IP Library › Granted Patent US 50,634

Granted Patent E1

US 50,634 · App. 18/147,888 · Granted Oct 14, 2025

Diaryl macrocycles as modulators of protein kinases

Inventors: Jingrong Jean Cui (Princeton, NJ); Yishan Li (Princeton, NJ); Evan W. Rogers (Princeton, NJ); Dayong Zhai (Princeton, NJ)

Assignee: Turning Point Therapeutics, Inc.

C07D498/18 C07B2200/13

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Quick Facts

Patent No.: US 50,634
App. No.: 18/147,888
Granted: Oct 14, 2025
Kind: E1

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Abstract

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

Claims (186)

1. A compound of the formula

wherein

each L 1 and L 2 is independently —C(R 1′ )(R 2′ )—, —O—, —N(R k′ )—, —S—, —S(O)— or —S(O) 2 —;

each R 1′ and R 2′ are independently H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl, —OR 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 3-6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)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 k′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)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 4′ is independently deuterium, halogen, —OR c′ , —OC(O)R e′ , —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 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl, or any two R 3′ groups or any two R 4′ groups taken together with the ring to which they are attached form a C 5-8 cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, mono- or bicyclic heteroaryl C 5-8 cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)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′ is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, —OR i′ , —OC(O)R i′ , —OC(O)NR i′ R j′ , —OS(O)R i′ , —OS(O) 2 R i′ , —OS(O)NR i′ R j′ , —OS(O) 2 NR i′ R j′ , —SR i′ , —S(O)R i′ , —S(O) 2 R i′ , —S(O)NR i′ R j′ , —S(O) 2 NR i′ R j′ , —NR i′ R j′ , —NR i′ C(O)R j′ , —NR i′ C(O)OR j′ , —NR i′ C(O)NR i′ R j′ , —NR i′ S(O)R j′ , —NR i′ S(O) 2 R j′ , —NR i′ S(O)NR i′ R j′ , —NR i′ S(O) 2 NR i′ R j′ , —C(O)R i′ , —C(O)OR i′ , —C(O)NR i′ R j′ , —PR i′ R j′ , —P(O)R i′ R j′ , —P(O) 2 R i′ R j′ , —P(O)NR i′ R j′ , —P(O) 2 NR i′ R j′ , —P(O)OR i′ , —P(O) 2 OR i′ , —CN, or —NO 2 ;

each R a′ , R b′ , R c′ , R d′ , R e′ , R f′ , R i′ and R j′ is independently selected from the group consisting of H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and heteroaryl;

m′ is 2, 3, 4, or 5;

n′ is 2, 3, or 4;

p′ is 0, 1, 2, 3, or 4; and

q′ is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein p′ is 1, and R 3′ is selected from the group consisting of 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 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, mono- or bicyclic heteroaryl C 5-8 cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)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 a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3′ is fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 .

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, of the formula

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 7′ is H, or R 7′ is methyl or ethyl, each unsubstituted or substituted with halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , C 3-6 cycloalkyl, or monocyclic heterocycloalkyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R k′ is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein -(L 1 ) n′ - is —CH 2 CH 2 —, —CH 2 —S—, —CH 2 —SO 2 —, —SO 2 —N(C 1-4 alkyl)-, —SO 2 —NH—, —CH 2 —O—, —CH(C 1-4 alkyl)-O—, —CH(CH 2 F)—O—, —CH(C 3-6 cycloalkyl)-O—; —CH 2 NH—, —CH(C 1-4 alkyl)-NH—, —CH(C 1-4 alkylOH)—NH—, —CH(C 1-4 alkyl-C 3-6 cycloalkyl)-NH—, —CH 2 —N(C 1-4 alkyl)-, —CH 2 —N(C 3-6 cycloalkyl)-, —CH 2 —N(C 1-4 alkylOH)—, —CH(C 1-4 alkyl)-N(C 1-4 alkyl)—, —CH(CO 2 C 1-4 alkyl)-NH—, —CH(C(O)NH 2 )—NH—, —CH(CO 2 C 1-4 alkyl)-N(C 1-4 alkyl), —CH(C(O)NH 2 )—N(C 1-4 alkyl)-, —CH(C(O)NH(C 1-4 alkyl))-NH—, —CH(C(O)NH(C 1-4 alkyl))-N(C 1-4 alkyl)-, —CH(C(O)N(C 1-4 alkyl) 2 )-NH—, or —CH(C(O)N(C 1-4 alkyl) 2 )-N(C 1-4 alkyl)-.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein -(L 2 ) m′ - is —O—(C(R 1′ )(R 2′ )) 2 —, —O—(C(R 1′ )(R 2′ )) 3 —, —O—(CH 2 ) 2 —, —O—(CH 2 ) 3 —, —N(R k′ )—(C(R 1′ )(R 2′ )) 2 —, —N(R k′ )—(C(R 1′ )(R 2′ )) 3 —, —S—(C(R 1′ )(R 2′ )) 2 —, —S—(C(R 1′ )(R 2′ )) 3 —, —SO—(C(R 1′ )(R 2′ )) 2 —, —SO 2 —(C(R 1′ )(R 2′ )) 2 —, —SO 2 —(C(R 1′ )(R 2′ )) 3 —, —SO 2 —N(R k′ )—(C(R 1′ )(R 2′ )) 2 — or —(C(R 1′ )(R 2 )) 3 —.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m′ is 3.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n′ is 2.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p′ is 1.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein q′ is 0.

13. A compound of the Formula (IV):

wherein

M is CH;

X 1 and X 1′ are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′ )—;

each R 1a and R 2a is independently H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, —C(O)OR a′ , —C(O)NR a′ R b′ , —NR a′ R b′ , —SR a′ , —S(O)R a′ , —S(O)NR a′ R b′ , —S(O) 2 R a′ , —S(O) 2 NR a′ R b′ or —OR a′ wherein each hydrogen atom in C 1-6 alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, —N(C 1-4 alkyl)C(O)C 1-4 alkyl, —NHC(O)NHC 1-4 alkyl, —N(C 1-4 alkyl)C(O)NHC 1-4 alkyl, —NHC(O)N(C 1-4 alkyl) 2 , —N(C 1-4 alkyl)C(O)N(C 1-4 alkyl) 2 , —NHC(O)OC 1-4 alkyl, —N(C 1-4 alkyl)C(O)OC 1-4 alkyl, —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O)NH(C 1-4 alkyl), —S(O) 2 NH(C 1-4 alkyl), —S(O)N(C 1-4 alkyl) 2 , —S(O) 2 N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

R 3a is H, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ;

R 3b is H;

R 7a is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —CN, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl;

each R k′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl;

wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl in R k′ is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl or —OR a′ ;

wherein each R a′ and R b′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or heteroaryl;

Z 1 is N;

Z 2 is CH;

Z 3 is CH;

Z 4 is N;

Z 5 is C;

Z 6 is CH;

Z 7 is N; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , having the Formula (V):

wherein

M is CH;

X 1 and X 1′ are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′ )—;

R 3a is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ;

R 3b is H;

R 7a is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl;

each R k′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl;

wherein each R a′ and R b′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or heteroaryl;

Z 1 is N;

Z 2 is CH;

Z 3 is CH;

Z 4 is N;

Z 5 is C;

Z 6 is CH;

Z 7 is N; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 , selected from the group consisting of

wherein

M is CH;

X 1 and X 1′ are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′)—;

R 3a is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ;

R 3b is H;

R 7a is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl;

each R k′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or mono- or bicyclic heteroaryl;

wherein each R a′ and R b′ is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, or heteroaryl;

Z 1 is N;

Z 2 is CH;

Z 3 is CH;

Z 4 is N;

Z 5 is C;

Z 6 is CH;

Z 7 is N; and

m′ is 2 or 3;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 selected from the group consisting of

(13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;

2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;

(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and

12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 selected from the group consisting of 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-t][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;

11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;

11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;

11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxylate;

11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide;

13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;

11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide;

6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;

14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;

13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;

11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide;

11-fluoro-14-methyl-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide;

12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

(14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hex ahydro-4H-1,16-ethenop yrazolo [4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-methyl(6,6,7,7- 2 H 4 )-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

(7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

(7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

(7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;

11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one;

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;

11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8-oxide;

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8,8-dioxide;

(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one;

(6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;

(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and

11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 having the formula

or a pharmaceutically acceptable salt thereof.

19. A crystalline form of the free base of the compound of the formula

having a powder X-ray diffraction peak at 10.68±2 degrees, 11.96±2 degrees, 15.26±2 degrees, 19.64±2 degrees, 21.94±2 degrees, 23.96±2 degrees, 26.82±2 degrees, or a combination thereof.

20. A pharmaceutical composition comprising (a) at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.

21. A compound of the formula

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising (a) a compound of the formula

or a pharmaceutically acceptable salt thereof, and (b) at least one pharmaceutically acceptable excipient.

23. A compound of the formula

24. A pharmaceutical composition comprising (a) a compound of the formula

and (b) at least one pharmaceutically acceptable excipient.

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025

From: CUI, JINGRONG JEAN; LI, YISHAN

To: TP THERAPEUTICS, INC.

Reel/Frame 071238/0177 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025

From: CUI, JINGRONG JEAN; LI, YISHAN; ROGERS, EVAN W.; ZHAI, DAYONG

To: TP THERAPEUTICS. INC.

Reel/Frame 071239/0276 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025

From: CUI, JINGRONG JEAN; LI, YISHAN; ROGERS, EVAN W.; ZHAI, DAYONG

To: TP THERAPEUTICS, INC.

Reel/Frame 071241/0606 →

CHANGE OF NAME Recorded May 28, 2025

From: TP THERAPEUTICS, INC.

To: TURNING POINT THERAPEUTICS, INC.

Reel/Frame 071430/0839 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 29, 2022

From: CUI, JINGRONG JEAN; LI, YISHAN; ROGERS, EVAN W.; ZHAI, DAYONG

To: TURNING POINT THERAPEUTICS, INC.

Reel/Frame 062234/0907 →

Continuity (4)

Provisional Application 62106301 · Jan 22, 2015

Provisional Application 62049326 · Sep 11, 2014

Provisional Application 61931506 · Jan 24, 2014

Reissue 15113583 · Jan 23, 2015

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