Inhibitors of fibroblast activation protein

Abstract

Compounds and compositions for modulating fibroblast activation protein (FAP) are described. The compounds and compositions may find use as therapeutic agents for the treatment of diseases, including hyperproliferative diseases.

1 . A compound of formula (A): 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: 
         R is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or C 6 -C 14  aryl, wherein the C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6 -C 14  aryl of R are independently optionally substituted by R d ; 
         R M  is hydrogen or optionally substituted C 1 -C 6  alkyl; 
         m is 0, 1, 2, 3, or 4; 
         n is 0, 1, 2, 3, or 4,
 wherein m+n is 1, 2, 3, or 4; 
 
         X is —C(═O)—, —O—, —CH(OH)—, —S—, —S(═O)—, or —S(═O) 2 —; 
         Y is 
       
       
         
           
           
               
               
           
         
          wherein:
 the wavy line represents the point of attachment to the rest of the molecule, 
 s is 1, 2, 3, or 4, 
 R 11  and R 12  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 4 -C 8  cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14  aryl, halogen, cyano, —OR 14 , —NR 15 R 16 , —SR 14 , —NO 2 , —C═NH(OR 14 ), —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 S(O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , or —P(O)(OR 15 )(OR 16 ), wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 4 -C 8  cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6 -C 14  aryl of R 11  and R 12  are each independently optionally substituted by one or more of R L ; 
 each R 13  is independently C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —NR 15 R 16 , —NO 2 , —C═NH(OR 14 ), —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 S(O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , or —P(O)(OR 15 )(OR 16 ), wherein the C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl of R 13  are each independently optionally substituted by one or more R L ; 
 
         each R 14  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 14  are independently optionally substituted by halogen, —OH, oxo, cyano, or C 1 -C 6  alkyl optionally substituted by halogen, —OH, or oxo; 
         R 15  and R 16 , independently of each other and independently at each occurrence, are hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 15  and R 16  are independently optionally substituted by halogen, —OH, oxo, cyano, or C 1 -C 6  alkyl, optionally substituted by halogen, —OH, or oxo,
 or R 15  and R 16  are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, cyano, or C 1 -C 6  alkyl optionally substituted by halogen, —OH, or oxo; 
 
         R d , independently at each occurrence, is halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —OR 14 , —NR 15 R 16 , cyano, or nitro; and 
         each R L  is independently halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, C 6 -C 14  aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 S(O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , —P(O)(OR 15 )(OR 16 ), —NR 15 R 16 , cyano, oxo, or nitro, wherein (1) the C 1 -C 6  alkoxy is optionally substituted by halogen, —OH, oxo, cyano, C 1 -C 6  alkoxy, or C 1 -C 6  alkyl optionally substituted by halogen, —OH, or oxo, (2) the C 1 -C 6  alkyl is optionally substituted by 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is further optionally substituted by C 1 -C 6  alkyl, (3) the 5- to 10-membered heteroaryl is optionally substituted by oxo, and (4) the C 3 -C 8  cycloalkenyl is optionally substituted by halogen, —OH, oxo, cyano, C 1 -C 6  alkoxy, or C 1 -C 6  alkyl. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIa): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIb): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIc): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X is —C(═O)—. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R is hydrogen or C 1 -C 6  alkyl. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 11  is hydrogen, halogen, or C 1 -C 6  alkyl. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 12  is hydrogen, halogen, or C 1 -C 6  alkyl. 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 1. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 2. 
     
     
         16 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. 
       
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating a disease or disorder mediated by fibroblast activation protein (FAP) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. 
     
     
         19 .- 38 . (canceled)