6,7-Dihydro-5H-benzo[7]annulene Compounds as Selective Estrogen Receptor Degraders for Treating Cancer

Important Compound Classes

Title

Substituted 6,7-Dihydro-5H-benzo[7]annulene Compounds and Their Derivatives, Process for Their Preparation and Therapeutic Uses Thereof

Patent Publication Number

WO 2022/084298 A1

URL: https://patents.google.com/patent/WO2022084298A1/en

Publication Date

April 28, 2022

Priority Applications

EP 20306236.9 and EP 21306282.1

Priority Dates

October 19, 2020, and September 16, 2021

Inventors

Bernardelli, P.; Bianciotto, M.; El Ahmad, Y.; Halley, F.; Mougenot, P.; Petit, F.; Slowinski, F.; Terrier, C.

Assignee Company

Sanofi, France

Disease Area

Cancer

Biological Target

Estrogen receptors

Summary

The estrogen receptors (ERs) belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation, and differentiation in target tissues. ERs are found in two forms: the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ), respectively encoded by the ESR1 and ESR2 genes. ERα and ERβ are ligand-activated transcription factors which are activated by the hormone estrogen.

ERα is mainly expressed in reproductive tissues such as the uterus, ovaries, breasts, bone, and white adipose tissue. Abnormal ERα leads to cancer and metabolic, cardiovascular, and neurodegenerative diseases. ERα is expressed in 50–80% of breast tumors. The etiological role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment. Although endocrine therapies have contributed enormously to a reduction in breast cancer development, endocrine therapies display resistance. One of the new strategies to counterforce such resistance is to shut down the ERα signaling by removing ERα from the tumor cells using selective estrogen receptor degraders (SERDs).

The present application describes a series of novel substituted 6,7-dihydro-5H-benzo[7]annulene compounds as SERDs for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ and R₂ = H or D; R₃ = H, COOH or OH;

R_3′ and R_3″ = H, CH₃, OCH₃, Cl, F, or CN;

R₄ and R_4′ = H or F; R₅ = H, F, or (C₁–C₃)alkyl;

R₆ = phenyl group, wherein the phenyl group is optionally substituted by 1–3 substituents selected from halogen, (C₁–C₆)alkyl, optionally substituted with CN or OH; (C₁–C₆)fluoroalkyl, (C₃–C₆)cycloalkyl, (C₁–C₆)alkoxy, (C₁–C₆)fluoroalkoxy, trifluoromethylsulfonyl, (C₁–C₄)alkylthio, (C₁–C₄)fluoroalkylthio;

R₇ = (C₁–C₃)alkyl, halogen, CN, (C₁–C₃)fluoroalkyl;

R₈ = H or F; R₉ = H or (C₁–C₃)alkyl;

X = CH₂, O or S;

Y = −CH=, −N=, or −CR″=, where R″ = (C₁–C₃)alkyl, halogen, CN, or (C₁–C₃)fluoroalkyl;

m = 0 or 1; and n = 0, 1, or 2

Key Structures

Biological Assay

In vitro estrogen receptor degradation activity using a breast cancer cell ERα in cell Western assay was performed. The compounds described in this application were tested for their ability to degrade estrogen receptor. The estrogen receptor degradation IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds tested for estrogen receptor degradation and the biological data obtained from testing representative examples.^1,2,3,4,5,6

Claims

Total claims: 29

Compound claims: 25

Pharmaceutical composition claims: 1

Method of preparation claims: 2

Medicament claims: 1

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.