WO2021254470A1 - Dérivé de 6-oxo-3,6-dihydropyridine, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé de 6-oxo-3,6-dihydropyridine, son procédé de préparation et son utilisation en médecine Download PDF

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WO2021254470A1
WO2021254470A1 PCT/CN2021/100799 CN2021100799W WO2021254470A1 WO 2021254470 A1 WO2021254470 A1 WO 2021254470A1 CN 2021100799 W CN2021100799 W CN 2021100799W WO 2021254470 A1 WO2021254470 A1 WO 2021254470A1
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group
general formula
alkyl
cycloalkyl
pharmaceutically acceptable
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PCT/CN2021/100799
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Chinese (zh)
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杨方龙
瞿健
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202180040987.8A priority Critical patent/CN115916772A/zh
Publication of WO2021254470A1 publication Critical patent/WO2021254470A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a 6-oxo-3,6-dihydropyridine derivative, a preparation method thereof, and application in medicine.
  • the present disclosure relates to 6-oxo-3,6-dihydropyridine derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as GLP-1 receptors.
  • Use of body agonists in the treatment of diabetes is a 6-oxo-3,6-dihydropyridine derivatives represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as GLP-1 receptors.
  • Diabetes mellitus is a multi-cause metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of sugar, lipid and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very ancient disease. It is caused by the absolute or relative lack of insulin in the human body. The blood glucose concentration increases, and then a large amount of sugar is excreted from the urine, and symptoms such as polydipsia, polyuria, polyphagia and weight loss appear. .
  • Type II diabetes that is, insulin-independent diabetic patients
  • Type II diabetic patients that is, insulin-independent diabetic patients
  • these patients are resistant to insulin, which stimulates glucose and lipid metabolism in the main insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even if the plasma insulin level increases, the patient’s significant resistance to insulin cannot be overcome.
  • Insulin resistance is not only caused by the decrease in the number of insulin receptors, but also insulin receptor defects. So far, this mechanism has not been fully understood. Insulin-responsive resistance results in the inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, and cannot effectively inhibit the lipolysis of adipose tissue and the production and secretion of liver glucose.
  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower digestive tract. GLP-1 plays a corresponding role by binding to its widespread specific receptors. At present, it is clear that the organs where GLP-1 receptors exist are pancreatic islet cells, gastrointestinal, lung, brain, kidney, hypothalamus and cardiovascular system, liver There may be GLP-1 receptors in adipose tissue and skeletal muscle. GLP-1 not only acts on ⁇ cells to promote insulin secretion, but also acts on ⁇ cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes.
  • the response of ⁇ cells to GLP-1 is defective after eating. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Since the human body's own GLP-1 has a very short duration of action (intravenous injection t1/2 ⁇ 1.5 minutes), the human body's own GLP-1 is not suitable for the clinical treatment of diabetes.
  • Peptide GLP-1 receptor agonists can reduce fasting and postprandial glucose and improve blood sugar in type II diabetes patients.
  • Peptide GLP-1 receptor agonists such as liraglutide, exenatide, etc.
  • Peptide GLP-1 receptor agonists can reduce fasting and postprandial glucose and improve blood sugar in type II diabetes patients.
  • the peptide GLP-1 has poor oral bioavailability and inconvenient administration, it is highly desirable to develop small molecule GLP-1 receptor agonists with good oral bioavailability.
  • GLP-1 receptor small molecule agonists include WO2009111700A2, WO2010114824A1, WO2018109607A1, WO2019239319A1 and WO2018056453A1.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form, or its pharmaceutically acceptable salt:
  • G 1 , G 2 and G 3 are the same or different, and each independently is CR 6 or N;
  • W 1 and W 2 are the same or different, and are each independently selected from O atom, S atom, NR 7 and CR 8 R 9 ;
  • R 1 is selected from a hydrogen atom, an alkyl group, a heterocyclylalkyl group, a heteroarylalkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, Wherein said alkyl, heterocyclylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkane One of group, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or substituted by multiple substituents;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently Optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl Substituted by one or more substituents in the group and heteroaryl group;
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently Optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl Substituted by one or more substituents in the group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently Optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl Substituted by one or more substituents in the group and heteroaryl group;
  • R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 7 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 8 and R 9 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro Group, hydroxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;
  • n 0, 1, 2 or 3;
  • t 0, 1, 2 or 3;
  • p 0, 1, 2, 3, 4, or 5.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I-1) or (I-2) or a tautomer, a mesoform, or an exoisomer Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , n, p, and t are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II) or a tautomer, meso, racemate, or enantiomer , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 to R 5 , n, p, and t are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II-1) or (II-2) or a tautomer, meso, or exogen Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 to R 5 , n, p, and t are as defined in the general formula (I).
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-1) The compound represented by formula (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or its pharmaceutically acceptable , Wherein R 4 is a C 1-6 alkyl group.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-1) The compound represented by formula (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or its pharmaceutically acceptable
  • R 4 is a C 1-6 alkyl group; preferably, the C 1-6 alkyl group is a methyl group.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-1) The compound represented by formula (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or its pharmaceutically acceptable A salt of, wherein R 1 is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally selected from halogen, hydroxy, C 1-6 alkoxy, 3 to 6 membered cycloalkyl and 3 to The 6-membered heterocyclic group is substituted by one or more substituents.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula (II-1) The compound represented by formula (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or its pharmaceutically acceptable A salt of, wherein R 1 is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally selected from halogen, hydroxy, C 1-6 alkoxy, 3 to 6 membered cycloalkyl and 3 to The 6-membered heterocyclic group is substituted by one or more substituents; preferably, the C 1-6 alkyl group is substituted by a 3 to 6-membered heterocyclic group; more preferably, the C 1-6 alkyl group is Methyl, the 3- to 6-membered heterocyclic group is oxetanyl.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable A salt of, wherein R 3 is selected from C 1-6 alkyl, hydrogen atom and halogen.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable , Wherein R 3 is a hydrogen atom or halogen.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable A salt of, wherein R 5 is the same or different, and each is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt of, wherein R 5 is the same or different, and each is independently halogen.
  • the general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1) and general formula The compound shown in (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt, where p is 2.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IA-1) or (IA-2) or tautomers, mesosomes, racemates, enantiomers, and non-pairs thereof Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof Form, or its pharmaceutically acceptable salt,
  • R w is C 1-6 alkyl
  • R 1 to R 5 , p, t, and n are as defined in the general formula (IA).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IIA-1) or (IIA-2) or its tautomer, meso, racemate, enantiomer, and non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R w is C 1-6 alkyl
  • R 1 to R 5 , p, t, and n are as defined in the general formula (IA).
  • Typical intermediate compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method includes the following steps:
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (I-1) or (I-2) or its tautomer, meso, racemate, enantiomer , Diastereoisomer, or its mixture form or its pharmaceutically acceptable salt method, the method includes the following steps:
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method includes the following steps:
  • R w is C 1-6 alkyl
  • R 1 to R 5 , p, t, and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (II-1) or (II-2) or its tautomers, mesosomes, racemates, and enantiomers , Diastereoisomer, or its mixture form or its pharmaceutically acceptable salt method, the method includes the following steps:
  • R 1 to R 5 , p, t, and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formula (I), general formula (I-1), general formula (I-2), general formula (II), and general formula of the present disclosure.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A
  • the compound shown or its tautomer, mesosome, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or containing it Use of the pharmaceutical composition in the preparation of a medicament for stimulating GLP-1 receptor.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A
  • the pharmaceutical composition is prepared for the treatment and/or prevention of type I diabetes, type II diabetes, adult latent immune diabetes (LADA), young adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, Diabetes complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson's disease, dementia or insulin resistance drugs; It is preferably used in the preparation of medicines for the treatment and/or prevention of type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease; wherein, the type I diabetes is preferably special
  • the present disclosure also relates to a method for stimulating the GLP-1 receptor, which comprises administering to a desired patient a therapeutically effective amount of general formula (I), general formula (I-1), general formula (I-2), general formula ( II), general formula (II-1), general formula (II-2) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • a method for stimulating the GLP-1 receptor which comprises administering to a desired patient a therapeutically effective amount of general formula (I), general formula (I-1), general formula (I-2), general formula ( II), general formula (II-1), general formula (II-2) and the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a treatment and/or prevention of type I diabetes, type II diabetes, latent immune diabetes in adults (LADA), young adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, and diabetes complications
  • Methods for disease obesity, hyperglycemia, glucose intolerance, cardiovascular disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), Parkinson’s disease, dementia, or insulin resistance
  • the cardiovascular disease is preferably selected from atherosclerosis, hypertension, hyperlipidemia and coronary heart disease; it includes the general formula (I), general formula ( I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and the compounds shown in Table A or their
  • the present disclosure further relates to a general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and The compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or A pharmaceutical composition containing it, which is used as a medicine.
  • the present disclosure also relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A
  • the compound shown or its tautomer, mesosome, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or containing it The pharmaceutical composition of which is used as a GLP-1 receptor agonist.
  • the present disclosure further relates to general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2) and Table A
  • a “diabetic complication” is a complication caused by diabetes or hyperglycemia, and it may be an acute complex or a chronic complex.
  • the term "acute complex” includes ketoacidosis and infectious diseases (such as skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and "chronic complex” includes, for example, microvascular diseases (such as nephropathy, retinopathy). ), neuropathy (such as sensory nerve disorder, motor nerve disorder, autonomic nerve disorder) and gangrene.
  • the major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.
  • Chronic heart disease includes myocardial infarction and angina pectoris.
  • “Dementia” includes, for example, Alzheimer's disease, (early-onset dementia) EOD, vascular dementia, and diabetic dementia.
  • the active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (for example, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration.
  • the compounds of the present disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably in the form of a unit dose, or in a form in which the patient can self-administer in a single dose.
  • the expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.
  • a suitable unit dose can be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and suitable excipients for mixing to prepare aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure.
  • a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by adding water to prepare water-suspended dispersible powders and granules.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent, or one or more preservatives.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of the disease, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of the compound, or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atom alkyl group, more preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups can be substituted or unsubstituted.
  • the substituents are preferably independently selected from the group consisting of D atom, halogen, alkoxy, and halogenated alkyl. Group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or one of Multiple substituents.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which contains 1
  • a straight or branched chain group having to 20 carbon atoms preferably contains 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from alkenyl, alkynyl, and alkoxy.
  • substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo are substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • Alkenyl groups may be substituted or unsubstituted. When substituted, they are preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more substituents among, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkynyl group may be substituted or unsubstituted. When substituted, it is preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy One or more substituents among, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 Carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), more preferably contain 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group that shares one carbon atom (called a spiro atom) between the single rings. It may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include Etc.; preferably
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkyl
  • groups which are independently selected from the group consisting of D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkyl
  • One or more substitutions of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl base are independently selected from the group consisting of D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkyl
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, which contains 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, form sulfoxide or sulfone), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), where 1-3 are heteroatoms (e.g., 1, 2 and 3); more preferably, they contain 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, they contain 5 or 6 ring atoms, 1-3 of them are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine Group, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, in which one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • Atoms the sulfur may optionally be oxo (i.e. form sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated ⁇ -electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie, form a sulfoxide) Or sulfone), the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • the sulfur may be optionally oxo (i.e. form sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkanes Or Multiple substituents.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or multiple substituents.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived from the removal of one hydrogen atom from the parent ring atom, or the removal of two hydrogen atoms from the same or two different ring atoms of the parent.
  • Derivative residues namely "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, “heteroarylene”.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro.
  • the amino protecting group is preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.
  • hydroxyl protecting group is a suitable group for protecting a hydroxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for the hydroxyl protecting group.
  • the hydroxy protecting group may be (C 1-10 alkyl or aryl) 3 silyl group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C C 1-6 alkyl substituted with 1-6 alkyl or phenyl, most preferably C 1-4 alkyl substituted with C 1-4 alkoxy, for example: methyl, tert-butyl, allyl, benzyl , Methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, such as formyl, acetyl ,
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O ) O-, wherein alkyl and cycloalkyl are as defined above.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • in addition to using “deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the deuterated form of the compound is that each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize deuterated compounds.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques using deuterated reagents.
  • Deuterated reagents include but are not limited to deuterated borane and tri-deuterated borane in tetrahydrofuran.
  • Deuterated lithium aluminum hydride deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents.
  • substituents Those skilled in the art can determine possible or impossible substitutions (through experiments or theory) without making too much effort.
  • an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.
  • the salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • pharmaceutically acceptable refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically
  • the preparation method of the salt used includes the following steps:
  • the compound of general formula (IA) undergoes a hydrolysis reaction in the presence of a basic reagent to obtain a compound of general formula (I)
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • G 1 , G 2 , G 3 , W 1 , W 2 , R 1 to R 5 , p, t, and n are as defined in the general formula (I).
  • the preparation method of the salt used includes the following steps:
  • the compound of general formula (IIA) undergoes a hydrolysis reaction in the presence of a basic reagent to obtain a compound of general formula (II)
  • R w is C 1-6 alkyl
  • R 1 to R 5 , p, t, and n are as defined in the general formula (II).
  • R 1 to R 5 , p, t, and n are as defined in the general formula (II).
  • alkaline reagents include organic bases and inorganic bases.
  • the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropyl Lithium amide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • said inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide , Lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably lithium hydroxide or lithium hydroxide monohydrate.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkanes, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with Bruker AVANCE NEO 500M, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl Silane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.
  • the chiral HPLC analysis and determination used Agilent 1260DAD high performance liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm to 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. To 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, ranging from 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • ONE-Glo TM Luciferase Assay System ONE-Glo TM Luciferase Assay System, Promega, E6110
  • ONE-Glo TM Luciferase Assay System Promega, E6110
  • the downstream signaling pathway of GLP-1R is activated, causing the level of cAMP to rise, cAMP and CRE
  • the combination can initiate the transcription and expression of the luciferase gene downstream of CRE, and the reaction of luciferase and its substrate can emit fluorescence.
  • the fluorescence signal measured by the ONE-Glo TM reagent reflects the activity of the compound to stimulate the GLP-1 receptor.
  • CHO-K1/CRE-luc/GLP-1 receptor stable transduction cell line GLP-1 receptor plasmid self-built; CRE-luc plasmid Promega E8471. Digest the CHO-K1/CRE-luc/GLP-1 receptor cells, resuspend after centrifugation, mix the single cell suspension, and adjust the viable cell density to 2.5 with cell culture medium (DME/F-12+10% FBS) ⁇ 10 5 cells/ml, add 90 ⁇ L/well to a 96-well cell culture plate (Corning, #3903). The culture plate was incubated in an incubator for 16 hours (37°C, 5% CO 2 ).
  • DME/F-12+10% FBS cell culture medium
  • the compound was dissolved in DMSO and prepared as a stock solution with an initial concentration of 20 mM.
  • the initial concentration of the small molecule compound is 0.2mM, diluted 3 times, diluted 10 points, and the 11th point is DMSO.
  • Take another 96-well plate add 95 ⁇ L of cell culture medium (DME/F-12+10%FBS) to each well, then add 5 ⁇ L of test samples of different concentrations to each well, mix well, and then add 10 ⁇ L to the cell culture plate Samples to be tested with different concentrations per well, with two duplicate wells for each sample.
  • the culture plate was incubated in an incubator for 6 hours (37°C, 5% CO 2 ).
  • Table 1 EC 50 of the compounds of the present disclosure on GLP-1 receptor agonistic activity
  • the compound of the present disclosure has good agonistic activity on GLP-1 receptor.

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Abstract

L'invention concerne un dérivé de 6-oxo-3,6-dihydropyridine, son procédé de préparation et son utilisation en médecine. En particulier, la présente invention concerne un dérivé de 6-oxo-3,6-dihydropyridine tel que représenté dans la formule générale (I), et son procédé de préparation, et une composition pharmaceutique contenant le dérivé, et son utilisation en tant qu'agent thérapeutique, en particulier en tant qu'agoniste du récepteur GLP-1 et dans la préparation de médicaments pour le traitement et/ou la prévention du diabète.
PCT/CN2021/100799 2020-06-19 2021-06-18 Dérivé de 6-oxo-3,6-dihydropyridine, son procédé de préparation et son utilisation en médecine WO2021254470A1 (fr)

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WO2022202864A1 (fr) 2021-03-24 2022-09-29 塩野義製薬株式会社 Composition pharmaceutique contenant un agoniste du récepteur glp-1 comportant un cycle fusionné
WO2022246019A1 (fr) 2021-05-20 2022-11-24 Eli Lilly And Company Agonistes macrocycliques du récepteur du peptide 1 de type glucagon
WO2023038039A1 (fr) 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
WO2023057414A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certaines octahydrofuro 3,4-b]pyrazines utilisées en tant que modulateurs du récepteur glp-1
WO2023057429A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes et octahydrofuro[3,4-b]pyrazines utilisés en tant que modulateurs du récepteur glp-1
WO2023057427A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes utilisés en tant que modulateurs du récepteur glp-1
WO2023111145A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab Certains 3-azabicyclo[3.1.0] hexanes utilisés en tant que modulateurs du récepteur de glp-1
WO2023111144A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab 3-azabicyclo [3.1.0] hexanes en tant que modulateurs du récepteur glp-1
WO2023169436A1 (fr) 2022-03-08 2023-09-14 广州市联瑞制药有限公司 Composé benzo bicyclique, son procédé de préparation et son application
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
WO2024102625A1 (fr) 2022-11-11 2024-05-16 Eli Lilly And Company Agonistes de récepteur du peptide 1 de type glucagon
WO2024107781A1 (fr) 2022-11-16 2024-05-23 Eli Lilly And Company Agonistes du récepteur du glucagon-like peptide 1
US12024507B2 (en) 2021-10-25 2024-07-02 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists

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WO2019239319A1 (fr) * 2018-06-13 2019-12-19 Pfizer Inc. Agonistes du récepteur glp-1 et leurs utilisations
WO2019239371A1 (fr) * 2018-06-15 2019-12-19 Pfizer Inc. Agonistes du récepteur glp-1 et leurs utilisations

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
WO2022202864A1 (fr) 2021-03-24 2022-09-29 塩野義製薬株式会社 Composition pharmaceutique contenant un agoniste du récepteur glp-1 comportant un cycle fusionné
WO2022246019A1 (fr) 2021-05-20 2022-11-24 Eli Lilly And Company Agonistes macrocycliques du récepteur du peptide 1 de type glucagon
WO2023038039A1 (fr) 2021-09-08 2023-03-16 塩野義製薬株式会社 Médicament destiné à la prévention et au traitement de maladies liées à l'activité anti-obésité
KR20240056719A (ko) 2021-09-08 2024-04-30 시오노기 앤드 컴파니, 리미티드 항비만 작용이 관여하는 질환의 예방 및 치료용 의약
WO2023057414A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certaines octahydrofuro 3,4-b]pyrazines utilisées en tant que modulateurs du récepteur glp-1
WO2023057427A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes utilisés en tant que modulateurs du récepteur glp-1
WO2023057429A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes et octahydrofuro[3,4-b]pyrazines utilisés en tant que modulateurs du récepteur glp-1
US12024507B2 (en) 2021-10-25 2024-07-02 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
WO2023111144A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab 3-azabicyclo [3.1.0] hexanes en tant que modulateurs du récepteur glp-1
WO2023111145A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab Certains 3-azabicyclo[3.1.0] hexanes utilisés en tant que modulateurs du récepteur de glp-1
WO2023169436A1 (fr) 2022-03-08 2023-09-14 广州市联瑞制药有限公司 Composé benzo bicyclique, son procédé de préparation et son application
WO2024102625A1 (fr) 2022-11-11 2024-05-16 Eli Lilly And Company Agonistes de récepteur du peptide 1 de type glucagon
WO2024107781A1 (fr) 2022-11-16 2024-05-23 Eli Lilly And Company Agonistes du récepteur du glucagon-like peptide 1

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