# US 10,246,466 B2 · Diaryl macrocycles as modulators of protein kinases

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- Number: US 10,246,466 B2
- Document ID: US10246466B2
- Status: Granted
- Kind: B2
- Application number: 15/609,962
- Filed: 2017-05-31
- Published: 2017-11-23
- Granted: 2019-04-02
- Earliest claimed: 2014-01-24
- Assignees: TP Therapeutics, Inc.
- Applicants: Tp Therapeutics, Inc.
- Inventors: Jingrong Jean Cui; Yishan Li; Evan W. Rogers; Dayong Zhai
- Web page: https://patentgrep.com/patent/US10246466B2

## CPC

- C07D 498/18: Bridged systems
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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

### Claim 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′ is independently H, deuterium, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, 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)Re′, —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)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, 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.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R3′ is independently fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R3′ is fluoro or chloro.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7′ is H or 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, cycloalkyl, or monocyclic heterocycloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Rk′ is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

### Claim 6 (depends on 1)

The compound of claim 1, 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)-.

### Claim 7 (depends on 6)

The compound of claim 6, 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—.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m′ is 3; or 4; or 5.

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein n′ is 2.

### Claim 10 (depends on 9)

The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein p′ is 1 or 2.

### Claim 11 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein q′ is 0.

### Claim 12

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′, —S(O)2Ra′, —S(O)2NRa′ 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 and R3b are each independently H, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3;
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;
wherein Z1, Z5, and Z7 are each N, and Z2, Z3, Z4, and Z6 are each independently C(Rx), wherein each Rx when present is independently H, deuterium, halogen, C1-4alkyl, —O—C1-4alkyl, —OH, —NH2, —NH(C1-4alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF3,
and
m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound of 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′, —S(O)2Ra′, —S(O)2NRa′, 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(C4alkyl)C(O)OC4alkyl, —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 and R3b are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3;
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;
wherein Z1, Z5, and Z7 are each N, and Z2, Z3, Z4, and Z6 are each independently C(Rx), wherein each Rx when present is independently H, deuterium, halogen, C1-4alkyl, —O—C1-4alkyl, —OH, —NH2, —NH(C1-4alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF3,
and
m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 14

A compound 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′, —S(O)2Ra′, —S(O)2NRa′ 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 and R3b are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF3;
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; and
wherein Z1, Z5, and Z7 are each N, and Z2, Z3, Z4, and Z6 are each independently C(Rx), wherein each Rx when present is independently H, deuterium, halogen, C1-4alkyl, —O—C1-4alkyl, —OH, —NH2, —NH(C1-4alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF3,
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein M is CH; Z1, Z5 and Z7 are N; Z2, Z3, Z4 and Z6 are C(Rx), wherein each Rx when present is H; X1 is —N(Rk′)—; and X1′ is —O—.

### Claim 16 (depends on 1)

The compound of claim 1 selected from the group consisting of (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;
(7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrlo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;
8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;
(5R)-3-fluoro-5-methyl-14,15-dihydro-5H, 10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;
3-fluoro-5-methyl-14,15-dihydro-5H, 10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;
(5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;
3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;
(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H, 13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one;
12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H, 13H-1,15-(azenometheno)pyrrolo[3,4-f][1, 10,4]benzodioxazacyclotridecin-4(5H)-one;
(7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1, 10,4]benzodioxazacyclotridecin-16(13H)-one;
8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1, 10,4]benzodioxazacyclotridecin-16(13H)-one;
12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;
12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;
12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;
12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)imidazo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;
9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;
8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;
8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;
8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-16(13H)-one;
12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenometheno)pyrrolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;
(8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5, 1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;
10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one;
(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;
9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;
10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; and
10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one; or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

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