Macrocyclic 1,3-bridged 6-chloro-7-pyrazol-4-yl-1 h-indole-2-carboxylate and 6-chloro-7-pyrimidin-5-yl-1h-indole-2-carboxylate derivatives as mcl-1 inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2024190893-A1
Application number	US-202218546116-A
Country	US
Kind code	A1
Filing date	Feb 11, 2022
Priority date	Feb 12, 2021
Publication date	Jun 13, 2024
Grant date	—

Abstract

The present invention relates to compounds of formula (I) wherein XI is as myeloid cell leukemia-1 (MCL-1) inhibitors for the treatment of cancer, such as e.g. prostate, lung, pancreatic, breast, ovarian, and cervical cancer, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). An exemplary compound is e.g. compound 1

First claim

1 . A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein
X 1 represents

wherein
R 1 , R 1a , R 1b , R 1c , and R 2 each independently represent hydrogen; or C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of Het 1 , —OR 3 , and —NR 4a R 4b ;
Het 1 represents morpholinyl or tetrahydropyranyl;
R 3 represents hydrogen, C 1-4 alkyl, —C 2-4 alkyl-O—C 1-4 alkyl, —C 2-4 alkyl-OH, or —C 2-4 alkyl-O—C 2-4 alkyl-O—C 1-4 alkyl;
R 4a and R 4b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
X 2 represents

which can be attached to the remainder of the molecule in both directions;
Y 1 represents —O—, —S—, —S(═O)—, —S(═O) 2 —, or —N(R x )—;
R x represents hydrogen, methyl, C 2-6 alkyl, —C(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, C 3-6 cycloalkyl, —C(═O)—C 3-6 cycloalkyl, or —S(═O) 2 —C 3-6 cycloalkyl; wherein C 2-6 alkyl, —C(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, C 3-6 cycloalkyl, —C(═O)—C 3-6 cycloalkyl, and —S(═O) 2 —C 3-6 cycloalkyl are optionally substituted with one, two or three substituents selected from the group consisting of halo, C 1-4 alkyl and C 1-4 alkyl substituted with one, two or three halo atoms;
Y 2 represents —CH 2 —, —S— or —S(═O) 2 —;
R y represents halo;
n represents 0, 1 or 2;
m represents 0 or 1;
or a pharmaceutically acceptable salt, or a solvate thereof.

2 . The compound according to claim 1 , wherein
R 1 , R 1a , R 1b , R 1c , and R 2 each independently represent hydrogen; or C 1-6 alkyl optionally substituted with one —OR 3 ; R 3 represents hydrogen, C 1-4 alkyl, or —C 2-4 alkyl-O—C 1-4 alkyl; Y 1 represents —S—, —S(═O)—, or —S(═O) 2 —; Y 2 represents —CH 2 — or —S—; n represents 0 or 1.

3 . The compound according to claim 1 , wherein Formula (I) is limited to Formula (I-y)

4 . The compound according to claim 1 , wherein
X 1 represents

5 . The compound according to claim 1 , wherein
X 1 represents

6 . The compound according to claim 1 , wherein
n represent 1; and R y represents fluoro.

7 . The compound according to claim 1 , wherein
Y 1 represents —S—, —S(═O)—, or —S(═O) 2 —.

8 . The compound according to claim 1 , wherein
m represents 0.

9 . The compound according to claim 1 , wherein
m represents 1.

10 . A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.

11 . A process for preparing a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to claim 1 .

12 - 14 . (canceled)

15 . A method of treating cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in claim 1 .

16 . The method according to claim 15 , wherein cancer is selected from prostate, lung, pancreatic, breast, ovarian, cervical, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL).

Assignees

• Janssen Pharmaceutica Nv

Inventors

• DE BOECK Benoît Christian Albert Ghislain
• Rombouts Frederik Jan Rita
• Jerhaoui Soufyan

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D515/18 Primary

  Bridged systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title