# US 2021/0277008 A1 · Imidazo[1,2-b]pyridazine derivatives as trk inhibitors

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

- Number: US 2021/0277008 A1
- Document ID: US20210277008A1
- Status: Published application
- Kind: A1
- Application number: 17/260,892
- Filed: 2019-07-19
- Published: 2021-09-09
- Earliest claimed: 2018-07-19
- Assignees: BenevolentAI Bio Limited
- Applicants: BenevolentAI Bio Limited
- Inventors: Alan Brown; Angela Glen
- Web page: https://patentgrep.com/patent/US20210277008A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to certain imidazo[1,2-b]pyridazine compounds and the pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk. (I) wherein R1, R2, R3, R4 and R5 are as defined herein.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof;
wherein:
R1 is selected from H, —XR7, (C1-C6)alkyl, (C3-C8)cycloalkyl, and a C-linked 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S;
X is selected from —CH2—;
R2 is selected from H and —SR6;
R3 is selected from H and halo;
R4 is selected from H and (C1-C3)alkyl
R5 is selected from H and halo;
R6 is methyl;
R7 is phenyl substituted by hydroxy wherein the hydroxyphenyl is optionally further substituted by halo;
provided that if R2 is H then R1 is XR7.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R1 is selected from —XR7, (C1-C6)alkyl, (C3-C8)cycloalkyl, and a C-linked 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S.

### Claim 3 (depends on 1, 2)

A compound according to claim 1 or 2 wherein R1 is selected from (C1-C6)alkyl and (C3-C8)cycloalkyl.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein R4 is (C1-C6)alkyl.

### Claim 5 (depends on 1, 2)

A compound according to claim 1 or 2 wherein R1 is selected from —XR7 and a C-linked 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S.

### Claim 6 (depends on 5)

A compound according to claim 5 wherein R1 is selected from —XR7 and a C-linked 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N and O.

### Claim 7

A compound according to any preceding claim wherein R2 is —SR6.

### Claim 8

A compound according to any preceding claim wherein R3 is H or fluoro.

### Claim 9

A compound according to any preceding claim wherein R4 is H.

### Claim 10

A compound according to any preceding claim wherein R5 is H or fluoro.

### Claim 11

A compound according to any preceding claim wherein R7 is phenyl substituted by hydroxy wherein the hydroxyphenyl is optionally further substituted by fluoro.

### Claim 12

A compound of Formula Ia:
or a pharmaceutically salt or solvate thereof, wherein R1, R2, R3, R4 and R5 are as defined in any preceding claim.

### Claim 13

A compound according to claim wherein said compound is selected from:
N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3R)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
N′-cyano-N-ethyl-6-[4-fluoro-2-[5-fluoro-3-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
N′-cyano-N-ethyl-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
N-butyl-N′-cyano-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
N′-cyano-N-cyclohexyl-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide; and
N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3-hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboximidamide;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 14

A compound according to claim wherein said compound is selected from:
(Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3R)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
(Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3S)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
(Z)-N′-cyano-N-ethyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-3-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
(Z)-N′-cyano-N-ethyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
(Z)-N-butyl-N′-cyano-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
(Z)-N′-cyano-N-cyclohexyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide; and
(Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3-hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboximidamide;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

A pharmaceutical composition comprising a compound according to any of claims 1 to 14 and one or more pharmaceutically acceptable excipients.

### Claim 16 (depends on 15)

A pharmaceutical composition according to claim 15 in combination with one or more other therapeutic agents.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

A compound according to any of claims 1 to 14 for use as a pharmaceutical.

### Claim 18

A compound as defined in any of the preceding claims for use in treating or preventing a condition or disorder which is mediated by Trk.

### Claim 19 (depends on 18)

A compound according to claim 18 for use according to claim 18 wherein the condition or disorder is mediated by TrkA, TrkB, and TrkC.

### Claim 20 (depends on 18, 19)

A compound according to claim 18 or 19 for use according to claim 18 or 19 wherein the condition or disorder is atopic dermatitis.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

Use of a compound as defined in any of claims 1 to 14 in the manufacture of a medicament for treating or preventing a condition or disorder which is mediated by Trk.

### Claim 22 (depends on 21)

Use according to claim 21 wherein the condition or disorder is mediated by TrkA, TrkB, and TrkC.

### Claim 23 (depends on 21, 22)

Use according to claim 21 or 22 wherein the condition or disorder is atopic dermatitis.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

A method for preventing or treating a condition or disorder which is mediated by Trk which comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any of claims 1 to 14.

### Claim 25 (depends on 24)

A method according to claim 24 wherein the condition or disorder is mediated by TrkA, TrkB, and TrkC.

### Claim 26 (depends on 24, 25)

A method according to claim 24 or 25 wherein the condition or disorder is atopic dermatitis.