Macrocycle compounds for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2025268894-A1
Application number	US-202519025165-A
Country	US
Kind code	A1
Filing date	Jan 16, 2025
Priority date	Jul 20, 2022
Publication date	Aug 28, 2025
Grant date	—

Abstract

The present invention relates to compounds of formula (I),wherein R1 to R7, A1 and A2 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

First claim

1 . A compound of formula (I),

wherein
R 1 is

3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C 1-6 alkyl)oxoimidazolidinyl;
wherein R 8 is C 1-6 alkyl;
R 9 is ((C 1-6 alkyl) 2 amino) azetidinyl, C 1-6 alkylpiperazinyl, haloazetidinyl, haloC 1-6 alkylamino, haloC 1-6 alkylaminoazetidinyl, haloC 1-6 alkylpiperazinyl, hydroxy (C 1-6 alkyl) piperidinyl or morpholinyl;

R 2 is C 1-6 alkyl;
R 3 is H or halogen;
R 4 is H or halogen;
R 5 is C 1-6 alkyl or haloC 1-6 alkyl;
R 6 is C 1-6 alkoxyC 1-6 alkyl;
R 7 is morpholinyl, (haloC 1-6 alkyl) piperazinyl or C 1-6 alkylpiperazinyl;
A 1 is thiazolylene;
A 2 is C 1-6 alkylene;
with the proviso that R 3 and R 4 are not H simultaneously;
or a pharmaceutically acceptable salt thereof.

2 . A compound of formula (Ia),

wherein
R 1 is

3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazinyl or (C 1-6 alkyl)oxoimidazolidinyl;
wherein R 8 is C 1-6 alkyl;
R 9 is ((C 1-6 alkyl) 2 amino) azetidinyl, C 1-6 alkylpiperazinyl, haloazetidinyl, haloC 1-6 alkylamino, haloC 1-6 alkylaminoazetidinyl, haloC 1-6 alkylpiperazinyl, hydroxy (C 1-6 alkyl) piperidinyl or morpholinyl;

R 2 is C 1-6 alkyl;
R 3 is H or halogen;
R 4 is H or halogen;
R 5 is C 1-6 alkyl or haloC 1-6 alkyl;
R 6 is C 1-6 alkoxyC 1-6 alkyl;
R 7 is morpholinyl, (haloC 1-6 alkyl) piperazinyl or C 1-6 alkylpiperazinyl;
A 1 is thiazolylene;
A 2 is C 1-6 alkylene;
with the proviso that R 3 and R 4 are not H simultaneously;
or a pharmaceutically acceptable salt thereof.

3 . A compound according to claim 1 or 2 , wherein R 1 is

wherein R 8 is C 1-6 alkyl; R 9 is C 1-6 alkylpiperazinyl, haloC 1-6 alkylpiperazinyl or morpholinyl.

4 . A compound according to any one of claims 1-3 , wherein R 1 is

wherein R 8 is methyl; R 9 is 4-methylpiperazin-1-yl, 4-(2,2,2-trifluoroethyl) piperazin-1-yl or morpholinyl.

5 . A compound according to any one of claims 1-4 , wherein R 1 is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl) piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino.

6 . A compound according to any one of claims 1-5 , wherein R 2 is isopropyl.

7 . A compound according to any one of claims 1-6 , wherein R 3 is H or fluoro.

8 . A compound according to any one of claims 1-7 , wherein R 3 is fluoro.

9 . A compound according to any one of claims 1-8 , wherein R 4 is H or fluoro.

10 . A compound according to any one of claims 1-9 , wherein R 4 is H.

11 . A compound according to any one of claims 1-10 , wherein R 5 is haloC 1-6 alkyl.

12 . A compound according to any one of claims 1-11 , wherein R 5 is 2,2,2-trifluoroethyl.

13 . A compound according to any one of claims 1-12 , wherein R 6 is 1-methoxyethyl.

14 . A compound according to any one of claims 1-13 , wherein R 7 is (haloC 1-6 alkyl) piperazinyl.

15 . A compound according to any one of claims 1-14 , wherein R 7 is 4-(2,2,2-trifluoroethyl) piperazin-1-yl.

16 . A compound according to any one of claims 1-15 , wherein A 1 is

wherein bond “a” connects to indole ring.

17 . A compound according to any one of claims 1-16 , wherein A 2 is dimethylmethylene.

18 . A compound according to claim 1 or 2 , wherein
R 1 is

wherein R 8 is C 1-6 alkyl; R 9 is C 1-6 alkylpiperazinyl, haloC 1-6 alkylpiperazinyl or morpholinyl;
R 2 is C 1-6 alkyl;
R 3 is halogen;
R 4 is H;
R 5 is haloC 1-6 alkyl;
R 6 is C 1-6 alkoxyC 1-6 alkyl;
R 7 is (haloC 1-6 alkyl) piperazinyl;
A 1 is

wherein bond “a” connects to indole ring;
A 2 is C 1-6 alkylene;
or a pharmaceutically acceptable salt thereof.

19 . A compound according to claim 18 , wherein
R 1 is methyl-(4-methylpiperazine-1-carbonyl)amino, methyl-[4-(2,2,2-trifluoroethyl) piperazine-1-carbonyl]amino or methyl(morpholine-4-carbonyl)amino; R 2 is isopropyl; R 3 is fluoro; R 4 is H; R 5 is 2,2,2-trifluoroethyl; R 6 is (1S)-1-methoxyethyl; R 7 is 4-(2,2,2-trifluoroethyl) piperazin-1-yl; A 1 is

wherein bond “a” connects to indole ring;
A 2 is dimethylmethylene;
or a pharmaceutically acceptable salt thereof.

20 . A compound selected from:
3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1 (25),2,5 (28),19,22 (26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1 (25),2,5 (28),19,22 (26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1 (25),2,5 (28), 19,22 (26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; 3-(dimethylamino)-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia--9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1 (25),2,5 (28), 19,22 (26),23-hexaen 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1-carboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1 (25),2,5 (28), 19,22 (26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl) piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosa-1(25),2,5 (28),19,22 (26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-morpholine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetr

Assignees

• Hoffmann La Roche

Inventors

• Chen Jianguo
• Guo Lei
• Liu Haixia
• Shen Hong
• Zhang Weixing
• Zhao Dan
• Zhu Wei

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/504 Primary

  forming part of bridged ring systems · CPC title

• C07D513/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title