3-(heteroaryl)alanine derivatives-inhibitors of leukocyte adhesion mediated by vla-4

Abstract

Disclosed are certain 3-(heteroaryl)alanine derivatives which bind VLA-4 and inhibit leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an aryl, heteroaryl, cycloalkyl, or heterocyclic group wherein said aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where each R is independently hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O) 2 —R′] 2  and —N[S(O) 2 —NR′] 2  where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
 HetAr is a nitrogen containing heteroaryl or a nitrogen containing substituted heteroaryl group; 
 Alk is an alkylene group of 1 to 4 carbons; 
 m is 0 or 1; 
 R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
 X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
 and enantiomers, diasteromers and pharmaceutically acceptable salts thereof; 
 and further wherein the compound of Formula (I) has a binding affinity to VLA-4 as expressed by an IC 50  of about 15μM or less. 
 
     
     
         2 . The compound of  claim 1  wherein HetAr is a nitrogen containing substituted heteroaryl group. 
     
     
         3 . The compound of  claim 1  wherein HetAr is a nitrogen containing heteroaryl group that is substituted with a substituent selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino oxysulfonyl, aryl and substituted aryl. 
     
     
         4 . The compound of  claim 1  wherein HetAr is a nitrogen containing heteroaryl group is substituted with a group of formula —O-Z-NR 11 R 11′  or —O-Z-R 12  wherein R 11  and R 11′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R 11  and R 11′  are joined to form a heterocycle or a substituted heterocycle, R 12  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —SO 2 —. 
     
     
         5 . The compound of  claim 4  wherein the nitrogen containing heteroaryl group is substituted with a group of formula —OC(O)NR 11 R 11′  wherein R 11  and R 11′  are independently selected from the group consisting of alkyl or R 11  and R 11′  are joined to form a heterocycle or a substituted heterocycle. 
     
     
         6 . The compound of  claim 5  wherein the nitrogen containing heteroaryl group is substituted with —OC(O)N(CH 3 ) 2 . 
     
     
         7 . The compound of  claim 1  wherein HetAr is a nitrogen containing heteroaryl group is subsituted with an aryl or substituted aryl group. 
     
     
         8 . The compound of  claim 1  wherein A is a heteroaryl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen. 
     
     
         9 . The compound of  claim 8  wherein A is 1-oxo-1,2,5-thiadiazole, 1,1-dioxo-1,2,5-thiadiazole, pyridazine, pyrimidine or pyrazine ring which is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen. 
     
     
         10 . The compound of  claims 1  to  9  wherein R 1  is hydrogen, and X is hydroxyl. 
     
     
         11 . The compound of  claim 1  wherein the compound has formula IIa, IIb, IIc, IId, or IIe: 
       
         
           
           
               
               
           
         
       
       wherein:
 HetAr is a nitrogen containing heteroaryl group substituted with a substituent selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, tioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino, aryl, substituted aryl, and oxysulfonyl; 
 R 5  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; 
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and —SO 2 R 10  where R 10  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 
 R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; 
 R 16  and R 17  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and 
 R 18  is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; 
 R 20  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; 
 R 21  is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; 
 b is 1 or 2; and 
 X is hydroxyl; and 
 and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. 
 
     
     
         12 . The compound of  claim 11  wherein the compound is selected from formula IIc, IId or IIe. 
     
     
         13 . The compound of  claim 11  or 12 wherein HetAr is a nitrogen containing heteroaryl group which is substituted with a group of formula —O-Z-NR 11 R 11′  or —O-Z-R 12  wherein R 11  and R 11′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R 11  and R 11′  are joined to form a heterocycle or a substituted heterocycle, R 12  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —SO 2 —. 
     
     
         14 . The compound of  claim 13  wherein the nitrogen containing heteroaryl group is substituted with a group of formula —OC(O)NR 11 R 11′  wherein R 11  and R 11′  are independently selected from the group consisting of alkyl or R 11  and R 11′  are joined to form a heterocycle or a substituted heterocycle. 
     
     
         15 . The compound of  claim 14  wherein the nitrogen containing heteroaryl group is substituted with —OC(O)N(CH 3 ) 2  and is at the para position of the heteroaryl group. 
     
     
         16 . The compound of  claim 11  or  12  wherein HetAr is a nitrogen containing heteroaryl group which is substituted with an aryl or substituted aryl group. 
     
     
         17 . A method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claims 1  to  16 . 
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claims 1 - 16 .