Claims for Patent: RE50634

Summary for Patent: RE50634

Title:	Diaryl macrocycles as modulators of protein kinases
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.
Inventor(s):	Jingrong Jean Cui, Yishan LI, Evan W. ROGERS, Dayong Zhai
Assignee:	Turning Point Therapeutics Inc
Application Number:	US18/147,888
Patent Claims:	1. A compound of the formula wherein each L1 and L2 is independently —C(R1′)(R2′)—, —O—, —N(Rk′)—, —S—, —S(O)— or —S(O)2—; each R1′ and R2′ are independently H, deuterium, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl, —ORa′, —OC(O)Ra′, —OC(O)NRa′Rb′, —OS(O)Ra′, —OS(O)2Ra′, —SRa′, —S(O)Ra′, —S(O)2Ra′, —S(O)NRa′Rb′, —S(O)2NRa′Rb′, —OS(O)NRa′Rb′, —OS(O)2NRa′Rb′, —NRa′Rb′, —NRa′C(O)Rb′, —NRa′C(O)ORb′, —NRa′C(O)NRa′Rb′, —NRa′S(O)Rb′, —NRa′S(O)2Rb′, —NRa′S(O)NRa′Rb′, —NRa′S(O)2NRa′Rb′, —C(O)Ra′, —C(O)ORa′, —C(O)NRa′Rb′, —PRa′Rb′, —P(O)Ra′Rb′, —P(O)2Ra′Rb′, —P(O)NRa′Rb′, —P(O)2NRa′Rb′, —P(O)ORa′, —P(O)2ORa′, —CN, or —NO2, or R1′ and R2′ taken together with the carbon or carbons to which they are attached form a C3-6cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl, —ORe′, —OC(O)Re′, —OC(O)NRe′Rf′, —OS(O)Re′, —OS(O)2Re′, —OS(O)NRe′Rf′, —OS(O)2NRe′Rf′, —SRe′, —S(O)Re′, —S(O)2Re′, —S(O)NRe′Rf′, —S(O)2NRe′Rf′, —NRe′Rf′, —NRe′C(O)Rf′, —NRe′C(O)ORf′, —NRe′C(O)NRe′Rf′, —NRe′S(O)Rf′, —NRe′S(O)2Rf′, —NRe′S(O)NRe′Rf′, —NRe′S(O)2NRe′Rf′, —C(O)Re′, —C(O)ORe′, —C(O)NRe′Rf′, —PRe′Rf′, —P(O)Re′Rf′, —P(O)2Re′Rf′, —P(O)NRe′Rf′, —P(O)2NRe′Rf′, —P(O)ORe′, —P(O)2ORe′, —CN, or —NO2; each Rk′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl, —ORe′, —OC(O)Re′, —OC(O)NRe′Rf′, —OS(O)Re′, —OS(O)2Re′, —OS(O)NRe′Rf′, —OS(O)2NRe′Rf′, —SRe′, —S(O)Re′, —S(O)2Re′, —S(O)NRe′Rf′, —S(O)2NRe′Rf′, —NRe′Rf′, —NRe′C(O)Rf′, —NRe′C(O)ORf′, —NRe′C(O)NRe′Rf′, —NRe′S(O)Rf′, —NRe′S(O)2Rf′, —NRe′S(O)NRe′Rf′, —NRe′S(O)2NRe′Rf′, —C(O)Re′, —C(O)ORe′, —C(O)NRe′Rf′, —PRe′Rf′, —P(O)Re′Rf′, —P(O)2Re′Rf′, —P(O)NRe′Rf′, —P(O)2NRe′Rf′, —P(O)ORe′, —P(O)2ORe′, —CN, or —NO2; each R3′ and R4′ is independently deuterium, halogen, —ORc′, —OC(O)Re′, —OC(O)NRc′Rd′, —OC(═N)NRc′Rd′, —OS(O)Rc′, —OS(O)2Rc′, —OS(O)NRc′Rd′, —OS(O)2NRc′Rd′, —SRc′, —S(O)Rc′, —S(O)2Rc′, —S(O)NRc′Rd′, —S(O)2NRc′Rd′, —NRc′Rd′, —NRc′C(O)Rd′, —NRc′C(O)ORd′, —NRc′C(O)NRc′Rd′, —NRc′C(═N)NRc′Rd′, —NRc′S(O)Rd′, —NRc′S(O)2Rd′, —NRc′S(O)NRc′Rd′, —NRc′S(O)2NRc′Rd′, —C(O)Rc′, —C(O)ORc′, —C(O)NRc′Rd′, —C(═N)NRc′Rd′, —PRc′Rd′, —P(O)Rc′Rd′, —P(O)2Rc′Rd′, —P(O)NRc′Rd′, —P(O)2NRc′Rd′, —P(O)ORc′, —P(O)2ORc′, —CN, —NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl, or any two R3′ groups or any two R4′ groups taken together with the ring to which they are attached form a C5-8cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, mono- or bicyclic heteroaryl C5-8cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl, —ORe′, —OC(O)Re′, —OC(O)NRe′Rf′, —OS(O)Re′, —OS(O)2Re′, —OS(O)NRe′Rf′, —OS(O)2NRe′Rf′, —SRe′, —S(O)Re′, —S(O)2Re′, —S(O)NRe′Rf′, —S(O)2NRe′Rf′, —NRe′Rf′, —NRe′C(O)Rf′, —NRe′C(O)ORf′, —NRe′C(O)NRe′Rf′, —NRe′S(O)Rf′, —NRe′S(O)2Rf′, —NRe′S(O)NRe′Rf′, —NRe′S(O)2NRe′Rf′, —C(O)Re′, —C(O)ORe′, —C(O)NRe′Rf′, —PRe′Rf′, —P(O)Re′Rf′, —P(O)2Re′Rf′, —P(O)NRe′Rf′, —P(O)2NRe′Rf′, —P(O)ORe′, —P(O)2ORe′, —CN, or —NO2; R7′ is H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, —ORi′, —OC(O)Ri′, —OC(O)NRi′Rj′, —OS(O)Ri′, —OS(O)2Ri′, —OS(O)NRi′Rj′, —OS(O)2NRi′Rj′, —SRi′, —S(O)Ri′, —S(O)2Ri′, —S(O)NRi′Rj′, —S(O)2NRi′Rj′, —NRi′Rj′, —NRi′C(O)Rj′, —NRi′C(O)ORj′, —NRi′C(O)NRi′Rj′, —NRi′S(O)Rj′, —NRi′S(O)2Rj′, —NRi′S(O)NRi′Rj′, —NRi′S(O)2NRi′Rj′, —C(O)Ri′, —C(O)ORi′, —C(O)NRi′Rj′, —PRi′Rj′, —P(O)Ri′Rj′, —P(O)2Ri′Rj′, —P(O)NRi′Rj′, —P(O)2NRi′Rj′, —P(O)ORi′, —P(O)2ORi′, —CN, or —NO2; each Ra′, Rb′, Rc′, Rd′, Re′, Rf′, Ri′ and Rj′ is independently selected from the group consisting of H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 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 R3′ is selected from the group consisting of deuterium, halogen, —ORc′, —OC(O)Rc′, —OC(O)NRc′Rd′, —OC(═N)NRc′Rd′, —OS(O)Rc′, —OS(O)2Rc′, —OS(O)NRc′Rd′, —OS(O)2NRc′Rd′, —SRc′, —S(O)Rc′, —S(O)2Rc′, —S(O)NRc′Rd′, —S(O)2NRc′Rd′, —NRc′Rd′, —NRc′C(O)Rd′, —NRc′C(O)ORd′, —NRc′C(O)NRc′Rd′, —NRc′C(═N)NRc′Rd′, —NRc′S(O)Rd′, —NRc′S(O)2Rd′, —NRc′S(O)NRc′Rd′, —NRc′S(O)2NRc′Rd′, —C(O)Rc′, —C(O)ORc′, —C(O)NRc′Rd′, —C(═N)NRc′Rd′, —PRc′Rd′, —P(O)Rc′Rd′, —P(O)2Rc′Rd′, —P(O)NRc′Rd′, —P(O)2NRc′Rd′, —P(O)ORc′, —P(O)2ORc′, —CN, —NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, and mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, mono- or bicyclic heteroaryl C5-8cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl, —ORe′, —OC(O)Re′, —OC(O)NRe′Rf′, —OS(O)Re′, —OS(O)2Re′, —OS(O)NRe′Rf′, —OS(O)2NRe′Rf′, —SRe′, —S(O)Re′, —S(O)2Re′, —S(O)NRe′Rf′, —S(O)2NRe′Rf′, —NRe′Rf′, —NRe′C(O)Rf′, —NRe′C(O)ORf′, —NRe′C(O)NRe′Rf′, —NRe′S(O)Rf′, —NRe′S(O)2Rf′, —NRe′S(O)NRe′Rf′, —NRe′S(O)2NRe′Rf′, —C(O)Re′, —C(O)ORe′, —C(O)NRe′Rf′, —PRe′Rf′, —P(O)Re′Rf′, —P(O)2Re′Rf′, —P(O)NRe′Rf′, —P(O)2NRe′Rf′, —P(O)ORe′, —P(O)2ORe′, —CN, or —NO2, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3′ is fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3. 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 R7′ is H, or R7′ is methyl or ethyl, each unsubstituted or substituted with halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CO2H, —CO2C1-4alkyl, —CONH2, C3-6cycloalkyl, or monocyclic heterocycloalkyl. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein each Rk′ is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein -(L1)n′- is —CH2CH2—, —CH2—S—, —CH2—SO2—, —SO2—N(C1-4alkyl)-, —SO2—NH—, —CH2—O—, —CH(C1-4alkyl)-O—, —CH(CH2F)—O—, —CH(C3-6cycloalkyl)-O—; —CH2NH—, —CH(C1-4alkyl)-NH—, —CH(C1-4alkylOH)—NH—, —CH(C1-4alkyl-C3-6cycloalkyl)-NH—, —CH2—N(C1-4alkyl)-, —CH2—N(C3-6cycloalkyl)-, —CH2—N(C1-4alkylOH)—, —CH(C1-4alkyl)-N(C1-4alkyl)—, —CH(CO2C1-4alkyl)-NH—, —CH(C(O)NH2)—NH—, —CH(CO2C1-4alkyl)-N(C1-4alkyl), —CH(C(O)NH2)—N(C1-4alkyl)-, —CH(C(O)NH(C1-4alkyl))-NH—, —CH(C(O)NH(C1-4alkyl))-N(C1-4alkyl)-, —CH(C(O)N(C1-4alkyl)2)-NH—, or —CH(C(O)N(C1-4alkyl)2)-N(C1-4alkyl)-. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein -(L2)m′- is —O—(C(R1′)(R2′))2—, —O—(C(R1′)(R2′))3—, —O—(CH2)2—, —O—(CH2)3—, —N(Rk′)—(C(R1′)(R2′))2—, —N(Rk′)—(C(R1′)(R2′))3—, —S—(C(R1′)(R2′))2—, —S—(C(R1′)(R2′))3—, —SO—(C(R1′)(R2′))2—, —SO2—(C(R1′)(R2′))2—, —SO2—(C(R1′)(R2′))3—, —SO2—N(Rk′)—(C(R1′)(R2′))2— or —(C(R1′)(R2))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; X1 and X1′ are independently —C(R1a)(R2a)—, —S—, —S(O)—, —S(O)2—, —O— or —N(Rk′)—; each R1a and R2a is independently H, deuterium, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, —C(O)ORa′, —C(O)NRa′Rb′, —NRa′Rb′, —SRa′, —S(O)Ra′, —S(O)NRa′Rb′, —S(O)2Ra′, —S(O)2NRa′Rb′ or —ORa′ wherein each hydrogen atom in C1-6alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, NHC(O)C1-4alkyl, —N(C1-4alkyl)C(O)C1-4alkyl, —NHC(O)NHC1-4alkyl, —N(C1-4alkyl)C(O)NHC1-4alkyl, —NHC(O)N(C1-4alkyl)2, —N(C1-4alkyl)C(O)N(C1-4alkyl)2, —NHC(O)OC1-4alkyl, —N(C1-4alkyl)C(O)OC1-4alkyl, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, —SC1-4alkyl, —S(O)C1-4alkyl, —S(O)2C1-4alkyl, —S(O)NH(C1-4alkyl), —S(O)2NH(C1-4alkyl), —S(O)N(C1-4alkyl)2, —S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a is H, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3; R3b is H; R7a is H, C1-6alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —CN, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl; each Rk′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl in Rk′ is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl or —ORa′; wherein each Ra′ and Rb′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or heteroaryl; Z1 is N; Z2 is CH; Z3 is CH; Z4 is N; Z5 is C; Z6 is CH; Z7 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; X1 and X1′ are independently —C(R1a)(R2a)—, —S—, —S(O)—, —S(O)2—, —O— or —N(Rk′)—; each R1a and R2a is independently H, deuterium, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, —C(O)ORa′, —C(O)NRa′Rb′, —NRa′Rb′, —SRa′, —S(O)Ra′, —S(O)NRa′Rb′, —S(O)2Ra′, —S(O)2NRa′Rb′ or —ORa′ wherein each hydrogen atom in C1-6alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, NHC(O)C1-4alkyl, —N(C1-4alkyl)C(O)C1-4alkyl, —NHC(O)NHC1-4alkyl, —N(C1-4alkyl)C(O)NHC1-4alkyl, —NHC(O)N(C1-4alkyl)2, —N(C1-4alkyl)C(O)N(C1-4alkyl)2, —NHC(O)OC1-4alkyl, —N(C1-4alkyl)C(O)OC1-4alkyl, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, —SC1-4alkyl, —S(O)C1-4alkyl, —S(O)2C1-4alkyl, —S(O)NH(C1-4alkyl), —S(O)2NH(C1-4alkyl), —S(O)N(C1-4alkyl)2, —S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3; R3b is H; R7a is H, C1-6alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl; each Rk′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl in Rk′ is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl or —ORa′; wherein each Ra′ and Rb′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or heteroaryl; Z1 is N; Z2 is CH; Z3 is CH; Z4 is N; Z5 is C; Z6 is CH; Z7 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; X1 and X1′ are independently —C(R1a)(R2a)—, —S—, —S(O)—, —S(O)2—, —O— or —N(Rk′)—; each R1a and R2a is independently H, deuterium, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, —C(O)ORa′, —C(O)NRa′Rb′, —NRa′Rb′, —SRa′, —S(O)Ra′, —S(O)NRa′Rb′, —S(O)2Ra′, —S(O)2NRa′Rb′ or —ORa′ wherein each hydrogen atom in C1-6alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, NHC(O)C1-4alkyl, —N(C1-4alkyl)C(O)C1-4alkyl, —NHC(O)NHC1-4alkyl, —N(C1-4alkyl)C(O)NHC1-4alkyl, —NHC(O)N(C1-4alkyl)2, —N(C1-4alkyl)C(O)N(C1-4alkyl)2, —NHC(O)OC1-4alkyl, —N(C1-4alkyl)C(O)OC1-4alkyl, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, —SC1-4alkyl, —S(O)C1-4alkyl, —S(O)2C1-4alkyl, —S(O)NH(C1-4alkyl), —S(O)2NH(C1-4alkyl), —S(O)N(C1-4alkyl)2, —S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3; R3b is H; R7a is H, C1-6alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC1-4alkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CO2H, —CO2C1-4alkyl, —CONH2, —CONH(C1-4alkyl), —CON(C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl; each Rk′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl in Rk′ is independently optionally substituted by deuterium, halogen, C1-6alkyl, C1-6haloalkyl or —ORa′; wherein each Ra′ and Rb′ is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or heteroaryl; Z1 is N; Z2 is CH; Z3 is CH; Z4 is N; Z5 is C; Z6 is CH; Z7 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(6,6,7,7-2H4)-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.