Novel Cyclic Cyanoenone Derivatives as KEAP1Modulators for Treating Neurodegenerative Diseases

Important Compound Classes

Title

Cyclic Cyanoenone Derivatives as Modulators of KEAP1

Patent Publication Number

WO 2022/013408 A2

URL: https://patents.google.com/patent/WO2022013408A2/en

Publication Date

January 20, 2022

Priority Application

EP 20186249.7

Priority Date

July 16, 2020

Inventors

Altman, M.; Candito, D. A.; Christian, A. H.; DiPietro, O.; Lu, M.; Mansoor, U. F.; Mennie, K. M.; Musacchio, A. J.; Palani, A.; Reutershan, M. H.; Shaw, D. M.; Liu, P.; St-Gallay, S.

Assignee Company

Merck Sharp & Dohme Corp., USA; and MSD R&D Innovation Centre Limited, Great Britain

Disease Area

Neurodegenerative diseases

Biological Target

KEAP1

Summary

Nuclear factor erythroid 2-related factor 2 (NRF2; gene name NFE2L2) is a basic leucine zipper (bZIP) transcription factor and a member of the Cap’n’Collar (CNC) family of transcription factors. It serves as a master regulator of the cellular response to oxidative stress. Oxidative stress occurs when cumulative damage by free radicals, generated in response to physiological stress, is no long adequately neutralized by antioxidants, leading to lipid peroxidation and cellular damage. Oxidative stress is implicated in various pathologies, including neurodegenerative disease, cardiovascular disease, cancer, and diabetes.

Under normal physiological conditions, Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic actin-bound repressor protein, maintains low levels of NRF2 by promoting its CUL3-RBX1-mediated ubiquitination and subsequent proteasomal degradation. The KEAP1/NRF2 system appears to not only trigger the mechanisms to lower the oxidative stress but also eliminate the oxidatively damaged proteins. Small molecules that promote NRF2 activation, by either blocking the NRF2-KEAP1 interaction (protein–protein inhibitors) or mimicking the oxidation of sulfhydryl groups on specific cysteines on KEAP1 (electrophile), are predicted to target multiple pathways contributing to neuronal dysfunction and loss across a broad range of neurodegenerative disorders.

The present application describes a series of novel cyclic cyanoenone derivatives as KEAP1 modulators for the treatment of neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Down’s syndrome, Friedreich’s ataxia, frontotemporal dementia, Huntington’s disease, and Parkinson’s disease. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ and R₂ = H, halogen, C_1–6alkyl, −O-C_1–6alkyl, -NR₅-C_1–6alkyl, C_3–6cycloalkyl, or 3- to 6-membered saturated or unsaturated heterocyclic ring comprising 1–3 heteroatoms selected from O, S and N, wherein S is optionally oxidized to SO or SO₂, wherein C_1–6alkyl, −O–C_1–6alkyl, and C_3–6cycloalkyl are optionally substituted with one or more halogens and wherein the heterocyclic ring is optionally substituted with one or more substituents selected from halogen, OH, C_1–6alkyl, and −O–C_1–6alkyl;

R₃ = H, C_1–6alkyl, C_3–6cycloalkyl, C_6–10aryl, or 3- to 9-membered saturated or unsaturated heterocyclic ring comprising 1–4 heteroatoms selected from O, S, and N, wherein S is optionally oxidized to SO or SO₂, wherein C_1–6alkyl, and C_3–6cycloalkyl are optionally substituted with one or more halogens, and wherein C_6–10aryl and 3- to 9-membered saturated or unsaturated heterocyclic ring are optionally substituted with 1–3 substituents R₆;

R₃ = NR₇R₈, NR₇C(O)R₈, NR₇S(O)_nR₈, CONR₉R₁₀, S(O)_nNR₉R₁₀, C_6–10aryl, or 3- to 9-membered saturated or unsaturated heterocyclic ring comprising 1–4 heteroatoms selected from O, S, and N, wherein S is optionally oxidized to SO or SO₂, and wherein C_6–10aryl and 3- to 9-membered saturated or unsaturated heterocyclic ring are optionally substituted with 1–3 substituents R₁₁; and

m = 0, 1, or 2.

Key Structures

Biological Assay

The PathHunter U2OS KEAP1-NRF2 Nuclear Translocation Cellular assay was performed. The compounds described in this application were tested for their ability to inhibit KEAP1. The KEAP1 EC₅₀ (nM) are shown in the table below.

Biological Data

The following table shows representative compounds tested for KEAP1 inhibition. The biological data obtained from testing the representative examples are also listed in the table.

Claims

Total claims: 15

Compound claims: 14

Pharmaceutical composition claims: 1

The author declares no competing financial interest.