Small molecule modulators of cytokine activity

1. An isolated compound having the structure:

or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;

wherein m is an integer from 1 to 4;

p is an integer from 1 to 6;

each occurrence of R 1 and R 4 is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, —CONH 2 , —SO 2 OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a or —C(═O)OR a ; wherein n is 0-2, R R is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;

R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;

R b and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;

R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic; and

R e , for each occurrence, is independently hydrogen or aliphatic.

2. The compound of claim 1 , wherein:

m is an integer from 1 to 4;

p is an integer from 1 to 6;

each occurrence of R 1 and R 4 is independently hydrogen, halogen, hydroxyl, —NO 2 , —NH 2 , —CN, an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety, —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a , —OPO 2 OR a or —C(═O)OR a ; wherein n is 0-2, R R is an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety;

R a , for each occurrence, is independently hydrogen or an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety;

R b and R c , for each occurrence, are independently hydrogen hydroxy, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety;

R d , for each occurrence, is independently hydrogen, —N(R e ) 2 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and

R e , for each occurrence, is independently hydrogen or alkyl.

3. The compound of claim 2 having the structure:

wherein p, R 1 and R 4 are as defined in claim 2 .

4. The compound of claim 2 having the structure:

wherein p and R 4 are as defined in claim 2 .

5. The compound of claim 2 having the structure:

wherein p and R 4 are as defined in claim 2 .

6. The compound of claim 2 having the structure:

wherein p and R 4 are as defined in claim 2 .

7. The compound of claim 2 having the structure:

wherein m, R 1 and R a are as defined in claim 2 .

8. The compound of claim 2 having the structure:

wherein m, R 1 , R b and R c are as defined in claim 2 .

9. The compound of claim 1 , wherein at least one occurrence of R 1 is —NO 2 .

10. The compound of claim 1 , wherein at least one occurrence of R 1 is —NH 2 .

11. The compound of claim 1 , wherein at least one occurrence of R 1 is —COOH, —C(═O)OCH 3 , —COCH 3 , —CONH 2 , —SO 2 OH, —SO 2 CH 3 , —SO 2 CF 3 , —OPO 2 OH, —NHC(═O)CH 3 , —NHC(═O)CF 3 , —NHSO 2 CH 3 or —NHSO 2 CF 3 .

12. The compound of claim 1 , wherein at least one occurrence of R 1 is halogen.

13. The compound of claim 1 , wherein at least one occurrence of R 1 is an optionally substituted N-linked heterocyclic group.

14. The compound of claim 13 , wherein the N-linked heterocyclic group is an optionally substituted N-pyrrolyl.

15. The compound of claim 1 , wherein at least one occurrence of R 1 is an aliphatic moiety.

16. The compound of claim 1 , wherein at least one occurrence of R 1 is a lower alkyl moiety.

17. The compound of claim 1 , wherein at least one occurrence of R 4 is an aliphatic group.

18. The compound of claim 1 , wherein each occurrence of R 4 is independently an aliphatic group.

19. The compound of claim 18 , wherein the aliphatic group is an optionally substituted cyclic or acyclic C 6-12 alkyl, C 6-12 alkenyl, or C 6-12 alkynyl group.

20. The compound of claim 18 , wherein R 4 an optionally substituted -(alkyl)aryl group.

21. The compound of claim 1 , wherein at least one occurrence of R 4 is —NR b R c ; wherein R b and R c are independently hydrogen, hydroxy, SO 2 R d , or an alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl moiety; R d is hydrogen, —N(R e ) 2 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and R e is hydrogen or alkyl.

22. The compound of claim 1 , wherein at least one occurrence of R 4 is —NH 2 .

23. The compound of claim 1 , wherein at least one occurrence of R 4 is —C(═O)OR a ; wherein R a is hydrogen or an optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety.

24. The compound of claim 1 , wherein at least one occurrence of R 4 is —CO 2 H.

25. The compound of claim 1 , wherein m is 0 or 1.

26. The compound of claim 1 , wherein p is 0 or 1.

27. The compound of claim 1 having one of the following structures:

28. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier, adjuvant or vehicle; and

a compound of claim 1 .

29. A method for treating or lessening the severity of fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis, multiple sclerosis, metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher disease, or Alexander's disease in a subject comprising administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound according to claim 1 .

30. The method of claim 29 wherein the method is for treating or lessening the severity of a disease or condition selected from liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke, traumatic head injury, spinal cord injury, and other cerebrovascular diseases; myocardial ischemia; atherosclerosis; peripheral vascular disease; diabetes; renal failure; renal fibrosis, lung fibrosis or idiopathic pulmonary fibrosis; and multiple sclerosis.

31. The method of claim 29 wherein the method is for the treatment of wounds for acceleration of healing; promoting vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of isehemia/reperfusion injury in the brain, heart, liver, kidney, or other tissues or organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus.

32. The method of claim 29 wherein the compound has one of the following structures: