Search

CN-122003402-A - Imidazolyl and dinitrophenyl derivatives and uses thereof

CN122003402ACN 122003402 ACN122003402 ACN 122003402ACN-122003402-A

Abstract

The present invention relates to compounds of formula (I) or (II), stereoisomers thereof, deuterated derivatives thereof, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives, and pharmaceutical compositions thereof, and uses thereof. Formula (I) and formula (II).

Inventors

  • DENG XIAOBING
  • SU YANING
  • TIAN WENJIA
  • CHEN HUILING
  • WANG YANHONG
  • CAO SHUO
  • DONG JINGYING
  • ZHOU YISUI

Assignees

  • 北京双鹤润创科技有限公司

Dates

Publication Date
20260508
Application Date
20240510
Priority Date
20231120

Claims (7)

  1. 1. The following compounds, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: 、 、 Or (b) 。
  2. 2. The following compounds, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: 。
  3. 3. The following compounds, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts of the stereoisomers, or pharmaceutically acceptable salts of the deuterated derivatives: 。
  4. 4. A pharmaceutical composition comprising a compound of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, and at least one pharmaceutically acceptable excipient.
  5. 5. A method of treating a subject suffering from a mitochondrial related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, or the pharmaceutical composition of claim 4, wherein the disease is obesity, excessive body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes (T2 DM), dyslipidemia, cardiovascular disease, heart disease, or atherosclerosis.
  6. 6. The compound according to any one of claims 1 to 3, its deuterated derivative, its stereoisomer, its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 4 for use in the manufacture of a medicament for the treatment of a mitochondrial related disease or disorder, wherein the disease is obesity, hyperlipidemia, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes (T2 DM), dyslipidemia, cardiovascular disease, heart disease or atherosclerosis.
  7. 7. The compound of any one of claims 1 to 3, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the deuterated derivative, or the pharmaceutical composition of claim 4 for use in treating a mitochondrial related disease or disorder, wherein the disease is obesity, hyperlipidemia, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes (T2 DM), dyslipidemia, cardiovascular disease, heart disease, or atherosclerosis.

Description

Imidazolyl and dinitrophenyl derivatives and uses thereof Cross Reference to Related Applications The present application claims priority from international patent application PCT/CN2023/132521 filed on 11/20 of 2023, which is incorporated herein by reference in its entirety. Technical Field The present invention relates to compounds useful for modulating mitochondrial activity, reducing obesity, treating diseases including diabetes and diabetes-related complications, compositions comprising the compounds, and methods of using the compounds. Background Obesity has become a global epidemic and more than 6 million people are affected worldwide. Obesity is often associated with numerous metabolic disorders and diseases, such as insulin resistance, type 2 diabetes, and cardiovascular disease. Mitochondria play a vital role in energy metabolism, while impaired mitochondrial function is associated with obesity. Mitochondrial uncoupling agents are compounds capable of dissipating the proton gradient of the mitochondrial inner membrane, which can lead to inefficient ATP production. This decoupling may lead to increased mitochondrial respiration, which may reduce the energy stored in the form of fat, resulting in weight loss. The mechanism of action of mitochondrial uncoupling agents in terms of energy expenditure makes them attractive targets for developing obesity therapies. Various mitochondrial uncoupling agents have been identified and studied for their potential therapeutic efficacy in the treatment of obesity. One of the most well known decoupling agents is 2, 4-Dinitrophenol (DNP), which has been used in the past for weight loss but has been disabled later due to its toxicity. However, newer mitochondrial uncoupling agents have been developed, including carbonyl cyanide-4- (trifluoromethoxy) phenylhydrazone (FCCP) and 2,3, 5-triiodo-L-thyronine (T3), which show promising results in preclinical studies. Although studies have shown that mitochondrial uncoupling agents have potential efficacy in treating obesity, there are concerns about their safety and potential side effects. The development of safe and effective mitochondrial uncoupling agents for the treatment of obesity remains a popular research area. Disclosure of Invention The following disclosure is provided herein: [1] a compound of formula (I) or formula (II), a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a deuterated derivative thereof: Formula (I) formula (II) R 1 is independently at each occurrence selected from hydrogen, deuterium, -C 1-6 alkyl, halogenated C 1-6 alkyl or-C 1-6 alkoxy, -C 1-6 alkyl, Halogenated C 1-6 alkyl or-C 1-6 alkoxy optionally substituted with one or more R 11 groups, said R 11 being selected from deuterium, Halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogenated C 1-6 alkyl, -C 1-6 alkoxy, -CN, -COOH, -NH 2、-NH(C1-6 alkyl), -N (C 1-6 alkyl) 2、-OH、-O(C1-6 alkyl), -SH, -S (C 1-6 alkyl), -C (=o) (C 1-6 alkyl), -S (=o) (C 1-6 alkyl), -S (=o) 2(C1-6 alkyl), -C (=o) NH 2、-C(=O)NH(C1-6 alkyl), -C (=o) N (C 1-6 alkyl) 2、-NHC(=O)(C1-6 alkyl), -N (C 1-6 alkyl) C (=o) (C 1-6 alkyl), -C (=o) O (C 1-6 alkyl), -O-C (=o) (C 1-6 alkyl), -S (=o) NH 2、-S(=O)NH(C1-6 alkyl), -S (=o) N (C 1-6 alkyl) 2、-NHS(=O)(C1-6 alkyl), -N (C 1-6 alkyl) S (=o) (C 1-6 alkyl), -S (=o) 2NH2、-S(=O)2NH(C1-6 alkyl), -S (=o) 2N(C1-6 alkyl) 2, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein R 11 is optionally substituted with one or more deuterium; R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -halogenated C 1-3 alkyl, -C 2-3 alkoxy, -CN, -COOH, -NH 2、-NH(C1-3 alkyl), -N (C 1-3 alkyl) 2、-OH、-O(C1-3 alkyl), -SH, -S (C 1-3 alkyl), -C (=o) (C 1-6 alkyl), and, -S (=o) (C 1-6 alkyl), -S (=o) 2(C1-6 alkyl), -C (=o) NH 2、-C(=O)NH(C1-3 alkyl), -C (=o) N (C 1-3 alkyl) 2、-NHC(=O)(C1-3 alkyl, -N (C 1-3 alkyl) C (=o) (C 1-3 alkyl), -C (=o) O (C 1-3 alkyl), -O-C (=o) (C 1-3 alkyl), -S (=o) NH 2、-S(=O)NH(C1-3 alkyl), -S (=o) N (C 1-3 alkyl) 2、-NHS(=O)(C1-3 alkyl), -N (C 1-3 alkyl) S (=o) (C 1-3 alkyl), -S (=o) 2NH2、-S(=O)2NH(C1-3 alkyl), -S (=o) 2N(C1-3 alkyl) 2、-NHS(=O)2(C1-3 alkyl), -N (C 1-3 alkyl) S (=o) 2(C1-3 alkyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said-C 1-3 alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -haloC 1-3 alkyl, -C 2-3 alkoxy, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl each independently optionally substituted with one or more substituents selected from deuterium, halogen, halogenated C 1-3 alkyl, -CN, -NH 2、-C1-3 alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -halogenated C 1-3 alkyl, -C 2-3 alkoxy, -CN, -COOH, -NH 2、-NH(C1-3 alkyl), -N (C 1-3 a