Substituted Heteroaryls

Abstract

The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R 1 , R 2 , R 3 , and R 4 are as described herein.

We claim: 
     
         1 . The compound of  claim 1  of Formula (IB) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H, (C 1 -C 6 )alkyl, halo-substituted (C 1 -C 3 )alkyl, —S(O) 2 (R 1a ), or C(O)R 1a , where R 1a  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkylamino, or di-(C 1 -C 3 )alkylamino; 
 R 2  is (C 3 -C 6 )cycloalkyl or 5- to 6-membered heterocycle containing one N, O, or S heteroatom, where said cycloalkyl and said heterocycle are optionally substituted with one to two substituents each independently halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —CF 3 , or cyano; and 
 R 4  is quinolinyl or 5- to 6-membered heteroaryl containing one to two N heteroatoms and optionally one O or S heteroatom, where said heteroaryl and said quinolinyl are optionally substituted with one to two R 4a , where each R 4a  is independently (C 1 -C 6 )alkyl optionally substituted with one to three hydroxy, —CF 3 , cyano, (C 1 -C 6 )alkoxy, halo, amino, (C 1 -C 3 )alkylamino, di-(C 1 -C 3 )alkylamino, —CO 2 R 4b  (C 1 -C 6 )alkylCO 2 R 4b , —C(O)N(R 4 ) 2 , —P(O)(OR 4b ) 2 , —(C 1 -C 6 )alkylP(O)(OR 4b ) 2 , —P(O)(OR 4b )(C 1 -C 3 alkyl), (C 1 -C 3 )alkylsulfonyl, —SO 3 H, —NHC(O)R 4c  or aryl(C 1 -C 6 )alkyl, where the aryl of said arylalkyl is optionally substituted with (C 1 -C 6 )alkyl, —CF 3 , cyano, (C 1 -C 6 )alkoxy, halo, amino, (C 1 -C 3 )alkylamino, or di-(C 1 -C 3 )alkylamino; 
 
       R 4b  at each occurrence is independently hydrogen, (C 1 -C 6 )alkyl or benzyl; and 
       R 4c  at each occurrence is independently CO 2 H or (C 1 -C 6 )alkyl optionally substituted with one to three hydroxy; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         3 . A method of treating or delaying the progression or onset of Type II diabetes and diabetes-related disorders in mammals comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.