CN-121986097-A - SMARCA2 inhibitors useful for the treatment of SMARCA 4-deficient cancers

Abstract

The present invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, processes for preparing said compounds, and the use of said compounds as SMARCA2 protein inhibitors, and their use in the treatment of SMARCA 4-deficient cancers, such as SMARCA 4-deficient non-small cell lung cancer (NSCLC). (I)

Inventors

• I. Stansfield
• J. B. Decani
• D. J.C. Bertolt
• B. C.A. D'Urberville
• L. Saraz
• E. Basel
• C. Obrador Slobet
• A. X. Jones
• P. J. Kravchuk
• W.M. Jones
• K. W. Khimkin

Assignees

• 詹森药业有限公司

Dates

Publication Date

20260505

Application Date

20240926

Priority Date

20230927

Claims (15)

1. 1. A compound having the structure of formula (I): (I) Or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 is selected from: r 2 is selected from: R 3 is hydrogen or hydroxy.
2. 2. The compound of claim 1, selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or (b) ; ; ; (*R); ; (*R),(3-α, 4-β, 5-α); (*S),(3-α, 4-β, 5-α); (*S),(3-α, 4-β, 5-α); ; (Cis); ; ; ; ; r, (cis); s), (cis); (cis); And pharmaceutically acceptable salts, tautomers or stereoisomers thereof.
3. 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, and at least one pharmaceutically acceptable excipient.
4. 4. A compound according to any one of claims 1 to 2 for use in therapy.
5. 5. A compound according to any one of claims 1 to 2 for use in the treatment of SMARCA 4-deficient cancers.
6. 6. The compound for use according to claim 5, wherein the SMARCA 4-deficient cancer is SMARCA 4-deficient non-small cell lung cancer (NSCLC).
7. 7. A compound according to any one of claims 1 to 2 for use in the treatment of a disease state or condition mediated by SMARCA2 protein.
8. 8. The compound for use according to claim 7, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC).
9. 9. Use of a compound according to any one of claims 1 to 2 for the manufacture of a medicament for the treatment of cancer or NSCLC.
10. 10. An in vitro method of modulating SMARCA2 activity, the method comprising contacting the SMARCA2 protein or portion thereof with a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof.
11. 11. A method for treating SMARCA 4-deficient cancer, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 2.
12. 12. The method of claim 11, wherein the SMARCA 4-deficient cancer is SMARCA 4-deficient NSCLC.
13. 13. A method for treating a disease state or condition mediated by the SMARCA2 protein, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 2.
14. 14. The method of claim 13, wherein the disease or condition is selected from cancer or NSCLC.
15. 15. The method of any one of claims 11 to 14, wherein the subject is a mammal.

Description

SMARCA2 inhibitors useful for the treatment of SMARCA 4-deficient cancers Cross reference The present application claims the benefit of U.S. application Ser. No. 63/585,680 filed on 27, 9, 2023, which is hereby incorporated by reference in its entirety. Technical Field The present invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, processes for preparing said compounds, and the use of said compounds as SMARCA2 protein inhibitors, and their use in the treatment of SMARCA 4-deficient cancers, such as SMARCA 4-deficient non-small cell lung cancer (NSCLC). Background Switch/sucrose nonfermentable complexes (SWI/SNF), also known as BAF complexes, are multi-subunit complexes that modulate chromatin structure by two mutually exclusive helicase/ATPase catalytic subunit activities, SWI/SNF-related, matrix-related, chromatin actin-dependent regulatory factors, subfamily A, member 2 (SMARCA 2, BRAHMA or BRM) and SWI/SNF-related, matrix-related, chromatin actin-dependent regulatory factors, subfamily A, member 4 (SMARCA 4 or BRG 1). The core and regulatory subunits combine ATP hydrolysis with the perturbation of histone-DNA contact, providing access points for transcription factors and homologous DNA elements that facilitate gene activation and suppression. Mutations in the genes encoding the twenty typical SWI/SNF subunits were observed in nearly 20% of all cancers, with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer and renal clear cell carcinoma. Despite their high homology and their putative overlapping function, SMARCA2 and SMARCA4 have been reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, whereas SMARCA2 inactivation is not common in tumor progression. In fact, many types of cancers have been shown to be SMARCA 4-associated (e.g., cancers with SMARCA4 mutations or SMARCA4 deletions, e.g., lack of expression), including, for example, lung cancer (such as non-small cell lung cancer or NSCLC). SMARCA2 has been demonstrated to be one of the most important essential genes in SMARCA 4-related or mutant cancer cell lines. This is because SMARCA 4-deficient patient populations or cells are entirely dependent on SMARCA2 activity-i.e., SMARCA2 is more incorporated into the complex to compensate for SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA 4-associated/defective cancers. The co-occurrence of a deletion of two (or more) gene expression leading to cell death is referred to as synthetic lethality. Thus, synthetic lethality may be useful in the treatment of certain SMARCA2/SMARCA 4-related cancers. There is a continuing need for effective treatments for diseases that can be treated by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, the non-specific effects and inability to selectively target and modulate SMARCA2 remain a hurdle to developing effective therapies. Thus, small molecule therapeutics that target SMARCA2 would be very useful. It is an object of the present invention to provide compounds that are selective for SMARCA2 over SMARCA 4. It is an object of the present invention to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA 4-deficient cancers. It is an object of the present invention to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA 4-deficient NSCLC. Disclosure of Invention The present invention relates to a compound having the structure of formula (I): (I) Or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 is selected from: r 2 is selected from: R 3 is hydrogen or hydroxy. The invention also relates to compounds disclosed in the claims. The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, and at least one pharmaceutically acceptable excipient. The invention further relates to compounds provided herein for use in therapy, in particular in the treatment of SMARCA 4-deficient cancers. In some embodiments, the SMARCA 4-deficient cancer is SMARCA 4-deficient non-small cell lung cancer (NSCLC). The invention further relates to compounds provided herein for use in treating a disease state or condition mediated by SMARCA2 protein. In one embodiment, the disease state or condition mediated by SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC). The invention further relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment of cancer or NSCLC. The invention further relates to an in vitro method of modulating SMARCA2 activity comprising contacting a SMARCA2 protein or a portion thereof with a compound of the invention or a pharmaceutically acceptable salt thereof. The invention further relat