Dipeptidyl peptidase-iv inhibitors

Abstract

The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.

1 . A compound of formula (I):
   A-B-D  (I)   
     or a pharmaceutically acceptable salt thereof, 
     wherein A is: 
     
       
         
         
             
             
         
       
       B is: 
     
     
       
         
         
             
             
         
       
       D is: 
     
     
       
         
         
             
             
         
       
       Y is divalent and is: a bond, CR 4 R 5 , O, NR 4 , S, S═O, S(═O) 2 , C(═O), (C═O)N(R 4 ), S(═O) 2 N(R 4 ), C═N—OR 4 , —C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 R 5 ) C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 R 5 )C(R 4 R 5 )C(R 4 R 5 )C(R 4 R 5 )—, —C(R 4 )═C(R 5 )—, —C(R 4 R 5 )NR 4 —, —C(R 4 R 5 )O—, —C(R 4 R 5 )S(═O) t —, —(C═O)O—, —(C═NR a )N(R 4 )—, —(C═NR a )—, N(C═O)NR 4 NR 5 , N(C═O)R 4 , N(C═O)OR 4 , NS(═O) 2 NR 4 NR 5 , or NS(═O) 2 R 4 ; 
       R 1  and R 2  are independently: hydrogen, —F, —Cl, —CONR 4 R 5 , or —CO 2 R 4 ; 
       R 3  is CONR 4 R 5 , tetrazolyl or oxadiazolonyl; 
       R a  is hydrogen, CN, NO 2 , alkyl, haloalkyl, S(O) t NR 4 R 5 , S(O) t R 4 , C(O)OR 4 , C(O)R 4 , or C(O)NR 4 R 5 ; 
       each occurrence of R 4  and R 5  are each independently: hydrogen or alkyl, or R 4  and R 5  when taken together with a nitrogen to which they are attached form a 3- to 8-membered ring containing carbon atoms and may optionally contain a heteroatom selected from O, S, or NR 50 ; 
       R 50  is, in each occurrence, R 20 , CN, NO 2 , S(O) t NR 20 R 21 , S(O) t R 20 , C(O)OR 20 , C(O)R 20 C(═NR a )NR 20 R 21 , C(═NR 20 )NR 21 R a , C(═NOR 20 )R 21  or C(O)NR 20 R 21 ; 
       each occurrence of R 20  and R 21  are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl; 
       each occurrence of R 7  and R 8  are each independently: halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C(═NR a )NHR 4 , (C 0 -C 6 )-alkyl-C(═NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C(═NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)—NH—CN, O—(C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , S(O) t —(C 1 -C 6 )-alkyl-C(O)OR 4 , S(O) t —(C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)NR 4 —(C 0 -C 6 )-alkyl-NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —C(O)R 5 , (C 0 -C 6 )-alkyl-NR 4 —C(O)OR 4 , (C 0 -C 6 )-alkyl-NR 4 —C(O)—NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —SO 2 NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —SO 2 R 4 , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl; 
       R 9  is H or C 1-6  alkyl; 
       R 10  is halogen, CF 3 , COR 4 , OR 4 , NR 4 R 5 , NO 2 , CN, SO 2 OR 4 , CO 2 R 4 , CONR 4 R 5 , CO 2 H, SO 2 NR 4 R 5 , S(O) t R 4 , SO 3 H, OC(O)R 4 , OC(O)NR 4 R 5 , NR 4 C(O)R 5 , NR 4 CO 2 R 5 , (C 0 -C 6 )-alkyl-C(═NR a )NHR 4 , (C 0 -C 6 )-alkyl-C(═NR 4 )NHR a , (C 0 -C 6 )-alkyl-NR 4 C(═NR 4 )NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)OR 4 , (C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)—NH—CN, O—(C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , S(O) t —(C 0 -C 6 )-alkyl-C(O)OR 4 , S(O) t —(C 0 -C 6 )-alkyl-C(O)NR 4 R 5 , (C 0 -C 6 )-alkyl-C(O)NR 4 —(C 0 -C 6 )-alkyl-NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —C(O)R 5 , (C 0 -C 6 )-alkyl-NR 4 —C(O)OR 4 , (C 0 -C 6 )-alkyl-NR 4 —C(O)—NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —SO 2 NR 4 R 5 , (C 0 -C 6 )-alkyl-NR 4 —SO 2 R 4 , hydrogen, B(OH) 2 , alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl; 
       Q b  is CH or N; 
       U is —C(O)—, —C(═NR 4 )—, —(CR 4 R 5 —) p , NR 50 , S(═O) 2 , C(═O), (C═O)N(R 4 ), N(R 4 )(C═O), S(═O) 2 N(R 4 ), N(R 4 )S(═O) 2 , C═N—OR 4 , —C(R 4 )═C(R 5 )—, —C(R 4 R 5 ) p NR 50 —, N(R 50 )C(R 4 R 5 ) p —, —O—C(R 4 R 5 )—, —C(R 4 R 5 )S(═O) t —, —(C═O)O—, —(C═NR a )N(R 4 )—, —(C═NR a )—, N(C═O)NR 4 NR 5 , N(C═O)R 4 , N(C═O)OR 4 , NS(═O) 2 NR 4 NR 5 , or NS(═O) 2 R 4 ; 
       W is —CH 2 —, —S—, —CHF— or —CF 2 —; 
       Z is C; 
       p is 0 to 6; and 
       t is 0, 1, or 2. 
     
   
   
       2 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 Q b  is CH;   U is (—CH 2 —) p ;   p is 1;   R 7  and R 8  are each independently H or alkyl; and   R 9  is H.   
   
   
       3 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 D is:   
     
       
         
         
             
             
         
       
     
   
   
       4 . A compound of  claim 1 , or a pharmaceutically acceptable salt, thereof, wherein:
 Y is —CH 2 —CH 2 —.   
   
   
       5 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 Y is —CH 2 —CH 2 —;   D is   
     
       
         
         
             
             
         
       
       Q b  is CH; 
       U is (—CH 2 —) p ; 
       p is 1; and 
       R 9  is H. 
     
   
   
       6 . A compound of  claim 1 , or a pharmaceutically acceptable salt, thereof, wherein:
 A is:   
     
       
         
         
             
             
         
       
     
   
   
       7 . A compound of  claim 1 , or a pharmaceutically acceptable salt, thereof, wherein:
 A is:   
     
       
         
         
             
             
         
       
       Y is —CH 2 —CH 2 —; 
       D is 
     
     
       
         
         
             
             
         
       
       Q b  is CH. 
     
   
   
       8 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       9 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       10 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       11 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       12 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       13 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       14 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       15 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       16 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       17 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       18 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       19 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       20 . A compound according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       21 . A pharmaceutical composition comprising a compound in accordance with  claim 1 , or a pharmaceutically acceptable salt thereof. 
   
   
       22 . A method of treating type-2 diabetes comprising administering to a patient in need thereof an effective amount of a compound in accordance with  claim 1 , or a pharmaceutically acceptable salt thereof. 
   
   
       23 . A pharmaceutical composition comprising a compound in accordance with  claim 7 , or a pharmaceutically acceptable salt thereof. 
   
   
       24 . A method of treating type-2 diabetes comprising administering to a patient in need thereof an effective amount of a compound in accordance with  claim 7 , or a pharmaceutically acceptable salt thereof.