Macrocycles for use in treating disease

Abstract

The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer.

1 . A compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  and R 2  is independently H, deuterium, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, —OR a , —OC(O)R a , —OC(O)R a , —OC(O)NR a R b , —OS(O)R a , —OS(O) 2 R a , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —OS(O)NR a R b , —OS(O) 2 NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR a R b , —NR a S(O)R b , —NR a S(O) 2 R b , —NR a S(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —PR a R b , —P(O)R a R b , —P(O) 2 R a R b , —P(O)NR a R b , —P(O) 2 NR a R b , —P(O)OR a , —P(O) 2 OR a , —CN, or —NO 2 ; or R 1  and R 2  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl; wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 each R 3  and R 3′  is independently H, deuterium, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, —OR a , —OC(O)R a , —OC(O)R a , —OC(O)NR a R b , —OS(O)R a , —OS(O) 2 R a , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —OS(O)NR a R b , —OS(O) 2 NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR a R b , —NR a S(O)R b , —NR a S(O) 2 R b , —NR a S(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —PR a R b , —P(O)R a R b , —P(O) 2 R a R b , —P(O)NR a R b , —P(O) 2 NR a R b , —P(O)OR a , —P(O) 2 OR a , —CN, or —NO 2 , wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; or R 3  and R 3′  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl; wherein each hydrogen atom in C 3 -C 6  cycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6 haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 each R 4  and R 5  is independently hydrogen, deuterium, halogen, —OR c , —OC(O)R c , —OC(O)NR c R d , —OC(═N)NR c R d , —OS(O)R c , —OS(O) 2 R c , —OS(O)NR c R d , —OS(O) 2 NR c R d , —SR c , —S(O)R c , —S(O) 2 R c , —S(O)NR c R d , —S(O) 2 NR c R d , —NR c R d , —NR c C(O)R d , —NR c C(O)OR d , —NR c C(O)NR c R d , —NR c C(═N)NR c R d , —NR c S(O)R d , —NR c S(O) 2 R d , —NR c S(O)NR c R d , —NR c S(O) 2 NR c R d , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(═N)NR c R d , —PR c R d , —P(O)R c R d , —P(O) 2 R c R d , —P(O)NR c R d , —P(O) 2 NR c R d , —P(O)OR c , —P(O) 2 OR c , —CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, C 5 -C 8  cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 R 6  is H, deuterium, or C 1 -C 6  alkyl, wherein each hydrogen atom in C 1 -C 6  alkyl is independently optionally substituted by deuterium, halogen, —OR e , —SR e , or —NR e R f ; 
 each R 7  is independently hydrogen or deuterium; 
 each R a , R b , R c , R d , R e , and R is independently selected from the group consisting of H, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, and 5- to 7-membered heteroaryl; and 
 n is 0, 1, 2, or 3; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1. 
     
     
         5 . The compound of  claim 1 , having the formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 1 , having the formula IIa 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 1 , having the formula III 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , having the formula IIIa 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1  and R 2 , when present, is independently H, deuterium, C 1 -C 6  alkyl, or R 1  and R 2  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3  and R 3′  is independently H, deuterium, C 1 -C 6  alkyl, or R 3  and R 3′  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3′  is H or deuterium. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4  is H or deuterium. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is fluoro. 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is H. 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 7  is H. 
     
     
         16 . The compound of  claim 1 , selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient. 
     
     
         18 . A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the formula I 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof, 
       wherein
 each R 1  and R 2  is independently H, deuterium, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, —OR a , —OC(O)R a , —OC(O)R a , —OC(O)NR a R b , —OS(O)R a , —OS(O) 2 R a , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —OS(O)NR a R b , —OS(O) 2 NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR a R b , —NR a S(O)R b , —NR a S(O) 2 R b , —NR a S(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —PR a R b , —P(O)R a R b , —P(O) 2 R a R b , —P(O)NR a R b , —P(O) 2 NR a R b , —P(O)OR a , —P(O) 2 OR a , —CN, or —NO 2  or R 1  and R 2  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl; wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR, —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 each R 3  and R 3′  is independently H, deuterium, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, —OR a , —OC(O)R a , —OC(O)R a , —OC(O)NR a R b , —OS(O)R a , —OS(O) 2 R a , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR a R b , —S(O) 2 NR a R b , —OS(O)NR a R b , —OS(O) 2 NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR a R b , —NR a S(O)R b , —NR a S(O) 2 R b , —NR a S(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —PR a R b , —P(O)R a R b , —P(O) 2 R a R b , —P(O)NR a R b , —P(O) 2 NR a R b , —P(O)OR a , —P(O) 2 OR a , —CN, or —NO 2 , wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R, —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R, —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; or R 3  and R 3′  taken together with the carbon atom to which they are attached combine to form a C 3 -C 6  cycloalkyl: wherein each hydrogen atom in C 3 -C 6  cycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6 haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR, —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 each R 4  and R 5  is independently hydrogen, deuterium, halogen, —OR c , —OC(O)R c , —OC(O)NR c R d , —OC(═N)NR c R d , —OS(O)R c , —OS(O) 2 R c , —OS(O)NR c R d , —OS(O) 2 NR c R d , —SR c , —S(O)R c , —S(O) 2 R c , —S(O)NR c R d , —S(O) 2 NR c R d , —NR c R d , —NR c C(O)R d , —NR c C(O)OR d , —NR c C(O)NR c R d , —NR c C(═N)NR c R d , —NR c S(O)R d , —NR c S(O) 2 R d , —NR c S(O)NR c R d , —NR c S(O) 2 NR c R d , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(═N)NR c R d , —PR c R d , —P(O)R c R d , —P(O) 2 R c R d , —P(O)NR c R d , —P(O) 2 NR c R d , —P(O)OR c , —P(O) 2 OR c , —CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, mono- or bicyclic heteroaryl, C 5 -C 8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —OR e , —OC(O)R e , —OC(O)NR e R f , —OC(═N)NR e R f , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR e R f , —OS(O) 2 NR e R f , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR e R f , —S(O) 2 NR e R f , —NR e R f , —NR e C(O)R f , —NR e C(O)OR f , —NR e C(O)NR e R f , —NR e S(O)R f , —NR e S(O) 2 R f , —NR e S(O)NR e R f , —NR e S(O) 2 NR e R f , —C(O)R e , —C(O)OR e , —C(O)NR e R f , —PR e R f , —P(O)R e R f , —P(O) 2 R e R f , —P(O)NR e R f , —P(O) 2 NR e R f , —P(O)OR e , —P(O) 2 OR e , —CN, or —NO 2 ; 
 R 6  is H, deuterium, or C 1 -C 6  alkyl, wherein each hydrogen atom in C 1 -C 6  alkyl is independently optionally substituted by deuterium, halogen, —OR e , —SR e , or —NR e R f ; 
 each R 7  is independently hydrogen or deuterium; 
 each R a , R b , R c , R d , R e , and R f  is independently selected from the group consisting of H, deuterium, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, and 5- to 7-membered heteroaryl; and 
 n is 0, 1, 2, or 3. 
 
     
     
         19 . The method of  claim 18 , wherein the subject is a human.