WO2021197464A1 - 稠合咪唑类衍生物、其制备方法及其在医药上的应用 - Google Patents

稠合咪唑类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2021197464A1
WO2021197464A1 PCT/CN2021/085229 CN2021085229W WO2021197464A1 WO 2021197464 A1 WO2021197464 A1 WO 2021197464A1 CN 2021085229 W CN2021085229 W CN 2021085229W WO 2021197464 A1 WO2021197464 A1 WO 2021197464A1
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group
general formula
alkyl
aryl
cycloalkyl
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PCT/CN2021/085229
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English (en)
French (fr)
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杨方龙
杨倩
贺峰
陶维康
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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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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CA3172285A priority Critical patent/CA3172285A1/en
Priority to JP2022559748A priority patent/JP2023520003A/ja
Priority to US17/907,458 priority patent/US20230126875A1/en
Priority to CN202180019894.7A priority patent/CN115244056A/zh
Priority to EP21779335.5A priority patent/EP4130003A4/en
Publication of WO2021197464A1 publication Critical patent/WO2021197464A1/zh

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    • 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
    • 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
    • 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

  • the present disclosure belongs to the field of medicine, and relates to a fused imidazole derivative, a preparation method thereof, and application in medicine.
  • the present disclosure relates to a fused imidazole derivative represented by the general formula (I), its preparation method and pharmaceutical composition containing the derivative, and its use as a GLP-1 receptor agonist in the treatment of diabetes .
  • 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 I diabetic patients that is, insulin-dependent diabetic patients, produce little or no insulin by themselves. Insulin is a hormone used in the body to regulate glucose utilization.
  • Type II diabetic patients that is, insulin-independent diabetic patients and non-diabetic patients have the same or higher plasma insulin levels.
  • 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 responsive resistance leads to the inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissues, and cannot effectively inhibit lipolysis of adipose tissue and the production and secretion of liver glucose.
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 plays a corresponding role by binding to its widespread specific receptors.
  • 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. In patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes, there is generally no significant difference in serum GLP-1 levels.
  • 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. Because the body's own GLP-1 has a very short duration of action (intravenous injection t1/2 ⁇ 1.5 minutes), the body's own GLP-1 is not suitable for the clinical treatment of diabetes.
  • Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) have the effect of reducing fasting and postprandial glucose and improving blood sugar in type II diabetic patients.
  • Peptide GLP-1 receptor agonists such as liraglutide, exenatide, etc.
  • the peptide GLP-1 has poor oral bioavailability and inconvenient administration, it is highly desirable for small molecule GLP-1 receptor agonists with good oral bioavailability.
  • GLP-1 receptor small molecule agonists include WO2009111700, WO2010114824, WO2018109607, WO2019239319 and WO2018056453.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt:
  • Q is Q0 or Q2
  • G 1 , G 2 and G 3 are the same or different, and each independently is a CR 7 or N atom;
  • Z 1 , Z 2 , Z 3 and Z 4 are the same or different, and each independently is a CR 8 or N atom;
  • Y is selected from O atom, S atom, NR 9 and CR 10 R 11 ;
  • W 1 and W 2 are the same or different, and are each independently selected from O atom, S atom, NR 12 and CR 13 R 14 ;
  • R a and R b are identical or different and are each independently selected from hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro Group, hydroxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally selected From halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group;
  • R 1 is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 5 is the same or different, and 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 6 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 7 and R 8 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;
  • R 9 and R 12 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero Aryl;
  • R 10 , R 11 , R 13 and R 14 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, Cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4 or 5;
  • t 0, 1, 2 or 3;
  • p 0, 1, 2, 3, 4, or 5.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt:
  • Q is Q1 or Q2
  • G 1 , G 2 and G 3 are the same or different, and each independently is a CR 7 or N atom;
  • Z 1 , Z 2 , Z 3 and Z 4 are the same or different, and each independently is a CR 8 or N atom;
  • Y is selected from O atom, S atom, NR 9 and CR 10 R 11 ;
  • W 1 and W 2 are the same or different, and are each independently selected from O atom, S atom, NR 12 and CR 13 R 14 ;
  • R 1 is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Substituted by one or more substituents among hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 5 is the same or different, and 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 6 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 are optionally selected Selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;
  • R 7 and R 8 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;
  • R 9 and R 12 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a halogenated alkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero Aryl;
  • R 10 , R 11 , R 13 and R 14 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, Cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4 or 5;
  • 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, or diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (II), or tautomers, mesosomes, racemates, and enantiomers thereof Conformers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , Q and n are as defined in the general formula (I).
  • R 3 -R 6 , R 8 , m, p and t are as defined in the general formula (I).
  • R 3 -R 6 , m, p and t are as defined in the general formula (I).
  • the compound represented by the general formula (I) or general formula (II) or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III), or tautomers, mesoisomers, racemates thereof , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), general formula (II) or general formula (III) or its tautomer, meso form, racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (IIIaa), or tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 4 to R 6 , 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 Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein: G 1 is CH or N atom; G 2 and G 3 are both CH; Q is R 1 is R 2 is the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group; R 4 is a hydrogen atom or a C 1-6 alkyl group; R 5 is the same or different, and each is independently selected from a hydrogen atom, a halogen and C 1-6 alkyl; R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, and C 1-6 alkyl; n is 0 or 1; t is 0 or 1; and p is 0, 1 or 2.
  • the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein Q is R 1 is R 2 is the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group; R 4 is a hydrogen atom or a C 1-6 alkyl group; R 5 is the same or different, and each is independently selected from a hydrogen atom, a halogen and C 1-6 alkyl; R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, and C 1-6 alkyl; n is 0 or 1; t is 0 or 1; and p is 0, 1 or 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 In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , R 1 , R 2 , Q 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, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R w is C 1-6 alkyl
  • R 1 , R 2 , Q and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIIaaA), or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (IIIaa).
  • Typical intermediate compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises:
  • R w is C 1-6 alkyl
  • G 1 , G 2 , G 3 , R 1 , R 2 , Q 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, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises:
  • R w is C 1-6 alkyl
  • R 1 , R 2 , Q and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (III), or a tautomer, meso, racemate, enantiomer, or diastereomer thereof , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises:
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIaa), or a tautomer, meso, racemate, enantiomer, or diastereomer thereof , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises:
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (IIIaa).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A of the present disclosure
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A or their tautomers, mesosomes, racemates Use of isomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them in the preparation of drugs for stimulating GLP-1 receptors.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A or their tautomers, mesosomes, racemates Isomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them are prepared for the treatment and/or prevention of type I diabetes, type II diabetes, Idiopathic type I diabetes, latent immune diabetes in adults (LADA), young adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose tolerance Bad, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease , Dementia, insulin resistance or liver insulin resistance; preferably in the preparation for the treatment and/or prevention of type I diabetes, type II diabetes, obesity,
  • the present disclosure also relates to a method for stimulating GLP-1 receptor, which comprises administering to a patient a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or table
  • a method for stimulating GLP-1 receptor comprises administering to a patient a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or table
  • the present disclosure also relates to a treatment and/or prevention of type I diabetes, type II diabetes, idiopathic type I diabetes, latent immune diabetes in adults (LADA), young adult-onset diabetes (MODY), malnutrition related Diabetes, gestational diabetes, complications of diabetes, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fat Methods for treating and/or preventing type I diabetes, type II diabetes, obesity, liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson’s disease, dementia, insulin resistance or liver insulin resistance; A method for diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease, which comprises administering to the required patient a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (IIIaa) Or the compounds shown in Table A or their tautomers, mesosomes, racemates, enantiomers,
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A or its tautomer, meso, exo Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as medicines.
  • the present disclosure also relates to compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A or their tautomers, mesosomes, racemates Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as GLP-1 receptor agonists.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A or their tautomers, mesosomes, racemates Isomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used for the treatment and/or prevention of type I diabetes, type II diabetes, Idiopathic type I diabetes, latent immune diabetes in adults (LADA), young adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, glucose tolerance Bad, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease , Dementia, insulin resistance or liver insulin resistance; more preferably type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic
  • 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 infections, soft tissue infections, biliary system infections, respiratory system infections, urinary tract infections), and "chronic complexes” include, 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 dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • 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 unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated 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 excipients suitable for the preparation of aqueous suspensions for mixing. 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 injection preparation may be a sterile injection 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 suspending 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, etc.; in addition, the best treatment mode such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be based on the traditional The treatment plan to verify.
  • 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 atoms, more preferably alkyl groups 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 group 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent When substituted, the substituent may be substituted at any available attachment point.
  • the substituent is preferably independently selected from the group consisting of D atom, halogen, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Or 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 of to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred is an alkylene group containing 1 to 6 carbon atoms.
  • alkylene examples 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, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkenyl, alkynyl, and alkoxy.
  • substituents of aryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo aryl, 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, the substituents are preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy Group, 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.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy Group, 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 (E.g. 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 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 single rings, which may contain one or more double bonds. 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. 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 cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 Five-membered and six-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. 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 ring, fused ring and bridged ring) fused on 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 indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, and alkoxy. , Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents.
  • alkoxy refers to -O-(alkyl), where the definition of alkyl is as described 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 D atom, halogen, alkoxy, halogenated alkyl, and halogenated alkoxy Group, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, sulfur, S( O) or S(O) 2 heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms (e.g.
  • heteroatoms e.g. 1, 2 and 3
  • monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, 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 selected from nitrogen, oxygen, sulfur, and S (O) or S(O) 2 heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds. 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 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of 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, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 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).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 , 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 rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, and alkoxy. , Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more 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 to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, the substituents 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.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g. 1, 2, 3, and 4) heteroatoms, 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 and the like.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from halogen, alkyl, and alkoxy. , Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more 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”, and “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 or 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 can 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 ,
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl 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), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O ) O-, wherein alkyl and cycloalkyl are as defined above.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature.
  • Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents.
  • Deuterated reagents include, but are not limited to, deuterated borane and tri-deuterated.
  • 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, and 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 a group, preferably 1 to 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents.
  • substituents Those skilled in the art can determine possible or impossible substitutions (through experiment 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 living body, facilitate the absorption of the active ingredient and then develop the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, 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 each 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 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.
  • 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.
  • 18 F-fluorine label 18 F isotope
  • 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
  • the preparation method of medicinal salt 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 , R 1 , R 2 , Q and n are as defined in the general formula (I).
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or
  • the preparation method of medicinal salt 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 , R 2 , Q and n are as defined in the general formula (II).
  • the compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IIIA) undergoes a hydrolysis reaction in the presence of a basic reagent to obtain a compound of general formula (III)
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (III).
  • the compound represented by the general formula (IIIaa) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or
  • the preparation method of medicinal salt includes the following steps:
  • R w is C 1-6 alkyl
  • R 1 , R 2 , R 4 to R 6 , n, p, and t are as defined in the general formula (IIIaa).
  • the alkaline reagents in the above schemes 1 to 4 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 Alkane, 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).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-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 for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 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 the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent 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, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent varies according to the polarity of the compound For adjustment, it is also possible to add a small amount of basic or acidic reagents such as triethylamine and acetic acid for adjustment.
  • TLC thin layer chromatography
  • TsOH is p-toluenesulfonic acid.
  • the crude compound 4b (102 mg, 0.20 mmol, p-toluenesulfonate) was dissolved in 10 mL of acetonitrile, compound 1c (50 mg, 0.17 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added, and the mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 4c (88 mg, yield: 85.9%).
  • the purpose of this experiment is to test the agonistic activity of the compound molecule on the GLP-1 receptor, and to evaluate the in vitro activity of the molecule based on the EC50 size.
  • This experiment uses the 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 increase, 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 transfection 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 ).
  • cell culture medium DME/F-12+10% FBS
  • 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.
  • Test Example 2 The effect of the compound of the present disclosure on the hERG potassium ion channel
  • the HEK293 cell line was transfected with pCDNA3.1(+) that has constructed the hERG gene, and then the monoclonal HEK293-hERG stable cell line was selected by adding G418.
  • the HEK293-hERG stable cell line was passaged in MEM/EBSS medium (10% FBS, 400 ⁇ g/ml G418, 1% MEM non-essential amino acid solution (100 ⁇ ), 1% sodium pyruvate solution) at a density of 1:4 Cultivate, and perform a fully automatic patch clamp experiment within 48-72 hours of incubation.
  • the cells were digested with 0.25% trypsin (life technologies, 12563-029), and the cells were collected by centrifugation, and extracellular fluid (140mM NaCl, 4mM KCl, 1mM MgCl 2 , 2mM CaCl 2 , 5mmMD glucose monohydrate, 10mM HEPES) , PH7.4, 298mOsmol) resuspend the cells to make a cell suspension.
  • the cell suspension is placed on the cell bank of the Patchliner instrument.
  • the Patchliner instrument uses a negative pressure controller to add cells to the chip (NPC-16), and the negative pressure attracts individual cells to the small holes of the chip.
  • the instrument When the whole-cell mode is formed, the instrument will obtain the hERG current according to the set hERG current and voltage program, and then the instrument will automatically change from low concentration to high concentration for compound perfusion.
  • the data analysis software provided by HEAK EPC10 patch clamp amplifier (Nanion) and Pathlinersoftware and Pathcontrol HTsoftware were used to analyze the currents at each concentration of the compound and the blank control current.
  • the compound of the present disclosure has a weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Abstract

本公开涉及稠合咪唑类衍生物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的稠合咪唑类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为GLP-1受体激动剂的用途和用于制备治疗和/或预防糖尿病的药物中的用途。通式中各基团如说明书中所定义。

Description

稠合咪唑类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种稠合咪唑类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的稠合咪唑类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为GLP-1受体激动剂在治疗糖尿病领域的用途。
背景技术
糖尿病是一种多病因的代谢疾病，特点是慢性高血糖，伴随因胰岛素分泌或作用缺陷引起的糖，脂和蛋白质代谢紊乱。糖尿病是一种非常古老的疾病，是由于人体内胰岛素绝对或相对缺乏而引起的血中葡萄糖浓度升高，进而糖大量从尿中排出，并出现多饮、多尿、多食、消瘦等症状。
通常来说，有两种类型的糖尿病。I型糖尿病人，即胰岛素依赖性糖尿病患者自身产生的胰岛素很少或几乎没有。胰岛素是体内用来调节葡萄糖利用的一种荷尔蒙。II型糖尿病人，即胰岛素非依赖型糖尿病患者与非糖尿病患者的血浆内胰岛素水平相同或更高。然而，此类患者却对胰岛素产生抵抗力，这些胰岛素对于主要的胰岛素敏感的组织细胞，如肌肉，肝脏，脂肪组织等的葡糖糖和脂类代谢起着刺激作用。即使血浆胰岛素水平提高，也无法克服患者对于胰岛素显著的抵抗力。
胰岛素抵抗力除了因为胰岛素受体数量的减少而产生，还有胰岛素受体缺陷，到目前为止此机制还未能完全理解。胰岛素应答性的抵抗力导致胰岛素无法在肌肉组织中，对葡萄糖摄取、氧化、存储进行激活，无法有效抑制脂肪组织脂解作用，和肝脏葡萄糖的产生和分泌。
胰高血糖素样肽-1(GLP-1)是下消化道L-细胞分泌的一种肠降血糖素激素。GLP-1通过与其广泛存在的特异性受体结合而发挥相应的作用，目前明确存在GLP-1受体的器官有胰岛细胞、胃肠、肺、脑、肾脏、下丘脑和心血管系统，肝脏、脂肪组积及骨骼肌中可能存在GLP-1受体。GLP-1不仅作用于β细胞促进胰岛素分泌，同时还作用于α细胞抑制胰高血糖素分泌。正常糖耐量、糖耐量受损和II型糖尿病患者中，血清GLP-1水平一般没有明显的差异。但是进食后β细胞对GLP-1的应答存在缺陷，在一定条件下，持续输注GLP-1后这种应答反应明显增强。由于人体自身GLP-1的作用持续时间十分短暂(静脉注射t1/2<1.5分钟)，因此人体自身GLP-1并不适合用于糖尿病的临床治疗。
肽类GLP-1受体激动剂(如利拉鲁肽，艾塞那肽等)具有通过降低空腹和餐后葡萄糖以及改善II型糖尿病患者血糖的作用。然而，因为肽类GLP-1的口服生物利用度差，服用不便，所以高度期望具有良好口服生物利用度的小分子GLP-1 受体的激动剂。
公开的GLP-1受体小分子激动剂专利申请包括WO2009111700、WO2010114824、WO2018109607、WO2019239319和WO2018056453等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021085229-appb-000001
其中：
Q为Q0或Q2，
Figure PCTCN2021085229-appb-000002
G 1、G 2和G 3相同或不同，且各自独立地为CR 7或N原子；
Z 1、Z 2、Z 3和Z 4相同或不同，且各自独立地为CR 8或N原子；
Y选自O原子、S原子、NR 9和CR 10R 11；
W 1和W 2相同或不同，且各自独立地选自O原子、S原子、NR 12和CR 13R 14；
R a和R b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 1选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环 基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 4选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7和R 8相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
R 9和R 12相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
R 10、R 11、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3、4或5；
m为0、1、2、3、4或5；
t为0、1、2或3；且
p为0、1、2、3、4或5。
本公开的目的在于提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021085229-appb-000003
其中：
Q为Q1或Q2，
Figure PCTCN2021085229-appb-000004
G 1、G 2和G 3相同或不同，且各自独立地为CR 7或N原子；
Z 1、Z 2、Z 3和Z 4相同或不同，且各自独立地为CR 8或N原子；
Y选自O原子、S原子、NR 9和CR 10R 11；
W 1和W 2相同或不同，且各自独立地选自O原子、S原子、NR 12和CR 13R 14；
R 1选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 4选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、 氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7和R 8相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
R 9和R 12相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
R 10、R 11、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3、4或5；
m为0、1、2、3、4或5；
t为0、1、2或3；且
p为0、1、2、3、4或5。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中G 1为CH或N原子；G 2和G 3均为CH；优选地，G 1、G 2和G 3均为CH。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021085229-appb-000005
其中：
R 1、R 2、Q和n如通式(I)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Z 1、Z 2和Z 3相同或不同，且各自独立地为CR 8，Z 4为N原子；R 8为氢原子或卤素。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Y为O原子或S原子。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中Z 1、Z 2和Z 3为CH，Z 4为N原子；和/或Y为O原子。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中W 1和W 2均为O原子。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Q选自Q3、Q4、Q5和Q6：
Figure PCTCN2021085229-appb-000006
R 3-R 6、R 8、m、p和t如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Q选自Q3、Q4和Q5：
Figure PCTCN2021085229-appb-000007
R 3-R 6、m、p和t如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Q为
Figure PCTCN2021085229-appb-000008
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021085229-appb-000009
R 1、R 2、R 4～R 6、n、p和t如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中为通式(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021085229-appb-000010
R 1、R 2、R 4～R 6、n、p和t如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1为C 1-6烷基，其中所述C 1-6烷基任选被选自卤素、羟基、C 1-6烷氧基、3至6元环烷基、3至6元杂环基中的一个或多个取代基所取代；优选地，R 1为C 1-6烷基，其中所述C 1-6烷基任选被一个3至6元杂环基取代；更优选地，R 1为
Figure PCTCN2021085229-appb-000011
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2相同或不同，各自独立地为氢原子或C 1-6烷基。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和氰基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4为氢原子或C 1-6烷基；优选为C 1-6烷基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；和/或R 6相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为0或1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对 映异构体、或其混合物形式、或其可药用的盐，其中t为0或1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中p为0、1或2；优选为2。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中：G 1为CH或N原子；G 2和G 3均为CH；Q为
Figure PCTCN2021085229-appb-000012
R 1为
Figure PCTCN2021085229-appb-000013
R 2相同或不同，各自独立地为氢原子或C 1-6烷基；R 4为氢原子或C 1-6烷基；R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；R 6相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；n为0或1；t为0或1；和p为0、1或2。
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Q为
Figure PCTCN2021085229-appb-000014
R 1为
Figure PCTCN2021085229-appb-000015
R 2相同或不同，各自独立地为氢原子或C 1-6烷基；R 4为氢原子或C 1-6烷基；R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；R 6相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；n为0或1；t为0或1；和p为0、1或2。
表A 本公开的典型化合物包括但不限于：
Figure PCTCN2021085229-appb-000016
Figure PCTCN2021085229-appb-000017
Figure PCTCN2021085229-appb-000018
本公开的另一方面涉及通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
Figure PCTCN2021085229-appb-000019
其中：
R w为C 1-6烷基；
G 1、G 2、G 3、R 1、R 2、Q和n如通式(I)中所定义。
本公开的另一方面涉及通式(IIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
Figure PCTCN2021085229-appb-000020
其中：
R w为C 1-6烷基；
R 1、R 2、Q和n如通式(II)中所定义。
本公开的另一方面涉及通式(IIIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
Figure PCTCN2021085229-appb-000021
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(III)中所定义。
本公开的另一方面涉及通式(IIIaaA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
Figure PCTCN2021085229-appb-000022
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(IIIaa)中所定义。
本公开的典型中间体化合物包括但不限于：
Figure PCTCN2021085229-appb-000023
Figure PCTCN2021085229-appb-000024
Figure PCTCN2021085229-appb-000025
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021085229-appb-000026
通式(IA)的化合物发生水解反应，得到通式(I)的化合物，
其中：
R w为C 1-6烷基；
G 1、G 2、G 3、R 1、R 2、Q和n如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的 盐的方法，该方法包括：
Figure PCTCN2021085229-appb-000027
通式(IIA)的化合物发生水解反应，得到通式(II)的化合物，
其中：
R w为C 1-6烷基；
R 1、R 2、Q和n如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021085229-appb-000028
通式(IIIA)的化合物发生水解反应，得到通式(III)的化合物，
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2021085229-appb-000029
通式(IIIaaA)的化合物发生水解反应，得到通式(IIIaa)的化合物，
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(IIIaa)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式 (I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于激动GLP-1受体的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防I型糖尿病、II型糖尿病、特发性I型糖尿病、成人隐匿性免疫性糖尿病(LADA)、年青的成年发病型糖尿病(MODY)、营养不良相关性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、高血糖症、葡萄糖耐受不良、心血管疾病、动脉粥样硬化、高血压、高脂血症、冠心病、脑梗塞、中风、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、帕金森病、痴呆、胰岛素抗性或肝脏胰岛素抗性的药物中的用途；优选在制备用于治疗和/或预防I型糖尿病、II型糖尿病、肥胖症、糖尿病并发症、非酒精性脂肪性肝炎或心血管疾病的药物中的用途。
本公开还涉及一种激动GLP-1受体的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防I型糖尿病、II型糖尿病、特发性I型糖尿病、成人隐匿性免疫性糖尿病(LADA)、年青的成年发病型糖尿病(MODY)、营养不良相关性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、高血糖症、葡萄糖耐受不良、心血管疾病、动脉粥样硬化、高血压、高脂血症、冠心病、脑梗塞、中风、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、帕金森病、痴呆、胰岛素抗性或肝脏胰岛素抗性的方法；优选治疗和/或预防I型糖尿病、II型糖尿病、肥胖症、糖尿病并发症、非酒精性脂肪性肝炎或心血管疾病的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作药物。
本公开还涉及通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合 物形式，或其可药用盐，或包含其的药物组合物，其用作GLP-1受体激动剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IIIaa)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于治疗和/或预防I型糖尿病、II型糖尿病、特发性I型糖尿病、成人隐匿性免疫性糖尿病(LADA)、年青的成年发病型糖尿病(MODY)、营养不良相关性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、高血糖症、葡萄糖耐受不良、心血管疾病、动脉粥样硬化、高血压、高脂血症、冠心病、脑梗塞、中风、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、帕金森病、痴呆、胰岛素抗性或肝脏胰岛素抗性；更优选I型糖尿病、II型糖尿病、肥胖症、糖尿病并发症、非酒精性脂肪性肝炎或心血管疾病。
“糖尿病并发症”是糖尿病或高血糖症引起的并发症，并且其可以是急性复合体或者慢性复合体。术语“急性复合体”包括酮酸症和感染性疾病(例如皮肤感染、软组织感染、胆道系统感染、呼吸系统感染、泌尿道感染)，“慢性复合体”包括例如微血管病(例如肾病、视网膜病)、神经病(例如感觉神经障碍、运动神经障碍、自主神经障碍)和坏疽。主要糖尿病复合体包括糖尿病视网膜病变、糖尿病肾病和糖尿病神经病。
“冠心病”包括心肌梗塞和心绞痛。
“痴呆”包括例如阿尔茨海默氏病、(早发性痴呆)EOD、血管性痴呆和糖尿病性痴呆。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成持续释放剂型，例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆。
本公开治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者的体重和化合物的相对功效而改变。不过，作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以 不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021085229-appb-000030
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021085229-appb-000031
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021085229-appb-000032
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选茚满基、四氢萘基。
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括氧杂环丁基、吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为 单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021085229-appb-000033
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021085229-appb-000034
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021085229-appb-000035
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021085229-appb-000036
等。
杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021085229-appb-000037
芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021085229-appb-000038
Figure PCTCN2021085229-appb-000039
杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为(三甲基硅)乙氧基甲基和叔丁氧羰基。
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基(MOM)，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。所述羟基保护基优选为对硝基苯甲酰基。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”或氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基、环烷基如上所定义。
本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发 挥生物活性。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021085229-appb-000040
通式(IA)的化合物在碱性试剂存在下发生水解反应，得到通式(I)的化合物
其中：
R w为C 1-6烷基；
G 1、G 2、G 3、R 1、R 2、Q和n如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021085229-appb-000041
通式(IIA)的化合物在碱性试剂存在下发生水解反应，得到通式(II)的化合物
其中：
R w为C 1-6烷基；
R 1、R 2、Q和n如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021085229-appb-000042
通式(IIIA)的化合物在碱性试剂存在下发生水解反应，得到通式(III)的化合物
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(III)中所定义。
方案四
本公开通式(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2021085229-appb-000043
通式(IIIaaA)的化合物在碱性试剂存在下发生水解反应，得到通式(IIIaa)的化合物
其中：
R w为C 1-6烷基；
R 1、R 2、R 4～R 6、n、p和t如通式(IIIaa)中所定义。
上述方案一至四中碱性试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾；优选氢氧化锂或氢氧化锂一水合物。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：正己烷/二氯甲烷体系，D：乙酸乙酯/二氯甲烷/正己烷，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
TsOH为对甲苯磺酸。
实施例1
(S)-2-((6-((4-氰基-2-氟苄基)氧基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸1
Figure PCTCN2021085229-appb-000044
第一步
3-氟-4-((1',2',3',6'-四氢-[2,4'-联吡啶]-6-基)氧基)甲基)苯甲腈1b
6-((4-氰基-2-氟苄基)氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯1a(96mg，234.4595μmol，采用专利申请“WO2018109607”中说明书第51页的中间体4公开的方法制备而得)溶于乙酸乙酯(5mL)，加入对甲苯磺酸一水合物(133mg，699.2014μmol)，在60℃搅拌4小时。冷却，过滤，用乙酸乙酯(10mL)洗涤，收集有机相，干燥，过滤，减压浓缩得化合物1b(126mg)，产物不经纯化直接用于下一步。
MS m/z(ESI):310.1[M+1]。
第二步
(S)-2-((6-((4-氰基-2-氟苄基)氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯1d
(S)-2-(氯甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯1c(55mg，186.6096μmol，采用专利申请WO2018109607中说明书第69页的中间体23公开的方法制备而得)，化合物1b(121mg，185.0889μmol)溶于乙腈(10mL)，加入碳酸钾(128mg，926.1571μmol)，50℃下搅拌5小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1d(105mg，产率：99％)。
MS m/z(ESI):568.1[M+1]。
第三步
(S)-2-((6-((4-氰基-2-氟苄基)氧基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸1
化合物1d(105mg，184.9865μmol)溶于乙腈(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(6mg，250.5397μmol)，40℃搅拌过夜。浓缩，柠檬酸溶液调pH至5-6，加乙腈2mL，溶解后，高效液相制备得1(20mg，产率：19％)。
MS m/z(ESI):554.2[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.26(s,1H),7.88(d,J＝9.9Hz,1H),7.81(d,J＝8.3Hz,1H),7.74–7.59(m,4H),7.09(d,J＝7.5Hz,1H),6.77(d,J＝8.1Hz,1H),6.70(d,J＝4.4Hz,1H),5.49(s,2H),5.11–5.01(m,1H),4.79(dd,J＝15.2,7.3Hz,1H),4.64(dd,J＝15.3,2.8Hz,1H),4.50–4.43(m,1H),4.41–4.31(m,1H),4.06(d,J＝13.5Hz,1H),3.91(d,J＝13.5Hz,1H),3.30–3.12(m,3H),2.73(q,J＝5.3Hz,2H),2.65(dd,J＝11.1,7.1Hz,1H),2.48(s,1H),2.39(t,J＝9.5Hz,1H)。
实施例2
2-((4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸2
Figure PCTCN2021085229-appb-000045
Figure PCTCN2021085229-appb-000046
第一步
4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶2b
将4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯2a(65mg，0.15mmol，采用专利申请WO2019239319中说明书第55页的中间体C5公开的方法制备而得)溶于乙酸乙酯(5mL)中，加入对甲苯磺酸一水合物(70mg，0.37mmol)，60℃搅拌4小时，冷却，过滤，乙酸乙酯(10mL)洗涤，收集有机相，干燥，过滤，减压浓缩得到标题化合物2b(75mg，二对甲苯磺酸盐)，不经纯化直接用于下一步。
MS m/z(ESI):346.1[M+1]。
第二步
2-((4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯2c
将化合物2b(75mg，0.14mmol，二对甲苯磺酸盐)溶于10mL乙腈中，加入化合物1c(40mg，0.14mmol)和碳酸钾(94mg，0.68mmol)，加热至50℃搅拌5小时。冷至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物2c(35mg，产率：42.7％)。
MS m/z(ESI):604.1[M+1]。
第三步
2-((4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸2
将化合物2c(35mg，0.06mmol)溶于5mL乙腈，室温下加入氢氧化锂一水合物(3mg，0.07mmol)和1mL水，40℃反应16小时。冷至室温，浓缩除去乙腈，剩余物用柠檬酸溶液调节pH到6～7，加乙腈溶解后，经高效液相色谱法制备得到标题化合物2(20mg，产率：58.5％)。
MS m/z(ESI):590.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ12.80(brs,1H),8.26(s,1H),7.81(d,1H),7.66(d,1H),7.57-7.54(m,2H),7.33(d,1H),6.87-6.81(m,3H),6.39-6.36(m,1H),5.08-5.04(m,1H),4.82-4.76(m,1H),4.68-4.63(m,1H),4.48-4.43(m,1H),4.39-4.33(m,1H),4.08-4.03(m,1H),3.92-3.88(m,1H),3.29-3.12(m,4H),2.79-2.63(m,3H),2.55-2.36(m,4H)。
实施例3
2-((6-(1-(4-氯-2-氟苄基)乙氧基)-3',6'-二氢-[2,4’-联吡啶]-1'(2'H)-基)甲基)-1-((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸3
Figure PCTCN2021085229-appb-000047
第一步
2-氯-6-(1-(4-氯-2-氟苯基)乙氧基)吡啶3c
叔丁醇钾(672mg，5.98mmol)加入于四氢呋喃(10mL)中，室温加入1-(4-氯-2-氟苯基)乙醇3b(523mg，2.99mmol)，在该温度下搅拌45分钟，加入2,6-二氯吡啶3a(444mg，3.00mmol)，室温搅拌1小时。加水50mL，乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥，过滤，浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得 残余物，得到标题化合物3c(700mg，产率：81.7％)。
第二步
6-(4-氯-2-氟苯基)乙氧基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯3e
化合物3c(309mg，999.32μmol)，无水碳酸钠(317mg，2.99mmol)，四三苯基膦钯(58mg，50.19μmol)，水(4mL)，二氧六环(16mL)，氩气保护下，90℃搅拌过夜。TLC显示反应完毕。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3e(188mg，产率：43.5％)。
MS m/z(ESI):433.1[M+1]。
第三步
6-(1-(4-氯-2-氟苯基)乙氧基)-1’2’,3’,6’-四氢-2,4’-联吡啶3f
化合物3e(188mg，434.26μmol)溶于乙酸乙酯(5mL)，加入对甲苯磺酸(206mg，1.08mmol)，60℃搅拌4小时，冷却，过滤，乙酸乙酯(10mL)洗涤，收集有机相，干燥，过滤，减压浓缩得到标题化合物3f(294mg，二对甲苯磺酸盐，产率：99.9％)。
MS m/z(ESI):333.1[M+1]。
第四步
2-((6-((4-氯-2-氟苯基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-((S)-氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯3g
化合物3f(270mg，398.69μmol，2TsOH)溶于乙腈(5mL)加入碳酸钾(135mg，976.80μmol)，加热至50℃搅拌5小时。冷至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到标题化合物3g(81mg，产率：69.6％)。
MS m/z(ESI):591.1[M+1]。
第五步
2-((6-(1-(4-氯-2-氟苯基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸3
化合物3g(80mg，135.3475μmol)溶于乙腈(5mL)和水(1mL)中。加入氢氧化锂一水合物(8mg，190.47μmol)，40℃搅拌过夜。浓缩，柠檬酸调pH至5-6。加水10mL，乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥，过滤，浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物3(35mg，产率：44.8％)。
MS m/z(ESI):577.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),8.26(d,J＝1.6Hz,1H),7.82(dd,J＝8.4,1.5Hz,1H),7.66(dd,J＝8.1,3.2Hz,1H),7.45(td,J＝8.2,2.7Hz,1H),7.41(dt,J＝10.2,1.6Hz,1H),7.24(dt,J＝8.4,1.5Hz,1H),7.03(dd,J＝7.5,2.4Hz,1H),6.72(d,J＝8.1Hz,1H),6.60(td,J＝3.7,1.9Hz,1H),6.35–6.26(m,1H),5.05(ddd,J＝7.4,5.0,2.7Hz,1H),4.79(dd,J＝15.2,7.3Hz,1H),4.64(dt,J＝15.4,3.1Hz,1H),4.51–4.42(m,1H),4.36(ddd,J＝6.1,3.2,1.8Hz,1H),4.06(dd,J＝13.5,3.4Hz,1H),3.90(dd,J＝13.5,5.6Hz,1H),3.27–3.12(m,2H),2.79–2.55(m,4H),2.46(s,1H),2.42– 2.29(m,2H),1.57(d,J＝6.6Hz,3H)。
实施例4
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸4
Figure PCTCN2021085229-appb-000048
第一步
(S)-4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶4-甲基苯磺酸盐4b
将(S)-4-(2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶-1(2H)-甲酸叔丁酯(4a，88mg，0.20mmol，采用专利申请WO2019239319中说明书第55页的实施例中间体C5公开的方法制备并手性拆分而得)溶于乙酸乙酯(5mL)中，加入对甲苯磺酸一水合物(94mg，0.49mmol)，60℃搅拌4小时，冷却，减压浓缩，用正己烷洗(20mL)得到粗品产物4b(102mg，对甲苯磺酸盐)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):345.9[M+1]。
第二步
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯4c
将粗品化合物4b(102mg，0.20mmol，对甲苯磺酸盐)溶于10mL乙腈中，加 入化合物1c(50mg，0.17mmol)和碳酸钾(117mg，0.85mmol)，加热至50℃搅拌5小时。冷至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物4c(88mg，产率：85.9％)。
MS m/z(ESI):604.1[M+1]。
第三步
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸4
将化合物4c(88mg，0.15mmol)溶于5mL乙腈，室温下加入氢氧化锂一水合物(7mg，0.17mmol)和1mL水，40℃反应16小时。冷至室温，减压浓缩除去乙腈，剩余物用柠檬酸溶液调节pH到6～7，加乙腈溶解后，经高效液相色谱法Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物4(50mg，产率：58.2％)。
MS m/z(ESI):590.2[M+1]。
1H NMR(500MHz,DMSO-d 6)δ12.80(brs,1H),8.27(s,1H),7.81(d,1H),7.66(d,1H),7.57-7.54(m,2H),7.33(d,1H),6.87-6.81(m,3H),6.39-6.36(m,1H),5.08-5.04(m,1H),4.82-4.76(m,1H),4.68-4.63(m,1H),4.48-4.43(m,1H),4.39-4.33(m,1H),4.17-4.06(m,1H),4.00-3.90(m,1H),3.32-3.19(m,2H),2.86-2.73(m,2H),2.70-2.64(m,1H),2.60-2.53(m,1H),2.46-2.34(m,2H),2.03(s,3H)。
实施例5
(S)-2-((6-(4-氰基-2-氟苄基)硫基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸5
Figure PCTCN2021085229-appb-000049
Figure PCTCN2021085229-appb-000050
第一步
4-(((6-溴吡啶-2-基)硫基)甲基)-3-氟苄腈5b
3-氟-4-(巯基甲基)苄腈5a(309mg，1.84mmol，采用专利申请US2012329788A1中说明书第26页的中间体I-2公开的方法制备而得)溶于甲苯(10mL)，加入2,6-二溴吡啶(450mg，1.89mmol，韶远化学科技(上海)有限公司)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(100mg，0.17mmol)，三(二亚苄基丙酮)二钯(90mg，0.10mmol)，N,N-二异丙基乙胺(600mg，4.64mmol)，在100℃微波反应1小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5b(225mg，产率：37.6％)。
MS m/z(ESI):325[M+1]。
第二步
6-((4-氰基-2-氟苄基)硫基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯5c
化合物5b(255mg，0.70mmol)溶于1，4-二氧六环(10mL)，加入N-叔丁氧羰基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(220mg，0.71mmol，韶远化学科技(上海)有限公司)，无水碳酸钠(220mg，2.08mmol)，四三苯基膦钯(40mg，0.03mmol)，水(3mL)，氮气氛下加热至90℃搅拌16小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5c(260mg，产率：87.8％)。
MS m/z(ESI):426.1[M+1]。
第三步
3-氟-4-(((1',2',3',6'-四氢-[2,4'-联吡啶]-6-基)硫基)甲基)苄腈对甲苯磺酸盐5d
化合物5c(125mg，0.29mmol)溶于乙酸乙酯(5mL)，加入对甲苯磺酸一水合 物(170mg，0.89mmol)，在60℃搅拌4小时。冷却，过滤，用乙酸乙酯(10mL)洗涤，收集有机相，干燥，过滤，减压浓缩得粗品标题产物5d(146mg)，产物不经纯化直接用于下一步。
MS m/z(ESI):326.1[M+1]。
第四步
(S)-2-((6-((4-氰基-2-氟苄基)硫基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯5e
化合物1c(80mg，0.27mmol)，化合物5d(146mg，0.29mmol)溶于乙腈(10mL)，加入碳酸钾(200mg，1.44mmol)，50℃下搅拌5小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5e(158mg，产率：99％)。
MS m/z(ESI):584.2[M+1]。
第五步
(S)-2-((6-(4-氰基-2-氟苄基)硫基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸5
化合物5e(150mg，0.26mmol)溶于6mL乙腈和水(V：V＝5：1)的混合溶剂中，加入氢氧化锂一水合物(13mg，0.31mmol)，40℃搅拌16小时。浓缩，柠檬酸溶液调pH至5～6，加入乙腈(2mL)，溶解后，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5(90mg，61.5％)。
MS m/z(ESI):570.1[M+1]。
1H NMR(500MHz,DMSO-d 6)δ12.71(brs,1H),8.26(s,1H),7.86–7.80(m,2H),7.71–7.59(m,4H),7.25(d,1H),7.17(d,1H),6.72(s,1H),5.08–5.04(m,1H),4.82–4.75(m,1H),4.67–4.63(m,1H),4.54(s,2H),4.49–4.44(m,1H),4.38–4.32(m,1H),4.09–3.91(m,2H),3.28–3.21(m,2H),3.17(s,2H),2.78–2.72(m,2H),2.69–2.62(m,1H),2.43–2.34(m,1H)。
实施例6
(S)-2-((6-(4-氰基-2-氟苄基)硫基-5-氟-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸6
Figure PCTCN2021085229-appb-000051
Figure PCTCN2021085229-appb-000052
第一步
4-(((6-氯-3-氟吡啶-2-基)硫基)甲基)-3-氟苯腈6a
3-氟-4-(巯基甲基)苄腈5a(280mg，1.67mmol)溶于甲苯(10mL)，加入2,6-二氯-3-氟吡啶(280mg，1.69mmol，南京药石科技股份有限公司)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(100mg，0.17mmol)，三(二亚苄基丙酮)二钯(80mg，0.09mmol)，N,N-二异丙基乙胺(550mg，4.26mmol)，在100℃微波反应1小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6a(128mg，产率：25.8％)。
MS m/z(ESI):297.0[M+1]。
第二步
6-((4-氰基-2-氟苄基)硫基)-5-氟-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯6b
化合物6a(128mg，0.43mmol)溶于1，4-二氧六环(10mL)，加入N-叔丁氧羰基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(22.15g，0.49mmol，韶远化学科技(上海)有限公司)，无水碳酸钠(100mg，0.94mmol)，四三苯基膦钯(50mg，0.04mmol)，水(2mL)，氮气氛下加热至90℃搅拌4小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6b(126mg，产率：65.9％)。
MS m/z(ESI):388.1[M-55]。
第三步
3-氟-4-(((5-氟-1',2',3',6'-四氢-[2,4'-联吡啶]-6-基)硫基)甲基)苄腈二对甲苯磺酸盐6c
化合物6b(126mg，0.28mmol)溶于乙酸乙酯(5mL)，加入对甲苯磺酸一水合 物(160mg，0.84mmol)，在60℃搅拌4小时。冷却，过滤，用乙酸乙酯(10mL)洗涤，收集有机相，干燥，过滤，减压浓缩得到粗品标题化合物6c(195mg)，产物不经纯化直接用于下一步。
第四步
(S)-2-((6-((4-氰基-2-氟苄基)硫基)-5-氟-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯6d
化合物1c(60mg，0.20mmol)，化合物6c(195mg，0.28mmol)溶于乙腈(10mL)，加入碳酸钾(150mg，1.09mmol)，50℃下搅拌5小时。冷至室温，浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6d(96mg，产率：78.4％)。
MS m/z(ESI):602.1[M+1]。
第五步
(S)-2-((6-(4-氰基-2-氟苄基)硫基-5-氟-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁基-2-基甲基)-1H-苯并[d]咪唑-6-羧酸6
化合物6d(86mg，0.14mmol)溶于6mL乙腈和水(V：V＝5：1)的混合溶剂中，加入氢氧化锂一水合物(8mg，0.19mmol)，40℃搅拌16小时。浓缩，柠檬酸溶液调pH至5-6，加入乙腈(2mL)，溶解后，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物6(26mg，31.0％)。
MS m/z(ESI):588.2[M+1]。
1H NMR(500MHz,DMSO-d 6)δ12.77(brs,1H),8.26(d,1H),7.85(dd,2H),7.81(dd,1H),7.67–7.60(m,4H),7.35(dd,1H),6.66(s,1H),5.09–5.04(m,1H),4.82–4.77(m,1H),4.67–4.63(m,1H),4.60(s,2H),4.49–4.44(m,1H),4.38–4.34(m,1H),4.08–3.91(m,2H),3.28–3.17(m,2H),2.78–2.71(m,2H),2.69–2.62(m,1H),2.54–2.51(m,1H),2.43–2.36(m,1H)。
实施例7
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸7
Figure PCTCN2021085229-appb-000053
Figure PCTCN2021085229-appb-000054
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯第并一[d步][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯7b
将粗品化合物4b(83mg，0.16mmol)溶于乙腈(5mL)中，加入化合物(S)-2-氯甲基-3-(氧杂环丁基-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯7a(45mg，0.15mmol，采用专利申请WO2019239371A1中说明书第85页的中间体P27公开的方法制备而得)和碳酸钾(100mg，0.72mmol)，加热至50℃搅拌5小时。冷至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物7b(64mg，产率：69.5％)。
MS m/z(ESI):605.1[M+1]。
第二步
2-((4-((S)-2-(4-氯-2-氟苯基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸7
将化合物7b(64mg，0.11mmol)溶于乙腈(5mL)中，室温下加入氢氧化锂一水合物(5mg，0.12mmol)和水(1mL)，40℃反应16小时。冷至室温，减压浓缩除去乙腈，剩余物用柠檬酸溶液调节pH到6～7，加乙腈溶解后，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7(15mg，产率：24.0％)。
MS m/z(ESI):591.0[M+1]。
1H NMR(500MHz,DMSO-d 6)δ8.14(d,1H),8.00(d,1H),7.57-7.53(m,2H),7.34-7.32(m,1H),6.87-6.81(m,3H),6.39-6.36(m,1H),5.18-5.13(m,1H),4.85-4.81 (m,1H),4.72-4.68(m,1H),4.49-4.44(m,1H),4.38-4.34(m,1H),4.12(d,1H),4.01(m,1H),3.28-3.23(m,2H),2.81-2.72(m,2H),2.69-2.64(m,1H),2.59-2.54(m,1H),2.48-2.39(m,2H),2.02(s,3H)。
生物学评价
测试例1、GLP-1受体激动活性评价
一、测试目的
本实验的目的是为了测试化合物分子对GLP-1受体的激动活性，根据EC50大小评价分子的体外活性。本实验使用ONE-Glo TM荧光素酶测试系统(ONE-Glo TM Luciferase Assay System,Promega,E6110)，在化合物分子作用下，GLP-1R下游信号通路被激活，引起cAMP水平升高，cAMP与CRE结合可启动CRE下游荧光素酶基因的转录表达，荧光素酶与其底物反应可发出荧光，通过ONE-Glo TM试剂测定荧光信号反映化合物激动GLP-1受体的活性。
二、实验方法
构建CHO-K1/CRE-luc/GLP-1受体稳转细胞株(GLP-1受体质粒自建；CRE-luc质粒Promega E8471)。将CHO-K1/CRE-luc/GLP-1受体细胞消化，离心后重悬，单细胞悬液混匀，用细胞培养液(DME/F-12+10％FBS)调整活细胞密度至2.5×10 5细胞/mL，以90μl/孔加入96孔细胞培养板(Corning,#3903)。将培养板在培养箱培养16小时(37℃，5％CO 2)。
用DMSO溶解化合物，配制成初始浓度为20mM的存储液。小分子化合物的起始浓度为0.2mM，3倍稀释，稀释10个点，第11个点为DMSO。另取一块96孔板，每孔加入95μL的细胞培养液(DME/F-12+10％FBS)，然后每孔加入5μL不同浓度的待测样品，混匀，接着向细胞培养板中加入10μL/孔的不同浓度的待测样品，每个样品两复孔。将培养板在培养箱孵育6小时(37℃，5％CO 2)。取出96孔细胞培养板，向每孔加入100μL ONE-Glo TM试剂，室温孵育10分钟。于酶标仪(EnVision 2105，PE)中，用酶标仪测定化学发光。
三、数据分析
用Microsoft Excel，Graphpad Prism 5对数据进行处理分析。得出化合物的EC 50值，结果参见下表1。
表1 本公开化合物对GLP-1受体激动活性的EC 50
实施例编号 EC 50(nM) Emax％
1 0.12 110
2 0.92 110
3 1.38 106
4 0.12 104
5 1.93 110
6 0.85 108
7 0.45 107
结论：本公开化合物对GLP-1受体具有好的激动活性。
测试例2.本公开化合物对hERG钾离子通道的作用
一、测试目的
应用全自动膜片钳在转染hERG钾通道的稳定细胞株上测试本公开化合物对hERG钾电流的阻断作用
二、测试方法
2.1实验材料与仪器
2.1.1实验材料：
试剂名称 供货公司 货号
FBS GIBCO 10099
丙酮酸钠溶液 sigma S8636-100ML
MEM非必需氨基酸溶液(100×) sigma M7145-100ML
G418硫酸盐 Enzo ALX-380-013-G005
MEM Hyclone SH30024.01B
hERG cDNA Origene -
pcDNA3.1(+) invitrogen V79020
HEK293人胚肾细胞 中科院细胞库 货号GNHu18
2.1.2实验仪器：
Figure PCTCN2021085229-appb-000055
2.2全自动膜片钳实验步骤
通过将已经构建了hERG基因的pCDNA3.1(+)转染HEK293细胞系，然后通过加入G418筛选出单克隆HEK293-hERG稳定细胞株。HEK293-hERG稳定细胞株按照1:4的密度在MEM/EBSS培养基(10％FBS，400μg/ml G418,1％MEM非必需氨基酸溶液(100×)，1％丙酮酸钠溶液)中进行传代培养，培养48-72小时之内进行全自动膜片钳实验。实验当天将细胞用0.25％胰酶(life technologies,12563-029)消化后，离心收集细胞，用细胞外液(140mM NaCl，4mM KCl，1mM  MgCl 2，2mM CaCl 2，5mMD一水葡萄糖，10mM HEPES，pH7.4，298mOsmol)重悬细胞制成细胞悬液。将细胞悬液放置在Patchliner仪器的细胞库上，Patchliner仪器利用负压控制器将细胞加到芯片(NPC-16)上，负压将单个细胞吸引在芯片的小孔上。当形成全细胞模式后，仪器将按照设定的hERG电流电压程序得到hERG电流，然后仪器自动的由低浓度到高浓度，进行化合物灌流。通过HEAK EPC10膜片钳放大器(Nanion)和Pathlinersoftware以及Pathcontrol HTsoftware提供的数据分析软件，对化合物各浓度下的电流以及空白对照电流进行分析。
2.3测试结果
本公开化合物对hERG钾电流的阻断作用通过以上的试验进行测定，测得的IC 50值见表2。
表2 本公开化合物对hERG钾离子通道的阻断作用的IC 50
实施例编号 IC 50(μM)
4 22
结论：本公开化合物对hERG的抑制作用弱，可降低由hERG通路引起的副作用。

Claims (21)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021085229-appb-100001
    其中：
    Q为Q0或Q2，
    Figure PCTCN2021085229-appb-100002
    G 1、G 2和G 3相同或不同，且各自独立地为CR 7或N原子；
    Z 1、Z 2、Z 3和Z 4相同或不同，且各自独立地为CR 8或N原子；
    Y选自O原子、S原子、NR 9和CR 10R 11；
    W 1和W 2相同或不同，且各自独立地选自O原子、S原子、NR 12和CR 13R 14；
    R a和R b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 1选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的 一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 4选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 7和R 8相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 9和R 12相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 10、R 11、R 13和R 14相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、氰基、氨基、硝基、羟基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3、4或5；
    m为0、1、2、3、4或5；
    t为0、1、2或3；且
    p为0、1、2、3、4或5。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其 中Q为Q1或Q2，
    Figure PCTCN2021085229-appb-100003
    其中：Y、Z 1、Z 2、Z 3、Z 4、W 1、W 2、R 3～R 6、m、p和t如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中G 1为CH或N原子；G 2和G 3均为CH；优选地，G 1、G 2和G 3均为CH。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021085229-appb-100004
    其中：
    R 1、R 2、Q和n如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Z 1、Z 2和Z 3均为CH，Z 4为N原子；和/或Y为O原子。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中W 1和W 2均为O原子。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中Q选自Q3、Q4和Q5：
    Figure PCTCN2021085229-appb-100005
    R 3-R 6、m、p和t如权利要求1中所定义。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021085229-appb-100006
    R 1、R 2、R 4～R 6、n、p和t如权利要求1中所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
    Figure PCTCN2021085229-appb-100007
    R 1、R 2、R 4～R 6、n、p和t如权利要求1中所定义。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其互变异构 体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1为C 1-6烷基，其中所述C 1-6烷基任选被选自卤素、羟基、C 1-6烷氧基、3至6元环烷基、3至6元杂环基中的一个或多个取代基所取代。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2相同或不同，各自独立地为氢原子或C 1-6烷基。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和氰基。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4为氢原子或C 1-6烷基；优选为C 1-6烷基。
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 5相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；和/或R 6相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021085229-appb-100008
    Figure PCTCN2021085229-appb-100009
  16. 一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，
    Figure PCTCN2021085229-appb-100010
    其中：
    R w为C 1-6烷基；
    G 1、G 2、G 3、R 1、R 2、Q和n如权利要求1中所定义。
  17. 根据权利要求16所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021085229-appb-100011
  18. 一种制备根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021085229-appb-100012
    通式(IA)的化合物发生水解反应，得到通式(I)的化合物，
    其中：
    R w为C 1-6烷基；
    G 1、G 2、G 3、R 1、R 2、Q和n如权利要求1中所定义。
  19. 一种药物组合物，所述药物组合物含有根据权利要求1～15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 根据权利要求1～15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求19所述的药物组合物在制备用于激动GLP-1受体的药物中的用途。
  21. 根据权利要求1～15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求19所述的药物组合物在制备用于治疗和/或预防I型糖尿病、II型糖尿病、特发性I型糖尿病、成人隐匿性免疫性糖尿病(LADA)、年青的成年发病型糖尿病(MODY)、营养不良相关性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、高血糖症、葡萄糖耐受不良、心血管疾病、动脉粥样硬化、高血压、高脂血症、冠心病、脑梗塞、中风、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、帕金森病、痴呆、胰岛素抗性或肝脏胰岛素抗性的药物中的用途；优选在制备用于治疗和/或预防I型糖尿病、II型糖尿病、肥胖症、糖尿病并发症、非酒精性脂肪性肝炎或心血管疾病的药物中的用途。
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