MACROCYCLIC COMPOUNDS FOR TREATING DISEASE

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.