WO2022116693A1 - 一类glp-1r受体激动剂化合物及其用途 - Google Patents

一类glp-1r受体激动剂化合物及其用途 Download PDF

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WO2022116693A1
WO2022116693A1 PCT/CN2021/123505 CN2021123505W WO2022116693A1 WO 2022116693 A1 WO2022116693 A1 WO 2022116693A1 CN 2021123505 W CN2021123505 W CN 2021123505W WO 2022116693 A1 WO2022116693 A1 WO 2022116693A1
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alkyl
group
alkoxy
compound
alkynyl
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PCT/CN2021/123505
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English (en)
French (fr)
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李本
余尚海
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苏州闻泰医药科技有限公司
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Priority to AU2021390614A priority Critical patent/AU2021390614B2/en
Priority to EP21899727.8A priority patent/EP4212527A4/en
Priority to JP2023537462A priority patent/JP7456699B2/ja
Priority to KR1020237012547A priority patent/KR102670046B1/ko
Publication of WO2022116693A1 publication Critical patent/WO2022116693A1/zh
Priority to US18/192,735 priority patent/US11773087B2/en
Priority to ZA2023/06748A priority patent/ZA202306748B/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the field of drug synthesis, in particular to a class of GLP-1R receptor agonist compounds and uses thereof.
  • GLP-1 receptor GLP-1 Receptor, GLP-1R
  • B family secretin family
  • 7-transmembrane G protein-coupled receptors GLP-1 receptor
  • GLP-1 Receptor GLP-1 Receptor
  • GLP-1R GLP-1 Receptor
  • Glucagon-like peptide-1 (GLP-1) is a natural ligand of GLP-1R receptor and is a polypeptide compound. It has two forms, GLP-1(7-37) and GLP-1(7-36) amide, which differ by only one amino acid sequence, and about 80% of the circulating activity of GLP-1 comes from GLP-1 (7-36) Amide. GLP-1 is expressed by the proglucagon gene. In pancreatic islet alpha cells, the main expression product of the proglucagon gene is glucagon, while in L cells of the intestinal mucosa, prohormone converting enzyme (PC1) Proglucagon is cleaved to its carboxy-terminal peptide sequence, GLP-1. The combination of GLP-1 and GLP-1R receptor can promote the synthesis and secretion of insulin, and also stimulate the proliferation of ⁇ cells and inhibit their apoptosis.
  • PC1 prohormone converting enzyme
  • GLP-1 mainly exerts hypoglycemic effect through the following aspects.
  • GLP-1 can act on islet beta cells, promote insulin gene transcription, insulin synthesis and secretion, stimulate the proliferation and differentiation of islet beta cells, inhibit islet beta cell apoptosis, and increase the number of islet beta cells.
  • GLP-1 can also act on islet ⁇ cells, strongly inhibit the release of glucagon, and act on islet ⁇ cells to promote the secretion of somatostatin, which can act as a paracrine hormone to participate in the inhibition of pancreatic hyperglycemia. Glucagon secretion.
  • GLP-1 can significantly improve the blood sugar of type 2 diabetes animal models or patients through various mechanisms, among which, it can promote the regeneration and repair of pancreatic ⁇ cells and increase the number of pancreatic ⁇ cells.
  • GLP-1 has a glucose-concentration-dependent hypoglycemic effect. GLP-1 exerts a hypoglycemic effect only when blood glucose levels are elevated, and does not further reduce it when blood glucose levels are normal.
  • GLP-1 reduces body weight through a variety of pathways, including inhibiting gastrointestinal motility and gastric juice secretion, inhibiting appetite and food intake, and delaying gastric emptying. GLP-1 also acts on the central nervous system (especially the hypothalamus), thereby causing the body to feel full and reduce appetite.
  • semaglutide a modified long-acting GLP-1 polypeptide, that in all randomized patients, after 68 weeks of treatment in obese patients, semaglutide 2.4mg Weight loss from a mean baseline of 105.3 kg was 14.9% in the treatment group and 2.4% in the placebo group; 86.4% of patients in the semaglutide 2.4 mg group lost ⁇ 5% body weight and 31.5% in the placebo group.
  • GLP-1 can significantly improve metabolic diseases by acting on GLP-1R receptors
  • many companies at home and abroad have developed various modified or unmodified GLP-1 short-acting (three times a day) or long-acting (once a day, Once a week) peptide drugs, this includes: exenatide, liraglutide, albiglutide, dulaglutide, benaglutide, lixisenatide, semaglutide, etc.
  • GLP-1 polypeptide and its modifications also faces many problems. Natural GLP-1 is easily degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, and its plasma half-life is less than 2 minutes. Continuous intravenous infusion or continuous subcutaneous injection is necessary to produce efficacy, which greatly limits the clinical application of GLP-1. Although the modified GLP-1 can prolong the half-life, the oral bioavailability is low, and there are still great challenges in oral administration. Therefore, there is an urgent need to develop oral small-molecule GLP-1R receptor agonist drugs.
  • DPP-IV dipeptidyl peptidase IV
  • WO2018109607 discloses the compound of the following general formula and a candidate drug PF-06882961 and Ref-01 (compounds 4A-01 and 3A-01 in the original document, hereinafter used as control compounds).
  • WO2019239371 discloses the following general formula compound and the following compound Ref-02 (Example 1 in the original document, hereinafter used as a reference compound).
  • the compounds of the present invention not only have high activity, but also show better pharmacokinetic properties.
  • the technical object of the present invention is to provide a class of compounds with GLP-1R receptor agonistic activity.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,
  • A is phenyl or a 5-6 membered heteroaryl containing one or two heteroatoms selected from O or N;
  • R 1 is selected from -H, halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 6-10 aryl group or -C 5-10 heteroaryl group containing one or two heteroatoms selected from O or N; the -C 1-6 alkyl group, -C 1-6 alkoxy group , -C 2-6 alkenyl, -C 2-6 alkynyl can be substituted by 0-3 F;
  • m is an integer of 0, 1, 2 or 3;
  • R 2 and R 3 are each independently selected from -H, deuterium, C 1-6 alkyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3-6 membered cycloalkyl group or contain a cycloalkyl group selected from O or N Heterocycloalkyl of one or two heteroatoms;
  • L is selected from -O-, -S-, -NR 11 - or -C(R 11 R 12 )-; said R 11 and R 12 are hydrogen or -C 1-6 alkyl;
  • R 4 is selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl or -C 2-6 alkynyl; the- C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl or -C 2-6 alkynyl may be substituted by 0-3 F;
  • n is an integer of 0, 1 or 2;
  • B is selected from:
  • R 5 is selected from -H, halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl or -C 2-6 alkynyl;
  • the -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 2-6 alkenyl group or -C 2-6 alkynyl group may be substituted by 0-3 F;
  • Subscript o is an integer of 0, 1 or 2;
  • R 6 and R 7 are each independently selected from -H, deuterium, -C 1-6 alkyl; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3-6-membered cycloalkyl group or contain a group selected from O or N 3-6 -membered heterocycloalkyl with one or two heteroatoms in 3-6 membered heterocycloalkyl with heteroatoms;
  • R 8 is selected from -C 1-3 alkyl, - methylene C 3-6 cycloalkyl or - methylene C 4 - 6 heterocycloalkane containing one or two heteroatoms selected from O or N wherein, the -C 1-3 alkyl group, methylene C 3-6 cycloalkyl group, methylene group C 4-6 heterocycloalkane containing one or two heteroatoms selected from O or N
  • the group may be selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl or containing selected One or more substitutions of 5-6 membered heteroaryl from one or two heteroatoms of O or N;
  • Z is selected from N or CR 13 ;
  • R 9 is selected from hydrogen, halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl or -C 2-6 alkynyl; the The -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 2-6 alkenyl group or -C 2-6 alkynyl group may be substituted by 0-3 F;
  • the subscript p is an integer of 0, 1 or 2;
  • R 10 is selected from -COOH or carboxyl isosteres
  • R 13 is selected from hydrogen, halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl or -C 2-6 alkynyl; the The -C 1-6 alkyl group, -C 1-6 alkoxy group, -C 2-6 alkenyl group or -C 2-6 alkynyl group may be substituted by 0-3 F;
  • the halogen is selected from F, Cl and Br.
  • the compound of the present invention has the structure shown in the following formula (II):
  • A is phenyl or pyridyl
  • R 1 is selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, the- C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl can be substituted by 0-3 F;
  • m is an integer of 0, 1 or 2;
  • R 2 and R 3 are each independently selected from -H, deuterium, C 1-6 alkyl;
  • R 4 is selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl or -C 1-6 alkoxy;
  • n is an integer of 0 or 1;
  • B is selected from:
  • R 5 is selected from halogen, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;
  • Subscript o is an integer of 0 or 1;
  • R 6 , R 7 are each independently selected from -H, deuterium, C 1-6 alkyl; or R 6 , R 7 together with the carbon atoms to which they are attached form a 3-6-membered cycloalkyl group or contain selected from O or N 3-6 membered heterocycloalkyl of one or two heteroatoms;
  • R 8 is selected from -C 1-3 alkyl, - methylene C 3-6 cycloalkyl or - methylene C 4-6 heterocycloalkane containing one or two heteroatoms selected from O or N wherein, the -C 1-3 alkyl group, methylene C 3-6 cycloalkyl group, methylene group C 4-6 heterocycloalkane containing one or two heteroatoms selected from O or N
  • the group may be selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl or containing selected One or more substitutions of 5-6 membered heteroaryl from one or two heteroatoms of O or N;
  • Z is selected from N or CR 13 ;
  • R 13 is selected from hydrogen, halogen, -CN, -OH, deuterium, -C 1-6 alkyl or -C 1-6 alkoxy.
  • the compound of the present invention has the structure shown in the following formula (III):
  • R 1 is selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, the- C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl can be substituted by 0-3 F;
  • m is an integer of 1 or 2;
  • A is phenyl, pyridyl
  • R 4 is selected from halogen, -OH, deuterium, -C 1-6 alkyl or -C 1-6 alkoxy;
  • n is an integer of 0 or 1;
  • B is selected from:
  • R 5 is selected from halogen, -OH, -C 1-6 alkyl or -C 1-6 alkoxy;
  • Subscript o is an integer of 0, 1 or 2;
  • R 8 is selected from -C 1-3 alkyl, -methylene C 3-6 cycloalkyl or -methylene C 4-6 heterocycloalkyl.
  • the compound of the present invention has the structure shown in the following formula (IV):
  • R 1 is selected from halogen, -CN, -OH, deuterium, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, the- C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl can be substituted by 0-3 F;
  • m is an integer of 1 or 2;
  • A is phenyl, pyridyl
  • R 4 is selected from halogen, -OH, deuterium, -C 1-6 alkyl or -C 1-6 alkoxy;
  • n is an integer of 0 or 1;
  • B is selected from:
  • R 5 is selected from -C 1-6 alkyl
  • the subscript o is an integer of 0 or 1.
  • the R 1 is selected from -F, -Cl, -Br, -CN, -C 1-6 alkyl, -C 1-6 alkane oxy, -C 2-6 alkenyl or -C 2-6 alkynyl;
  • the m is 2;
  • the A is phenyl
  • the R 4 is selected from -F, -Cl;
  • said B is selected from:
  • the compound according to the present invention is selected from one of the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compounds represented by the above-mentioned formulae (I) to (IV) of the present invention or pharmaceutically acceptable ones thereof
  • the salts are used as active ingredients, as well as pharmaceutically acceptable excipients.
  • the present invention provides the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as an active ingredient in the preparation of a medicament for the treatment of metabolism-related diseases by activating GLP-1R receptors the use of.
  • the metabolic-related disease is selected from the group consisting of glucose intolerance, hyperglycemia, dyslipidemia, type 1 diabetes (T1D), type 2 diabetes (T2D), hypertriglyceridemia, syndrome X, Insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypertension, obesity, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver fibrosis, Any of diseases such as liver cirrhosis and lethargy.
  • the present invention synthesizes a new type of GLP-1R receptor agonist compound, and it is confirmed by pharmacological experiments that the compound has good agonistic activity on GLP-1R receptor, so it can be used for the treatment of GLP-1R receptor-related metabolic diseases .
  • the compounds of the present invention also exhibit excellent drug metabolism properties.
  • salt refers to a cation and anion containing compound that can be produced by protonation of proton-accepting sites and/or deprotonation of proton-accepting sites.
  • protonation of proton-accepting sites leads to the formation of cationic species, the charge of which is balanced by the presence of physiological anions, while deprotonation of proton-available sites leads to the formation of anionic species, the charge of which is balanced by the presence of physiological cations And balance.
  • pharmaceutically acceptable salt means that the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with organic acids, such as glycolic acid , pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl acetate Sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-p-toluenesulfonic acid, camphoric acid
  • C1 -M alkyl refers to an alkyl group containing 1-M carbon atoms, eg, wherein M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
  • C1-6 alkyl refers to an alkyl group containing 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl , heptyl and octyl.
  • C3 -M cycloalkyl refers to a cycloalkyl group containing 3-M carbon atoms, eg, wherein M is an integer having the following values: 4, 5, 6, 7, 8.
  • C 3-6 cycloalkyl refers to a cycloalkyl group containing 3-6 carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to an aromatic system, which may be a single ring or multiple aromatic rings that are originally fused or linked together such that at least a portion of the fused or linked rings form a conjugated aromatic system.
  • Aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl.
  • Aryl may be optionally substituted, such as aryl or heterocycle which may be substituted with 1-4 groups selected from the group consisting of halogen, -CN, -OH, -NO2 , amino, alkyl, cycloalkane group, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
  • 1-4 groups selected from the group consisting of halogen, -CN, -OH, -NO2 , amino, alkyl, cycloalkane group, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
  • substituted means that the referenced group may be replaced by one or more additional groups, individually and independently selected from the group consisting of, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic , hydroxyl, alkoxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halogen, carbonyl, thiocarbonyl, nitro, haloalkane radicals, fluoroalkyl and amino groups, including mono- and di-substituted amino groups and their protected derivatives.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention can be in various forms, such as tablet, capsule, powder, syrup, solution, suspension Liquids and aerosols, etc., and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or instillation.
  • the unit dose of the formulation contains 0.05-200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably, the unit dose of the formulation contains 0.1 mg-100 mg of the compound of formula (I).
  • the compounds and pharmaceutical compositions represented by formula (I) of the present invention can be clinically used for mammals, including humans and animals, and can be administered through oral, nasal, skin, lung, or gastrointestinal tract or the like. Most preferred is oral administration.
  • the most preferred daily dose is 0.01-200 mg/kg body weight, taken in one time, or 0.01-100 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dose for an individual will depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the term "effective amount" may refer to an effective amount in a dose and for a period of time required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or condition of the disease at the time of treatment, the architecture of the particular target organ being administered, the size of the individual patient, or the severity of the disease or symptom.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation.
  • a typical formulation is prepared by mixing a compound represented by formula (I) of the present invention with a carrier, diluent or excipient.
  • Suitable carriers, diluents or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents , water and other substances.
  • solvents are generally selected on the basis of solvents considered by those skilled in the art to be safe and effective for administration to mammals.
  • safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible with water.
  • Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (eg, PEG400, PEG300), and the like.
  • the formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, Coloring agents, sweetening agents, flavoring agents, flavoring agents, or other known additives to bring the drug into an acceptable form for manufacture or use.
  • the two or more drugs can be used separately or in combination, preferably in the form of a pharmaceutical composition.
  • the compounds or pharmaceutical compositions of formula (I) of the present invention can be administered separately or together in any of the known forms of oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration drug to subjects.
  • compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids agents, coloring agents, sweetening agents, flavoring agents, flavoring agents, or other known additives to bring the pharmaceutical compositions into an acceptable form for manufacture or use.
  • Solid dosage forms for oral administration may include capsules, tablets, powders or granules.
  • the compounds or pharmaceutical compositions of the present invention are admixed with at least one inert excipient, diluent, or carrier.
  • Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; Solution blockers such as paraffin, etc.; absorption accelerators such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait.
  • the dosage form may also include
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil etc.); glycerin; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances, etc.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers
  • compositions may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.
  • excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.
  • a carrier such as a suspending agent such as ethoxyl may be further contained Polyisostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances, etc.
  • the compound represented by formula (I) of the present invention may be administered in other topical dosage forms, including creams, powders, sprays, and inhalants.
  • the drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any required preservatives, buffers or propellants.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be encompassed within the scope of the present invention.
  • kits eg, pharmaceutical packaging are also encompassed by the present disclosure.
  • Kits are provided that can contain a pharmaceutical composition or compound described herein and a container (eg, a vial, ampule, bottle, syringe, and/or subpack or other suitable container).
  • a container eg, a vial, ampule, bottle, syringe, and/or subpack or other suitable container.
  • provided kits can optionally further comprise a second container comprising a pharmaceutically acceptable excipient for diluting or suspending a pharmaceutical composition or compound described herein.
  • the pharmaceutical compositions or compounds described herein disposed in the first container and the second container are combined to form one unit dosage form.
  • kits described herein further comprise instructions for using the compounds or pharmaceutical compositions contained in the kits.
  • the kits described herein may also include information required by regulatory agencies such as the US Food and Drug Administration (FDA).
  • FDA US Food and Drug Administration
  • the information included in the kit is prescribing information.
  • the kits and instructions provide for treating and/or preventing a proliferative disease in a subject in need thereof.
  • the kits described herein may contain one or more additional pharmaceutical formulations as separate compositions.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the eluent systems used in the column chromatography include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone and petroleum system
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C petroleum ether and ethyl acetate system
  • D acetone and petroleum system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • Compound 1 was prepared using starting material 1-1 according to the following route.
  • Compound 2 was prepared in a manner similar to that of Example 1, substituting the starting material (3-fluoro-2-hydroxyphenyl)benzeneboronic acid for 1-1(2-hydroxyphenyl) .
  • Example 2 A similar synthesis was followed in Example 1, except that 1-(bromomethyl)-4-chloro-2-fluorobenzene was used instead of compound 1-5(4-(bromomethyl)- Compound 3 was prepared in the same manner as in Example 1 except for 3-fluorobenzonitrile).
  • Compound 4 was prepared in a similar synthetic manner to Examples 1 and 3, substituting the starting material (3-fluoro-2-hydroxyphenyl)benzeneboronic acid for 1-1(2-hydroxyphenyl).
  • Compound 5 was prepared in a similar synthetic manner to Examples 1 and 3, substituting the starting material (2-hydroxy-3-methoxyphenyl)benzeneboronic acid for 1-1(2-hydroxyphenyl).
  • Example 8 A similar synthesis was followed in Example 1, except that 1-(bromomethyl)-2-fluoro-4-fluorobenzene was used in place of compound 1-5(4-(bromomethyl)- Compound 8 was prepared in the same manner as in Example 1 except for 3-fluorobenzonitrile).
  • Example 10 The synthesis was carried out in a similar manner to Example 1, except that 4-chloro-1-(1-chloroethyl)-2-fluorobenzene was used instead of compound 1-5(4-(bromomethyl) in step 3 in Example 1 )-3-fluorobenzonitrile), compound 10 was prepared in the same manner as in Example 1.
  • Compound 11 was prepared according to the synthetic method similar to Example 1.
  • Compound 12 was prepared according to the synthetic method similar to Example 1.
  • Compound 14 was prepared according to the synthetic method similar to Example 1.
  • Compound 15 was prepared in the same manner as in Example 1.
  • Compound 16 was prepared according to the synthetic method similar to Example 1.
  • Compound 17 was prepared according to the synthetic method similar to Example 1.
  • Compound 19 was prepared according to the synthetic method similar to Example 1.
  • Compound 20 was prepared according to the synthetic method similar to Example 1.
  • Compound 21 was prepared in the same manner as in Example 1.
  • Compound 22 was prepared according to the synthetic method similar to Example 1.
  • Compound 23 was prepared according to the synthetic method similar to Example 1.
  • Compound 24 was prepared in the same manner as in Example 1.
  • Compound 25 was prepared in the same manner as in Example 1.
  • Compound 26 was prepared in the same manner as in Example 1.
  • Compound 26 was prepared in the same manner as in Example 1.
  • Compound 28 was prepared in the same manner as in Example 1.
  • Compound 30 was prepared according to the synthetic method similar to Example 1.
  • the purpose of this experiment is to verify the agonistic activity of the compounds of the present invention on the human GLP-1R receptor.
  • OptiPlate-384 White, PerkinElmer (Cat#6007290); 384 well plate for Echo, Labcyte (Cat#P-05525); EnVision, PerkinElmer; Vi-cell counter, Beckman (Cat#Vi-CELL TM XR Cell Viability Analyzer)
  • the reference compound polypeptide GLP-1 (7-37) was diluted 4-fold starting from 500 nM in DMSO using Bravo for a total of 10 points.
  • GLP-1R cells were resuspended in assay buffer at a concentration of 2.0xE5/mL cells.
  • the compounds of the present invention show good GLP-1R receptor agonistic activity.
  • Drug preparation Take a certain amount of drug, add 2% Klucel LF + 0.1% Tween 80 aqueous solution, and prepare a clear solution or uniform suspension.
  • the rats were fasted overnight and then intragastrically administered at a dose of 10 mg/kg.
  • Rats were given intragastric administration, and blood was collected from the tail vein before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and placed in a heparinized sample tube at 4°C, 3500 The plasma was separated by centrifugation at rpm for 10 minutes, stored at -20°C, and fed 2 hours after administration.
  • Determination of the content of the test compound in rat plasma after drug administration 50 ⁇ L of plasma samples were thawed at room temperature, and 130 ⁇ L of internal standard working solution (1000 ng/mL, acetonitrile, tolbutamide) was added, and vortexed for about 1 min Then, centrifuge at 13000rpm for 10min at 4°C. 50 ⁇ L of supernatant was mixed with 100 ⁇ L of 50% acetonitrile water and injected into LC/MS/MS for analysis.
  • internal standard working solution 1000 ng/mL, acetonitrile, tolbutamide
  • the compounds of the present invention have better absorption, higher drug exposure in blood, and have very excellent drug metabolism properties.
  • cynomolgus monkeys as test animals, the drug concentrations in plasma of cynomolgus monkeys at different times after intravenous injection and oral administration of compounds were tested.
  • Each group of examples selected 2 cynomolgus monkeys with similar body weight, and the dose of intravenous injection was 1 mg/kg, and the dose of oral administration was 50 mg/kg, and the single dose was administered.
  • Age of cynomolgus monkeys at the time of administration about 2-4 years old; body weight: 3.0-4.6 kg at the start of administration; 4; sex: male.
  • Intravenous group take the test product with a final concentration of 0.5 mg/mL for intravenous administration, the preparation solvent is 5% DMSO+45% PEG400+50% water, and the preparation is a clear solution.
  • Oral group take the test product with a final concentration of 10 mg/mL for oral administration, the preparation solvent is 5% DMSO+45% PEG400+50% water, and the preparation is a homogeneous suspension solution.
  • Determination of the content of the test compound in the plasma of cynomolgus monkeys after drug administration After the blood samples are collected, they are placed in a marked ice-bath centrifuge tube, and the plasma is quickly separated by centrifugation. Centrifugation conditions: 4000 rpm, 10 minutes, 4 °C , and the plasma was stored under -40°C for testing.
  • the compound of the present invention has significantly better pharmacokinetic properties in cynomolgus monkeys under the same formulation and dosage. After oral administration, the compound of the present invention has higher blood exposure, still has high blood drug concentration after 24 hours, and has significantly better oral bioavailability, which is suitable for oral administration.

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Abstract

本发明涉及一类GLP-1R受体激动剂化合物及其用途。具体地，本发明公开了下式（I）表示的化合物或其药学上可接受的盐。所述化合物可以用于通过激活GLP-1R受体来治疗代谢性相关疾病，如糖尿病和非酒精性脂肪肝病。

Description

一类GLP-1R受体激动剂化合物及其用途
本申请要求于2020年12月03日向中国专利局提交的名称为“一类GLP-1R受体激动剂化合物及其用途”，申请号为202011406013.0的发明专利申请以及于2021年3月29日向中国专利局提交的名称为“一类GLP-1R受体激动剂化合物及其用途”，申请号为202110334388.9的发明专利申请的优先权权益，在此以引用方式并入本文中。
技术领域
本发明涉及药物合成领域，具体而言，涉及一类GLP-1R受体激动剂化合物及其用途。
背景技术
GLP-1受体(GLP-1 Receptor，GLP-1R)，是一种7次跨膜的G蛋白偶联受体B家族(分泌素家族)中的胰高血糖素受体亚家族，它广泛分布于胰腺及胰腺外组织，如中枢神经系统、心血管、胃肠道、肺、肾脏、甲状腺、皮肤、淋巴细胞、间充质干细胞等。
胰高血糖素样肽-1(GLP-1)是GLP-1R受体的天然配体，是一种多肽化合物。其有两种形式，分别为GLP-1(7-37)和GLP-1(7-36)酰胺，这两者仅有一个氨基酸序列不同，GLP-1约80％的循环活性来自GLP-1(7-36)酰胺。GLP-1由胰高血糖素原基因表达，在胰岛α细胞中，胰高血糖素原基因的主要表达产物是胰高血糖素，而在肠黏膜的L细胞中，前激素转换酶(PC1)将胰高血糖素原剪切为其羧基端的肽链序列，即GLP-1。GLP-1与GLP-1R受体结合可促进胰岛素的合成与分泌，同时也刺激β细胞增殖，抑制其凋亡。
GLP-1主要通过以下几方面发挥降糖作用。
1)保护胰岛β细胞的作用
GLP-1可作用于胰岛β细胞，促进胰岛素基因的转录、胰岛素的合成和分泌，并可刺激胰岛β细胞的增殖和分化，抑制胰岛β细胞凋亡，增加胰岛β细胞数量。
此外，GLP-1还可作用于胰岛α细胞，强烈地抑制胰高血糖素的释放，并作用于胰岛δ细胞，促进生长抑素的分泌，生长抑素又可作为旁分泌激素参与抑制胰高血糖素的分泌。
研究证明，GLP-1可通过多种机制明显地改善2型糖尿病动物模型或患者的血糖情况，其中，促进胰岛β细胞的再生和修复，增加胰岛β细胞数量的作用尤为显著。
2)葡萄糖浓度依赖性降糖作用
GLP-1具有葡萄糖浓度依赖性降糖作用，只有在血糖水平升高的情况下，GLP-1才发挥降糖作用，而在血糖水平正常时，则不会使其进一步降低。
3)减轻体重
GLP-1是通过多种途径产生降低体重的作用，包括抑制胃肠道蠕动和胃液分泌，抑制食欲及摄食，延缓胃内容物排空。GLP-1还可作用于中枢神经系统(特别是下丘脑)，从而使人体产生饱胀感和食欲下降。
诺和诺德公司近日公布的索马鲁肽(一种修饰的长效GLP-1多肽)临床3期结果表明，在所有随机化患者中，肥胖患者治疗68周后，索马鲁肽2.4mg治疗组从 平均基线体重105.3公斤下降14.9％、安慰剂组体重下降2.4％；索马鲁肽2.4mg组有86.4％的患者体重减轻≥5％、安慰剂组为31.5％。
正因为GLP-1通过作用于GLP-1R受体能显著改善代谢类疾病，国内外很多公司都研发了各种修饰或未修饰的GLP-1短效(一天三次)或长效(一天一次、一周一次)多肽药物，这包括：艾塞那肽、利拉鲁肽、阿必鲁肽、度拉糖肽、贝那鲁肽、利司那肽、索马鲁肽等。
然而，将GLP-1多肽及其修饰物应用于临床也面临着很多问题，天然的GLP-1极易被体内的二肽基肽酶Ⅳ(DPP-Ⅳ)降解，其血浆半衰期不足2分钟，必须持续静脉滴注或持续皮下注射才能产生疗效，这大大限制了GLP-1的临床应用。而修饰的GLP-1虽然能够延长半衰期，但口服生物利用度低，在口服用药方面仍然存在非常大的挑战，因此迫切需要开发能够口服的小分子GLP-1R受体激动剂药物。
WO2018109607公布了如下通式化合物及一个候选药物PF-06882961及Ref-01(原文献中化合物4A-01及3A-01，在下文中用作对照化合物)。
Figure PCTCN2021123505-appb-000001
出乎意料的是，相比于PF-06882961及Ref-01，本发明中绝大多数化合物在显示很好活性的同时，还显示了更好的体内药代性质，更适合作为药物开发。
WO2019239371公开了如下通式化合物及以下化合物Ref-02(原文献中实施例1，在下文中用作对照化合物)。
Figure PCTCN2021123505-appb-000002
出乎意料的是，相比于化合物Ref-02，本发明中的化合物不但活性高，而且也显示了更优良的药代性质。
发明内容
本发明的技术目的是提供一类具有GLP-1R受体激动活性的化合物。
根据本发明的一个方面，本发明提供了一种以下式(I)表示的化合物或其药学上可接受的盐，
Figure PCTCN2021123505-appb-000003
其中，
A是苯基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基；
R 1选自-H、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6 炔基、-C 6-10芳基或含有选自O或N中的一个或两个杂原子的-C 5-10杂芳基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
下标m是0、1、2或3的整数；
R 2、R 3各自独立选自-H、氘、C 1-6烷基；或者R 2、R 3与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的杂环烷基；
L选自-O-、-S-、-NR 11-或-C(R 11R 12)-；所述R 11、R 12为氢或-C 1-6烷基；
R 4选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
下标n是0、1或2的整数；
B选自：
Figure PCTCN2021123505-appb-000004
R 5选自-H、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
下标o是0、1或2的整数；
R 6、R 7各自独立地选自-H、氘、-C 1-6烷基；或者R 6、R 7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；或者R 6与其相连的碳原子以及B环一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；
R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C 4- 6杂环烷基；其中，所述-C 1-3烷基、亚甲基C 3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代；
Z选自N或CR 13；
R 9选自氢、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
下标p是0、1或2的整数；
R 10选自-COOH或羧基等排体；
R 13选自氢、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
所述卤素选自F、Cl和Br。
优选地，本发明化合物具有如下式(II)所示的结构：
Figure PCTCN2021123505-appb-000005
其中，
A是苯基或吡啶基；
R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
下标m是0、1或2的整数；
R 2、R 3各自独立地选自-H、氘、C 1-6烷基；
R 4选自卤素、-CN、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
下标n是0或1的整数；
B选自：
Figure PCTCN2021123505-appb-000006
R 5选自卤素、-OH、-C 1-6烷基或-C 1-6烷氧基；
下标o是0或1的整数；
R 6、R 7各自独立地选自-H、氘、C 1-6烷基；或者R 6、R 7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；
R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基；其中，所述-C 1-3烷基、亚甲基C 3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代；
Z选自N或CR 13；
R 13选自氢、卤素、-CN、-OH、氘、-C 1-6烷基或-C 1-6烷氧基。
进一步优选地，本发明化合物具有如下式(III)所示的结构：
Figure PCTCN2021123505-appb-000007
其中，
R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
下标m是1或2的整数；
A是苯基、吡啶基；
R 4选自卤素、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
下标n是0或1的整数；
B选自：
Figure PCTCN2021123505-appb-000008
R 5选自卤素、-OH、-C 1-6烷基或-C 1-6烷氧基；
下标o是0、1或2的整数；
R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基C 4-6杂环烷基。
更进一步优选地，本发明化合物具有如下式(IV)所示的结构：
Figure PCTCN2021123505-appb-000009
其中，
R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
下标m是1或2的整数；
A是苯基、吡啶基；
R 4选自卤素、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
下标n是0或1的整数；
B选自：
Figure PCTCN2021123505-appb-000010
R 5选自-C 1-6烷基；
下标o是0或1的整数。
更进一步优选地，由式(IV)表示的本发明化合物结构中，所述R 1选自-F、-Cl、-Br、-CN、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；
优选地，所述m是2；
优选地，所述A是苯基；
优选地，所述R 4选自-F、-Cl；
优选地，所述B选自：
Figure PCTCN2021123505-appb-000011
更进一步优选地，下标o是0。
更进一步优选地，根据本发明的所述化合物选自以下化合物之一：
Figure PCTCN2021123505-appb-000012
Figure PCTCN2021123505-appb-000013
根据本发明的另一个方面，本发明提供了一种药物组合物，所述药物组合物包括治疗有效量的根据本发明上述式(I)至式(IV)表示的化合物或其药学上可接受的盐作为活性成分，以及药学上可接受的辅料。
根据本发明的另一个方面，本发明提供了上述化合物或其药学上可接受的盐，或上述药物组合物作为活性成分在制备用于通过激活GLP-1R受体来治疗代谢相关疾病的药物中的用途。
在具体实施方式中，所述代谢相关疾病选自葡萄糖耐受不良、高血糖症、血脂异常、1型糖尿病(T1D)、2型糖尿病(T2D)、高甘油三酯血症、综合征X、胰岛素抵抗、葡萄糖耐量降低(IGT)、糖尿病性血脂异常、高脂血症，动脉硬化，动脉粥样硬化、高血压、肥胖症、非酒精性脂肪肝、非酒精性脂肪肝炎、肝纤维化、肝硬化、嗜睡等疾病中的任一种。
有益效果
本发明合成一类新型的GLP-1R受体激动剂化合物，通过药理实验证实该类化合物对GLP-1R受体具有很好的激动活性，因此可以用于GLP-1R受体相关代谢疾病的治疗。此外，本发明的化合物还显示出优异的药物代谢性质。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
根据本发明，如果无另外说明，这里引用的所有术语具有与那些本领域的熟练人员理解本发明相同的含义。
如本文所用的术语“盐”是指含阳离子和阴离子的化合物，其可通过可接受质子部位的质子化和/或可供质子部位的去质子化来产生。值得注意的是，可接受质子部位的质子化导致形成阳离子类物质，其电荷通过生理阴离子的存在而平衡，而可供质子部位的去质子化导致形成阴离子类物质，其电荷通过生理阳离子的存在而平衡。
术语“药学上可接受的盐”指所述盐是药学上可接受的。药学上可接受的盐的例子包括但不限于：(1)酸加成盐，与无机酸形成，如盐酸、氢溴酸、硫酸、硝酸、磷酸等等；或与有机酸形成，如羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4对甲苯磺酸、樟脑酸、十二烷基硫酸、葡萄糖酸、谷氨酸、水杨酸、顺式-已二烯二酸等等；或(2)碱加成盐，和上述无机酸的任一种的共轭碱形成，其中共轭碱包含选自Na +、K +、Mg 2+、Ca 2+、NH xR 4-x +中的阳离子组分，其中NH xR 4-x +(R是C 1-4烷基，下标x是选自0、1、2、3或4的整数)表示季铵盐中的阳离子。应该理解，所有涉及药学上可接受的盐都包括相同酸加成盐的本文中所定义的溶剂加成形式(溶剂化物)或晶体形式(多晶型物)。
术语“C 1-M烷基”是指包含1-M个碳原子的烷基，例如其中M是具有下列数值的整数：2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30。例如术语“C 1-6烷基”是指含有1-6个碳原子的烷基。烷基的例子包括但不限于低级烷基，包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基。
术语“C 3-M环烷基”是指包含3-M个碳原子的环烷基，例如其中M是具有下列数值的整数：4、5、6、7、8。例如术语“C 3-6环烷基”是指含有3-6个碳原子的环烷基。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳香基”指芳族体系，可以是单环或原本稠合的或连接在一起的多芳环，从而使至少一部分稠合或连接的环形成共轭的芳系。芳基基团包括但不限制于：苯基、萘基、四氢萘基。芳基可被任选取代，如可被1-4个选自下组的基团所取代的芳基或杂环：卤素、-CN、-OH、-NO 2、氨基、烷基、环烷基、链烯基、炔基、烷氧基、芳氧基、取代的烷氧基、烷基羰基、烷基羧基、烷基氨基或芳硫基。
术语“取代”指参考基团可以被一个或多个额外基团所取代，额外基团单独地且独立的选自于，烷基，环烷基，芳基，杂芳基，杂脂环烃，羟基，烷氧基，烷硫基，芳硫基，烷亚砜基，芳亚砜基，烷砜基，芳砜基，氰基，卤基，羰基，硫代羰基，硝基，卤烷基，氟烷基和氨基，包括单取代和双取代的氨基基团及其被保护的衍生物。
本发明所提供的由式(I)表示的化合物或其药学上可接受的盐，和包含该化合物的药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。例如其制剂配方的单位剂量中包含0.05-200mg式(I)的化合物或其药学上可接受的盐，优选地，制剂配方的单位剂量中包含0.1mg-100mg式(I)的化合物。
本发明的由式(I)表示的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明中，术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。
典型的配方是通过混合本发明的式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物以可被接受的形式制造或使用。
本发明所述的如式(I)的化合物与至少一种其它药物的组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中，本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其药物组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等)；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
本发明的由式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
此外，本公开还涵盖了试剂盒(例如制药包装)。提供的试剂盒可以包含本文所述的药物组合物或化合物和容器(例如，药瓶、安瓿、瓶子、注射器和/或分装包装或其它合适的容器)。在一些实施方式中，提供的试剂盒可以任选地进一步包括第二容器，其包含用于稀释或悬浮本文所述的药物组合物或化合物的药用赋形剂。在一些实施方式中，设置在第一容器和第二容器中的本文所述的药物组合物或化合物组合形成一个单元剂量形式。
在某些实施方式中，本文所述试剂盒进一步包括包含于试剂盒中的用于使用所述化合物或药物组合物的用法说明。本文所述的试剂盒还可以包括管理机构(如美国食品药品监督管理局(FDA))所要求的信息。在某些实施方式中，在试剂盒中包括的信息为处方信息。在某些实施方式中，试剂盒和用法说明提供用于治疗需要其的受试者的增殖性疾病和/或预防需要其的受试者的增殖性疾病。本文所述的试剂盒可以包含一种或多种额外的药物制剂作为单独的组合物。
以下结合具体的实施例对本发明作进一步详细的说明，但本发明不限于以下实施例，实施例是为了更好的阐释本发明的某些具体体现而不能被解释为以任何方式限定本发明的范围。实施例中未注明的条件为常规条件。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。
以下实施例中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的测定使用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，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)。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
实施例中采用的柱层析的洗脱机体系包括有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮和石油醚体系，溶剂的体积比例根据化合物的极性不同而进行调节。
实验中所用缩写语：D：氘；h：小时；min：分钟；EA：乙酸乙酯；DMF：N,N-二甲基酰胺；ml：毫升；mmol：摩尔；Cs 2CO 3：碳酸铯；PdCl 2(dtbpf)：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；Boc：叔丁氧羰基；THF：四氢呋喃；DCM：二氯甲烷；DIPEA：二异丙基乙胺；TFA：三氟醋酸；TEA：三乙胺；THF：四氢呋喃；TBD：1,5,7-三氮杂二环[4.4.0]癸-5-烯；N：摩尔每升。
实施例1：化合物1的制备
Figure PCTCN2021123505-appb-000014
按照如下路线利用起始原料1-1制备化合物1。
Figure PCTCN2021123505-appb-000015
步骤1：中间体1-3的合成
将原料1-1(1.25g，9.0mmol)溶于二氧六环(10mL)中，加入中间体1-2(3.00g，9.0mmol)，Cs 2CO 3(4.42g，13.5mmol)，Pd(dppf)Cl 2(0.40g，5.4mmol),加热至100℃反应过夜。反应完全后，冷至室温，加入10mL水和20mL EA萃取，干燥浓缩有机相，柱层析得中间体1-3(1.90g，76％)。
1H NMR(400MHz,CDCl 3):7.20-7.09(m,2H),6.91-6.89(m,2H),5.85(brs,1H),4.08(brs,2H),3.64(t,J＝8.0Hz,2H),2.47(brs,2H),1.50(s,9H)；
MS m/z(ESI):276.1[M+1].
步骤2：中间体1-4的合成
将中间体1-3(400mg，1.45mmol)加入甲醇(6.0mL)中，加入5％Pd/C(80mg，20％)，室温反应过夜。反应完全后，过滤，滤液浓缩得到氢化产物1-4(320mg,75％)。
1H NMR(400MHz,CDCl 3):7.12-7.05(m,2H),6.87(t,J＝8.0Hz,1H),6.80(t,J＝8.0Hz,1H),4.23(brs,2H),3.09-3.02(m,1H),2.83(brs,2H),1.84-1.81(m,2H),1.65-1.59(m,2H),1.49(s,9H)；
步骤3：中间体1-6的合成
将中间体1-4(320mg，1.15mmol)、取代的苄溴化合物1-5(247mg，1.15mmol)溶于乙腈(10ml)中，加入碳酸钾(319mg，2.31mmol)，室温反应过夜。反应完成后，浓缩，加入10mL水，用EA萃取两次，无水硫酸钠干燥，浓缩得到白色固体粗品1-6(370mg,78％)
1H NMR(400MHz,CDCl 3):7.64(t,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.21-7.15(m,2H),7.02(t,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),5.21(s,2H),4.24(brs,2H),3.16-3.10(m,1H),2.82(brs,2H),1.83-1.80(m,2H),1.66-1.59(m,2H),1.48(s,9H).
步骤4：中间体1-7的合成
将中间体1-6(350mg，0.85mmol)加入DCM(20mL)中，加入TFA(2.0mL)，室温反应2.0h。反应完全后，浓缩，加入EA，用饱和碳酸氢钠水溶液调pH到8，分液，有机相干燥浓缩得中间体1-8(270mg)，无需纯化直接投入下一步反应.
步骤5：中间体1-9的合成
将中间体1-7(270mg，0.87mmol)、氯代物1-8(205mg，0.69mmol，参照WO2018109607合成)溶于二氧六环(6mL)中，加入DIPEA(393mg，3.0mmol)，加热到50℃反应，反应结束后，加入H 2O(5mL)和EA(15mL)萃取，干燥浓缩，柱层析纯化得中间体1-9(200mg,40％)。
1H NMR(400MHz,CDCl 3):8.18(s,1H),7.98(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.24-7.16(m,2H),7.01(t,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),5.26-5.23(m,1H),5.20(s,2H),4.76-4.61(m,3H),4.44-4.40(m,1H),4.00(s,2H),3.95(s,3H),3.07-2.98(m,3H),2.77-2.75(m,1H),2.50-2.45(m,1H),2.35-2.28(m,2H),1.85-1.83(m,2H),1.76-1.71(m,2H).
MS m/z(ESI):569.2[M+1].
步骤6：化合物1的合成
将中间体1-9(100mg，0.17mmol)加入MeCN/THF(4mL/4mL)的混合溶剂中，加入0.97N六元二环胍(TBD)(0.4mL)，室温反应过夜。继续补加0.97N TBD(1.0mL)反应2h。浓缩溶剂，加入水(6.0mL)，用1N柠檬酸水溶液调体系pH到5-6，加入EA(10mL),萃取得有机相，干燥浓缩，柱层析纯化得化合物1(70mg,72％)
1H NMR(400MHz,DMSO-d 6):12.74(brs,1H),8.28(s,1H),7.96(d,J＝8.0Hz,1H),7.80-7.74(m,3H),7.65(t,J＝8.0Hz,1H),7.22(t,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),5.25(s,2H),5.10(s,1H),4.82-4.79(m,1H),4.69-4.65(m,1H),4.51-4.48(m,1H),4.39-4.36(m,1H),4.04-3.94(m,1H),3.82-3.79(m,1H),3.01-2.89(m,3H),2.70-2.68(m,1H),2.45-2.43(m,1H),2.24-2.18(m,2H),1.70-1.60(m,4H).
MS m/z(ESI):555.1[M+1].
实施例2：化合物2的制备
Figure PCTCN2021123505-appb-000016
按照实施例1类似的合成方式，用起始原料(3-氟-2-羟基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物2。
1H NMR(400MHz,DMSO-d 6):8.19(s,1H),7.84(d,J＝8.0Hz,1H),7.74-7.66(m,3H),7.58(d,J＝8.0Hz,1H),7.06-6.96(m,3H),5.08(s,2H),5.01-4.99(m,1H),4.74-4.68(m,1H),4.58-4.55(m,1H),4.42-4.40(m,1H),4.29-4.27(m,1H),3.87(d,J＝16.0Hz,1H),3.72(d,J＝16.0Hz,1H),2.90-2.87(m,1H),2.76-2.63(m,3H),2.35-2.30(m,1H),2.04-1.91(m,2H),1.51-1.39(m,4H).
MS m/z(ESI):573.1[M+1].
实施例3：化合物3的制备
Figure PCTCN2021123505-appb-000017
按照实施例1类似的合成方式，除了在实施例1中的步骤3中采用1-(溴甲基)-4-氯-2-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外，以与实施例1中相同的方法制备得化合物3。
1H NMR(400MHz,DMSO-d 6):8.19(s,1H),7.74(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.51-7.47(m,2H),7.44(d,J＝8.0Hz,1H),7.11-7.08(m,2H),7.01(d,J＝8.0Hz,1H),6.87-6.84(m,1H),5.06(s,2H),5.01-4.99(m,1H),4.74-4.70(m,1H),4.58-4.55(m,1H), 4.42-4.40(m,1H),4.29-4.27(m,1H),3.87-3.75(m,2H),2.95-2.92(m,1H),2.79-2.70(m,2H),2.68-2.64(m,1H),2.35-2.31(m,1H),2.11-2.00(m,2H),1.60-1.55(m,4H).
MS m/z(ESI):564.2[M+1].
实施例4：化合物4的制备
Figure PCTCN2021123505-appb-000018
按照实施例1和3的类似合成方式，用起始原料(3-氟-2-羟基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物4。
1H NMR(400MHz,DMSO-d 6):12.74(brs,1H),8.28(s,1H),7.82(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.54-7.52(m,2H),7.36(d,J＝8.0Hz,1H),7.13-7.04(m,3H),5.08(s,2H),4.83-4.77(m,1H),4.67-4.64(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),4.04-3.92(m,2H),3.80-3.77(m,1H),2.95-2.90(m,1H),2.84-2.73(m,3H),2.43-2.40(m,1H),2.09-2.00(m,2H),1.58-1.41(m,4H).
MS m/z(ESI):582.0[M+1].
实施例5：化合物5的制备
Figure PCTCN2021123505-appb-000019
按照实施例1和3的类似合成方式，用起始原料(2-羟基-3-甲氧基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物5。
MS m/z(ESI):594.1[M+1].
实施例6：化合物6的制备
Figure PCTCN2021123505-appb-000020
按照实施例1和3的类似合成方式，用起始原料(2-羟基-3-甲氧基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物6。
1H NMR(400MHz,DMSO-d 6):12.71(brs,1H),8.27(s,1H),7.81(d,J＝8.0Hz,1H),7.79-7.54(m,3H),7.38(d,J＝8.0Hz,1H),7.23-7.21(m,1H),6.98(d,J＝8.0Hz,1H),6.77(d,J＝8.0Hz,1H),5.17(s,2H),5.10-5.05(m,1H),4.77-4.71(m,1H),4.62-4.58(m,1H),4.49-4.45(m,1H),4.38-4.36(m,1H),3.92-3.88(m,1H),3.77-3.74(m,1H),3.06-3.02(m,1H),2.95-2.93(m,1H),2.81-2.79(m,1H),2.67-2.63(m,1H),2.41-2.36(m,1H),2.13-2.00(m,4H),1.60-1.58(m,2H).
MS m/z(ESI):582.2[M+1].
实施例7：化合物7的制备
Figure PCTCN2021123505-appb-000021
将30mg化合物4溶解于5mL甲醇中，加入6mg Pd/C，室温氢化过夜，过滤浓缩得到化合物7(29mg)。
MS m/z(ESI):548.2[M+1].
实施例8：化合物8的制备
Figure PCTCN2021123505-appb-000022
按照实施例1类似的合成方式，除了在实施例1中的步骤3中采用1-(溴甲基)-2-氟-4-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外，以与实施例1中相同的方法制备得化合物8。
1H NMR(400MHz,DMSO-d 6):12.77(brs,1H),8.28(s,1H),7.82(d,J＝8.0Hz,1H),7.66-7.60(m,2H),7.37-7.32(m,1H),7.20-7.09(m,4H),6.95-6.92(m,1H),5.13(s,2H),5.05-4.99(m,1H),4.82-4.77(m,1H),4.67-4.64(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96-3.92(m,1H),3.81-3.77(m,1H),3.00-2.97(m,1H),2.87-2.84(m,2H),2.71-2.69(m,1H),2.44-2.40(m,1H),2.22-2.10(m,2H),1.67-1.58(m,4H).
MS m/z(ESI):548.2[M+1].
实施例9：化合物9的制备
Figure PCTCN2021123505-appb-000023
按照实施例1类似的合成方式，除了在实施例1中的步骤3中采用2-(溴甲基)-5-氯吡啶替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外，以与实施例1中相同的方法制备得化合物9。
1H NMR(400MHz,DMSO-d 6):12.83(brs,1H),8.66(s,1H),8.35-8.39(m,2H),8.10-8.05(m,1H),7.90-7.83(m,1H),7.66-7.56(m,2H),7.21-7.14(m,2H),7.01(d,J＝8.0Hz,1H),5.21(s,2H),5.12-5.05(m,1H),4.82-4.75(m,1H),4.67-4.60(m,1H),4.53-4.49(m,1H),4.38-4.36(m,1H),4.00-3.87(m,1H),3.76-3.74(m,1H),3.01-2.86(m,3H),2.71-2.65(m,1H),2.44-2.22(m,2H),1.95-1.89(m,1H),1.77-1.63(m,4H).MS m/z(ESI):547.2[M+1].
实施例10:化合物10的制备
Figure PCTCN2021123505-appb-000024
按照实施例1类似的合成方式，除了在实施例1中的步骤3中采用4-氯-1-(1-氯乙基)-2-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外，以与实施例1中相同的方法制备得化合物10。
1H NMR(400MHz,DMSO-d 6):12.71(brs,1H),8.30(s,1H),7.84(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.48-7.44(m,2H),7.31(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.06(t,J＝8.0Hz,1H),6.87(t,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),5.65(q,J＝8.0Hz,1H),5.12-5.10(m,1H),4.74-4.70(m,1H),4.51-4.48(m,1H),4.40-4.37(m,1H),4.04-3.99(m,1H),3.87-3.75(m,1H),2.98-2.90(m,3H),2.72-2.70(m,1H),2.43-2.41(m,1H),2.35-2.30(m,2H),1.68-1.65(m,4H),1.61(d,J＝8.0Hz,3H).
MS m/z(ESI):578.2[M+1].
实施例11:化合物11的制备
Figure PCTCN2021123505-appb-000025
按照实施例1类似的合成方式，制备得化合物11。
1H NMR(400MHz,DMSO-d 6):12.72(brs,1H),8.28(s,1H),7.78(d,J＝8.0Hz,1H),7.72(s,1H),7.64(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.22-7.18(m,2H),7.06(d,J＝8.0Hz,1H),6.96-6.93(m,1H),5.15(s,2H),5.10-5.05(m,1H),4.81-4.77(m,1H),4.67-4.63(m,1H),4.50-4.48(m,1H),4.37-4.33(m,1H),4.02-3.93(m,2H),3.82-3.80(m,1H),3.00-2.88(m,3H),2.69-2.65(m,1H),2.43-2.39(m,1H),2.22-2.16(m,2H),1.70-1.61(m,4H).
MS m/z(ESI):580.2[M+1].
实施例12:化合物12的制备
Figure PCTCN2021123505-appb-000026
按照实施例1类似的合成方式，制备得化合物12。
1H NMR(400MHz,DMSO-d 6):12.77(brs,1H),8.29(s,1H),7.83(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.43-7.40(m,1H),7.19-7.17(m,2H),7.11-7.05(m,3H),6.92-6.90(m,1H),5.10(s,2H),4.81-4.79(m,1H),4.67-4.63(m,1H),4.37-4.36(m,1H),4.04-3.84(m,3H),3.02-2.97(m,1H),2.89-2.84(m,2H),2.73-2.65(m,1H),2.43-2.40(m,1H),2.33(s,3H),2.22-2.16(m,2H),1.69-1.60(m,4H).
MS m/z(ESI):544.2[M+1].
实施例13:化合物13的制备
Figure PCTCN2021123505-appb-000027
按照实施例1类似的合成方式，制备得化合物13。
1H NMR(400MHz,DMSO-d 6):12.72(brs,1H),8.28(s,1H),7.81(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.61-7.53(m,2H),7.39(d,J＝8.0Hz,1H),7.22-7.18(m,1H),7.05-7.02(m,1H),6.77-6.73(m,1H),5.17(s,2H),5.08-5.05(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.51-4.46(m,1H),4.39-4.35(m,1H),3.96-3.93(m,1H),3.81-3.78(m,1H),2.99-2.97(m,1H),2.84-2.68(m,3H),2.40-2.38(m,1H),2.19-2.14(m,2H),1.66-1.63(m,4H)；
MS m/z(ESI):582.2[M+1].
实施例14:化合物14的制备
Figure PCTCN2021123505-appb-000028
按照实施例1类似的合成方式，制备得化合物14。
1H NMR(400MHz,DMSO-d 6):12.67(brs,1H),8.28(s,1H),7.82(d,J＝8.0Hz,1H),7.66(d,J＝8.0Hz,1H),7.59-7.51(m,2H),7.38(d,J＝8.0Hz,1H),7.13-7.09(m,1H),7.04-7.00(m,2H),5.13(s,2H),5.09-5.07(m,1H),4.83-4.76(m,1H),4.67-4.63(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),4.04-4.02(m,1H),4.00-3.95(m,1H),3.92-3.85(m,1H),3.00-2.96(m,1H),2.85-2.80(m,2H),2.72-2.70(m,1H),2.45-2.41(m,1H),2.22-2.21(m,2H),1.66-1.62(m,4H)
MS m/z(ESI):582.2[M+1].
实施例15:化合物15的制备
Figure PCTCN2021123505-appb-000029
按照实施例1类似的合成方式，制备得化合物15。
1H NMR(400MHz,DMSO-d 6):12.72(brs,1H),8.29(s,1H),7.83(d,J＝8.0Hz,1H),7.67(s,1H),7.41(d,J＝12.0Hz,1H),7.30-7.22(m,2H),7.05(d,J＝8.0Hz,1H),6.93-6.90(m,1H),6.58-6.56(m,1H),6.32(d,J＝8.0Hz,1H),5.84(brs,1H),5.11-5.10(m,1H),4.86-4.80(m,1H),4.70-4.67(m,1H),4.51-4.50(m,1H),4.36-4.33(m,3H),4.04-3.99(m,2H),3.86-3.83(m,1H),3.05-3.02(m,1H),2.92-2.85(m,1H),2.75-2.70(m,2H),2.42-2.34(m,3H),1.83-1.77(m,2H),1.60-1.55(m,2H).
MS m/z(ESI):563.2[M+1].
实施例16:化合物16的制备
Figure PCTCN2021123505-appb-000030
按照实施例1类似的合成方式，制备得化合物16。
MS m/z(ESI):577.2[M+1].
实施例17:化合物17的制备
Figure PCTCN2021123505-appb-000031
按照实施例1类似的合成方式，制备得化合物17。
MS m/z(ESI):580.2[M+1].
实施例18:化合物18的制备
Figure PCTCN2021123505-appb-000032
按照实施例1类似的合成方式，制备得化合物18。
1H NMR(400MHz,DMSO-d 6):8.24(s,1H),7.83(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.57-7.54(m,1H),7.42-7.39(m,1H),7.30-7.28(m,1H),7.02-6.99(m,1H),6.95-6.90(m,3H),5.07(s,2H),4.77-4.70(m,2H),4.61-4.57(m,2H),4.48-4.44(m,2H),4.33-4.30(m,2H),2.98-2.94(m,3H),2.67-2.65(m,1H),2.62-2.56(m,3H),2.40-2.35(m,2H).
MS m/z(ESI):565.2[M+1].
实施例19:化合物19的制备
Figure PCTCN2021123505-appb-000033
按照实施例1类似的合成方式，制备得化合物19。
MS m/z(ESI):564.2[M+1].
实施例20:化合物20的制备
Figure PCTCN2021123505-appb-000034
按照实施例1类似的合成方式，制备得化合物20。
1H NMR(400MHz,DMSO-d 6):12.74(brs,1H),8.24(s,1H),7.80(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.47-7.44(m,4H),7.33-7.31(m,4H),7.23-7.20(m,2H),7.06-7.00(m,1H),5.14(s,2H),4.91-4.88(m,1H),4.68-4.62(m,1H),4.54-4.50(m,1H),4.45-4.40(m,3H),4.34-4.31(m,1H),2.59-2.55(m,1H),2.30-2.34(m,1H).
MS m/z(ESI):557.1[M+1].
实施例21:化合物21的制备
Figure PCTCN2021123505-appb-000035
按照实施例1类似的合成方式，制备得化合物21。
MS m/z(ESI):563.2[M+1].
实施例22:化合物22的制备
Figure PCTCN2021123505-appb-000036
按照实施例1类似的合成方式，制备得化合物22。
MS m/z(ESI):565.2[M+1].
实施例23:化合物23的制备
Figure PCTCN2021123505-appb-000037
按照实施例1类似的合成方式，制备得化合物23。
MS m/z(ESI):590.2[M+1].
实施例24:化合物24的制备
Figure PCTCN2021123505-appb-000038
按照实施例1类似的合成方式，制备得化合物24。
MS m/z(ESI):508.1[M+1].
实施例25:化合物25的制备
Figure PCTCN2021123505-appb-000039
按照实施例1类似的合成方式，制备得化合物25。
MS m/z(ESI):602.2[M+1].
实施例26:化合物26的制备
Figure PCTCN2021123505-appb-000040
按照实施例1类似的合成方式，制备得化合物26。
MS m/z(ESI):566.2[M+1].
实施例27:化合物27的制备
Figure PCTCN2021123505-appb-000041
按照实施例1类似的合成方式，制备得化合物26。
MS m/z(ESI):566.2[M+1].
实施例28:化合物28的制备
Figure PCTCN2021123505-appb-000042
按照实施例1类似的合成方式，制备得化合物28。
MS m/z(ESI):578.2[M+1].
实施例29:化合物29的制备
Figure PCTCN2021123505-appb-000043
按照实施例1类似的合成方式，制备得化合物29。
MS m/z(ESI):578.2[M+1].
实施例30:化合物30的制备
Figure PCTCN2021123505-appb-000044
按照实施例1类似的合成方式，制备得化合物30。
MS m/z(ESI):592.2[M+1].
测试实施例1：GLP-1R cAMP Assay活性试验
本实验旨在验证本发明化合物对人GLP-1R受体的激动活性。
主要试剂：
cAMP Detection Kit,Cisbio(Cat#62AM4PEJ)
1M HEPES,Invitrogen(Cat#15630-106)
1X HBSS,Invitrogen(Cat#14025)
BSA,Sigma(Cat#B2064-100G)
IBMX,Sigma(Cat#I5879)
7-37,Hao Yuan(Cat#HY-P0055)
培养基：
靶点 宿主细胞系 克隆
GLP-1R HEK293 N/A
主要耗材与仪器：
OptiPlate-384,White,PerkinElmer(Cat#6007290)；
384 well plate for Echo,Labcyte(Cat#P-05525)；
EnVision,PerkinElmer；
Vi-cell counter,Beckman(Cat#Vi-CELL TM XR Cell Viability Analyzer)
实验方法：
a)化合物源板的准备：
使用Bravo在DMSO中从100uM开始4倍稀释化合物，共10点。
使用Bravo在DMSO中从500nM开始4倍稀释参比化合物多肽GLP-1(7-37)，共10点。
b)细胞悬浮液的制备：
1)在37℃水浴中快速解冻1小瓶GLP-1R细胞。
2)将细胞悬浮液转移到15ml锥形管中的10ml HBSS中。
3)在室温下以1000rpm离心细胞5分钟以沉淀细胞
4)轻轻吸出上清液，小心不要吸出细胞。
5)轻弹沉淀使细胞松弛，然后将细胞沉淀重悬于10ml HBSS中。使用无菌移液器上下移液以清除团块。
6)计数细胞的浓度并确定Vi-cell上的细胞活力。
7)将GLP-1R细胞以2.0xE5/mL细胞的浓度重新悬浮在测试缓冲液中。
8)将10μLGLP-1R细胞转移到OptiPlate-384孔板中。
c)化合物的转移：
1)使用Echo Transfer将100nL化合物转移到OptiPlate-384板上。
2)以1000rpm旋转平板5秒钟。
d)激动剂的HTRF cAMP分析：
1)在添加检测试剂之前，将板在室温下孵育30分钟。
2)使用电动多通道移液器分别添加10μL检测试剂。
3)用TopSeal-A膜覆盖384孔板，并在室温下孵育60分钟。
卸下TopSeal-A，在EnVision上阅读。
具体测试数据见下表1。
表1
化合物 EC 50,(nM) 化合物 EC 50,(nM) 化合物 EC 50,(nM)
1 3.4 2 0.8 3 0.9
4 0.7 5 15 6 8.1
7 5 8 3.2 9 34.8
10 26 11 2.9 12 1.0
13 5.8 14 3.7 15 7.5
16 >100 17 53 18 10.7
19 >100 20 24.6 21 >100
22 2.1 23 >100 24 >100
25 >100 26 1.8 27 2.3
28 >100 29 >100 30 >100
PF-06882961 0.8 Ref-01 1 Ref-02 1
结论：本发明中的化合物显示了很好的GLP-1R受体激动活性。
测试实施例2：大鼠药代动力学评价：
以大鼠为受试动物，测试了大鼠灌胃给予化合物后不同时刻血浆中药物浓度。研究本发明化合物在大鼠体内药物代谢动力学行为，评价其药物代谢特征。每组实施例选用3只体重相近的大鼠，口服给予剂量为10mg/kg，单次给药。动物给药后在15min、30min、1h、2h、4h、6h、8h、12h、24h时间点采集血液。采用LC-MS/MS分析方法检测血浆中化合物含量，方法的定量下限均为20ng/mL。使用代谢动力学数据分析软件WinNonlin 7.0对血浆中的浓度数据进行统计，利用非房室模型法(NCA)计算药代参数，具体见下表2。
实验方案：
实验药品：本发明化合物及对照化合物。
药物配置：取一定量药物，加入2％Klucel LF+0.1％Tween 80水溶液，配制成呈澄清溶液或均匀悬浮液。
给药：大鼠禁食过夜后灌胃给药，给药剂量为10mg/kg。
操作：大鼠灌胃给药，于给药前及给药后15min、30min、1h、2h、4h、6h、8h、12h、24h尾静脉采血，置于肝素化样品管中，4℃，3500转/分钟离心10分钟分离血浆，于-20℃保存，给药后2小时进食。
测定药物灌胃给药后大鼠血浆中待测化合物的含量：血浆样品室温解冻后分别取50μL，加入130μL的内标工作液(1000ng/mL，乙腈，甲苯磺丁脲)，涡旋约1min后，4℃，13000rpm条件下离心10min。取50μL上清液与100μL 50％乙腈水混合后进样LC/MS/MS分析。
药代动力学参数结果见表2。
表2：大鼠药物代谢数据
Figure PCTCN2021123505-appb-000045
结论：相比于对照化合物PF-06882961及Ref-01、Ref-02，本发明的化合物吸收更好，血液中药物的暴露量更高，具有非常优异的药物代谢性质。
测试实施例3：食蟹猴药代动力学评价
以食蟹猴为受试动物，测试了食蟹猴静注与口服给予化合物后不同时刻血浆中药物浓度。研究本发明化合物在食蟹猴体内药物代谢动力学行为，评价其药物代谢特征。每组实施例选用2只体重相近的食蟹猴，静注给予剂量为1mg/kg，口服给予剂量为50mg/kg，单次给药。
给药时食蟹猴周龄：约2-4周岁；体重：给药开始时3.0-4.6kg；4只；性别：雄性。
静脉组：取配制终浓度为0.5mg/mL的供试品用于静脉给药，配制溶剂为5％DMSO+45％PEG400+50％水，制剂呈澄清溶液。
口服组：取配制终浓度为10mg/mL的供试品用于口服给药，配制溶剂为5％DMSO+45％PEG400+50％水，制剂呈均一混悬溶液。
动物给药后在5min、15min、30min、1h、2h、4h、7h、12h、24h时间点采集血液。采用LC-MS/MS分析方法检测血浆中化合物含量，方法的定量下限均为20ng/mL。使用代谢动力学数据分析软件WinNonlin 7.0对血浆中的浓度数据进行统计，利用非房室模型法(NCA)计算药代参数，具体见下表3。
测定药物给药后食蟹猴血浆中待测化合物的含量：血液样本采集后放置于标记好的冰浴离心管中，迅速离心分离出血浆，离心条件：4000转/分钟，10分钟，4℃，血浆置于-40℃以下条件保存待测。
药代动力学参数结果见表3。
Figure PCTCN2021123505-appb-000046
结论：相比于对照化合物PF-06882961，在相同制剂和给药剂量下，在食蟹猴中，本发明化合物具有明显更优的药代性质。口服本发明化合物后，具有更高的血液暴露量，24小时后仍然具有很高的血药浓度，口服生物利用度明显更好，适合口服给药。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种以下式(I)表示的化合物或其药学上可接受的盐，
    Figure PCTCN2021123505-appb-100001
    其中，
    A是苯基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基；
    R 1选自-H、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、-C 6-10芳基或含有选自O或N中的一个或两个杂原子的-C 5-10杂芳基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
    下标m是0、1、2或3的整数；
    R 2、R 3各自独立选自-H、氘、C 1-6烷基；或者R 2、R 3与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的杂环烷基；
    L选自-O-、-S-、-NR 11-或-C(R 11R 12)-；所述R 11、R 12为氢或-C 1-6烷基；
    R 4选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
    下标n是0、1或2的整数；
    B选自：
    Figure PCTCN2021123505-appb-100002
    R 5选自-H、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
    下标o是0、1或2的整数；
    R 6、R 7各自独立地选自-H、氘、-C 1-6烷基；或者R 6、R 7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；或者R 6与其相连的碳原子以及B环一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；
    R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基；其中，所述-C 1-3烷基、亚甲基C 3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代；
    Z选自N或CR 13；
    R 9选自氢、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
    下标p是0、1或2的整数；
    R 10选自-COOH或羧基等排体；
    R 13选自氢、卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基可以被0-3个F取代；
    所述卤素选自F、Cl和Br。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物或其药学上可接受的盐具有如下式(II)所示的结构：
    Figure PCTCN2021123505-appb-100003
    其中，
    A是苯基或吡啶基；
    R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
    下标m是0、1或2的整数；
    R 2、R 3各自独立地选自-H、氘、C 1-6烷基；
    R 4选自卤素、-CN、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
    下标n是0或1的整数；
    B选自：
    Figure PCTCN2021123505-appb-100004
    R 5选自卤素、-OH、-C 1-6烷基或-C 1-6烷氧基；
    下标o是0、1或2的整数；
    R 6、R 7各自独立地选自-H、氘、C 1-6烷基；或者R 6、R 7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基；
    R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基；其中，所述-C 1-3烷基、亚甲基C 3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C 4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代；
    Z选自N或CR 13；
    R 13选自氢、卤素、-CN、-OH、氘、-C 1-6烷基或-C 1-6烷氧基。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物或其药学上可接受的盐具有如下式(III)所示的结构：
    Figure PCTCN2021123505-appb-100005
    其中，
    R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
    下标m是1或2的整数；
    A是苯基、吡啶基；
    R 4选自卤素、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
    下标n是0或1的整数；
    B选自：
    Figure PCTCN2021123505-appb-100006
    R 5选自卤素、-OH、-C 1-6烷基或-C 1-6烷氧基；
    下标o是0、1或2的整数；
    R 8选自-C 1-3烷基、-亚甲基C 3-6环烷基或-亚甲基C 4-6杂环烷基。
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物或其药学上可接受的盐具有如下式(IV)所示的结构：
    Figure PCTCN2021123505-appb-100007
    其中，
    R 1选自卤素、-CN、-OH、氘、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、所述-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基可以被0-3个F取代；
    下标m是1或2的整数；
    A是苯基、吡啶基；
    R 4选自卤素、-OH、氘、-C 1-6烷基或-C 1-6烷氧基；
    下标n是0或1的整数；
    B选自：
    Figure PCTCN2021123505-appb-100008
    R 5选自-C 1-6烷基；
    下标o是0或1的整数。
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其特征在于，由式(IV)表示的所述化合物或其药学上可接受的盐结构中，所述R 1选自-F、-Cl、-Br、-CN、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基或-C 2-6炔基；
    下标m是2；
    A是苯基；
    R 4选自-F、-Cl；
    B是
    Figure PCTCN2021123505-appb-100009
  6. 根据权利要求4所述的化合物或其药学上可接受的盐，其特征在于，下标o是0。
  7. 根据权利要求1至6所述的化合物或其药学上可接受的盐，其中，所述化合物选自以下化合物之一：
    Figure PCTCN2021123505-appb-100010
  8. 一种药物组合物，所述药物组合物包括治疗有效量的根据权利要求1至7中任意一项所述的化合物或其药学上可接受的盐作为活性成分，以及药学上可接受的辅料。
  9. 根据权利要求1至4中任意一项所述的化合物或其药学上可接受的盐或根据权利要求8所述的药物组合物作为活性成分在制备用于通过激活GLP-1R受体来治疗代谢相关疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其中，所述代谢相关疾病选自葡萄糖耐受不良、高血糖症、血脂异常、1型糖尿病(T1D)、2型糖尿病(T2D)、高甘油三酯血症、综合征X、胰岛素抵抗、葡萄糖耐量降低(IGT)、糖尿病性血脂异常、高脂血症，动脉硬化，动脉粥样硬化、高血压、肥胖症、非酒精性脂肪肝、非酒精性脂肪肝炎、肝纤维化、肝硬化、嗜睡等疾病中的任一种。
PCT/CN2021/123505 2020-12-03 2021-10-13 一类glp-1r受体激动剂化合物及其用途 WO2022116693A1 (zh)

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