WO2025237355A1 - Composé agoniste du récepteur glp-1, son procédé de préparation et son utilisation - Google Patents

Composé agoniste du récepteur glp-1, son procédé de préparation et son utilisation

Info

Publication number
WO2025237355A1
WO2025237355A1 PCT/CN2025/095000 CN2025095000W WO2025237355A1 WO 2025237355 A1 WO2025237355 A1 WO 2025237355A1 CN 2025095000 W CN2025095000 W CN 2025095000W WO 2025237355 A1 WO2025237355 A1 WO 2025237355A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
diabetes
pharmaceutically acceptable
preparation
type
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/095000
Other languages
English (en)
Chinese (zh)
Inventor
董光新
何鹏
于舟
邓塔
张锐
叶启军
张勇
张绍锋
张萧洁
李文雯
李海燕
黄沛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Diao Jiuhong Pharmaceutical Factory
Original Assignee
Chengdu Diao Jiuhong Pharmaceutical Factory
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Diao Jiuhong Pharmaceutical Factory filed Critical Chengdu Diao Jiuhong Pharmaceutical Factory
Publication of WO2025237355A1 publication Critical patent/WO2025237355A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention belongs to the field of pharmaceutical chemistry, specifically relating to a GLP-1 receptor agonist compound, its preparation method, and its application.
  • Glucagon-like peptide-1 is a peptide hormone secreted by L cells of the intestinal epithelium, widely distributed in the pancreas, stomach, small intestinal mucosa, and the heart, lungs, and central nervous system.
  • GLP-1R GLP-1 receptor
  • GLP-1 activates the intracellular cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathways, thereby exerting various effects, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting pancreatic ⁇ -cell apoptosis, delaying gastric emptying, and suppressing appetite.
  • cAMP cyclic adenosine monophosphate
  • MAPK mitogen-activated protein kinase
  • GLP-1 analogs have shown efficacy in reducing HbA1c and weight loss and have been developed as effective therapeutic agents for diabetes and obesity. GLP-1 analogs have also demonstrated efficacy in improving cardiovascular outcomes and preserving renal function in patients with diabetes, thus providing therapeutic opportunities for various metabolic disorders and related comorbidities.
  • GLP-1 receptor agonists are peptide drugs with extremely poor oral bioavailability, requiring injection administration. Examples include liraglutide, telposide, and dulaglutide. To date, no small-molecule GLP-1 receptor agonists have been approved for the treatment of diabetes or other metabolic disorders. Therefore, there is a high expectation for oral small-molecule GLP-1 receptor agonists with good efficacy.
  • the object of this invention includes providing a compound or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.
  • Another object of the present invention includes providing a pharmaceutical composition comprising any of the above-described compounds or their pharmaceutically acceptable salts, stereoisomers, solvates or hydrates, and pharmaceutically acceptable excipients.
  • Another object of the present invention includes providing a pharmaceutical formulation comprising any of the above-described compounds or their pharmaceutically acceptable salts, stereoisomers, solvates or hydrates, and pharmaceutically acceptable excipients.
  • Another object of the present invention includes providing the use of the above-described compound or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or the pharmaceutical composition or pharmaceutical formulation thereof, in the preparation of a GLP-1 receptor agonist drug.
  • Another object of the invention also includes the use of the above-described compounds or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof, or the pharmaceutical compositions or formulations thereof, in the treatment and/or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance and/or hepatic insulin resistance; preferably in the preparation of medicaments for the treatment and/or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease and/or dyslipidemia.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non
  • a compound or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof is provided, the compound being:
  • a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, one or more GLP-1 receptor agonists, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical formulation comprising the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, and one or more pharmaceutically acceptable excipients.
  • the formulations described herein are solid or liquid formulations.
  • a compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition or formulation described herein is provided for use as a medicine (i.e. for therapeutic purposes).
  • the use of the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or the pharmaceutical composition or formulation described herein, or the pharmaceutical preparation described herein, in the preparation of a GLP-1 receptor agonist drug is provided.
  • the GLP-1 receptor agonist is used to treat and/or prevent type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and/or hepatic insulin resistance; preferably for the treatment and/or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, and/or dyslipidemia.
  • type 1 diabetes type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NAS
  • use is provided in the preparation of a compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, or a pharmaceutical composition described herein, or a pharmaceutical formulation described herein, for the treatment and/or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and/or hepatic insulin resistance; preferably in the preparation of a medicament for the treatment and/or prevention of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, and/or dyslipidemia.
  • NAFLD non-alcoholic fatty
  • the type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, glucose intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and/or hepatic insulin resistance are associated with abnormal GLP-1 receptor activity.
  • a method for treating and/or preventing type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, dyslipidemia, cerebral infarction, stroke, Parkinson's disease, dementia, insulin resistance, and/or hepatic insulin resistance, comprising administering to a patient in need a therapeutically effective dose of the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, or the pharmaceutical composition described herein, or the pharmaceutical formulation described herein; the method is preferably a method for treating and/or preventing type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, metabolic syndrome, hyperglycemia, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cardiovascular disease, and/or dys
  • the use of the compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or the pharmaceutical composition or formulation described herein, or in the preparation of a GLP-1 receptor agonist is also provided.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared by combining a compound having specific substituents discovered in this invention with a pharmaceutically acceptable acid or base.
  • stereoisomer refers to compounds having the same chemical composition but different spatial arrangements of atoms and groups, including enantiomers, diastereomers, geometric isomers, transisomers, or conformational isomers.
  • racemate refers to a mixture of two equimolar enantiomers that lack optical activity, as well as mixtures thereof, such as racemic mixtures.
  • solvent as used in this invention describes a molecular complex comprising a compound having any of the above chemical formulas or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • solvent e.g., ethanol
  • hydrate is used.
  • composition refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component (i.e., excipient).
  • pharmaceutically acceptable chemical component includes, but is not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, humectants, osmotic pressure regulators, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, encapsulating agents, humectants, absorbents, flocculants and anti-flocculation agents, filter aids
  • patient refers to an animal, including human patients requiring treatment.
  • this invention can also be applied in veterinary practice to any mammal or other animal requiring such immune-targeted therapy, including but not limited to non-human primates, dogs, felines, pigs, horses, and any other animals.
  • treatment and other similar synonyms include relieving, reducing, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing underlying metabolic causes of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; improving a disease or condition; relieving symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition.
  • the term includes preventative purposes. The term also includes achieving therapeutic and/or preventative effects.
  • the compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds.
  • the compounds may be radiolabeled with radioactive isotopes such as deuterium (D), tritium ( 3H ), iodine-125 ( 125I ), or carbon-14 ( 14C ). All isotopic variations of the compounds of the present invention, whether radioactive or not, are covered within the scope of the present invention.
  • Compound 1 of the present invention has a good agonistic effect on GLP-1 receptor, and the agonistic effect is better than that of comparative compound LY3502970 and comparative compound DB01.
  • Compound 1 of the present invention has better oral absorption, higher exposure and Cmax, and its pharmacokinetic properties are significantly better than those of comparative compounds LY3502970 and DB01.
  • Figure 1 shows the blood glucose concentration curves of compound 1 of the present invention, comparative compound DB01, and solvent.
  • Figure 2 shows the blood glucose AUC (0-120 min) of compound 1 of the present invention, comparative compound DB01, and solvent.
  • reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL ⁇ 2), and the organic phases were combined.
  • Compound LY3502970 is compound 67 in patent CN 109790161B, and was prepared according to the method of that patent.
  • Compound DB01 is compound I-4 from patent CN 116003403A, prepared according to the method described in that patent application. MS m/z (ESI): 886.5 (M+H) + .
  • Log-grown GLP1R/CRE-LUC/HEK293 cells (purchased from Nanjing Kebai) were digested and resuspended in DMEM + 10% FBS medium, with the cell density adjusted to 3.5 ⁇ 105 /mL. 100 ⁇ L/well was added to a 96-well cell culture plate, and the plate was incubated overnight (37°C, 5% CO2 ).
  • the compound was dissolved in DMSO to prepare a stock solution with an initial concentration of 10 mM. This stock solution was then serially diluted 5-fold with DMSO and further diluted with complete culture medium to prepare working solutions of 20000, 4000, 800, 160, 32, 6.4, 1.28, 0.26, 0.05, and 0 nM, with a final DMSO concentration of 0.1%. 11 ⁇ L of the working solution was added to each well of a cell culture plate, with two replicates per well for each concentration. This resulted in final compound concentrations of 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.026, 0.005, and 0 nM. The culture plates were then incubated for 6 hours (37°C, 5% CO2 ).
  • Compound 1 of the present invention has a good agonistic effect on GLP-1 receptor, and the agonistic effect is better than that of comparative compound LY3502970 and comparative compound DB01.
  • the blood samples were placed in centrifuge tubes containing EDTA-K2 anticoagulant and centrifuged at 3000-4000 rpm for 10 min.
  • the supernatant plasma was transferred to another clean centrifuge tube, and the plasma drug concentration was detected using LC-MS/MS.
  • Pharmacokinetic parameters were calculated using a non-compartmental model. The results are shown in Table 2.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé ayant une activité agoniste du récepteur GLP-1 et un sel, un stéréoisomère, un solvate ou un hydrate pharmaceutiquement acceptable du composé, son procédé de préparation et son utilisation. Le composé peut être utilisé pour préparer un agoniste du récepteur GLP-1, et peut être utilisé pour préparer un médicament destiné au traitement et/ou à la prévention de maladies métaboliques.
PCT/CN2025/095000 2024-05-17 2025-05-15 Composé agoniste du récepteur glp-1, son procédé de préparation et son utilisation Pending WO2025237355A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410615927.X 2024-05-17
CN202410615927 2024-05-17

Publications (1)

Publication Number Publication Date
WO2025237355A1 true WO2025237355A1 (fr) 2025-11-20

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PCT/CN2025/095000 Pending WO2025237355A1 (fr) 2024-05-17 2025-05-15 Composé agoniste du récepteur glp-1, son procédé de préparation et son utilisation

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WO (1) WO2025237355A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109790161A (zh) * 2016-09-26 2019-05-21 中外制药株式会社 具有glp-1受体激动剂作用的吡唑并吡啶衍生物
CN115698003A (zh) * 2020-02-07 2023-02-03 加舒布鲁姆生物公司 杂环glp-1激动剂
CN116003403A (zh) * 2022-11-20 2023-04-25 药康众拓(北京)医药科技有限公司 一种氘代吲唑类化合物、药物组合物及其应用
CN116390926A (zh) * 2020-07-20 2023-07-04 上海诚益生物科技有限公司 四氢吡唑并-吡嗪基-二氢咪唑酮或四氢吡唑并-吡啶基-二氢咪唑酮化合物及其使用方法
CN117447493A (zh) * 2023-12-25 2024-01-26 药康众拓(北京)医药科技有限公司 氘代吲哚嗪类化合物、药物组合物及其应用
WO2024153070A1 (fr) * 2023-01-17 2024-07-25 Fochon Biosciences, Ltd. Agonistes de glp-1 r et leurs utilisations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109790161A (zh) * 2016-09-26 2019-05-21 中外制药株式会社 具有glp-1受体激动剂作用的吡唑并吡啶衍生物
CN115698003A (zh) * 2020-02-07 2023-02-03 加舒布鲁姆生物公司 杂环glp-1激动剂
CN116390926A (zh) * 2020-07-20 2023-07-04 上海诚益生物科技有限公司 四氢吡唑并-吡嗪基-二氢咪唑酮或四氢吡唑并-吡啶基-二氢咪唑酮化合物及其使用方法
CN116003403A (zh) * 2022-11-20 2023-04-25 药康众拓(北京)医药科技有限公司 一种氘代吲唑类化合物、药物组合物及其应用
WO2024153070A1 (fr) * 2023-01-17 2024-07-25 Fochon Biosciences, Ltd. Agonistes de glp-1 r et leurs utilisations
CN117447493A (zh) * 2023-12-25 2024-01-26 药康众拓(北京)医药科技有限公司 氘代吲哚嗪类化合物、药物组合物及其应用

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