Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

1 - 40 . (canceled) 
     
     
         41 . A method of treating low glucose tolerance comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar is phenyl which is unsubstituted or substituted with 1-5 of R 3 , wherein R 3  is independently selected from the group consisting of:
 (1) halogen, 
 (2) C 1-6 alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens, 
 (3) OC 1-6 alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens, and 
 (4) CN; 
 
 X is selected from the group consisting of:
 (1) N, and 
 (2) CR 2 ; 
 
 R 1  and R 2  are independently selected from the group consisting of:
 (1) hydrogen, 
 (2) CN, 
 (3) C 1-10 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 4 , OR 4 , NHSO 2 R 4 , SO 2 R 4 , CO 2 H, and CO 2 C 1-6 alkyl, wherein the CO 2 C 1-6 alkyl is linear or branched, 
 (4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 4 , OR 4 , NHSO 2 R 4 , SO 2 R 4 , CO 2 H, and CO 2 C 1-6 alkyl, wherein the CO 2 C 1-6 alkyl is linear or branched, and 
 (6) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, C 1-6 alkyl, and OC 1-6 alkyl, wherein the C 1-6 alkyl and OC 1-6 alkyl are linear or branched and optionally substituted with 1-5 halogens; 
 
 R 4  is C 1-6 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO 2 H, and
 CO 2 C 1-6 alkyl, wherein the CO 2 C 1-6 alkyl is linear or branched; 
 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method of treating low glucose tolerance comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.