EP-4739686-A1 - SMARCA2 INHIBITOR USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS

EP4739686A1EP 4739686 A1EP4739686 A1EP 4739686A1EP-4739686-A1

Abstract

The invention relates to a pharmaceutical compound and pharmaceutical compositions comprising said compound, to processes for the preparation of said compound and to the use of said compound as inhibitor of the SMARCA2 protein and to its use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

Inventors

STANSFIELD, IAN
JONES, Alexander Xenophon
JONES, WILLIAM MOORE
CALLAS, Christopher George
ROSANO, Robert J
KRAWCZUK, Paul John
WINTERS, MICHAEL PETER
SHIMKIN, Kirk Wayne
ALCÁZAR VACA, MANUEL JESÚS
BRAMBILLA, Marta
PANDE, Vineet
MEVELLEC, LAURENCE ANNE
De Boeck, Benoît Christian Albert Ghislain

Assignees

Janssen Pharmaceutica NV

Dates

Publication Date: 20260513
Application Date: 20240704

Claims (1)

JAB7161 -41- CLAIMS 1. A compound of the formula, , and pharmaceutically acceptable salts thereof. 2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1; and at least one pharmaceutically acceptable excipient. 3. A compound according to any one of claims 1 to 2 for use in therapy. 4. A compound according to any one of claims 1 to 2 for use in the treatment of a SMARCA4 deficient cancer. 5. The compound for the use of claim 4, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC). 6. A compound according to any one of claims 1 to 2 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein. 7. The compound for the use of claim 6, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC). 8. Use of a compound as defined in any one of claims 1 to 2 for the manufacture of a medicament for the treatment of cancer or NSCLC. 9. An in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2. 10. A method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 2. 11. The method of claim 10, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC. 12. A method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 2. JAB7161 -42- 13. The method of claim 12, wherein the disease or condition is selected from a cancer or NSCLC. 14. The method of any one of claims 10 to 13, wherein the subject is a mammal.

Description

JAB7161 -1- SMARCA2 INHIBITOR USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS FIELD OF THE INVENTION [0001] The invention relates to a pharmaceutical compound and pharmaceutical compositions comprising said compound, to processes for the preparation of said compound and to the use of said compound as inhibitor of the SMARCA2 protein and to its use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC). BACKGROUND OF THE INVENTION [0002] The Switch/Sucrose Non-Fermentable (SWI/SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase/ATPase catalytic subunits: SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI/ SNF-Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression. [0003] Mutations in the genes encoding the twenty canonical SWI/SNF subunits are 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), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non- small cell lung cancer or NSCLC). [0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4-related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity – i.e., there is a greater JAB7161 -2- incorporation of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA4-related/deficient cancers. The co- occurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2/SMARCA4-related cancers. [0005] There is an ongoing need for effective treatment for diseases that are treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, non-specific effects, and the inability to selectively target and modulate SMARCA2 remains an obstacle to the development of effective treatments. As such, small-molecule therapeutic agents that target SMARCA2 would be very useful. [0006] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4. [0007] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers. [0008] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC. SUMMARY OF THE INVENTION [0009] Embodiments of the present invention relate to certain uses and methods of use of 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)benzamide, or 3-chloro-5- ((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)benzamide having SMARCA2 modulating properties, and pharmaceutical compositions comprising this compound, to the use of said compound as inhibitor of the SMARCA2 protein, and to methods of treatment or use in the treatment of SMARCA4 deficient cancers, as described in the claims. [0010] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention. [0011] Embodiments of this invention are uses and methods of treatment using compounds of Formula JAB7161 -3- and pharmaceutically acceptable salts, isotopes, and stereoisomers thereof. [0012] An additional embodiment of the invention is a method of treating cancer or non- small-cell lung carcinoma (NSCLC) in a subject comprising administering an effective amount of a pharmaceutical composition, or use of a pharmaceutical composition for treating cancer or non-small-cell lung carcinoma (NSCLC), or a pharmaceutical composition for such use, comprising: the compound of the present invention; and pharmaceutically acce