Compounds and methods for treating inflammatory and fibrotic disorders

Abstract

Badger, et al., “Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function”, J. Pharmacol. Exp. Ther. 279:1453-61 (1996).

What is claimed is: 
     
       1. A compound of formula II (II)  
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, alkenylenearyl, and heteroaryl; 
         R 2  is selected from the group consisting of substituted or unsubstituted aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; haloalkylcarbonyl; cycloalkyl; hydroxylalkyl; sulfonamide; unsubstituted cycloheteroalkyl and cycloheteroarlkyl cycloheteroalkyl substituted with one to three substituents independently selected from alkyleneOH, C(O)NH 2 , NH 2 , aryl, haloalkyl, halo, and OH; or R 2  and R 1  together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring and wherein heteroaryl of R 2  is selected from the group consisting of thienyl, furyl, pyridyl, oxazoly, quinolyl, thiophenyl, isoquinolyl, pyrazolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl; 
         R 3  is selected from the group consisting of hydrogen, substituted or unsubstituted aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy; 
         R 4  is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; 
         X 1 , X 2 , X 3 , and X 4  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, substituted or unsubstituted aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydro aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X 2  and X 3  together form a 5- or 6-membered ring comprising —O(CH 2 ) n O—, wherein n is 1 or 2, wherein at least one of X 1 , X 2 , X 3 , and X 4  is not hydrogen; and 
         X 5  is hydrogen, 
         with the proviso that (a) at least one of X 1 , X 2 , X 3 , and X 4  is not selected from the group consisting of hydrogen, halo, alkoxy, and hydroxy; or (b) at least one of R 1 , R 2 , R 3 , or R 4  is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, and halo, hydroxy, and alkoxyalkyl,; or (c) R 2  is not unsubstituted phenyl or substituted phenyl; or (d) R 3  is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, unsubstituted phenyl, substituted phenyl, and hydroxy; or (e) R 4  is not selected from the group consisting of hydrogen, alkenyl, haloalkyl or alkoxy;  
         or a pharmaceutically acceptable salt, or ester thereof. 
       
     
     
       2. The compound of  claim 1 , wherein one of X 1 , X 2 , and X 3  is not hydrogen. 
     
     
       3. A compound having a structure of formula (III) or formula (IV) 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         wherein 
         R 3  is selected from the group consisting of hydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy; 
         R 4  is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; 
         X 1 , X 2 , X 3 , and X 4  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydro aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X 2  and X 3  together form a 5- or 6-membered ring comprising —O(CH 2 ) n O—, wherein n is 1 or 2, wherein at least one of X 1 , X 2 , X 3 , and X 4  is not hydrogen; 
         X 5  is hydrogen; and 
         X 8  is hydrogen or alkyl; and 
         X 6  and X 7  are independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X 6  and X 7  together form an optionally substituted 5 or 6 membered heterocyclic ring, 
         or a pharmaceutically acceptable salt, or ester thereof. 
       
     
     
       4. The compound of  claim 3 , wherein X 7  is hydrogen. 
     
     
       5. The compound of  claim 1 , wherein R 1  is selected from the group consisting of hydrogen, 4-pyridyl, cyclopropanyl, 2-furanyl, cyano, H 2 NSO 2 , (CH 3 ) 2 NSO 2 , fluoro, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl. 
     
     
       6. The compound of  claim 1 , wherein at least one of X 1 , X 2 , or X 3  is alkyl or cycloalkyl. 
     
     
       7. The compound of  claim 1 , wherein at least one of X 1 , X 2 , or X 3  is haloalkyl. 
     
     
       8. The compound of  claim 1 , wherein at least one of X 1 , X 2 , or X 3  is alkenyl. 
     
     
       9. The compound of  claim 1 , wherein at least one of X 1 , X 2 , or X 3  is amino. 
     
     
       10. The compound of  claim 1  having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       11. The compound of  claim 1 , wherein the compound exhibits an IC 50  in a range of about 100 μM to about 1000 μM for inhibition of p38 MAPK. 
     
     
       12. The compound of  claim 11 , wherein the compound exhibits an IC 50  is in the range of about 200 μM to about 800 μM. 
     
     
       13. The compound of  claim 1 , wherein the compound exhibits an EC 50  in the range of about 0.1 μM to about 1000 μM for inhibition of TNFα secretion in a bodily fluid in vivo. 
     
     
       14. A composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       15. The compound of  claim 2 , wherein R 2  is selected from the group consisting of substituted or unsubstituted aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, haloalkoxy, amino, CO 2 H, and CO 2 alkyl; haloalkylcarbonyl; cycloalkyl; hydroxylalkyl; sulfonamido; and unsubstituted cycloheteroalkyl; or R 2  and R 1  together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring. 
     
     
       16. The compound of  claim 15 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       17. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       18. The compound of  claim 3  having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       19. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and, or a pharmaceutically acceptable salt thereof.