JP-7857042-B2 - Novel aryl ether-substituted heterocyclic compounds as GLP1R agonists

Inventors

• 張龍
• ニュ，ザンミン
• 唐博文

Assignees

• 杭州徳睿智薬科技有限公司

Dates

Publication Date

20260512

Application Date

20220131

Priority Date

20210830

Claims (11)

1. A compound selected from compounds having the following structure .
2. A compound having the following structure, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, which has the following structure.
4. The compound according to claim 2, which is a pharmaceutically acceptable salt of a compound having the following structure.
5. A compound having the following structure, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5, which has the following structure.
7. The compound according to claim 5, which is a pharmaceutically acceptable salt of a compound having the following structure.
8. A pharmaceutical composition comprising at least one of the compounds described in any one of claims 1 to 7 in a therapeutically effective amount.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the production of a drug for the treatment of a disease related to the GLP1/GLP1R signaling pathway selected from overweight, obesity, diabetes, insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, eating disorders, weight gain due to the use of other drugs, hyperglycemia, dyslipidemia , NAFLD, cardiovascular disease, atherosclerosis, and peripheral vascular disease .
10. The use according to claim 9 , wherein the disease related to the GLP1/GLP1R signaling pathway is overweight or obesity.
11. The aforementioned diabetes is selected from T1D, T2DM, prediabetes, adult latent autoimmune diabetes, juvenile atypical diabetes (YOAD), young-onset adult-onset diabetes (MODY), diabetes associated with malnutrition, and gestational diabetes. The aforementioned lipid abnormalities are selected from hyperlipidemia, hypertriglyceridemia, and increased total cholesterol, or The use according to claim 9, wherein the NAFLD is selected from fatty degeneration, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.

Description

Detailed description of the invention This application claims priority to the prior applications filed with the China National Intellectual Property Administration on August 30, 2021, patent application number 202111017657.5, titled "Novel Aryl Ether-Substituted Heterocyclic Compounds as GLP1R Agonists," and filed with the China National Intellectual Property Administration on September 29, 2021, patent application number 202111168512.5, titled "Novel Aryl Ether-Substituted Heterocyclic Compounds as GLP1R Agonists." The entire text of these prior applications is incorporated herein by reference. [Technical Field] The present invention belongs to the field of medicinal chemistry and specifically includes a novel aryl ether-substituted heterocyclic compound having GLP1R agonist activity, a composition containing the compound, and a method of applying the compound to the manufacture of a drug for treating or preventing a disease related to GLP1/GLP1R. [Background technology] As material living standards rise, overweight and obesity are becoming more common in modern society. The population of patients with obesity-related complications such as diabetes and fatty liver disease is steadily increasing. According to reports and projections issued by the World Health Organization (WHO) and Chiken Consulting, by 2030 there will be 3.26 billion obese people worldwide, by 2029 there will be over 500 million people with diabetes worldwide, and over 1.5 billion people with non-alcoholic fatty liver disease worldwide. Currently, there are no effective treatments for fatty liver disease, and only six obesity treatments have been approved by the FDA, many of which are regulated drugs with weak therapeutic effects and significant side effects. While several drugs for treating type 2 diabetes are already on the market, the adherence rate to current blood glucose-lowering drugs (<7%) is not very high, and even the most active combination drugs have an adherence rate of only about 45%. Therefore, regardless of whether it is fatty liver disease, obesity, or diabetes, the development of new drugs is necessary to meet the needs of a wider range of patients. Glucagon-like peptide-1 (GLP-1) is a long-peptide hormone containing 30 or 31 amino acids. It is produced and secreted by enteroendocrine L cells and several nerve cells in the nucleus tractus solitarius of the brainstem during feeding. GLP-1 physiologically and glucose-dependently stimulates insulin secretion, reduces glucagon secretion, suppresses gastric emptying, decreases appetite, and stimulates β-cell proliferation. In non-clinical studies, GLP-1 stimulates the transcription of key genes for glucose-dependent insulin secretion and promotes β-cell regeneration, thereby enhancing the sustained capacity of β-cells (Meier, et al. Biodrugs. 2003; 17(2): 93-102). The GLP1 receptor is an ideal target proven useful in the treatment of metabolic diseases such as obesity, diabetes, and fatty liver, and several GLP1R agonist polypeptide drugs, such as dulaglutide and semaglutide, are already commercially available overseas for the treatment of diabetes and obesity. However, these polypeptides require injection, have low patient compliance, are expensive, have poor accessibility, place a heavy burden on healthcare providers, require refrigeration, are inconvenient to transport and store, and are difficult to combine with existing oral small molecule drugs for diseases with complex etiologies, such as non-alcoholic fatty liver disease, which require treatment with multiple drugs. Therefore, the development of small molecule oral GLP1R agonists is urgently needed. Currently, there are several publications and patent reports concerning oral small molecule GLP1 agonists. For example, Pfizer's PF-06882961 can achieve efficacy similar to, or even better than, GLP1 polypeptides (https://doi.org/10.1101/2020.09.29.319483). While its therapeutic efficacy and safety have been preliminaryly validated, PF-06882961 suffers from significant shortcomings in drug potential, including low oral absorption, extremely low bioavailability, a somewhat high clinical dose, high cost and gastrointestinal burden on patients, and the inability to achieve further improvements in blood glucose reduction and weight loss by further increasing the dose. Therefore, there is a need to develop new small molecule GLP1 agonists with superior drug potential to meet the needs of a wider range of patients. [Effects of the invention] The inventors have unexpectedly discovered that some of the novel aryl ether-substituted heterocyclic compounds of the structure of formula (I) of the present invention not only possess remarkable GLP1R agonist activity, but also exhibit superior pharmacokinetic properties (including a longer T1/2 and higher exposure) and bioavailability compared to the structurally known reference compound PF-06882961. They are expected to exhibit even better human PK properties and are therefore even more s