Macrocyclic compounds for treating disease

Abstract

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

1 . A compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 each L is independently —C(R 1 )(R 2 )— or X; with the proviso that, when t is 1, then L is —C(R 1 )(R 2 )—; 
 X is O, S, S(O) or S(O) 2 ; 
 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, or 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 or carbons to which they are attached form a C 3 -C 6  cycloalkyl or a 4- to 6-membered heterocycloalkyl, 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, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, —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 c C(O)R, —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 ; 
 M is CR3 or N; 
 M 1  is CR4; 
 each R 3 , 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, or R 4  and R 5  taken together with the ring to which they are attached form a C 5 -C 8  cycloalkyl, or a 5- to 8-membered heterocycloalkyl, 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 (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, 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, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 3 -C 6  cycloalkyl, or 5- to 7-membered heterocycloalkyl, —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 (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 7  and R 8  combine to form a C 3 -C 7  cycloalkyl, a 5- to 8-membered heterocycloalkyl, C 6 -C 10  aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C 3 -C 7  cycloalkyl, a 5- to 8-membered heterocycloalkyl, C 6 -C 10  aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, —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 ; 
 Y is O, S, NR 9 , or CR9R 10 ; 
 R 9  and R 10  are each 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, 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, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, —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 , or —P(O) 2 OR e ; 
 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, 5- to 7-membered heteroaryl; 
 each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6  is independently N, NH, C or CH; 
 p is 1, 2, 3, or 4; and 
 t is 1, 2, 3, 4, or 5; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein t is 3 or 4. 
     
     
         4 . The compound of  claim 1 , having the formula III 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3. 
     
     
         6 . The compound of  claim 1 , having the formula IV or V 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Y is O. 
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein M is CR 3 . 
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3  is H, deuterium, C 1 -C 6  alkyl or halogen. 
     
     
         10 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein M is N. 
     
     
         11 .- 28 . (canceled) 
     
     
         29 . A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A method of inhibiting RET or SRC, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.