Pyridone and pyridazone analogues as gpr119 modulators

Abstract

Novel compounds of structure Formula I: or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein Z, R 1 , R 2 , R 21 , T 1 , T 2 , T 3 and T 4 are defined herein, are provided which are GPR119 G protein-coupled receptor modulators. GPR119 G protein-coupled receptor modulators are useful in treating, preventing, or slowing the progression of diseases requiring GPR119 G protein-coupled receptor modulator therapy. Thus, the disclosure also concerns compositions comprising these novel compounds and methods of treating diseases or conditions related to the activity of the GPR119 G protein-coupled receptor by using any of these novel compounds or a composition comprising any of such novel compounds.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein:
 Z is CH; 
 R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's; 
 R 2  is cycloalkyl, aryl, heteroaryl, heterocyclyl, —S(O) 2 R 5 , —C(═O)NR 3 R 5 , —C(═O)R 5  or —C(═O)OR 5 , wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionally substituted with one or more R 6 's; 
 R 3  is hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each contain 1-4 heteroatoms selected from N, O and S; 
 R 5  is alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted with one or more R 6 's; 
 R 6 , at each occurrence, is independently selected from alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —S(O) 2 NR 9 C(═O)NR 9 R 9 , —C(═O)NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —C(═NR 14 )NR 9 R 9 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 10 , —S(O) 2 R 10 , ═O, —NR 9 C(═O)OR 8  and —NR 9 S(O 2 )R 8 , wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ; 
 R 8 , at each occurrence, is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl, each of which may be optionally substituted with one or more R 8a 's; 
 R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ; 
 R 9 , at each occurrence, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S; 
 
         R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , 
         —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;
 R 10 , at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S; 
 
         R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , 
         —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;
 R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; 
 R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, halo, —CN, —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —C(═O)NR 9 R 9 , —C(═O)R 10  or —OC(═O)R 10 ; 
 T 1  is hydrogen, halo, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; 
 T 2  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; 
 T 3  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; and 
 T 4  is hydrogen, halo, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; 
 
         provided that when R 1  is a 5- to 6-membered aryl or heteroaryl, T 1 , T 2 , T 3 , and T 4  can not all be hydrogen. 
       
     
     
         2 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein the compound of formula I is a compound of formula II(y): 
       
         
           
           
               
               
           
         
         wherein Z, R 1 , R 2 , R 21 , T 3  and T 4  are defined as in  claim 1 . 
       
     
     
         3 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein the compound of formula I is a compound of formula II(z): 
       
         
           
           
               
               
           
         
         wherein Z, R 1 , R 2 , and R 21  are defined as in  claim 1 . 
       
     
     
         4 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is cycloalkyl, aryl, heteroaryl, heterocyclyl, —S(O) 2 R 5 , —C(═O)R 5  or —C(═O)OR 5 , wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionally substituted with one or more R 6 's;   R 5  is alkyl, alkenyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —S(O) 2 NR 9 C(═O)NR 9 R 9 , —C(═O)NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —C(═NR 14 )NR 9 R 9 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 (═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 ,   
       —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;
 R 10 , at each occurrence, is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S; 
 R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , 
 
       —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;
 R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl; 
 R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, halo, —CN, —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OR 10 , —OH, —C(═O)NR 9 R 9 , —C(═O)R 10  or —OC(═O)R 10 ; 
 T 1  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; 
 T 2  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; 
 T 3  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's; and 
 T 4  is hydrogen, alkyl, aryl, alkenyl or alkynyl, wherein the alkyl, aryl, alkenyl and alkynyl may be optionally substituted with one or more R 6 's. 
 
     
     
         5 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(═O)R 5  or —C(═O)OR 5 , wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —S(O) 2 NR 9 C(═O)NR 9 R 9 , —C(═O)NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —C(═NR 14 )NR 9 R 9 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —S(O) 3 H, —P(O) 3 H 2 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, halo, —CN, —C(═O)OH, —C(═O)OR 10 , —OR 10 , —OH, —C(═O)NR 9 R 9  or —C(═O)R 10 ;   T 1  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's;   T 2  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's;   T 3  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's; and   T 4  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's.   
     
     
         6 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is aryl, heteroaryl, heterocyclyl, —C(═O)R 5  or —C(═O)OR 5 , wherein the aryl, heteroaryl and heterocyclyl may each be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl, cycloalkyl or heteroaryl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —S(O) 2 NR 9 C(═O)NR 9 R 9 , —C(═O)NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —C(═NR 14 )NR 9 R 9 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocyclyl, wherein the cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocyclyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl, heteroarylalkyl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —C(═NR 14 )NR 14 R 14 , —NHC(═NR 14 )NR 14 R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heteroaryl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, cycloalkyl, halo, —CN, —C(═O)OH, —C(═O)OR 10 , —OR 10 , —C(═O)NR 9 R 9  or —C(═O)R 10 ;   T 1  is hydrogen or alkyl, wherein the alkyl may be optionally substituted with one or more R 6 's;   T 2  is hydrogen or alkyl, wherein the alkyl may be optionally substituted with one or more R 6 's;   T 3  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's; and   T 4  is hydrogen or alkyl, wherein the alkyl may be optionally substituted with one or more R 6 's.   
     
     
         7 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is aryl, heteroaryl, —C(═O)R 5  or —C(═O)OR 5 , wherein the aryl and heteroaryl may each be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl or heteroaryl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —S(O) 2 NR 9 C(═O)NR 9 R 9 , —C(═O)NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocyclyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl, heteroarylalkyl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heterocyclyl, wherein the cycloalkyl, aryl, arylalkyl, heteroaryl and heterocyclyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —S(O) 2 NR 14 C(═O)NR 14 R 14 , —C(═O)NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heteroaryl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —CN, —C(═O)OH, —C(═O)OR 10 , —OR 10 , —C(═O)NR 9 R 9  or —C(═O)R 10 ;   T 1  and T 2  are hydrogen;   T 3  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's; and   T 4  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's.   
     
     
         8 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is aryl, heteroaryl or —C(═O)OR 5 , wherein the aryl and heteroaryl may each be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl or heteroaryl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)NR 9 S(O) 2 R 9 , —S(O) 2 NR 9 C(═O)OR 9 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 14 , —S(O) 2 NR 14 C(═O)OR 14 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heterocyclyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 10 , —S(O) 2 NR 14 C(═O)OR 10 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionally substituted with 0-3 R 10a , and the heteroaryl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)NR 14 S(O) 2 R 9 , —S(O) 2 NR 14 C(═O)OR 9 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heteroaryl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —CN, —C(═O)OR 10 , —OR 10 , —C(═O)NR 9 R 9  or —C(═O)R 10 ;   T 1 , T 2  and T 4  are hydrogen; and   T 3  is hydrogen, alkyl or aryl, wherein the alkyl or aryl may be optionally substituted with one or more R 6 's.   
     
     
         9 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl, arylalkyl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is heteroaryl or —C(═O)OR 5 , wherein the heteroaryl may be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl or heteroaryl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionally substituted with 0-5 R 8a , and the heteroaryl and heterocyclyl each contain 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, aryl and heteroaryl may each be optionally substituted with 0-3 R 10a , and the heteroaryl contains 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heteroaryl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —CN, —C(═O)OR 10 , —C(═O)NR 9 R 9  or —C(═O)R 10 ;   T 1 , T 2  and T 4  are hydrogen; and   T 3  is hydrogen or alkyl, wherein the alkyl may be optionally substituted with one or more R 6 's.   
     
     
         10 . The compound, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, of  claim 1 , wherein:
 Z is CH;   R 1  is aryl or heteroaryl, any of which may be optionally substituted with one or more R 6 's;   R 2  is heteroaryl or —C(═O)OR 5 , wherein the heteroaryl may be optionally substituted with one or more R 6 's;   R 5  is alkyl, aryl or heteroaryl, each of which may be optionally substituted with one or more R 6 's;   R 6 , at each occurrence, is independently selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 10 , —OCF 3 , —OCHF 2 , —OR 10 , —OH, —SH, —SR 10 , —C(═O)NR 9 R 9 , —NR 9 R 9 , —S(O) 2 NR 9 R 9 , —NR 9 S(O) 2 CF 3 , —C(═O)R 10 , —NR 9 C(═O)H, —NR 9 C(═O)R 10 , —OC(═O)R 10 , —S(═O)R 10 , —S(O) 2 R 10  and ═O, wherein the alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl may each be optionally substituted with 0-5 R 9a ;   R 8a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , ═O, —NR 14 C(═O)OR 14  and —NR 14 S(O 2 )R 14 ;   R 9 , at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl, may each be optionally substituted with 0-5 R 8a , and the heteroaryl contains 1-4 heteroatoms selected from N, O and S;   R 9a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14 , ═O and arylalkyl;   R 10 , at each occurrence, is independently selected from alkyl, cycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, aryl and heteroaryl may each be optionally substituted with 0-3 R 10a , and the heteroaryl contains 1-4 heteroatoms selected from N, O and S;   R 10a , at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(═O)OH, —C(═O)OR 14 , —OCF 3 , —OCHF 2 , —OR 14 , —OH, —SH, —SR 14 , —C(═O)NR 14 R 14 , —NR 14 R 14 , —S(O) 2 NR 14 R 14 , —NR 14 S(O) 2 CF 3 , —C(═O)R 14 , —NR 14 C(═O)H, —NR 14 C(═O)R 14 , —OC(═O)R 14 , —S(═O)R 14 , —S(O) 2 R 14 , —NR 14 C(═O)OR 14 , —NR 14 S(O 2 )R 14  and arylalkyl;   R 14 , at each occurrence, is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heteroaryl;   R 21  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aryl, halo, —CN, —C(═O)OR 10  or —C(═O)NR 9 R 9 ;   T 1 , T 2  and T 4  are hydrogen; and   T 3  is hydrogen or alkyl.   
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A pharmaceutical composition comprised of a therapeutically effective amount of a compound of  claim 1 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition of  claim 12 , further comprising a therapeutically effective amount of one or more other therapeutically active agents. 
     
     
         14 . A method of modulating the activity of the GPR119G protein-coupled receptor comprising administering to a mammalian patient in need thereof a therapeutically effective amount of at least one compound of  claim 1 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent. 
     
     
         15 . A method for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the GPR119G protein-coupled receptor comprising administering to a mammalian patient in need of prevention, inhibition, or treatment a therapeutically effective amount of at least one compound of  claim 1 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent wherein:
 (a) the diseases or disorders are selected from the group consisting of diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma; and   (b) the additional therapeutic agent is selected from the group consisting of anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, treatments for heart failure, treatments for peripheral arterial disease and anti-inflammatory agents.   
     
     
         16 . A pharmaceutical composition comprised of a therapeutically effective amount of a compound of  claim 11 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , further comprising a therapeutically effective amount of one or more other therapeutically active agents. 
     
     
         18 . A method of modulating the activity of the GPR119G protein-coupled receptor comprising administering to a mammalian patient in need thereof a therapeutically effective amount of at least one compound of  claim 11 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent. 
     
     
         19 . A method for preventing, inhibiting, or treating the progression or onset of diseases or disorders associated with the activity of the GPR119G protein-coupled receptor comprising administering to a mammalian patient in need of prevention, inhibition, or treatment a therapeutically effective amount of at least one compound of  claim 11 , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent wherein:
 (a) the diseases or disorders are selected from the group consisting of diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy and glaucoma; and   (b) the additional therapeutic agent is selected from the group consisting of anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, appetite suppressants, treatments for heart failure, treatments for peripheral arterial disease and anti-inflammatory agents.