Therapeutic compounds

Abstract

The invention provides compounds of formula (I), or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, wherein R 1 , R 2 , R 3 , HET, n, Q, X, Y, and Z are as described herein; compositions thereof; and uses thereof including treating Type 2 diabetes.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )arylalkyl, —NR a R b , hydroxy, cyano, aryl, or heteroaryl, wherein said —(C 1 -C 6 )alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three —COOH, —C(O)(C 1 -C 6 )alkoxy, —C(O)(C 1 -C 6 )alkyl, —C(O)NR a R b , cyano, halogen, nitro, trifluoromethyl, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 6 )cycloalkyl, or phenyl, wherein:  
 R a  and R b  are, independently, hydrogen, —(C 1 -C 6 )alkyl, aryl, or heteroaryl, or  
 R a  and R b , taken together with the nitrogen atom to which they are attached, form a four- to six-membered heterocyclic ring, wherein said ring optionally incorporates an additional one or two nitrogen, oxygen, or sulfur ring heteroatoms;  
 R 2  and R 3  are, independently, hydrogen, halogen, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;  
 Q is a covalent bond, —C(O)—, or —SO 2 —;  
 HET is a 7,8-dihydro-5H-pyrido[4,3-a]pyrimidyl or 7,8-dihydro-5H-pyrido[4,3-d]pyrimidyl optionally substituted with: (A) one to four —(C 1 -C 6 )alkyl, optionally substituted with one to six halogen atoms, —(C 1 -C 6 )alkoxy, cyano, halogen, hydroxy, or —NR a R b  or (B) —(C 1 -0 6 )arylalkyl, optionally substituted with one to six halogen atoms, —(C 1 -C 6 )alkoxy, cyano, halogen, hydroxy, or —NR a R b ;  
 n is 0 or 1;  
 when n is 0, X is —CH 2 —, and Y is —CH 2 —, —CHF—, or —CF 2 —;  
 or when n is 1, X is —CH 2 —, —CHF—, or —CF 2 —; and Y is —CH 2 —, —CH—, or —CF 2 —, provided that X and Y are not both —CH 2 —; and Z is hydrogen or cyano.  
 
     
     
         2 . The compound of  claim 1 , wherein: 
 R 1  is aryl or heteroaryl, optionally substituted independently with one to three cyano, halogen, nitro, trifluoromethyl, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )aikoxy, —(C 3 -C 6 )cycloalkyl, or phenyl;    R 2  is —H or —(C 1 -C 6 )alkyl; and    R 3  is —H or —(C 1 -C 6 )alkyl.    
     
     
         3 . (canceled)  
     
     
         4 . (canceled)  
     
     
         5 . (canceled)  
     
     
         6 . The compound of  claim 1  selected from the group consisting of 
 ((2S,4S)-4-(2-(trifluoromethy)-7,8-dihydropyrido[4,3-d]pyrimdin-6(5H)-yl)pyrrolidin-2-yl)-(3,3-difluoropyrrolidin-1-yl)-methanone,    ((S)-3-fluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone,    [(2S,4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-(3-fluoro-azetidin-1-yl)-methanone,    (3,3-difluoro-pyrrolidin-1-yl)-[(25,45)-4-(2-ethoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone,    (3-fluoro-azetidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone, and    ((3R*,4S*)-3,4-difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrrolidin-2-yl]-methanone; or a pharmaceutically acceptable salt of said compound.    
     
     
         7 . (canceled)  
     
     
         8 . A pharmaceutical composition comprising: 
 (a) a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound; and    (b) a pharmaceutically acceptable carrier, vehicle, diluent or excipient.    
     
     
         9 . A method of inhibiting dipeptidyl peptidase-IV in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         10 . A method of treating Type 2 diabetes in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         11 . A method of treating Type 1 diabetes in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         12 . A method of treating hyperglycemia in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         13 . A method of treating metabolic syndrome in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         14 . A method of treating impaired glucose tolerance in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         15 . A method of treating diabetic neuropathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compounds.  
     
     
         16 . A method of treating diabetic nephropathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         17 . A method of treating diabetic retinopathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         18 . A method of treating diabetic cardiomyopathy in a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound.  
     
     
         19 . The method of  claim 10  wherein said mammal is a human.  
     
     
         20 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.