WO2024041609A1 - Composé benzo bicyclique, son procédé de préparation et son utilisation - Google Patents

Composé benzo bicyclique, son procédé de préparation et son utilisation Download PDF

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WO2024041609A1
WO2024041609A1 PCT/CN2023/114710 CN2023114710W WO2024041609A1 WO 2024041609 A1 WO2024041609 A1 WO 2024041609A1 CN 2023114710 W CN2023114710 W CN 2023114710W WO 2024041609 A1 WO2024041609 A1 WO 2024041609A1
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alkyl
amino
hydroxyl
nitro
compound
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PCT/CN2023/114710
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Chinese (zh)
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余天柱
张仕国
关昕宇
杨文谦
王慧
李捍雄
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广州市联瑞制药有限公司
广州一品红制药有限公司
广州润霖医药科技有限公司
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Publication of WO2024041609A1 publication Critical patent/WO2024041609A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61P3/08—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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of chemical medicine, and in particular to a benzobicyclic compound and its preparation method and application.
  • Diabetes is a metabolic disease with multiple causes, 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 old disease. It is caused by the absolute or relative lack of insulin in the human body. The concentration of glucose in the blood increases, and then a large amount of sugar is excreted in the urine, and symptoms such as polydipsia, polyuria, polyphagia, and weight loss occur. .
  • diabetes can usually be divided into type I diabetes and type II diabetes.
  • Type I diabetes is caused by the autoimmune system attacking the beta cells of the pancreas, causing it to lose its ability to secrete insulin.
  • Type II diabetes begins with abnormal insulin resistance or cells not responding to insulin. Obesity is one of the main causes of insulin resistance, so obesity can be said to be the main risk factor for type II diabetes.
  • Type II diabetes patients account for about 90% of diabetes patients, so the disease has become a major public health problem in developed countries where obesity is a serious problem, as well as in China, where the number of obesity continues to rise.
  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 plays a corresponding role by binding to its widespread specific receptors. Currently, the organs in which GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system, liver There may be GLP-1 receptors in fat tissue and skeletal muscle. GLP-1 not only acts on ⁇ cells to promote insulin secretion, but also acts on ⁇ cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels between patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes.
  • Peptide GLP-1 receptor agonists can reduce fasting and postprandial glucose and improve blood sugar in patients with type II diabetes.
  • Peptide GLP-1 receptor agonists can reduce fasting and postprandial glucose and improve blood sugar in patients with type II diabetes.
  • the peptide GLP-1 has poor oral bioavailability and is inconvenient to take, there is an urgent clinical need for small molecule GLP-1 receptor agonists with good oral bioavailability.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can serve as an agonist of GLP-1 receptor.
  • the invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of diseases and/or conditions by agonizing GLP-1 receptors by said compound.
  • the present invention further describes the synthesis method of the compound.
  • the compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxidation compound of the compound represented by formula (I) substances, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • X is N or CR 16 ;
  • Y is O or S
  • R 2 is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl , C 1- 6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy or -C 1-6 alkylene-C 1-6 alkoxy;
  • R 3 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or -C 1-6 alkylene -R 15 , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and -C 1-6 alkylene
  • the group -R 15 may be independently optionally substituted by 1, 2 or 3 R 3a ;
  • R 15 is C 3-6 cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl;
  • R 3a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1 -6 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 Alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R 3b ;
  • R 3b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1 -6 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • R 4 , R 5 , R 8 and R 9 are each independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano or C 1-6 alkyl, and the C 1-6 alkyl groups can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • Ring B is a 5-6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl
  • Each R b is independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano or C 1-6 alkyl, and the C 1-6 alkyl can be independently optional Ground is substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 16 are each independently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro or C 1- 6 alkyl, the C 1-6 alkyl can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • the compounds of the present invention have the structure represented by Formula (II), Formula (III), Formula (IV) or Formula (V):
  • the X, Y, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R b and n has the meaning described in the present invention.
  • R is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxy Alkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy or -C 1-3 alkylene-C 1-3 alkoxy ;
  • R 4 , R 5 , R 8 and R 9 are each independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano or C 1-3 alkyl, and the C 1-3 alkyl groups can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • Each R b is independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano or C 1-3 alkyl, and the C 1-3 alkyl can be independently optional Ground is substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 16 are each independently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro or C 1- 3 alkyl, the C 1-3 alkyl can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro.
  • R2 is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, -CHF2 , - CF 3 , -CHFCH 2 F , -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy group, n-propoxy group, isopropoxy group, N-methylamino group, N-ethylamino group, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3
  • R 4 , R 5 , R 8 and R 9 are each independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl or Isopropyl, the methyl, ethyl, n-propyl and isopropyl groups can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • Each R b is independently H, D, F, Cl, Br, I, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl or isopropyl, and the methyl, Ethyl, n-propyl and isopropyl can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano, amino or nitro;
  • R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 and R 16 are each independently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, methyl, Ethyl, n-propyl or isopropyl, the methyl, ethyl, n-propyl and isopropyl can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, hydroxyl, cyano , amino or nitro substitution.
  • R3 is H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or -C 1-3 alkylene-R 15 , the C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and - C 1-3 alkylene-R 15 may be independently optionally substituted by 1, 2 or 3 R 3a ;
  • R 15 is C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;
  • R 3a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1 -3 alkylamino, C 3-6 cycloalkyl or 5-6 membered heterocyclyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 Alkylamino, C 3-6 cycloalkyl and 5-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R 3b ;
  • R 3b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1 -3 alkylamino, C 5-6 cycloalkyl or 5-6 membered heterocyclyl.
  • R is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propyl Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or -CH 2 R 15 , so The above-mentioned methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperid
  • R 15 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, morpholinyl,
  • R 3a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl or morpholinyl , the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidinyl, pyrroli
  • R 3b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl or morpholinyl .
  • R3 is H
  • the compound of the present invention is a compound with one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound with one of the following structures , hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:
  • the present invention relates to a pharmaceutical composition, which contains the compound described in formula (I) of the present invention, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated substances, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and their pharmaceutically acceptable carriers, excipients, diluents, auxiliaries, vehicles or their combinations.
  • the present invention relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicaments for preventing, treating or alleviating GLP-1 receptor agonist-mediated diseases in patients.
  • the disease mediated by the GLP-1 receptor agonist of the invention is diabetes, non-alcoholic fatty liver disease, or obesity.
  • the diabetes of the present invention is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, adult-onset diabetes of the young, and adolescent-onset atypical diabetes. , malnutrition-related diabetes or latent autoimmune diabetes in adults.
  • the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
  • substituents When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be identically or differently substituted at each position.
  • alkyl as used herein includes 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or A saturated straight-chain or branched-chain monovalent hydrocarbon group with 1-2 carbon atoms, in which the alkyl group can be independently optionally substituted by one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (- CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl Base-2-butyl (-C(CH 3 ), methyl
  • alkyl and its prefix “alkyl” as used herein include both straight and branched saturated carbon chains.
  • alkylene or “alkylene” as used herein refers to a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene base, ethylene and isopropylene, etc.
  • alkylene refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The alkylene group contains 1-3 carbon atoms; in still some embodiments, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
  • alkynyl means a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one The position is in an unsaturated state, that is, one CC is an sp triple bond, in which the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention.
  • Specific examples of the alkynyl group include, but Not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), etc.
  • halogen refers to F, Cl, Br or I.
  • unsaturated as used herein means a moiety containing one or more degrees of unsaturation.
  • alkoxy refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an oxygen atom.
  • the alkoxy group is a C 1-4 alkoxy group; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • the alkoxy group may be independently unsubstituted or substituted by one or more substituents described herein.
  • alkylthio refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through a sulfur atom.
  • the alkylthio group is a C 1-4 alkylthio group; such examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • the alkylthio group may be independently unsubstituted or substituted by one or more substituents described herein.
  • alkylamino refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an N atom.
  • the alkylamino group is C 1-4 alkylamino group; such examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, butylamino group, and the like.
  • the alkylamino groups may be independently unsubstituted or substituted by one or more substituents described in the present invention.
  • cycloalkyl or "cycloalkane” means a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 12 carbon atoms, which is a saturated ring or contains one or more unsaturated bonds. rings, but never contain aromatic rings.
  • the cycloalkyl group contains 3-10 carbon atoms;
  • the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms.
  • Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, and never include aromatic rings, where At least one ring atom is a heteroatom.
  • heterocyclyl or “heterocycle” contains 3-10 ring atoms; in one embodiment, “heterocyclyl” or “heterocycle” contains 3-8 ring atoms; in another In one embodiment, “heterocyclyl” or “heterocycle” contains 5-8 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 3-6 ring atoms; further In one embodiment, “heterocyclyl” or “heterocycle” contains 5-6 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 4-6 ring atoms; unless otherwise Note that the heterocyclyl group can be a carbon group or a nitrogen group, and the heteroatom has the meaning as described in the present invention.
  • heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxanyl, dithianyl, thioxanyl, homopiperazinyl,
  • Examples of oxidized sulfur atoms in heterocyclyl groups include, but are not limited to, sulfolane groups and 1,1-dioxothiomorpholinyl groups.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, in which at least one ring is aromatic Each ring contains a ring of 3-7 atoms and has one or more attachment points to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl groups may independently be optionally substituted with one or more substituents described herein.
  • heteroaryl means monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, at least one of which is an aromatic ring, and At least one ring system contains one or more heteroatoms, each of which contains a ring of 5-7 atoms and has one or more points of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or “heteroaromatic compound.”
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the heteroaryl group consisting of 5 to 10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.
  • heteroaryl groups include, but are not limited to: furyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (such as 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), Triazolyl, thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazol
  • haloalkyl or haloalkoxy means an alkyl or alkoxy group substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl, trifluoromethoxy wait.
  • hydroxyalkyl means an alkyl group substituted with one or more hydroxyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.
  • aminoalkyl means an alkyl group substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, and the like.
  • a ring system formed by a substituent bonded to a ring means that the substituent may be substituted at any substitutable position on the ring.
  • formula (a) represents that the substituent R may be mono- or poly-substituted at any possible substituted position on the pyridine ring.
  • a linking bond is attached to a ring to form a ring system (as shown in formula b), which means that the linking bond can be attached to the rest of the molecule at any attachable position on the ring system.
  • Formula b represents that any possible attachment position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example, R, S containing an asymmetric center Configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers, geometric isomers or conformational isomers thereof are within the scope of the invention.
  • the structural formulas and compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • isomeric forms such as enantiomers, diastereomers, geometric isomers or conformational isomers
  • nitrogen oxides, Hydrates, solvates, metabolites pharmaceutically acceptable salts and prodrugs.
  • individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts and prodrugs of the compounds are also within the scope of the invention.
  • the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.
  • Methodabolite refers to the product obtained through metabolism in the body of the specific compound described in the present invention or its pharmaceutically acceptable salt, analog or derivative, which exhibits the same behavior as formula (I) in vivo or in vitro Compounds with similar activity.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, or enzymatic cleavage, etc. Accordingly, the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so.
  • racemic mixtures 50:50 Mixtures of enantiomers are called racemic mixtures or racemates, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • tautomer or “tautomeric form” refers to isomers of structures of different energies that can be converted into each other through a low energy barrier.
  • proton tautomers i.e., proton-shifting tautomers
  • tautomers by proton migration such as keto-enol and imine-enamine isomerizations.
  • Valence (valency) tautomers include recombination of bonding electrons.
  • “Pharmaceutically acceptable salts” used in the present invention refer to organic salts and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • Pharmaceutically acceptable salts formed from nontoxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates.
  • Organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods recorded in books and literature, such as ion exchange method Get these salts.
  • Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, and bisulfate.
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • Hydrophilrate in the present invention refers to an association in which solvent molecules are water.
  • Solvents that form solvates include, but are not limited to: water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • esters in the present invention refers to a compound of formula (I) containing a hydroxyl group forming an ester that is hydrolyzable in vivo.
  • esters are, for example, pharmaceutically acceptable esters which hydrolyze in humans or animals to yield the parent alcohol.
  • the hydrolyzable ester groups of the compound of formula (I) containing hydroxyl groups include, but are not limited to: phosphate group, acetoxymethoxy group, 2,2-dimethylpropionyloxymethoxy group, alkanoyl group, Benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.
  • the "nitrogen oxide” of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • the N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), for example by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride. )reaction.
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug used in the present invention represents a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonate esters. , carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound.
  • prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent.
  • phosphate esters which are obtained by phosphorylation of the hydroxyl group of the parent.
  • GLP-1 receptor agonist refers to a substance that agonizes GLP-1 receptor activity.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless further stated, wherein the substituents are as defined in the present invention.
  • the following reaction schemes and examples serve to further illustrate the present invention.
  • the reagents were purchased from commodity suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagents Co., Ltd., Shanghai Merrill Chemical Technology Co., Ltd., and Shanghai McLean Biochemical Technology Co., Ltd., and were used without further purification.
  • general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Ocean Chemical Factory.
  • Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile are obtained by drying with molecular sieves.
  • Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane and methanol were of analytical grade.
  • reaction bottles are plugged with appropriate rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.
  • the silica gel column was purchased from Tianjin Bona Agel Technology Co., Ltd. using Flash silica gel column.
  • Silica gel (300-400 mesh) was purchased from Qingdao Marine Chemical Factory.
  • 1H NMR spectra were recorded using a Bruker 500MHz nuclear magnetic resonance spectrometer. 1H NMR spectrum uses CDCl 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • MS mass spectrometry
  • Ring B' and ring B" are 5-6 membered heterocyclyl groups containing nitrogen atoms. Unless otherwise stated , each ring B, 14 , R 15 , R b and n have the definitions as described in the present invention. Boc is a commonly used protecting group tert-butoxycarbonyl.
  • the compound represented by formula ( 9 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) and the compound represented by formula ( 2 ) are reacted to obtain the compound represented by formula ( 3 ).
  • the compound represented by formula ( 3 ) reacts with polyphosphoric acid to obtain the compound represented by formula ( 4 ).
  • the compound represented by formula ( 4 ) is brominated to obtain the compound represented by formula ( 5 ).
  • the compound represented by formula ( 5 ) and the compound represented by formula ( 6 ) react to obtain the compound represented by formula ( 7 ).
  • the compound represented by formula ( 7 ) and the compound represented by formula ( 8 ) react to obtain the compound represented by formula ( 9 ).
  • the compound represented by formula ( 11 ) can be prepared by this reaction scheme 2: the compound represented by formula ( 10 ) is oxidized to obtain the compound represented by formula ( 11 ).
  • the compound represented by formula ( 19 ) can be prepared by reaction scheme 3: the compound represented by formula ( 12 ) and the compound represented by formula ( 13 ) are reacted to obtain the compound represented by formula ( 14 ).
  • the compound represented by formula ( 14 ) reacts under acidic conditions to obtain the compound represented by formula ( 15 ).
  • the compound represented by formula ( 15 ) is reacted with di-tert-butyl dicarbonate to obtain the compound represented by formula ( 16 ).
  • the compound represented by formula ( 16 ) is reduced to obtain the compound represented by formula ( 17) .
  • the compound represented by formula ( 17 ) and the compound represented by formula ( 11 ) are reacted to obtain the compound represented by formula ( 18 ).
  • the compound represented by formula ( 18 ) is reacted with 2-chloro-1,1,1-trimethoxyethane to obtain the compound represented by formula ( 19 ).
  • the compound represented by formula ( 24 ) can be prepared by reaction scheme 4: the compound represented by formula ( 9 ) and the compound represented by formula ( 20 ) are reacted to obtain the compound represented by formula ( 21 ).
  • the compound represented by formula ( 21 ) is N-boc removed to obtain the compound represented by formula ( 22 ).
  • the compound represented by formula ( 22 ) and the compound represented by formula ( 19 ) are reacted to obtain the compound represented by formula ( 23 ).
  • the compound represented by formula ( 23 ) is hydrolyzed to obtain the compound represented by formula ( 24 ).
  • the compound represented by formula ( 25 ) can be prepared by reaction scheme 5: the compound represented by formula ( 5 ) and the compound represented by formula ( 8 ) are reacted to obtain the compound represented by formula ( 25 ).
  • the compound represented by formula ( 21 ) can also be prepared by reaction scheme 6: the compound represented by formula ( 6 ) and the compound represented by formula ( 26 ) are reacted to obtain the compound represented by formula ( 27 ). The compound represented by formula ( 27 ) and the compound represented by formula ( 25 ) are reacted to obtain the compound represented by formula ( 21 ).
  • the compound represented by formula ( 31 ) can be prepared by reaction scheme 7: the compound represented by formula ( 27 ) and the compound represented by formula ( 5 ) are reacted to obtain the compound represented by formula ( 28 ).
  • the compound represented by formula ( 28 ) is N-Boc removed to obtain the compound represented by formula ( 29 ).
  • the compound represented by formula ( 29 ) and the compound represented by formula ( 19 ) are reacted to obtain the compound represented by formula ( 30 ).
  • the compound represented by formula ( 30 ) is hydrolyzed to obtain the compound represented by formula ( 31 ).
  • the compound represented by formula ( 40 ) can be prepared by reaction scheme 8: the compound represented by formula ( 6 ) is reacted with benzyl bromide to obtain formula ( 32 ) The compounds shown. The compound represented by formula ( 32 ) and the compound represented by formula ( 33 ) are reacted to obtain the compound represented by formula ( 34 ). The compound represented by formula ( 34 ) is debenzylated to obtain the compound represented by formula ( 35 ). The compound represented by formula ( 35 ) and the compound represented by formula ( 36 ) are reacted to obtain the compound represented by formula ( 37 ). The compound represented by formula ( 37 ) is N-Boc removed to obtain the compound represented by formula ( 38 ). The compound represented by formula ( 38 ) and the compound represented by formula ( 19 ) are reacted to obtain the compound represented by formula ( 39 ). The compound represented by formula ( 39 ) is hydrolyzed to obtain the compound represented by formula ( 40 ).
  • the compound represented by formula ( 42 ) can be prepared through the reaction scheme 9: methyl 2-hydroxyacetate and tert-butyldiphenylchlorosilane are reacted to obtain the compound represented by formula ( 41 ).
  • the compound represented by formula ( 41 ) reacts with ammonia gas to obtain the compound represented by formula ( 42 ).
  • the compound represented by formula ( 19 ) can also be prepared by this reaction scheme 10: the compound represented by formula ( 43 ) is brominated to obtain the compound represented by formula ( 44 ). The compound represented by formula ( 44 ) and the compound represented by formula ( 42 ) are reacted to obtain the compound represented by formula ( 45 ). The compound represented by formula ( 45 ) is subjected to bromination reaction to obtain the compound represented by formula ( 46 ). The compound represented by formula ( 46 ) is reacted with Lawson's reagent to obtain the compound represented by formula ( 47 ). The compound represented by formula ( 47 ) and the compound represented by formula ( 48 ) are reacted to obtain the compound represented by formula ( 49 ).
  • the compound represented by formula ( 49 ) forms an intramolecular ring to obtain the compound represented by formula ( 50 ).
  • the compound represented by formula ( 50 ) is deprotected by TBDPS to obtain the compound represented by formula ( 51 ).
  • the compound represented by formula ( 51 ) is chlorinated to obtain the compound represented by formula ( 19 ).
  • the compound represented by formula ( 59 ) can also be prepared through the reaction scheme 11: the compound represented by formula ( 51 ) and the compound represented by formula ( 52 ) are reacted to obtain the compound represented by formula ( 53 ). The compound represented by formula ( 53 ) is reduced to obtain the compound represented by formula ( 54 ). The compound represented by formula ( 54 ) is oxidized to obtain the compound represented by formula ( 55 ). The compound represented by formula ( 55 ) and the compound represented by formula ( 56 ) are reacted to obtain the compound represented by formula ( 57 ). The compound represented by formula ( 57 ) and the compound represented by formula ( 36 ) are reacted to obtain the compound represented by formula ( 58 ). The compound represented by formula ( 58 ) is hydrolyzed to obtain the compound represented by formula ( 59 ).
  • Step 6 Synthesis of 5-((2,4-dimethoxybenzyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester
  • Step 7 Synthesis of 5-amino-4-nitrophenol-2-carboxylic acid methyl ester
  • Step 8 Synthesis of 5-((tert-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester
  • Step 9 Synthesis of 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylic acid methyl ester
  • Step 12 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]-1'(2 Synthesis of 'H)-carboxylic acid tert-butyl ester
  • Step 13 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine synthesis
  • Step 14 (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Dipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxy Synthesis of acid methyl ester
  • Step 15 (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Dipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxy Synthesis of Acid
  • Step 2 Synthesis of 6-hydroxy-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)-carboxylic acid tert-butyl ester
  • Step 3 Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
  • Step 6 (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Synthesis of Methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
  • Step 7 (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 1 6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)- Synthesis of tert-butyl carboxylate
  • Step 2 Synthesis of 6-((4-chlorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine
  • Step 3 (S)-2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]- 1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester synthesis
  • Step 4 (S)-2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]- Synthesis of 1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid
  • Step 1 Synthesis of 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
  • Step 3 Synthesis of 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 5 (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1 Synthesis of -(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 6 (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1 Synthesis of -(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 1 4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxy Synthesis of tert-butyl acid ester
  • Step 2 Synthesis of 4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine
  • Step 3 (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydro Synthesis of pyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 4 (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydro Synthesis of pyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 4 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1( Synthesis of 2H)-tert-butylcarboxylate
  • Step 5 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl) Synthesis of pyrimidines
  • Step 6 (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid Synthesis of methyl lipids
  • Step 7 (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid Synthesis
  • Step 2 Synthesis of tert-butyl 4-(6-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate
  • 2-(Benzyloxy)-6-bromopyridine (6g, 22.72mmol), piperazine-1-carboxylic acid tert-butyl ester (8.46g, 45.44mmol), 1,1'-binaphthyl-2,2' - Bisdiphenylphosphine (2.83g, 4.54mmol), tris(dibenzylideneacetone)dipalladium (2.08g, 2.27mmol), potassium tert-butoxide (5.1g, 45.44mmol) were added to 50 mL of toluene solution , replaced with nitrogen three times, and placed at 100°C for reaction for 20 minutes.
  • Step 3 Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
  • Step 6 (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 7 (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 1 Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
  • Step 3 (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
  • Step 4 (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 1 Synthesis of methyl 2-((tert-butyldiphenylsilyl)oxy)acetate
  • Step 3 Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
  • Step 7 Synthesis of 5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylic acid methyl ester
  • Step 8 Synthesis of methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate
  • Step 9 Synthesis of 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)ethylthioamino)-3-fluorothiophene-2-carboxylic acid methyl ester
  • Step 10 (S,Z)-4-bromo-5-((2-((tert-butyldiphenylsilyl)oxy)-1-((oxetan-2-ylmethyl) Synthesis of )amino)ethylene)amino)-3-fluorothiophene-2-carboxylic acid methyl ester
  • Step 11 (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H -Synthesis of thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 12 (S)-6-fluoro-2-(hydroxymethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Synthesis of methyl carboxylate
  • Step 13 (S)-2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Synthesis of methyl carboxylate
  • Step 14 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl Synthesis of methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
  • Step 15 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl Synthesis of 6-fluoro-1-(oxetan-2-ylmethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid
  • Step 1 (S)-2-((6-((4-4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-Bipyridin]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d ] Synthesis of imidazole-5-carboxylic acid methyl ester
  • Step 2 (S)-2-((6-((4-4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-Bipyridin]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d ]Synthesis of imidazole-5-carboxylic acid
  • Step 1 Synthesis of methyl 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
  • Step 5 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxy Synthesis of heterocyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 6 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid
  • Step 2 Synthesis of methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
  • Step 6 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxy Synthesis of heterocyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 7 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxy Synthesis of heterocyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
  • Step 1 (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole- Synthesis of 5-carboxylic acid methyl ester
  • Step 2 (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole- Synthesis of 5-carboxylic acid
  • Step 1 Ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate synthesis
  • Step 2 Synthesis of ethyl 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
  • Step 5 (S)-2-(3-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetane-2ylmethyl)-1H-thieno[ Synthesis of 2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 6 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)- Synthesis of 1-(oxetan-2ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester
  • Step 7 2-((4-(6-(((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)pyridin-2-yl)-3-fluorobenzene yl)methyl)-1-(((2S)-oxetan-2-yl)methyl)thienyl[2,3-d]imidazole-5-carboxylic acid
  • the cells were constructed by Shanghai WuXi AppTec New Drug Development Co., Ltd., as shown in Table 1 below.
  • the experimental buffer is shown in Table 4 below.
  • the final concentration of the detection reagent preparation is shown in Table 5 below.
  • the compound to be tested is diluted 10 times 4 times, with a starting concentration of 100 ⁇ M, and the automatic pipetting workstation completes the dilution.
  • Table 1 shows the agonistic effects (EC 50 ) of the compounds provided in some examples of the present invention.
  • mice male, 6-8 weeks old, weighing 20-30 grams, purchased from Vitong Lever (Beijing) Experimental Animal Technology Co., Ltd.
  • Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, the experimental water was ultrapure water, and the remaining reagents were commercially available analytical grade.
  • mice are administered intravenously or intragastrically. Blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h later. Collect 30 ⁇ L of whole blood from each PK sampling point into EDTA-K2 anticoagulant blood collection tubes and centrifuge at 4°C within 30 minutes to collect plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or cryopreserved until analysis.
  • Mobile phase Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), perform gradient elution according to the table.
  • the compound of the present invention is well absorbed orally in mice, with high exposure and bioavailability.
  • references to the terms "one embodiment,””someembodiments,””anexample,””specificexamples,” or “some examples” or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.

Abstract

La présente invention concerne un composé benzo bicyclique et son utilisation dans un médicament, et concerne en particulier un nouveau composé benzo bicyclique et une composition pharmaceutique comprenant le composé. La présente invention concerne également un procédé de préparation du composé, et l'utilisation du composé ou de la composition pharmaceutique dans la préparation d'un médicament pour le traitement d'une maladie et/ou d'un trouble médié par un agoniste du récepteur GLP-1, et en particulier, son utilisation dans la préparation d'un médicament pour le traitement du diabète, d'une stéatose hépatique non alcoolique et de l'obésité.
PCT/CN2023/114710 2022-08-24 2023-08-24 Composé benzo bicyclique, son procédé de préparation et son utilisation WO2024041609A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020263695A1 (fr) * 2019-06-28 2020-12-30 Eli Lilly And Company Agonistes du récepteur du peptide de type glucagon 1
WO2021081207A1 (fr) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Composés modulateurs de glp-1r
WO2021112538A1 (fr) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Agoniste du récepteur glp-1
CN113480534A (zh) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用
CN113853371A (zh) * 2019-04-12 2021-12-28 上海齐鲁锐格医药研发有限公司 Glp-1r激动剂及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113853371A (zh) * 2019-04-12 2021-12-28 上海齐鲁锐格医药研发有限公司 Glp-1r激动剂及其用途
WO2020263695A1 (fr) * 2019-06-28 2020-12-30 Eli Lilly And Company Agonistes du récepteur du peptide de type glucagon 1
WO2021081207A1 (fr) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Composés modulateurs de glp-1r
WO2021112538A1 (fr) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Agoniste du récepteur glp-1
CN113480534A (zh) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用

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