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US-20260124197-A1 - NOVEL HETEROBICYCLIC COMPOUND FOR INHIBITING YAP-TEAD INTERACTION AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

US20260124197A1US 20260124197 A1US20260124197 A1US 20260124197A1US-20260124197-A1

Abstract

Provided are a compound, selected from compounds of Formula 1, enantiomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof, methods of preparing the same, and use thereof.

Inventors

  • Ji Sook Kim
  • Joo Yun BYUN
  • Kwee Hyun Suh
  • Young Gil Ahn
  • Ji Hee YOON
  • Young Kyo JEON
  • Seung Hyun Jung
  • Seon Yeong HAN

Assignees

  • HANMI PHARM. CO., LTD.

Dates

Publication Date
20260507
Application Date
20231012
Priority Date
20221013

Claims (14)

  1. 1 . A compound selected from compounds of Formula 1 below, enantiomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof: wherein, in Formula 1 above, R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 carbocyclyl, or haloC 1-6 alkyl; R 3 is hydrogen, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, or cyano; {circle around (A)} is carbocyclyl or heterocyclyl; {circle around (B)} is C 6-10 aryl or C 4-10 heteroaryl; L 1 is absent, bonded, or C 1-3 alkylene, or C 1-3 alkylene substituted with a halogen; each R 4 and each R 5 are independently hydrogen, halogen, cyano, amino, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, haloC 1-6 alkoxy, mono-(C 1-3 alkyl)-substituted carbamoyl (—(CO)—NH(C 1-3 alkyl)), di-(C 1-3 alkyl)-substituted carbamoyl (—(CO)—N(C 1-3 alkyl) 2), C 1-3 alkylsulfinyl (—(SO)—(C 1-3 alkyl)), C 1-3 alkylsulfonyl (—SO 2 —(C 1-3 alkyl)), substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 2-6 heterocyclyl, substituted or unsubstituted C 4-10 heteroaryl; X and Y are each independently —C— or —N—; and m and n are each independently an integer from 0 to 3.
  2. 2 . The compound of claim 1 , wherein {circle around (A)} is C 6-10 aryl, C 1-10 heteroaryl, C 6-14 fused heteroaryl, or C 2-6 heterocyclyl, wherein C 1-10 heteroaryl, C 6-14 fused heteroaryl, or C 2-6 heterocyclyl comprises 1 to 4 heteroatoms each independently selected from N, O, and S.
  3. 3 . The compound of claim 1 , wherein {circle around (A)} is a phenyl group, a pyridinyl group, a pyrazinyl group, a pyrazolyl group, an imidazolyl group, a thiophenyl group, a furanyl group, an oxazole group, an azetidinyl group, or
  4. 4 . The compound of claim 1 , wherein {circle around (B)} is a phenyl group or a pyridinyl group.
  5. 5 . The compound of claim 1 , wherein R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or haloC 1-6 alkyl.
  6. 6 . The compound of claim 1 , wherein L 1 is a bond; each of R 4 and each of R 5 are each independently hydrogen, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, haloC 1-6 alkoxy, mono-(C 1-3 alkyl)-substituted carbamoyl (—(CO)—NH(C 1-3 alkyl)), di-(C 1-3 alkyl)-substituted carbamoyl (—(CO)—N(C 1-3 alkyl) 2 ), C 1-3 alkylsulfonyl (—SO 2 —(C 1-3 alkyl)), substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 2-6 heterocycloalkyl.
  7. 7 . The compound of claim 1 , wherein L 1 is C 1-3 alkylene; each of R 4 and each of R 5 are each independently hydrogen, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, di-(C 1-3 alkyl)-substituted carbamoyl (—(CO)—N(C 1-3 alkyl) 2 ), C 1-3 alkylsulfonyl (—SO 2 —(C 1-3 alkyl)), substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 2-6 heterocycloalkyl.
  8. 8 . The compound of claim 1 , wherein R 5 is each hydrogen, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-6 cycloalkyl, or phenyl, or C 3-6 cycloalkyl or phenyl substituted with any one or more substituents selected from halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkoxy.
  9. 9 . The compound of claim 1 , wherein R 5 is each hydrogen, halogen, cyano, methyl, ethyl, propyl, 1-butyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.
  10. 10 . The compound of claim 1 , wherein the compound is selected from the following compounds, enantiomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof: N-methyl-3-(3-methylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-pyrazol-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-indole-5-sulfonamide; 3-(1-isopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-ethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-ethyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-sulfonamide; 3-(2-fluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-chlorophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N-methyl-3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-cyclobutyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-cyclohexylphenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N,N-dimethyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(3-fluoropyridin-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 1-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 3-(furan-3-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(5-methylfuran-2-yl)-1-phenyl-1H-indole-5-sulfonamide; 3-(2,3-difluorophenyl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-indole-5-sulfonamide; 1-(3-chloro-4-(trifluoromethyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-(2-fluorobenzyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(furan-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(2-methyloxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide; N-methyl-3-(5-(trifluoromethyl) furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-(oxetan-3-yl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(5-chlorofuran-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-(2-methoxyethyl)-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-(p-tolyl)-1H-indole-5-sulfonamide; 1-(4-(t-butyl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-1H-indole-5-sulfonamide; N-methyl-3-(oxazol-5-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methyl-1H-indole-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-sulfonamide; 3-(1-cyclopropyl-1H-imidazol-4-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indazol-5-sulfonamide; 3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; 3-(3-fluoroazetidin-1-yl)-N-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide; N,N-dimethyl-2-(4-(5-(N-methylsulfamoyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)-1H-imidazole-1-yl) acetamide; and N-methyl-3-(1-(2-(methylsulfonyl)ethyl)-1H-imidazol-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-sulfonamide.
  11. 11 . A method for treating or preventing a disease caused by transcriptional enhancer associate domain (TEAD) activation in a subject, the method comprising administering to the subject a pharmaceutical composition comprising, as an active ingredient, the compound of claim 1 .
  12. 12 . The method of claim 11 , wherein the pharmaceutical composition inhibits Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.
  13. 13 . The method of claim 11 , wherein the disease is a cancer or tumor.
  14. 14 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable additive.

Description

TECHNICAL FIELD The present disclosure relates to a pharmaceutical composition including a heterobicyclic compound that inhibits Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding, wherein the compound according to the present disclosure may directly inhibit YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer. BACKGROUND ART A Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. YAP and tafazzin (TAZ) are transcriptional co-activators of a Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inactivation of a Hippo signaling pathway promotes YAP/TAZ translocation to a nucleus, where YAP/TAZ interacts with transcriptional enhancer associate domain (TEAD) transcription factors and co-activates an expression of target genes and promotes cell proliferation. Target genes such as connective tissue growth factor (CTGF) and Cyr61, AXL receptor tyrosine kinase, and MYC, which are strongly correlated with tumor development, are regulated by TEAD. TEAD has also been shown to be overexpressed in breast cancer stem cells and breast cancer, ovarian cancer, germ cell tumor, renal cell carcinoma, medulloblastoma, and gastric cancer, etc. Overactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been associated with numerous cancers. In addition, recent studies have reported that resistance to EGFR tyrosine kinase inhibitors Tarceva (erlotinib), Iressa (gefitinib) or Tagrisso (osimertinib) is associated with YAP overexpression or amplification along with epithelial-mesenchymal transition (EMT) phenotypic changes. The inventors of the present disclosure have completed the present disclosure by developing a novel heterobicyclic compound for the inhibition of YAP-TEAD protein interactions. PRIOR ARTS Patent Documents (Patent Document 1) International Publication No. WO2019/040380(Patent Document 2) International Publication No. WO2020/243415 Non-Patent Documents (Non-patent Document 1) Semin. Cancer Biol. 2022, 85, 33(Non-patent Document 2) Nat. Rev. Drug Discov. 2014, 13 (1), 63(Non-patent Document 3) Cancer Res. 2011, 71 (3), 873(Non-patent Document 4) J. Cell Mol. Med. 2017, 21 (11), 2663(Non-patent Document 5) Cancer Cell 2020, 37, 104(Non-patent Document 6) Cells 2021, 10, 2715(Non-patent Document 7) Genes Cancer 2017, 8 (3-4), 497 DISCLOSURE OF INVENTION Technical Problem An objective of the present disclosure is to provide a novel heterobicyclic compound with high inhibitory activity against YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer. Another objective of the present disclosure is to provide a pharmaceutical composition including the aforementioned compound as an active ingredient for treating or preventing dysregulation of the Hippo signaling pathway, specifically related diseases caused by TEAD activation. Other objectives and advantages of the present application will become apparent from the following detailed description in conjunction with the appended claims. Anything not set forth herein may be readily recognized and inferred by one of ordinary skill in the art of the present application or a similar art and is hereby omitted. Solution to Problem According to an embodiment of the present disclosure, provided is a compound selected from compounds of Formula 1 below, enantiomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable salts thereof. According to an embodiment of the present disclosure, provided is a pharmaceutical composition for treating or preventing dysregulation of the Hippo signaling pathway, specifically related diseases caused by TEAD activation, the pharmaceutical composition including, as an active ingredient, the compound selected from the compounds of Formula 1, the enantiomers, diastereomers, solvates and hydrates thereof, and the pharmaceutically acceptable salts thereof. Advantageous Effects of Invention A novel heterobicyclic compound that has a structure of Formula 1 of the present disclosure has excellent inhibitory activity against YAP-TEAD binding, and may be useful as a therapeutic agent for a number of diseases involving the Hippo pathway, which plays a key role in the development of cancer. MODE FOR THE INVENTION The following describes the present disclosure in more detail. All technical terms used in the present disclosure, unless otherwise defined, are used as commonly understood by one of ordinary skill in the relevant field of the present disclosure. In addition, while suitable methods or samples are described herein, similar or equivalent methods are also included within the scope of the present disclosure. According to an embodiment of the present disclosure, provided is a compound selected from compounds of Formula 1 below, enantiomers, diastereomers, solvates and hydrates thereof, and pharmaceutically acceptable s