Monocyclic Heteroaryl Compounds

Abstract

This invention relates to compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.

1 . A compound of the Formula I, a tautomer, an individual isomer, a mixture of isomers or a pharmaceutically acceptable salt, solvate or hydrate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ring T represents a 5-membered monocyclic heteroaryl ring, comprising 1-3 heteroatoms selected from O, N and S; 
 Ring A represents a 5- or 6-membered aryl or heteroaryl ring; 
 Ring B represents a 5- or 6-membered aryl or heteroaryl ring; 
 L 1  is selected from NR 1 C(O) and C(O)NR 1 ; 
 each R a , R b  and R t , is independently selected from the group consisting of halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —R 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 4 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein Y is independently a bond, —O—, —S— or —NR 3 —; 
 each R 1 , R 2  and R 3  is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle and heteroaryl, and in addition, NR 2 R 3  moiety may be 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; 
 each R 4  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; 
 m is 0, 1, 2, 3 or 4; 
 n is 0, 1, 2 or 3; 
 p is 0, 1, 2, 3, 4 or 5; 
 r is selected 0, 1 or 2. 
 
     
     
         2 . A compound according to  claim 1  wherein Ring T is a monocyclic 5-membered ring selected from: 
       
         
           
           
               
               
           
         
       
       and is optionally substituted on carbon or heteroatom with 1-3 R t  groups. 
     
     
         3 . A compound of  claim 1  having the Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ring C represents a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms selected from O, N and S(O) r  and is optionally substituted on carbon or heteroatom(s) with 1-5 groups; 
 R e , at each occurrence, is independently selected from the group consisting of halo, ═O, ═S, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 4 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein Y is independently a bond, —O—, —S— or —NR 3 —; 
 R 2  and R 3  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 alternatively, NR 2 R 3  moiety may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; 
 each occurrence of R 4  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle moieties is optionally substituted; 
 v is 0, 1, 2, 3, 4 or 5 
 t is 0, 1, 2, 3, or 4. 
 
     
     
         4 . A compound according to  claim 3 , wherein Rings A and B are aryl. 
     
     
         5 . A compound of  claim 3  wherein Ring C is a heteroaryl ring. 
     
     
         6 . A compound of  claim 5  wherein Ring C is an imidazole ring. 
     
     
         7 . A compound of  claim 3  selected from the formulae IIa, IIb and IIc: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 7  wherein R t  is independently selected from —CH 3 , or —C(O)NH 2 , v is 1, n is 0 or 1, m is 1, t is 1, R a  is —CH 3 , R b  is CF 3  and R c  is —CH 3 . 
     
     
         9 . A compound of  claim 1  having the Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ring D represents a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from N, O, S(O), and is optionally substituted with 1-5 R d  groups; 
 L 2  is (CH 2 ) z , O(CH 2 ) x , NR 3 (CH 2 ) x , S(CH 2 ) x  or (CH 2 ) x NR 3 C(O)(CH 2 ) x  and the linkage unit can be used in either direction; 
 R d , at each occurrence, is selected from the group consisting of halo, ═O, ═S, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 4 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein Y is independently a bond, —O—, —S— or —NR 3 —; 
 R 2  and R 3  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 alternatively, NR 2 R 3  moiety may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O) r ; 
 each occurrence of R 4  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle moieties is optionally substituted; 
 w is selected from 0, 1, 2, 3, 4 or 5; 
 x is 0, 1, 2 or 3; 
 z is 1, 2, 3 or 4; and 
 t is 0, 1, 2, 3, or 4. 
 
     
     
         10 . A compound according to  claim 9  wherein Rings A and B are aryl. 
     
     
         11 . A compound of  claim 9  wherein Ring D is a substituted or unsubstituted piperazine ring and L 2  is CH 2 . 
     
     
         12 . A compound of  claim 9  wherein Ring D is a substituted or unsubstituted heteroaryl. 
     
     
         13 . A compound of  claim 11  selected from Formulae IIIa, IIIb and IIIc: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 13  wherein R t  is independently selected from —CH 3  and —C(O)NH 2 , n is 0 or 1, m is 1, t is 1, R a  is methyl, R b  is CF 3 , one of R d  is selected from methyl and CH 2 CH 2 OH. 
     
     
         15 . A method for treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any of  claims 1 - 14  or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         16 . A composition comprising a compound of any of  claims 1 - 14  or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier, diluent or vehicle.