# US 2019/0169207 A1 · Diaryl macrocycles as modulators of protein kinases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0169207 A1
- Document ID: US20190169207A1
- Status: Published application
- Kind: A1
- Application number: 16/204,566
- Filed: 2018-11-29
- Published: 2019-06-06
- 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/US20190169207A1

## 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 inacrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

## Claims

### Claim at position 1

-56. (canceled)

### Claim 57

A compound of the following Formula (I-A):
wherein
Ring A′ and Ring B′ are each independently a monocyclic or bicyclic aryl or heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A′ and Ring B′ comprises at least one nitrogen ring member; provided that B′ is not of the formula
each L1 and L2 is independently —C(R1′)(R2′)—, —O—, —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, —ORc′, —OC(O)Rc′, —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)Rc′, —C(O)ORc′, —C(O)NRc′Rf′, —PRc′Rf′, —P(O)Rc′Rf′, —P(O)2Rc′Rf′, —P(O)NRc′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, C6-10aryl, 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)Re′, —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′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′, 13 P(O)2ORc′, —CN, —NO2, C16alkyl, 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′, —S(O)Ri′, —S(O)2Ri′, —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 58 (depends on 57)

The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein Ring A′ is monocyclic aryl or heteroaryl and Ring B′ is bicyclic heteroaryl..

### Claim 59 (depends on 57)

The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein Ring A′ is phenyl or pyridyl.

### Claim 60 (depends on 57)

The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein Ring B′ is:

### Claim 61 (depends on 57)

The compound of claim 57, 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 62 (depends on 61)

The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein each R3′ is fluoro or chloro.

### Claim 63 (depends on 57)

The compound of claim 57, 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 64 (depends on 57)

The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein each Rk′ is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

### Claim 65 (depends on 57)

The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein -(L1)n′- is —CH2CH2—, —CH2—S—, —CH2—SO2—, —SO2—N(C1-4alkyl)—, —SO2—NH—, —CH2—O—, —CH(C1-4 alkyl)—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 66 (depends on 65)

The compound of claim 65, 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 67 (depends on 66)

The compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein m′ is 3; or 4; or 5.

### Claim 68 (depends on 67)

The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein n′ is 2, 3 or 4.

### Claim 69 (depends on 68)

The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein p′ is 0, 1 or 2.

### Claim 70 (depends on 69)

The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein q′ is 0, 1 or 2.

### Claim 71

A compound of the Formula (IV):
wherein
M is CH or N;
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;
each Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is independently N, NH, or 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, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is N or NH, provided that the compound does not comprise a moiety of the formula
and m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 72

A compound of the Formula (V):
wherein
M is CH or N;
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;
each Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is independently N, NH, or 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, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is N or NH, provided that the compound does not comprise a moiety of the formula
and m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 73

A compound selected from the group consisting of
wherein
M is CH or N;
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;
each Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is independently N, NH, or 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, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is N or NH, provided that the compound does not comprise a moiety of the formula
and m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.

### Claim 74 (depends on 1)

The compound of claim 1, selected from the group consisting of (7R)-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;
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-d]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-d]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-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)pyrrolol[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;
(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolol[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; and
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; or a pharmaceutically acceptable salt thereof.

### Claim 75 (depends on 57)

A pharmaceutical composition comprising (a) at least one compound according to claim 57, or a pharmaceutically acceptable salt thereof, and (b) at least one pharmaceutically acceptable excipient.

### Claim 76 (depends on 57)

A method of treating cancer, pain, a neurological disease, an autoimmune disease, or inflammation, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 57, or a pharmaceutically acceptable salt thereof.