Novel Bicyclic Dione Compounds as KRAS Inhibitors for Treating Cancer.

pubs.acs.org/acsmedchemlett Patent Highlight Novel Bicyclic Dione Compounds as KRAS Inhibitors for Treating Cancer Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2022, 13, 893−894 ACCESS Read Online Metrics & More Article Recommendations Important Compound Classes. The present application describes a series of novel bicyclic dione compounds as KRAS inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment. Definitions. X = N or CR5; R1 = H, D, C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, halo, CN, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NR c 1 R d 1 , NR c 1 S(O)R b 1 , NR c 1 S(O) 2 R b 1 , NR c 1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , S(O)2NRc1Rd1, and BRh1Ri1; wherein said C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, are optionally substituted with 1, 2, 3, or 4 substituents selected from Rg; R2 = H, C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, wherein C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4− 10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from R20; Cy = C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, wherein 4−10 membered heterocycloalkyl and 5−10 membered heteroaryl, each has at least one ring forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms selected from N, O and S; R3 = C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, wherein C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from R30; and Title. Bicyclic Dione Compounds as Inhibitors of KRAS Patent Publication Number. WO 2022/072783 A1 URL: https://patents.google.com/patent/ WO2022072783A1/en Publication Date. April 7, 2022 Priority Application. US 63/086,776 Priority Date. October 2, 2020 Inventors. Huang, T.; Wang, X.; Yao, W. Assignee Company. Incyte Corporation, USA Disease Area. Cancer Biological Target. KRAS Summary. RAS proteins are part of the family of small GTPases that are activated by growth factors and various extracellular stimuli. The RAS family regulates intracellular signaling pathways responsible for growth, migration, survival, and differentiation of cells. Somatic mutations in RAS may result in uncontrolled cell growth and malignant transformation, while activation of RAS proteins is tightly regulated in normal cells. The RAS family is comprised of three members: KRAS, NRAS, and HRAS. RAS mutant cancers account for about 25% of human cancers. KRAS is the most frequently mutated isoform, accounting for 85% of all RAS mutations, whereas NRAS and HRAS are found mutated in 12% and 3% of all RAS mutant cancers, respectively. The majority of RAS mutations occur at amino acid residues 12, 13, and 61. KRAS G12D mutations predominate in pancreatic cancers (51%), followed by colorectal adenocarcinomas (45%) and lung cancers (17%), while KRAS G12V are associated with pancreatic cancers (30%), followed by colorectal adenocarcinomas (27%) and lung cancers (23%). In contrast, KRAS G12C mutations predominate in non-small-cell lung cancer (NSCLC), comprising 11−16% of lung adenocarcinomas and 2−5% of pancreatic and colorectal adenocarcinomas. The role of mutant KRAS as an oncogenic driver is further supported by extensive in vivo experimental evidence showing that mutant KRAS is required for early tumor onset and maintenance in animal models. Published 2022 by American Chemical Society Received: May 10, 2022 Published: May 26, 2022 893 https://doi.org/10.1021/acsmedchemlett.2c00221 ACS Med. Chem. Lett. 2022, 13, 893−894 ACS Medicinal Chemistry Letters pubs.acs.org/acsmedchemlett Patent Highlight R4 = C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl, wherein wherein C1−6 alkyl, C2−6 alkenyl, C2−6 alkynyl, C1−6 haloalkyl, C3−10 cycloalkyl, 4−10 membered heterocycloalkyl, C6−10 aryl, 5−10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from R40. Key Structures. Claims. Total claims: 49 Compound claims: 38 Pharmaceutical composition claims: 1 Use of compound claims: 10 ■ AUTHOR INFORMATION Corresponding Author Ram W. Sabnis − Smith, Gambrell & Russell LLP, Atlanta, Georgia 30309, United States; orcid.org/0000-00017289-0581; Email: Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.2c00221 Notes The author declares no competing financial interest. ■ RECENT REVIEW ARTICLES (1) Han, Z.; Zhou, D.; Wang, J.; Jiang, B.; Liu, X. Reflections on drug resistance to KRAS inhibitors and gene silencing/editing tools for targeting mutant KRAS in cancer treatment. Biochim. Biophys. Acta, Rev. Cancer 2022, 1877, 188677. (2) Drosten, M.; Barbacid, M. Targeting KRAS mutant lung cancer: light at the end of the tunnel. Mol. Oncol. 2022, 16, 1057. (3) Zhang, J.; Zhang, J.; Liu, Q.; Fan, X.; Leung, E. L.; Yao, X.; Liu, L. Resistance looms for KRAS G12C inhibitors and rational tackling strategies. Pharmacol. Ther. 2022, 229, 108050. (4) Rohatgi, A.; Govindan, R. Targeting KRAS G12C mutation in lung adenocarcinoma. Lung Cancer 2022, 165, 28. (5) Reck, M.; Carbone, D. P.; Garassino, M.; Barlesi, F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann. Oncol. 2021, 32, 1101. (6) Luo, J. KRAS mutation in pancreatic cancer. Semin. Oncol. 2021, 48, 10. Biological Assay. The KRAS G12C exchange assay and KRAS G12C pERK assay were performed. The compounds described in this application were tested for their ability to inhibit KRAS. The KRAS G12C exchange IC50 and KRAS G12C pERK IC50 are shown in the table below. Biological Data. The table below shows representative compounds tested for KRAS G12C exchange and KRAS G12C pERK inhibition and the biological data obtained from testing the representative examples. For IC50: “+” means ≤100 nM; “++” means >100 nM to ≤ 1 μM; and “+++” means >1 μM to ≤ 5 μM. 894 https://doi.org/10.1021/acsmedchemlett.2c00221 ACS Med. Chem. Lett. 2022, 13, 893−894  (...truncated)