1,8-naphthyridinone compounds and uses thereof

Abstract

1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.

1 . (canceled) 
     
     
         2 : A compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
 R 1 , R 2 , R 3 , and R 5  are each H; 
 A is a 5- to 10-membered heteroaryl optionally substituted with R 6 ; 
 B is phenyl; 
 each R 6  is independently, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —OR 8 , —SR 8 , —NR 9 R 10 , —NO 2 , —C═NH(OR 8 ), —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 8 C(O)R 9 , —NR 8 C(O)OR 9 , —NR 8 C(O)NR 9 R 10 , —S(O)R 8 , —S(O) 2 R 8 , —NR 8 S(O)R 9 , —C(O)NR 8 S(O)R 9 , —NR 8 S(O) 2 R 9 , —C(O)NR 8 S(O) 2 R 9 , —S(O)NR 9 R 10 , —S(O) 2 NR 9 R 10 , —P(O)(OR 9 ) (OR 10 ), C 3 -C 6  cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, —(C 1 -C 3  alkylene)CN, —(C 1 -C 3  alkylene)OR 8 , —(C 1 -C 3  alkylene)SR 8 , —(C 1 -C 3  alkylene)NR 9 R 10 , —(C 1 -C 3  alkylene)CF 3 , —(C 1 -C 3  alkylene)NO 2 , —(C 1 -C 3  alkylene)C(O)R 8 , —(C 1 -C 3  alkylene)OC(O)R 8 , —(C 1 -C 3  alkylene)C(O)OR 8 , —(C 1 -C 3  alkylene)C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)OC(O)NR 9 R 10 , —(C 1 -C 3  alkylene)NR 8 C(O)R 9 , —(C 1 -C 3  alkylene)NR 8 C(O)OR 9 , —(C 1 -C 3 alkylene)NR 8 C(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O)R 8 , —(C 1 -C 3  alkylene)S(O) 2 R 8 , —(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —C(O)(C 1 -C 3  alkylene)NR 8 S(O)R 9 , —(C 1 -C 3  alkylene)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)C(O)NR 8 S(O) 2 R 9 , —(C 1 -C 3  alkylene)S(O)NR 9 R 10 , —(C 1 -C 3  alkylene)S(O) 2 NR 9 R 10 , —(C 1 -C 3  alkylene)P(O)(OR 9 )(OR 10 ), —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-12-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), wherein each R 6  is independently optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12 , —C(O)R 11 , —CN, —S(O)R 11 , —S(O) 2 R 11 , —P(O)(OR 11 )(OR 12 ), —(C 1 -C 3  alkylene)OR 11 , —(C 1 -C 3  alkylene)NR 11 R 12 , —(C 1 -C 3  alkylene)C(O)R 11 , —(C 1 -C 3  alkylene)S(O)R 11 , —(C 1 -C 3  alkylene)S(O) 2 R 11 , —(C 1 -C 3  alkylene)P(O)(OR 11 )(OR 12 ), C 3 -C 8  cycloalkyl, or C 1 -C 6  alkyl optionally substituted by oxo, —OH or halogen; 
 R 8  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), or —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(C 6 -C 14  aryl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl), and —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl) are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —P(O)(OR 13 )(OR 14 ), phenyl optionally substituted by halogen, or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo; 
 R 9  and R 10  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, 3-6 membered heterocyclyl, —(C 1 -C 3  alkylene)NR 11 R 12 , —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl) or —(C 1 -C 3  alkylene)(C 6  aryl), wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 6 -C 14  aryl, 5-6-membered heteroaryl, 3-6 membered heterocyclyl, —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 1 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 1 -C 3  alkylene)(5-6-membered heteroaryl) and —(C 1 -C 3  alkylene)(C 6  aryl) are independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14  or C 1 -C 6  alkyl optionally substituted by halogen, —OH or oxo;
 or R 9  and R 10  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14  or C 1 -C 6 alkyl optionally substituted by halogen, oxo or —OH; 
 
 R 11  and R 12  are each independently hydrogen, C 1 -C 6  alkyl optionally substituted by halogen or oxo, C 2 -C 6  alkenyl optionally substituted by halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by halogen or oxo;
 or R 11  and R 12  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by halogen or oxo; and 
 
 R 13  and R 14  are each independently hydrogen, C 1 -C 6  alkyl optionally substituted by halogen or oxo, C 2 -C 6  alkenyl optionally substituted by halogen or oxo, or C 2 -C 6  alkynyl optionally substituted by halogen or oxo; 
 or R 13  and R 14  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by oxo or halogen. 
 
       
     
     
         3 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is a 10-membered heteroaryl optionally substituted with R 6 . 
     
     
         4 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is a 9-membered heteroaryl optionally substituted with R 6 . 
     
     
         5 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of indolyl, isoindolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, and thienopyridinyl, each of which is optionally substituted by R 6 . 
     
     
         6 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of indolyl, isoindolyl, indazolyl, benzoimidazolyl, benzotriazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, and triazolopyridinyl, each of which is optionally substituted with R 6 . 
     
     
         7 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is benzoimidazolyl optionally substituted with R 6 . 
     
     
         8 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is indazolyl optionally substituted with R 6 . 
     
     
         9 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       each of which is optionally substituted with R 6 . 
     
     
         10 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted with R 6 . 
     
     
         11 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is 
       
         
           
           
               
               
           
         
       
       which is optionally substituted with 1-3 R 6 . 
     
     
         12 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is 
       
         
           
           
               
               
           
         
       
       which is optionally substituted with 1-3 R 6 . 
     
     
         13 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is 
       
         
           
           
               
               
           
         
       
       which is optionally substituted with 1-3 R 6 . 
     
     
         14 : The compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is optionally substituted with one or more groups selected from C 1 -C 6  alkyl, halogen, —CN, —OH, and —OC 1 -C 6  alkyl. 
     
     
         15 : A pharmaceutical composition comprising a compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         16 : A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         17 : A method of treating disease mediated by an adenosine signaling pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         18 : A method of inhibiting an adenosine receptor of subtype A 2a , A 2b  or A 3  in a cell, comprising administering a compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cell. 
     
     
         19 : The method of  claim 20 , wherein the adenosine receptor is of subtype A 2a . 
     
     
         20 : A kit comprising a compound of  claim 2 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.