Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor

Abstract

Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.

1 . At least one compound of formula 1: 
       
         
           
           
               
               
           
         
         and/or at least one pharmaceutically acceptable salt thereof wherein 
         X is N, Y is selected from —O—, —S—, and —N(R 7 )— and R 1  is selected from aryl and heteroaryl, each of which is optionally substituted with one or more groups selected from halo, —CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , —C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle; or 
         X is N, Y is absent and R 1  is a fused bicyclic heteroaryl optionally substituted with one or more groups selected from halo, —CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , —C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle; or 
         X is C(R 6 ), Y is selected from —O—, —S—, and —N(R 7 )— or Y is absent, and R 1  is heteroaryl optionally substituted with one or more groups selected from halo, —CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , —C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14  and lower alkyl substituted with heterocycle; 
         R 2  and R 3  are independently selected from hydrogen, and alkyl, or R 2  and R 3 , together with the carbon to which they are attached, form a ring chosen from 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycle; 
         R 4  is selected from halo, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, each of which, except for halo, is optionally substituted with one or more groups selected from
 lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 , 
 lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy, 
 cycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy, 
 heterocycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy, 
 heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy, 
 heteroaryloxy optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy, 
 aryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy, 
 heteroaryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy, 
 halo, cyano, —C(O)R 11 , —C(O)OR 11 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 ; 
 
         R 5  is selected from hydrogen, halo, OH, NH 2 , CF 3 , —CF 2 H, alkyl, alkenyl, and alkynyl; 
         R 6  is selected from hydrogen, —OH, —NH 2 , —NHC(O)R 11 , halo and alkyl; 
         R 7  is selected from hydrogen and lower alkyl; 
         each n is independently 0, 1, or 2; 
         R 11 , R 12 , R 13 , and R 14  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycle, each of which except for hydrogen, is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy, or R 13  and R 14 , with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy and further optionally includes one or two additional heteroatoms in the heterocycle ring wherein the one or two additional heteroatoms are selected from —O—, —S—, and —N(R 15 )—; and 
         R 15  is selected from hydrogen, lower alkyl, —C(O)R 11 , —C(O)OR 11 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 ; 
         provided that
 R 1  is not optionally substituted phenyl or optionally substituted 4-pyridinyl; 
 when X is N, R 2  is hydrogen or methyl, R 3  and R 5  are hydrogen, and Y is absent, then R 1  is not quinolin-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2-3-dihydro-benzofuran-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl; and 
 when X is N, R 2 , R 3  and R 5  are hydrogen, and Y is —O— or —N(R 7 )—, and R 1  is quinolin-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2-3-dihydro-benzofuran-5-yl, or 2,3-dihydro-benzo[1,4]dioxin-6-yl, then R 4  is optionally substituted heteroaryl. 
 
       
     
     
         2 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein X is N. 
     
     
         3 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein X is C(R 6 ). 
     
     
         4 . At least one compound of  claim 3 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 6  is selected from hydrogen and lower alkyl. 
     
     
         5 . At least one compound of  claim 4 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 6  is hydrogen. 
     
     
         6 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein Y is —O—. 
     
     
         7 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein Y is —S—. 
     
     
         8 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein Y is —N(R 7 )—. 
     
     
         9 . At least one compound of  claim 8 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 7  is hydrogen or methyl. 
     
     
         10 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein Y is absent. 
     
     
         11 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 1  is 8-10 membered heteroaryl optionally substituted with one or more groups selected from halo, —CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , —C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle. 
     
     
         12 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 1  is a ring system selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each of said ring systems is optionally substituted with one or more groups selected from halo, CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , C(O)OR 11 , —ON, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle. 
     
     
         13 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 1  is a ring system selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . (canceled) 
     
     
         15 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 5  is hydrogen. 
     
     
         16 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 4  is aryl optionally substituted with one or more groups selected from
 lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ,   lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy,   heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   heteroaryloxy optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   aryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   heteroaryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   halo, cyano, —C(O)R 11 , —C(O)OR 11 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 .   
     
     
         17 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 4  is heterocycle optionally substituted with one or more groups selected from
 lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ,   lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy,   heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   halo, cyano, —C(O)R 11 , —C(O)OR 11 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 .   
     
     
         18 . (canceled) 
     
     
         19 . At least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, wherein R 4  is heteroaryl optionally substituted with one or more groups selected from
 lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ,   lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy,   heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy,   halo, cyano, —C(O)R 11 , —C(O)OR 11 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 .   
     
     
         20 .- 22 . (canceled) 
     
     
         23 . A method of inhibiting the activity of c-Met comprising contacting the receptor with an effective amount of at least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof. 
     
     
         24 . A method of treating cancer responsive to inhibition of c-Met comprising administering to a subject in recognized need thereof an effective amount of at least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof. 
     
     
         25 . A method for treating cancer responsive to inhibition of c-Met comprising:
 administering to a subject in recognized need thereof an effective amount of at least one compound of  claim 1 , and/or at least one pharmaceutically acceptable salt thereof, and administering to the subject an amount of an anti-neoplastic agent, wherein said anti-neoplastic agent is different from said at least one compound of any one of  claims 1  to  21 , and/or at least one pharmaceutically acceptable salt thereof.