Tyrosine derivatives

Abstract

The compounds of the invention are inhibitors of alpha4 containing integrin-mediated binding to ligands such as VCAM-1 and MAdCAM.

1 . A compound of the formula I, II or III:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z is H or lower alkyl;  
 A has the structure:  
                     
 in which  
 B is cyanoalkyl, a carbocycle or a heterocycle optionally substituted with one or more R 1  substituents;  
 q is 0-3;  
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently are hydrogen, alkyl, amino, alkylamino, dialkylamino, nitro, urea, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfinyl, sulfonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkanoyl, alkanoylamino, cycloalkanoylamino, aryl, arylalkyl, halogen, or alkylphosphonyl, and R 1 , R 2 , R 3 , R 4  and R 5  are substituted with 0-3 substituents selected from the group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, oxo, cyano, carbocyclyl, heterocyclyl, heteroaryl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkanoylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, aryl, aroyl, heterocyclylcarbonyl, halogen and lower alkylphosphonyl; or two of R 1  to R 5  together form a carbocycle or heterocyclic ring;  
 Y is H, alkoxy, alkoxyalkoxy, aryloxy, alkylaminoalkoxy, dialkylaminoalkoxy, alkylamino, arylamino, heterocyclyl or heteroarylalkyl, where each of the forgoing may be substituted or unsubstituted;  
 X 1  is H, C(O)OR, C(O)NRaRb, C(O)R, or C(O)SR, wherein R, Ra and Rb, individually, is hydrogen or alkyl, alkoxy, aryl, heterocyclyl, heteroaryl, substituted with 0-4 substituents selected from the group consisting of halogen, hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl, aralkyloxycarbonyl, alkylenedioxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, and alkoxy lower alkyl; wherein said heterocyclyl, heteroaryl, aryl, aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl and aralkyloxycarbonyl is optionally substituted with halogen, hydroxyl, amino, carboxyl, nitro, cyano, alkyl and alkoxy; and wherein Ra and Rb together with the nitrogen to which they are attached may form a heterocyclyl or heteroaryl group substituted with 0-5 substituents R or Rd; wherein Rd has the structure  
                     
 wherein X′ is a divalent linker selected from the group consisting of C(O)NRa, C(O) or a bond;  
 X 2  and X 3  are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, aryl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; and wherein X 1  and X 2  or X 3  may be bonded together to form a heterocylic or heteroaryl ring(s); or X 3  and Z together form a heterobicyclic ring;  
 X 1′ , X 2′ , X 3′  and X 4′  are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, alkenyl, alkynyl, arylalkyl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound according to  claim 1 , having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z is H or lower alkyl;  
 A has the structure:  
                     
 in which R 1 , R 2 , R 3 , R 4  and R 5 , independently are hydrogen, alkyl, amino, alkylamino, dialkylarnino, nitro, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, alkanoyl, aryl, arylalkyl, halogen, or alkylphosphonyl, and R 1 , R 2 , R 3 , R 4  and R 5  are substituted with 0-3 substituents selected from the group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, cyano, heterocylyl, heteroaryl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, aryl, halogen and lower alkylphosphonyl;  
 Y is H, alkoxy, alkoxyalkoxy, aryloxy, aminoalkylalkoxy, diaminoalkylalkoxy, alkylamino, arylamino, heterocyclyl or heteroarylalkyl, where each of the forgoing may be substituted or unsubstituted;  
 X 1  is H, C(O)OR, C(O)NRaRb, C(O)R, or C(O)SR, wherein R, Ra and Rb, individually, is hydrogen or alkyl, aryl, heterocyclyl, heteroaryl, substituted with 0-4 substituents selected from the group consisting of halogen, hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; and wherein Ra and Rb together with the nitrogen to which they are attached may form a heterocyclyl or heteroaryl group substituted with 0-4 substituents R;  
 X 2  and X 3  are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, aryl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; and wherein X 1  and X 2  or X 3  may be bonded together to form a heterocylic or heteroaryl ring(s);  
 or  
                     
 wherein  
 Z is H or lower alkyl;  
 A has the structure:  
                     
 in which R 1 , R 2 , R 3 , R 4  and R 5 , independently are hydrogen, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkylsulfinyl, sulfonyl, alkylsulfonyl, alkanoyl, aryl, arylalkyl, halogen, or alkylphosphonyl, and R 1 , R 2 , R 3 , R 4  and R 5  are substituted with 0-3 substituents selected from the group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, cyano, heterocylyl, heteroaryl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, aryl, halogen and lower alkylphosphonyl;  
 Y is H, alkoxy, alkoxyalkoxy, aryloxy, aminoalkylalkoxy, diaminoalkylalkoxy, alkylamino, arylamino, heterocyclyl or heteroarylalkyl, where each of the forgoing may be substituted or unsubstituted;  
 X 1 , X 2  and X 3  are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, alkenyl, alkynyl, arylalkyl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . The compound of  claim 2  having structure I.  
     
     
         4 . The compound of  claim 2 , having structure II.  
     
     
         5 . The compound of one of claims  2 , wherein X 1  X 2 , X 3  are each independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocylyl, or heteroaryl.  
     
     
         6 . The compound of  claim 5 , wherein X 1  is C(O)OR, C(O)R, or C(O)SR.  
     
     
         7 . The compound of  claim 5 , wherein X 1  is C(O)NRaRb.  
     
     
         8 . The compound of  claim 5 , wherein X 1  is C(O)NRaRb and wherein Ra and Rb together with the nitrogen to which they are attached form a 5-membered or 6-membered heterocyclyl or heteroaryl group substituted with 0-4 substituents R.  
     
     
         9 . The compound of  claim 7 , wherein X 1  is a member selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein X 1  is  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 7 , wherein X 1  is C(O)NRaRb and wherein Ra and Rb are independently hydrogen, substituted or unsubstituted alkyl, aryl, heterocyclyl, or heteroaryl.  
     
     
         12 . The compound of  claim 11 , wherein X 1  is a member selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 11 , wherein R 1 , R 5  or both are not hydrogen.  
     
     
         14 . The compound of  claim 1 , wherein X 2 , X 3 , Z or a combination thereof are hydrogen.  
     
     
         15 . The compound of  claim 1 , wherein A is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein A is  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , wherein X 2  is a member selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , wherein the compound has S stereochemical configuration.  
     
     
         19 . A composition, comprising the compound of  claim 1  and a carrier or excipient.  
     
     
         20 . A medicament, comprising the compound of claim I and a therapeutically inert carrier or excipient.  
     
     
         21 . A medicament for treating a disease or condition associated with binding of alpha4beta7 to MAdCAM-1 or alpha4beta1 to VCAM-1, comprising the compound of  claim 1  and a therapeutically inert carrier or excipient.  
     
     
         22 . A medicament for treating rheumatoid arthritis, asthma, psoriasis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, pouchitis, Crohn's disease, Celiac disease, nontropical Sprue, graft-versus-host disease, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, pericholangitis, chronic sinusitis, chronic bronchitis, pneumonitis, collagen disease, eczema or systemic lupus erythematosis, comprising the compound of  claim 1  and a therapeutically inert carrier or excipient.  
     
     
         23 . A method for treating a disease or condition associated with binding of alpha4beta7 to MAdCAM-1 or alpha4beta1 to VCAM-1, comprising administering an effective amount of the compound of  claim 1  to a mammal in need thereof.  
     
     
         24 . A method for treating rheumatoid arthritis, asthma, psoriasis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, pouchitis, Crohn's disease, Celiac disease, nontropical Sprue, graft-versus-host disease, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, pericholangitis, chronic sinusitis, chronic bronchitis, pneumonitis, collagen disease, eczema or systemic lupus erythematosis, comprising administering an effective amount of the compound of  claim 1  to a mammal in need thereof.