enantiomer, diastereomer or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein B is H or NH 2 ; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein B is H; or a pharmaceutically acceptable salt thereof.

4. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The compound of claim 1 , in which E is Z n -NR 2 R 3 , or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , which is of formula

in which X is O; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 , which is selected from:

5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)amine;

N-(2-(dimethylamino)ethyl)-N-((5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl)methyl)methanesulfonamide;

N-(2-(dimethylamino)ethyl)-N-((5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl)methyl)acetamide; and pharmaceutically acceptable salts thereof.

8. The compound of claim 1 , in which E is Z n -(C═O)R 4 , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , which is of formula:

in which X is O; or a pharmaceutically acceptable salt thereof.

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

[5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl]morpholin-4-yl-methanone;

[5-(4-fluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-(4-methylpiperazin-1-yl)methanone;

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

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

3-{[5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester; and pharmaceutically acceptable salt thereof.

11. The compound of claim 9 , which is (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (1-carbamoyl-3-dimethylaminopropyl)amide; or a and pharmaceutically acceptable salt thereof.

12. The compound of claim 9 , which is (S)-methyl 2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)-4-(dimethylamino)butanoate; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 9 , which is (S)-5-(2,4-difluorophenoxy)-N-(4-(dimethylamino)-1-hydroxybutan-2-yl)-1-isobutyl-1H-indazole-6-carboxamide; or a pharmaceutically acceptable salt thereof.

14. The compound of claim 9 , which is (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (1-hydroxymethyl-3-isopropylaminopropyl)amide; or a pharmaceutically acceptable salt thereof.

15. The compound of claim 9 , which is (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (3-dimethylamino-1-dimethylcarbamoylpropyl)amide; or a pharmaceutically acceptable salt thereof.

16. The compound of claim 9 , which is (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (3-dimethylamino-1-methylcarbamoylpropyl)amide; or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , in which E is Z n -(C═O)R 5 , or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , which is 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , in which E is Z n -OR 5 , or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 , which is selected from:

{3-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-propyl}dimethylamine;

5-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazole;

5-(2,4-difluorophenoxy)-1-isobutyl-6-(3-piperazin-1-yl-propoxy)-1H-indazole;

5-(2,4-difluorophenoxy)-1-isobutyl-6-(morpholin-2-ylmethoxy)-1H-indazole;

1-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol; and pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , which is {3-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]-propyl}dimethylamine; or a pharmaceutically acceptable salt thereof.

22. The compound of claim 20 , which is 5-(2,4-difluorophenoxy)-1-isobutyl-6-(piperidin-4-ylmethoxy)-1H-indazole; or a pharmaceutically acceptable salt thereof.

23. The compound of claim 20 , which is 5-(2,4-difluorophenoxy)-1-isobutyl-6-(morpholin-2-ylmethoxy)-1H-indazole; or a pharmaceutically acceptable salt thereof.

24. The compound of claim 5 , which is selected from:

N′-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamine;

[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-piperidin-4-yl-amine;

[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-piperidin-3-ylmethylamine; and pharmaceutically acceptable salt thereof.

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

(S)-2- {[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-dimethylaminobutyric acid;

(S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (1-hydroxymethyl-3-piperidin-1-ylpropyl)amide;

(S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid [1-(2-dimethylaminoethyl)-2-hydroxy-2-methylpropyl]amide;

(S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid {1-hydroxymethyl-3-[(2-methoxyethyl)methylamino]propyl}amide;

(S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid [3-dimethylamino-1-(2-hydroxyethylcarbamoyl)propyl]amide; and pharmaceutically acceptable salt thereof.

26. A compound of the Formula

wherein

Ar 1 is aryl or heteroaryl, each of which may be substituted or unsubstituted;

A is H, OH, an amine protecting group, Z n -NR 2 R 3 , Z n -NR 2 (C═O)R 2 , Z n -SO 2 R 2 , Z n -SOR 2 , Z n -SR 2 , Z n -OR 2 , Z n -(C═O)R 2 , Z n -(C═O)OR 2 , Z n -O—(C═O)R 2 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 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;

R 2 and R 3 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, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 may he substituted or unsubstituted,

or R 2 together with R 3 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, NH 2 , or substituted or unsubstituted methyl;

E is Z n -SO 2 R 4 ;

R 4 is NH(CHR 6 )(CH 2 ) m OR 5 where m is an integer from 1 to 4, or NR 2 R 3 ;

R 5 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, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 , wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar 1 may be substituted or unsubstituted;

R 6 is a natural amino acid side chain, Z n -NR 2 R 3 , Z n -OR 5 , Z n -SO 2 R 5 , Z n -SOR 5 , or Z n -SR 5 ; and

n is 0 or 1, or a resolved enantiomer, diastereomer or pharmaceutically acceptable salt thereof.

27. The compound of claim 26 , which is selected from:

5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonic acid (3-dimethylaminopropyl)amide;

(S)-methyl 2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonamido)-4-(dimethylamino)butanoate;

5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonic acid [2-(1-methylpyrrolidin-2-yl)-ethyl]amide;

5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonic acid (2-dimethylaminoethyl)amide; and pharmaceutically acceptable salt thereof.

28. A composition comprising a compound of claim 26 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. The composition of claim 28 , in which the compound is 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonic acid (3-dimethylaminopropyl)amide; or a pharmaceutically acceptable salt thereof.

30. The composition of claim 4 , in which the compound is (S)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (1-carbamoyl-3-dimethylamino-propyl)amide; pharmaceutically acceptable salt thereof.

31. The composition of claim 4 , in which the compound is 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)amine; or a pharmaceutically acceptable salt thereof.

32. The composition of claim 4 , in which the compound is {3-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yloxy]propyl}dimethylamine; or a pharmaceutically acceptable salt thereof.

33. The composition of claim 4 , in which the compound is N′-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamine; or a pharmaceutically acceptable salt thereof.