Methods of treating autoimmune and inflammatory diseases and disorders

Abstract

Heterocyclic compounds, compositions comprising them, and methods of their use for the treatment, prevention and management of inflammatory and autoimmune diseases and disorders are disclosed. Particular compounds are of formula I:

1 . A method of treating or managing an inflammatory or autoimmune disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is an optionally substituted heterocycle; 
 R 1  is hydrogen or optionally substituted lower alkyl; 
 R 5  is OR 5A  or OC(O)R 5A ; 
 R 6  is OR 6A  or OC(O)R 6A ; 
 R 7  is OR 7A  or OC(O)R 7A ; 
 R 8  is hydrogen, CH 2 OR 8A  or CH 2 OC(O)R 8A ; and 
 each of R 5A , R 6A , R 7A  and R 8A  is independently hydrogen or lower alkyl. 
 
     
     
         2 . The method of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is N or NR 9 ; 
 Y is CR 4 , N, NR 9 , O or S; 
 Z is CR 4 , CHR 4 , N, NR 9 , O or S; 
 R 1 , is hydrogen or optionally substituted lower alkyl; 
 each R 4  is independently OR 4A , OC(O)R 4A , hydrogen, halogen, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; 
 R 5  is OR 5A  or OC(O)R 5A ; 
 R 6  is OR 6A  or OC(O)R 6A ; 
 R 7  is OR 7A  or OC(O)R 7A ; 
 R 8  is hydrogen, CH 2 OR 8A  or CH 2 OC(O)R 8A ; 
 each R 9  is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and 
 each of R 4A , R 5A , R 6A , R 7A  and R 8A  is independently hydrogen or lower alkyl. 
 
     
     
         3 . The method of  claim 2 , wherein X is N. 
     
     
         4 . The method of  claim 2 , wherein Y is NR 4 . 
     
     
         5 . The method of  claim 2 , wherein Y is O. 
     
     
         6 . The method of  claim 2 , wherein Z is CHR 4 . 
     
     
         7 . The method of  claim 2 , wherein R 4  is hydrogen. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 2 , wherein one or more of R 5 , R 6 , R 7 , and R 8  is hydroxyl or acetate. 
     
     
         11 . The method of  claim 10 , wherein all of R 5 , R 6 , and R 7  are hydroxyl. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is CR 4 , CHR 4 , N, NR 9 , O or S; 
 Y is CR 4 , CHR 4 , N, NR 9 , O or S; 
 Z is CR 4 , CHR 4 , N, NR 9 , O or S; 
 R 1  is hydrogen or optionally substituted lower alkyl; and 
 R 3  is optionally substituted alkyl; 
 each R 4  is independently OR 4A , OC(O)R 4A , hydrogen, halogen, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; 
 R 5  is OR 5A  or OC(O)R 5A ; 
 R 6  is OR 6A  or OC(O)R 6A ; 
 R 7  is OR 7A  or OC(O)R 7A ; 
 R 8  is hydrogen, CH 2 OR 8A  or CH 2 OC(O)R 8A ; 
 each R 9  is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and 
 each of R 4A , R 5A , R 6A , R 7A  and R 8A  is independently hydrogen or lower alkyl. 
 
     
     
         14 . The method of  claim 13 , wherein X is N. 
     
     
         15 . The method of  claim 13 , wherein Y is CHR 4 . 
     
     
         16 . The method of  claim 13 , wherein Z is S. 
     
     
         17 . The method of  claim 13 , wherein R 4  is hydrogen. 
     
     
         18 . The method of  claim 13 , wherein R 4  is optionally substituted lower alkyl. 
     
     
         19 . The method of  claim 13 , wherein one or more of R 5 , R 6 , R 7 , and R 8  is hydroxyl or acetate. 
     
     
         20 . The method of  claim 19 , wherein all of R 5 , R 6 , and R 7  are hydroxyl. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the compound is:
 (1R,2S,3R)-1-(2-(5-methylisoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol;   (1R,2S,3R)-1-(2-(5-ethylisoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol;   (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol;   (1R,2S,3R)-1-(2-(2-methylthiazol-4-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol;   (1R,2S,3R)-1-(2-(1-benzyl-1H-1,2,4-triazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol hydrochloride;   (1R,2S,3R)-1-(1H,1′H-2,2′-biimidazol-5-yl)butane-1,2,3,4-tetraol;   (1R,2S,3R)-1-(2-(5-methoxy-4,5-dihydroisoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol; or   (1R,2S,3R)-1-(2-(5-methyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the compound is (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol. 
     
     
         27 . The method of  claim 1 , wherein the disease or disorder is ankylosing spondylitis, asthma, atopic dermatitis, Behcet's disease, graft-vs-host disease, Kawasaki syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, pollinosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, transplant rejection, type 1 diabetes, or uveitis. 
     
     
         28 . The method of  claim 27 , wherein the disease or disorder is multiple sclerosis. 
     
     
         29 . The method of  claim 27 , wherein the disease or disorder is rheumatoid arthritis. 
     
     
         30 . A method of treating or managing multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol. 
     
     
         31 . A method of treating or managing rheumatoid arthritis, comprising administering to a patient in need thereof a therapeutically effective amount of (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol.