Oxoacridinyl acetic acid derivatives and methods of use

Abstract

Compounds of Formula I or pharmaceutically acceptable salts or esters thereof capable of binding to and modulating the activity of a stimulator of interferon genes (STING) protein are provided. Methods involving compounds of Formula I as effective modulators of STING are also provided.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, wherein
 X is C(R X ) 2 , O, S, CH═CH, or a bond; 
 each R X  is independently H, CH 3 , CF 3 , CF 2 H, or F, or two R X  together form ═O, ═CH 2 , or ═CF 2 , or two R X , together with the carbon atom to which they are bonded, form a cyclopropyl; 
 Z 1  is (C(R Z ) 2 ) p -T 1 ; 
 p is 1, 2, 3, 4, 5, or 6; 
 each R Z  is independently H, C 1 -C 4  alkyl, C 1 -C 4  alkyl substituted with one or more halogen, or halogen; 
 T 1  is C(O)R 1 , C(O)OR 1 , C(O)N(R 1 ) 2 , NR 1 C(O)R 1 , C(S)R 1 , C(S)N(R 1 ) 2 , NR 1 C(S)R 1 , C(O)NHS(O) 2 R S , C(O)NHCOR 1 , C(O)NHOH, or C(O)NHCN; 
 R S  is R 1 , C 3 -C 8  cycloalkyl, heterocyclyl comprising one 5- or 6-membered rings and 1-2 heteroatoms selected from N, O, and S, or C 6 -C 10  aryl, wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more groups independently selected from C 1 -C 4  alkyl; 
 each R 1  is independently H, C 1 -C 4  alkyl, or C 1 -C 4  alkyl substituted with one or more halogen; 
 m is 0, 1, or 2; 
 each Y is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, CN, OH, O—(C 1 -C 6  alkyl), S—(C 1 -C 6  alkyl), O—(C 2 -C 4  alkenyl), O—(C 2 -C 4  alkynyl), NH 2 , NH—C 1 -C 6  alkyl, N—(C 1 -C 6  alkyl) 2 , S(O)—(C 1 -C 6  alkyl), S(O) 2 —(C 1 -C 6  alkyl), or Q-T, wherein the alkyl, alkenyl, or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH 2 , N 3 , halogen, O—(C 1 -C 6  alkyl), S—(C 1 -C 6  alkyl), NH—C 1 -C 6  alkyl, and N—(C 1 -C 6  alkyl) 2 , or two Y, together with the two adjacent carbon atoms to which they are bonded, form a 5- to 7-membered carbocycle or phenyl; 
 n is 2, 3, or 4; 
 each Z is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, CN, OH, O—(C 1 -C 6  alkyl), S—(C 1 -C 6  alkyl), O—(C 2 -C 4  alkenyl), O—(C 2 -C 4  alkynyl), NH 2 , NH—C 1 -C 6  alkyl, N—(C 1 -C 6  alkyl) 2 , S(O)—(C 1 -C 6  alkyl), S(O) 2 —(C 1 -C 6  alkyl), or Q-T, wherein the alkyl, alkenyl, or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH 2 , N 3 , halogen, O—(C 1 -C 6  alkyl), S—(C 1 -C 6  alkyl), NH—C 1 -C 6  alkyl, and N—(C 1 -C 6  alkyl) 2 ; 
 each Q is independently a bond, NH, N(C 1 -C 3  alkyl), O, S, S(O), S(O) 2 , Q′, NH-Q′, N(C 1 -C 3  alkyl)-Q′, O-Q′, S-Q′, S(O)-Q′, or S(O) 2 -Q′; 
 each Q′ is independently a carbon linker comprising one or more C(R Q ) 2 , C(R Q ) 2 —C(R Q ) 2 , CR Q ═CR Q , or C≡C; 
 each R Q  is independently H or C 1 -C 3  alkyl; 
 each T is independently C(O)—C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclyl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, C 6 -C 10  aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R T ; 
 each R T  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, OH, CN, halogen, O—(C 1 -C 6  alkyl), O—(C 1 -C 6  haloalkyl), S—(C 1 -C 6  alkyl), NH 2 , NH—C 1 -C 6  alkyl, N—(C 1 -C 6  alkyl) 2 , NHS(O) 2 —(C 1 -C 6  alkyl), (CH 2 ) q —C 3 -C 8  cycloalkyl, (CH 2 ) q -heterocyclyl, (CH 2 ) q -phenyl, or (CH 2 ) q -heteroaryl, wherein the heterocyclyl or heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S; and 
 q is 0, 1, 2, or 3, 
 wherein when X is C(O) and each R Z  is H: 
 m and n are not both 0; and 
 wherein the compound of Formula I is substituted with Z at least at the 3-position and the 4-position.