Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt)

Abstract

The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below: Formula (I)

1 - 28 . (canceled) 
     
     
         29 . A compound of Formula IB: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R is an aryl, heteroaryl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocycloalkyl, arylalkyl-, (heteroaryl)alkyl-, (C 3 -C 8  cycloalkyl)alkyl-, (C 3 -C 8  cycloalkenyl)alkyl-, (heterocycloalkyl)alkyl-, (aryloxy)alkyl-, (heteroaryloxy)alkyl-, (C 3 -C 8  cycloalkyloxy)alkyl-, (C 3 -C 8  cycloalkenyloxy)alkyl- or (heterocycloalkyloxy)alkyl-, wherein the heteroatom of each of said heteroaryl and heterocycloalkyl numbers 1, 2 or 3, and is independently selected from N, S or O, further wherein each of said aryl, heteroaryl and heterocycloalkyl may independently be either substituted or fused with an aryl or heteroaryl, still further wherein any of said aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , -alkyl, -alkenyl, -alkynyl, -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, or (alkoxyalkyl) amino-, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; 
         G is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being optionally substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , -alkyl, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; 
         R 3  is H, alkyl or arylalkyl-; 
         A is aryl, heteroaryl, heterocycloalkyl or C 3  to Cs cycloalkyl, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being optionally substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , -alkyl, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; 
         Q is C(O), S(O), S(O) 2 , or —CH 2 —C(O); 
         n is 0, 1, 2, 3, 4, 5 or 6; and 
         z is 0, 1 or 2. 
       
     
     
         30 . The compound of  claim 29 , wherein R is heteroaryl. 
     
     
         31 . The compound of  claim 29 , wherein R is (heteroaryl)alkyl. 
     
     
         32 . The compound of  claim 29 , wherein A is heterocycloalkyl. 
     
     
         33 . The compound of  claim 29 , wherein A is aryl. 
     
     
         34 . The compound of  claim 29 , wherein Q is S(O) 2 . 
     
     
         35 . The compound of  claim 29 , wherein G is optionally substituted heteroaryl. 
     
     
         36 . The compound of  claim 29 , wherein G is optionally substituted aryl. 
     
     
         37 . The compound of  claim 30 , wherein A is heterocycloalkyl. 
     
     
         38 . The compound of  claim 37 , wherein Q is S(O) 2 . 
     
     
         39 . The compound of  claim 38 , wherein G is optionally substituted heteroaryl. 
     
     
         40 . The compound of  claim 38 , wherein G is optionally substituted aryl. 
     
     
         41 . The compound of  claim 31 , wherein A is aryl. 
     
     
         42 . The compound of  claim 41 , wherein Q is S(O) 2 . 
     
     
         43 . The compound of  claim 42 , wherein G is optionally substituted heteroaryl. 
     
     
         44 . The compound of  claim 42 , wherein G is optionally substituted aryl. 
     
     
         45 . The compound of  claim 43 , wherein n is 0. 
     
     
         46 . The compound of  claim 31 , wherein R is (heteroaryl)alkyl, and alkyl is straight or branched. 
     
     
         47 . The compound of  claim 31 , wherein R is (heteroaryl)alkyl, and alkyl is cyclized. 
     
     
         48 . The compound of  claim 31 , wherein R is (pyridinyl)alkyl.