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:

1 - 28 . (canceled) 
     
     
         29 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein,
 W is —C(O)—; 
 R is aryl or bicyclic heteroaryl;
 wherein said heteroaryl contains 1, 2, or 3 heteroatoms independently selected from N, S, and O, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein each of said aryl or heteroaryl is either unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkoxy, hydroxyl, hydroxyalkyl, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
 wherein each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is either unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxyalkyl, aryloxy, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 1  and R 2  are the same or they are different, and are independently selected from H, C 1  to C 7  alkyl, C 1  to C 7  alkoxy, C 1  to C 4  hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and
 wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein R 1  and R 2  are each unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, hydroxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, carboxy, (alkoxyalkyl)amino, alkylamine, aminocarbonyl, —CHO, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 3  is H; and 
 n is 4, 5, or 6; 
 
       wherein the compound of Formula II is obtained by a process comprising a step of treating an acid: 
       
         
           
           
               
               
           
         
       
       with an amine: 
       
         
           
           
               
               
           
         
       
       in the presence of a base. 
     
     
         30 . The compound of  claim 29 , wherein the acid is: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 30 , wherein the process of obtaining the compound of Formula II further comprises addition of a coupling agent. 
     
     
         32 . The compound of  claim 31 , wherein the coupling agent is EDCI, HATU, or HOBt, and the base is K 2 CO 3 , Cs 2 CO 3 , DIEA, NaOH, or KOH. 
     
     
         33 . The compound of  claim 29 , wherein the acid is: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 33 , wherein the base is TEA. 
     
     
         35 . A composition comprising a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein,
 W is —C(O)—; 
 R is aryl or bicyclic heteroaryl;
 wherein said heteroaryl contains 1, 2, or 3 heteroatoms independently selected from N, S, and O, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein each of said aryl or heteroaryl is either unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkoxy, hydroxyl, hydroxyalkyl, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
 wherein each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is either unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxyalkyl, aryloxy, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 1  and R 2  are the same or they are different, and are independently selected from H, C 1  to C 7  alkyl, C 1  to C 7  alkoxy, C 1  to C 4  hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and
 wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein R 1  and R 2  are each unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, hydroxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, carboxy, (alkoxyalkyl)amino, alkylamine, aminocarbonyl, —CHO, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 3  is H; and 
 n is 4, 5, or 6; 
 
       and further comprising an acid: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The composition of  claim 35 , further comprising an amine: 
       
         
           
           
               
               
           
         
       
     
     
         37 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein,
 W is —C(O)—; 
 R is aryl or bicyclic heteroaryl;
 wherein said heteroaryl contains 1, 2, or 3 heteroatoms independently selected from N, S, and O, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein each of said aryl or heteroaryl is unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkoxy, hydroxyl, hydroxyalkyl, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
 wherein each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is either unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxyalkyl, aryloxy, (alkoxyalkyl)amino, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 1  and R 2  are the same or they are different, and are independently selected from H, C 1  to C 7  alkyl, C 1  to C 7  alkoxy, C 1  to C 4  hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and
 wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O; and 
 wherein R 1  and R 2  are each unsubstituted or 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 , —CF 3 , —CHF 2 , —CH 2 F, alkyl, hydroxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, carboxy, (alkoxyalkyl)amino, alkylamine, aminocarbonyl, —CHO, —N(R 3 )—C(O)-alkyl, —N(R 3 )—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 
 R 3  is H; and 
 n is 4, 5, or 6; 
 
       wherein the compound is obtained by a process comprising treating a first amine: 
       
         
           
           
               
               
           
         
       
       with a first acid: 
       
         
           
           
               
               
           
         
       
       in the presence of a first base to give the compound of Formula II. 
     
     
         38 . The compound of  claim 37 , wherein the first acid is: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 38 , wherein the process of obtaining a compound of Formula II further comprises addition of a first coupling agent selected from EDCI, HATU, and HOBt. 
     
     
         40 . The compound of  claim 39 , wherein the first base is K 2 CO 3 , Cs 2 CO 3 , DIEA, NaOH, and KOH. 
     
     
         41 . The compound of  claim 37 , wherein the first acid is: 
       
         
           
           
               
               
           
         
       
       and the first base is TEA. 
     
     
         42 . The compound of  claim 37 , wherein the first amine is obtained by a process of treating a protected amine: 
       
         
           
           
               
               
           
         
       
       with a strong acid. 
     
     
         43 . The compound of  claim 42 , wherein the strong acid is TFA or HCl. 
     
     
         44 . The compound of  claim 42 , wherein the protected amine is obtained by a process of treating a second acid: 
       
         
           
           
               
               
           
         
       
       with a second amine: 
       
         
           
           
               
               
           
         
       
       in the presence of a second base. 
     
     
         45 . The compound of  claim 44 , wherein the second acid is: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 45 , wherein the process of obtaining the protected amine further comprises addition of a second coupling agent. 
     
     
         47 . The compound of  claim 46 , wherein the second coupling agent is EDCI, HATU, or HOBt, and the second base is K 2 CO 3 , Cs 2 CO 3 , DIEA, NaOH, or KOH. 
     
     
         48 . The compound of  claim 44 , wherein the second acid is: 
       
         
           
           
               
               
           
         
       
       and the second base is TEA.