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, mono- or bi-cyclic 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 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 bi-cyclic heteroaryl, or 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 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 ;

M is CR 3 or N;

M 1 is CR 4 ;

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 bi-cyclic 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 bi-cyclic 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, 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 bi-cyclic 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 bi-cyclic 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 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 7 and R 8 combine to form a C 3 -C 7 cycloalkyl, 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, 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 CR 9 R 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 bi-cyclic 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 bi-cyclic 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, or 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

wherein n is 2 or 3;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein n is 2.

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 N.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 , when present, is H, deuterium, C 1 -C 6 alkyl or halogen.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is F.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently H or C 1 -C 6 alkyl, and each R 2 is independently H, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 4-, 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl(C 6 -C 10 aryl), —NH 2 , —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)OH, —NHS(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl(C 6 -C 10 aryl), —NH 2 , —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)OH, —NHS(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

14. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a tetrahydrofuran ring, a cyclobutane ring, cyclopentane ring, or cyclohexane ring.

15. The compound of claim 1 , selected form the group consisting of

wherein

M is CR 3 or N;

M 1 is CR 4 ;

X is O, S, S(O), or S(O) 2 ;

R 1 and R 2 are each independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, —OR a , —SR a , —NR a R b , —C(O)OR a , or —C(O)NR a R b ; 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 and C 6 -C 10 aryl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl(C 6 -C 10 aryl), —NH 2 , —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)OH, —NHS(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

R 3 , R 4 , and R 5 are each independently H, fluoro, chloro, bromo, C 1 -C 6 alkyl, —OH, —CN, —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 or —CF 3 ;

R 6 is H, C 1 -C 6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

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, —OH, —OC 1 -C 6 alkyl, —OC(O)C 1 -C 6 alkyl, —OC(O)NH 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)N(C 1 -C 6 alkyl) 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —OS(O)NH 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 NH 2 , —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —SH, —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH 2 , —S(O)NH(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)OH, —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OH, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHS(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , —P(O) 2 (C 1 -C 6 alkyl) 2 , —P(O)NH 2 , —P(O)NH(C 1 -C 6 alkyl), —P(O)N(C 1 -C 6 alkyl) 2 , —P(O) 2 NH 2 , —P(O) 2 NH(C 1 -C 6 alkyl), —P(O) 2 N(C 1 -C 6 alkyl) 2 , —P(O)OH, —P(O)OC 1 -C 6 alkyl, —P(O) 2 OH, —P(O) 2 OC 1 -C 6 alkyl, —CN, or —NO 2 ;

Y is O, S, NR 9 , or CR 9 R 10 ; and

R 9 and R 10 are each independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is optionally substituted by a halogen, —OH, —OC 1 -C 6 alkyl, —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O) 2 NH 2 , —SH, —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)N(C 1 -C 6 alkyl) 2 , —S(O)NH(C 1 -C 6 alkyl), —S(O)NH 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH 2 , —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OH, —NHC(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —NHC(O)N(C 1 C 6 alkyl) 2 , —NHC(O)NH(C 1 C 6 alkyl), —NHC(O)NH 2 , —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —NHS(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)NH 2 , —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O) 2 NH 2 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(OX)(C 1 -C 6 alkyl) 2 , —P(O) 2 (C 1 -C 6 alkyl) 2 , —P(O)N(C 1 -C 6 alkyl) 2 , —P(O) 2 N(C 1 -C 6 alkyl) 2 , —P(O)OC 1 -C 6 alkyl, or —P(O) 2 OC 1 -C 6 alkyl.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein M is N.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, deuterium, C 1 -C 6 alkyl or halogen.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 5 is F.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 4-, 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl(C 6 -C 10 aryl), —NH 2 , —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)OH, —NHS(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(OX)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl(C 6 -C 10 aryl), —NH 2 , —OC(O)C 1 -C 6 alkyl, —OC(O)N(C 1 -C 6 alkyl) 2 , —OC(O)NH(C 1 -C 6 alkyl), —OC(O)NH 2 , —OC(═N)N(C 1 -C 6 alkyl) 2 , —OC(═N)NH(C 1 -C 6 alkyl), —OC(═N)NH 2 , —OS(O)C 1 -C 6 alkyl, —OS(O) 2 C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(O)NH 2 , —N(C 1 -C 6 alkyl)C(O)NH(C 1 -C 6 alkyl), —NHC(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, —NHC(O)OH, —N(C 1 -C 6 alkyl)C(O)OH, —NHS(O)C 1 -C 6 alkyl, —NHS(O) 2 C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —NHS(O)NH 2 , —NHS(O) 2 NH 2 , —N(C 1 -C 6 alkyl)S(O)NH 2 , —N(C 1 -C 6 alkyl)S(O) 2 NH 2 , —NHS(O)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 1 -C 6 alkyl), —NHS(O)N(C 1 -C 6 alkyl) 2 , —NHS(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —OS(O)N(C 1 -C 6 alkyl) 2 , —OS(O) 2 N(C 1 -C 6 alkyl) 2 , —OS(O)NH(C 1 -C 6 alkyl), —OS(O) 2 NH(C 1 -C 6 alkyl), —OS(O)NH 2 , —OS(O) 2 NH 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

21. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 combine to form a tetrahydrofuran ring, a cyclobutane ring, cyclopentane ring, or cyclohexane ring.

22. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein X is O.

23. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.

25. A method of ameliorating the worsening of cancer comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is thyroid medullary carcinoma, non-small cell lung cancer, or colorectal cancer.

26. A method of inhibiting RET or SRC kinase, comprising contacting a cell comprising one or more of RET or SRC kinase with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the contacting is in vitro, ex vivo, or in vivo.

27. A pharmaceutical composition comprising a compound of claim 23 , or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.

28. A method of ameliorating the worsening of cancer comprising administering to a subject an effective amount of a compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein the cancer is thyroid medullary carcinoma, non-small cell lung cancer, or colorectal cancer.

29. A method of inhibiting RET or SRC kinase, comprising contacting a cell comprising one or more of RET or SRC kinase with an effective amount of a compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein the contacting is in vitro, ex vivo, or in vivo.