Urea compounds and compositions as SMARCA2/BRM ATPase inhibitors

Patent metadata

Field	Value
Publication number	US-11958846-B2
Application number	US-201917268512-A
Country	US
Kind code	B2
Filing date	Aug 12, 2019
Priority date	Aug 17, 2018
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a BRM-mediated and/or BRG1-mediated disease or disorder: Formula (I) wherein R1 through R6 are as defined herein.

First claim

What is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, of formula I:

in which:
R 1 is selected from hydrogen, amino and hydroxy-substituted C 1-2 alkyl;
R 2 is hydrogen;
R 3 is selected from C 1-2 alkyl and halo-substituted-C 1-2 alkyl;
R 4 is hydrogen;
R 5 is selected from hydrogen and halo; and
R 6 is selected from hydrogen and halo.

2. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 in which:
R 1 is selected from hydrogen, amino and hydroxy-methyl;
R 2 is hydrogen;
R 3 is selected from methyl, difluoromethyl and trifluoromethyl;
R 4 is hydrogen;
R 5 is selected from hydrogen, chloro and fluoro; and
R 6 is selected from hydrogen and fluoro.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, selected from:

4. A compound according to claim 3 which is

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

6. A pharmaceutical combination, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

7. A pharmaceutical combination of claim 6 , wherein said one or more therapeutically active agents are independently selected from anti-cancer agents.

8. A method of treating a BRM-mediated and/or a BRG1-mediated disorder or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said disorder or disease is a solid tumor, leukemia or lymphoma.

9. The method of claim 8 , wherein said disorder or disease is malignancy which is characterized by BRG1-deficiency and/or BRM-deficiency.

10. The method of claim 9 , wherein BRG1-deficiency and/or BRM-deficiency is a malignancy which is characterized by BRG1 mutation and/or BRM mutation.

11. The method of claim 8 , wherein said disorder or disease is selected from non-small cell lung carcinoma, lung adenocarcinoma, lung carcinoma, large cell lung carcinomas, non-small cell lung carcinoma, lung squamous cell carcinoma, small cell lung cancer, skin cutaneous melanoma, desmoplastic melanoma, uveal melanoma, small cell carcinoma of the ovary, ovarian rhabdoid tumor, cutaneous squamous cell carcinoma, glioma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, ovarian serous cystadenocarcinoma, bladder urothelial carcinoma, primary central nervous system lymphoma, esophageal carcinoma, bladder cancer, bladder cancer plasmacytoid variant, stomach adenocarcinoma, adenoid cystic carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, pancreatic cancer, colorectal adenocarcinoma, cholangiocarcinoma, sarcoma, head and neck cancers, cervical and endocervical cancers, medulloblastoma, cutaneous T cell lymphoma, liver hepatocellular carcinoma, kidney renal papillary cell carcinoma, breast cancer, mantle cell lymphoma, gallbladder carcinoma, testicular germ cell cancers, kidney renal cell clear cell carcinoma, prostate cancer, pediatric ewing sarcoma, thymoma, kidney chromophobe, renal non-clear cell carcinoma, pheochromocytoma and paraganglioma, thyroid cancers, malignant peripheral nerve sheath tumor, neuroendocrine prostate cancer, head and neck squamous cell carcinoma, adrenocortical carcinoma, cervical and endocervical cancers, cutaneous squamous cell carcinoma, testicular germ cell cancer, glioblastoma, glioblastoma multiforme, Ewing's sarcoma, clear cell renal cell carcinoma, neuroblastoma, diffuse large B cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, malignant rhabdoid tumors, epithelioid sarcomas, familial schwannomatosis, renal medullary carcinomas, synovial sarcoma, and meningiomas.

Assignees

• Novartis Ag

Inventors

• Adair Christopher
• Nakajima Katsumasa
• Ntaganda Rukundo
• Papillon Julien
• Smith Troy Douglas

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title