WO2024041609A1 - Benzo bicyclic compound, preparation method therefor, and use thereof - Google Patents

Benzo bicyclic compound, preparation method therefor, and use thereof 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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French (fr)
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/en

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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.

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Abstract

The present invention relates to a benzo bicyclic compound and use thereof in a medicament, and specifically relates to a novel benzo bicyclic compound and a pharmaceutical composition comprising the compound. The present invention also relates to a method for preparing the compound, and use of the compound or the pharmaceutical composition in the preparation of a medicament for treating a GLP-1 receptor agonist-mediated disease and/or disorder, and particularly, to use thereof in the preparation of a medicament for treating diabetes, non-alcoholic fatty liver disease and obesity.

Description

苯并双环类化合物及其制备方法和应用Benzodicyclic compounds and their preparation methods and applications
本申请主张如下优先权：This application claims the following priority rights:
CN202211021965.X，申请日2022年8月24日。CN202211021965.X, application date is August 24, 2022.
技术领域Technical field
本发明涉及化学医药技术领域，具体涉及一种苯并双环类化合物及其制备方法和应用。The invention relates to the technical field of chemical medicine, and in particular to a benzobicyclic compound and its preparation method and application.
背景技术Background technique
糖尿病是一种多病因的代谢疾病，特点是慢性高血糖，伴随因胰岛素分泌或作用缺陷引起的糖、脂和蛋白质代谢紊乱。糖尿病是一种非常古老的疾病，是由于人体内胰岛素绝对或相对缺乏而引起的血中葡萄糖浓度升高，进而糖大量从尿中排出，并出现多饮、多尿、多食、消瘦等症状。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. .
根据糖尿病发病机制分类，通常可将糖尿病划分为I型糖尿病和II型糖尿病。I型糖尿病是由于自身免疫系统攻击胰岛β细胞从而丧失分泌胰岛素的功能。II型糖尿病则是始于胰岛素抵抗作用异常或细胞对胰岛素没有反应；肥胖是胰岛素抵抗的主要原因之一，因此肥胖可以说是II型糖尿病的主要危险因素。II型糖尿病患者占糖尿病患者人数的90％左右，因此该病在肥胖问题严重的发达国家、以及肥胖人数不断攀升的中国成为主要的公共卫生健康问题。According to the classification of diabetes pathogenesis, 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.
胰高血糖素样肽-1(GLP-1)是下消化道L-细胞分泌的一种肠降血糖素激素。GLP-1通过与其广泛存在的特异性受体结合而发挥相应的作用，目前明确存在GLP-1受体的器官有胰岛细胞、胃肠、肺、脑、肾脏、下丘脑和心血管系统，肝脏、脂肪组积及骨骼肌中可能存在GLP-1受体。GLP-1不仅作用于β细胞促进胰岛素分泌，同时还作用于α细胞抑制胰高血糖素分泌。正常糖耐量、糖耐量受损和II型糖尿病患者中，血清GLP-1水平一般没有明显的差异。但是进食后β细胞对GLP-1的应答存在缺陷，在一定条件下，持续输注GLP-1后这种应答反应明显增强。由于人体自身GLP-1的作用持续时间十分短暂(静脉注射t1/2<1.5分钟)，因此人体自身GLP-1并不适合用于糖尿病的临床治疗。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 β cells to promote insulin secretion, but also acts on α 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. However, there is a defect in the response of β cells to GLP-1 after eating. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Since the action duration of the body's own GLP-1 is very short (t 1/2 <1.5 minutes after intravenous injection), the body's own GLP-1 is not suitable for clinical treatment of diabetes.
肽类GLP-1受体激动剂(如利拉鲁肽，艾塞那肽等)具有降低空腹和餐后葡萄糖以及改善II型糖尿病患者血糖的作用。然而，因为肽类GLP-1的口服生物利用度差，服用不便，所以临床亟需具有良好口服生物利用度的小分子GLP-1受体的激动剂。Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) can reduce fasting and postprandial glucose and improve blood sugar in patients with type II diabetes. However, because 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.
目前，科研工作者已经开展了一些研究以期找到能够有效激动GLP-1受体的治疗药剂。PCT申请WO2018109607、WO2019239319、WO2019239371、WO2020103815、WO2020207474、WO2020263695、WO2021154796、WO2021112538、WO2021096304、WO2021096284、WO2021081207、WO2021018023和WO2021254470、WO2021249492、WO2022007979、WO2022031994、WO2022040600、WO2022068772和WO2022116693披露了诸多小分子化合物，其作为GLP-1受体激动剂用于预防或治疗糖尿病。然而，临床仍然亟需更多更好的GLP-1受体激动剂。At present, scientific researchers have carried out some studies in order to find therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications WO2018109607, WO2019239319, WO2019239371, WO2020103815, WO2020207474, WO2020263695, WO2021154796, WO2021112538, WO2021096304, WO2021096284, WO 2021081207, WO2021018023 and WO2021254470, WO2021249492, WO2022007979, WO2022031994, WO2022040600, WO2022068772 and WO2022116693 disclose many small molecule compounds as GLP- 1 Receptor agonists are used to prevent or treat diabetes. However, there is still an urgent clinical need for more and better GLP-1 receptor agonists.
发明内容Contents of the invention
本发明提供一种化合物，或其药物组合物，其可作为GLP-1受体的激动剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过所述化合物激动GLP-1受体来治疗疾病和/或病症。本发明又进一步描述了所述化合物的合成方法。本发明的化合物显示出优良的生物活性及药代动力学性质。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.
具体地说：Specifically:
一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
In one aspect, 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,
其中：in:
X为N或CR16；X is N or CR 16 ;
Y为O或S；Y is O or S;
R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基、C1-6烷氨基、C1-6卤代烷氧基或-C1-6亚烷基-C1-6烷氧基；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;
R3为H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基或-C1-6亚烷基-R15，所述C1- 6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基和-C1-6亚烷基-R15可独立任选地被1、2或3个R3a取代；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 ;
R15为C3-6环烷基、3-8元杂环基或5-10元杂芳基；R 15 is C 3-6 cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl;
R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基或3-6元杂环基，所述C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基和3-6元杂环基可独立任选地被1、2或3个R3b取代；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 ;
R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基或3-6元杂环基；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;
R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
环B为5-6元杂环基、苯基或5-6元杂芳基；Ring B is a 5-6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl;
各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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为0、1、2、3、4、5、6、7或8。n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
在一些实施方案中，本发明化合物具有式式(II)、式(III)、式(IV)或式(V)所示结构：In some embodiments, the compounds of the present invention have the structure represented by Formula (II), Formula (III), Formula (IV) or Formula (V):
其中，所述X、Y、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、Rb和n具有本发明所述的含义。 Wherein, 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.
在一些实施方案中，R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3氨基烷基、C1-3烷氧基、C1-3烷氨基、C1-3卤代烷氧基或-C1-3亚烷基-C1-3烷氧基；In some embodiments, 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 ;
R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基或C1- 3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代。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.
在一些实施方案中，R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、羟基甲基、羟基乙基、氨甲基、氨乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、N-甲氨基、N-乙氨基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、-CH2OCH3、-CH2OCH2CH3、-CH2CH2OCH3或-CH2CH2OCH2CH3；In some embodiments, 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 or -CH 2 CH 2 OCH 2 CH 3 ;
R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代。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.
在一些实施方案中，R3为H、C1-3烷基、C2-3烯基、C2-3炔基、C3-6环烷基、3-6元杂环基或-C1-3亚烷基-R15，所述C1-3烷基、C2-3烯基、C2-3炔基、C3-6环烷基、3-6元杂环基和-C1-3亚烷基-R15可独立任选地被1、2或3个R3a取代；In some embodiments, 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 ;
R15为C3-6环烷基、3-6元杂环基或5-10元杂芳基；R 15 is C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;
R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C3-6环烷基或5-6元杂环基，所述C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C3-6环烷基和5-6元杂环基可独立任选地被1、2或3个R3b取代；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 ;
R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C5-6环烷基或5-6元杂环基。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.
在一些实施方案中，R3为H、甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、乙炔基、炔丙基、1-丙 炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基或-CH2R15，所述甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基和-CH2R15可独立任选地被1、2或3个R3a取代；In some embodiments, 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, piperidinyl, piperazinyl, morpholinyl and -CH 2 R 15 can be independently optionally substituted by 1, 2 or 3 R 3a ;
R15为环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、 R 15 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, morpholinyl,
R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基，所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基可独立任选地被1、2或3个R3b取代；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, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl and morpholinyl can be independently optionally substituted by 1, 2 or 3 R 3b ;
R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基。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 .
在一些实施方案中，R3为H、 In some embodiments, R3 is H,
在一些实施方案中，本发明所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：


In some embodiments, 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:


一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。On the one hand, 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.
一方面，本发明涉及前面所述的化合物或其药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻患者GLP-1受体激动剂介导的疾病。In one aspect, 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.
其中一些实施方案是，本发明所述的GLP-1受体激动剂介导的疾病为糖尿病、非酒精性脂肪肝病或肥胖。In some embodiments, the disease mediated by the GLP-1 receptor agonist of the invention is diabetes, non-alcoholic fatty liver disease, or obesity.
其中一些实施方案是，本发明所述的糖尿病为I型糖尿病、II型糖尿病、妊娠糖尿病、特发性I型糖尿病、早发型II型糖尿病、青年人的成年型糖尿病、青少年发作的非典型糖尿病、营养不良相关性糖尿病或成人隐匿性自身免疫性糖尿病。In some embodiments, 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.
另一方面，本发明涉及式(I)所包含的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在 下面作更加具体完整的描述。The foregoing description summarizes certain aspects of the invention but is not limited to these aspects. These and other aspects will be covered in A more specific and complete description is given below.
定义和一般术语Definitions and general terms
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明申请所控制的范围。The present invention will list the documents corresponding to the determined specific content in detail, and the examples will be accompanied by illustrations of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents which may fall within the field of existing inventions as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which could be used in the practice of the present invention. This invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ from or conflict with the present application, including but in no way limited to the definition of terms, the usage of terms, the techniques described, or the scope of control like the present application.
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75，thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。This invention shall apply the following definitions unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemical Medicines, 75, thEd, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The content is integrated with references.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprises" is an open expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.
像这里所描述的化合物可以任选地被一个或多个取代基所取代，如本发明中的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于氢、F、Cl、Br、I、硝基、氰基、氧代(＝O)、羟基、烷基、羟基烷基、烷氨基、氨基烷基、卤代烷氧基、环烷基、氨基、芳基、杂环基、杂芳基、烯基、炔基、环烷基氧基、烷氧基、烷氧基烷基、卤代烷基、-COOH、-亚烷基-C(＝O)O-烷基、-亚烷基-S(＝O)2-烷基、-亚烷基-S(＝O)2-氨基、-S(＝O)2-烷基、-S(＝O)2-氨基、-S(＝O)2OH、-O-亚烷基-C(＝O)O-烷基、-O-亚烷基-S(＝O)2-烷基、-O-亚烷基-S(＝O)2-氨基、-O-亚烷基-S(＝O)2OH、-C(＝O)NH2、-C(＝O)NH-烷基、-C(＝O)N(烷基)-烷基、-C(＝O)NHS(＝O)2-烷基、-C(＝O)NHS(＝O)2-氨基、-C(＝O)NHS(＝O)2OH、-N(卤代烷基)-烷基、-N(烷基)-S(＝O)2-烷基、-NHS(＝O)2-烷基、-NHS(＝O)2-卤代烷基、-N(烷基)S(＝O)2-卤代烷基、-N(烷基)S(＝O)2-烷氨基、-NHC(＝O)-烷基、-NHC(＝O)-卤代烷基、-N(烷基)C(＝O)-卤代烷基、-N(烷基)C(＝O)-烷氨基、-N(烷基)C(＝O)O-烷基、-NHC(＝O)O-烷基、-NHC(＝O)O-卤代烷基、-N(烷基)C(＝O)O-卤代烷基、-N(烷基)C(＝O)O-氨基烷基、-NHC(＝O)-NH2、-NHC(＝O)NH-(烷基)、-NHC(＝O)NH(卤代烷基)、-NHC(＝O)N(烷基)-烷基、-OC(＝O)-烷基、-OC(＝O)-氨基、-OC(＝O)-烷氨基、-OC(＝O)-氨基烷基、-OC(＝O)-烷氧基、-C(＝O)N(烷基)S(＝O)2-烷基、-C(＝O)N(烷基)S(＝O)2-氨基、-C(＝O)NH-S(＝O)2OH、-C(＝NH)NH2、-C(＝NH)NH-烷基、-C(＝NH)N(烷基)-烷基、-C(＝N-烷基)-NH2、-C(＝O)NH-亚烷基-S(＝O)2OH、-C(＝O)NHC(＝O)OH、-C(＝O)NHC(＝O)O-烷基、-C(＝O)N(烷基)C(＝O)O-烷基、-C(＝O)NH-亚烷基-C(＝O)OH和-C(＝O)NH-亚烷基-C(＝O)O-烷基，等等。Compounds such as those described herein may be optionally substituted with one or more substituents, such as compounds of the general formula of the present invention, or as specific examples, subclasses, and classes of compounds encompassed by the present invention. . It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted," means that one or more hydrogen atoms in a given structure are substituted with a specified substituent. Unless otherwise indicated, an optionally substituted group may be substituted with a substituent at each substitutable position of the group. 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. The substituents mentioned therein can be, but are not limited to hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl Base, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH , -alkylene-C(=O)O-alkyl, -alkylene-S(=O) 2 -alkyl, -alkylene-S(=O) 2 -amino, -S(=O ) 2 -Alkyl, -S(=O) 2 -Amino, -S(=O) 2 OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S (=O) 2 -alkyl, -O-alkylene-S(=O) 2 -amino, -O-alkylene-S(=O) 2 OH, -C(=O)NH 2 , - C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O) 2 -alkyl, -C(=O)NHS(= O) 2 -amino, -C(=O)NHS(=O) 2 OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O) 2 -alkyl, -NHS( =O) 2 -alkyl, -NHS(=O) 2 -haloalkyl, -N(alkyl)S(=O) 2 -haloalkyl, -N(alkyl)S(=O) 2 -alkylamino , -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, -N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino , -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O) O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH 2 , -NHC(=O)NH-(alkyl), -NHC(=O )NH(halogenated alkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino , -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O) 2 -alkyl, -C(=O) N(alkyl)S(=O) 2 -amino, -C(=O)NH-S(=O) 2 OH, -C(=NH)NH 2 , -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH 2 , -C(=O)NH-alkylene-S(=O) 2 OH, -C (=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C (=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and so on.
本发明使用的术语“烷基”包括1-20个碳原子，或1-10个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子，或1-2个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。烷基基团更进一步的实例包括，但并不限于甲基(Me，-CH3)、乙基(Et，-CH2CH3)、正丙基(n-Pr，-CH2CH2CH3)、异丙基(i-Pr，-CH(CH3)2)、正丁基(n-Bu，-CH2CH2CH2CH3)、异丁基(i-Bu，-CH2CH(CH3)2)、仲丁基(s-Bu，-CH(CH3)CH2CH3)、叔丁基(t-Bu，-C(CH3)3)、正戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、正己基(- CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)、正庚基和正辛基等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”或“亚烷基”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于亚甲基、亚乙基和亚异丙基等等。The term "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. Further examples of 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 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 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1 -Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (- CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 ) (CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C (CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkyl" as used herein include both straight and branched saturated carbon chains. The term "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.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一些实施方案中，亚烷基基团含有1-6个碳原子；在另一些实施方案中，亚烷基基团含有1-4个碳原子；在又一些实施方案中，亚烷基基团含有1-3个碳原子；还在一些实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。The term "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.
术语“烯基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp2双键，其中烯基基团可以独立且任选地被一个或多个本发明所描述的取代基所取代，包括基团有“反”，“顺”或“E”，“Z”的定位，其中烯基具体的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)等等。The term "alkenyl" 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 unsaturated, that is, one CC is an sp 2 double bond, in which the alkenyl group can be independently and optionally substituted by one or more substituents described in the present invention, including groups with "anti", ""cis" or "E", "Z" positioning, where specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), etc. .
术语“炔基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp三键，其中炔基基团可以独立且任选地被一个或多个本发明所描述的取代基所取代，其中炔基具体的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)等等。The term "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.
术语“杂原子”表示一个或多个O、S、N、P和Si，包括C，N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3，4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)；或杂环中的-CH2-被氧化，形成-C(＝O)-的形式。The term "heteroatom" means one or more O, S, N, P, and Si, including C, N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or in heterocycles A form in which the hydrogen on the nitrogen atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted NR) in the pyrrolidinyl group; or -CH 2 - in the heterocycle is oxidized to form -C(=O)-.
术语“卤素”是指F、Cl、Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“氘”是指重氢，D。The term "deuterium" refers to heavy hydrogen, D.
在本发明中所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。The term "unsaturated" as used herein means a moiety containing one or more degrees of unsaturation.
本发明中所使用的术语“烷氧基”或“烷基氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到化合物分子的其它部分上。一些实施例中，烷氧基为C1-4烷氧基；这样的实例包括，但并不限于甲氧基、乙氧基、丙氧基和丁氧基等。并且所述烷氧基可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an oxygen atom. In some embodiments, 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. And the alkoxy group may be independently unsubstituted or substituted by one or more substituents described herein.
本发明中所使用的术语“烷硫基”或“烷基硫基”，涉及到烷基，像本发明所定义的，通过硫原子连接到化合物分子的其它部分上。一些实施例中，烷硫基为C1-4烷硫基；这样的实例包括，但并不限于甲硫基、乙硫基、丙硫基和丁硫基等。并且所述烷硫基可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through a sulfur atom. In some embodiments, 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. And the alkylthio group may be independently unsubstituted or substituted by one or more substituents described herein.
本发明中所使用的术语“烷氨基”或“烷基氨基”，涉及到烷基，像本发明所定义的，通过N原子连接到化合物分子的其它部分上。一些实施例中，烷氨基为C1-4烷氨基；这样的实例包括，但并不限于甲氨基、乙氨基、丙氨基和丁氨基等。并且所述烷氨基可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an N atom. In some embodiments, 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. And the alkylamino groups may be independently unsubstituted or substituted by one or more substituents described in the present invention.
术语“环烷基”或“环烷烃”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环碳环体系，为饱和环或含一个或多个不饱和键的环，但绝不包含芳香环。在一实施方案中，环烷基包含3-10个碳原子； 在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。这样的实例包括，但并不限于环丙基、环丁基、环戊基和环己基等。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。The term "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. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; In another embodiment, 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.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，绝不包含芳香环，其中至少一个环原子为杂原子。在一实施方案中，“杂环基”或“杂环”包含3-10个环原子；在一实施方案中，“杂环基”或“杂环”包含3-8个环原子；在另一实施方案中，“杂环基”或“杂环”包含5-8个环原子；在又一实施方案中，“杂环基”或“杂环”包含3-6个环原子；还在一实施方案中，“杂环基”或“杂环”包含5-6个环原子；再在一实施方案中，“杂环基”或“杂环”包含4-6个环原子；除非另外说明，杂环基可以是碳基或氮基，杂原子具有如本发明所述的含义。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、2-吡咯啉基、3-吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基和2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH2-基团被-C(＝O)-取代的实例包括，但不限于：2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于环丁砜基和1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。The terms "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. In one embodiment, "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. Examples of 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, homopiperidinyl, oxeptanyl, thieptanyl, oxaza base, diazepine base, thiazepine base and 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of the -CH 2 - group in the heterocyclyl group substituted by -C(=O)- include, but are not limited to: 2-oxopyrrolidyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinedione groups. 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.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环是芳香族的，其中每一个环包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "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. The term "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.
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香环，且至少一个环体系包含一个或多个杂原子，其中每一个环包含5-7个原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1、2、3或4个独立选自O，S和N的杂原子，其中氮原子可以被进一步氧化。The term "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. The term "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. In one embodiment, 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.
杂芳基基团的实例包括，但并不限于：呋喃基、咪唑基(如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基、恶唑基(如2-噁唑基、4-噁唑基、5-噁唑基)、吡咯基(如N-吡咯基、2-吡咯基、3-吡咯基)、吡啶基、嘧啶基(如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基、噻唑基(如2-噻唑基、4-噻唑基、5-噻唑基)、四唑基(如5-四唑基)、三唑基、噻吩基(如2-噻吩基、3-噻吩基)、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、吲哚啉基、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基和[1,2,4]三唑并[1,5-a]吡啶基，等等。Examples of 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-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indole Base (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinoline base, 1,3-benzodioxenyl, indolinyl, isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo[1, 2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2 ,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1, 5-a]pyridyl, etc.
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。The term "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.
术语“羟基烷基”表示烷基基团被一个或多个羟基所取代，这样的实例包含，但并不限于，羟基甲基、羟基乙基等。 The term "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.
术语“氨基烷基”表示烷基基团被一个或多个氨基所取代，这样的实例包含，但并不限于，氨甲基、氨乙基等。The term "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.
像本发明所描述的，取代基画一个键连接到环上形成的环体系代表取代基在该环上任何可取代的位置都可以取代。例如，式(a)代表取代基R可以在吡啶环上任何可能被取代的位置上单取代或多取代。
As described in this invention, 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. For example, formula (a) represents that the substituent R may be mono- or poly-substituted at any possible substituted position on the pyridine ring.
像本发明所描述的，一个连接键连接到环上形成的环体系(如式b所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式b代表八氢环戊烯并[c]吡咯环上任何可能连接的位置均可与分子其余部分相连。
As described in the present invention, 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.
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless otherwise clearly stated, the descriptions used throughout this article are "each...and...independently is", "...and...each independently is" and "...and...are independently "is" can be interchanged and should be understood in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or it can also be expressed in the same group, that the specific options expressed by the same symbols do not affect each other. The specific options expressed between them do not affect each other.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，几何异构或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体、几何异构体或构象异构体的混合物都属于本发明的范围。Unless otherwise indicated, 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.
除非其他方面表明，本发明所描述的结构式和所述的化合物包括所有的同分异构形式(如对映异构，非对映异构，几何异构或构象异构)、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药。因此，本发明的化合物的单个立体化学异构体、对映异构体、非对映异构体、几何异构体、构象异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药的化合物也属于本发明的范围。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, 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. Thus, 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. Additionally, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.
“代谢产物”是指本发明所述的具体的化合物或其药学上可接受的盐、类似物或衍生物在体内通过代谢作用所得到的产物，其在体内或体外表现出与式(I)化合物类似的活性。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、或酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" 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.
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50 的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。Reference is generally made to the following literature for the definitions and conventions of stereochemistry used in this invention: SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the symbol of the plane polarized light rotation of the compound. (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are often called enantiomeric mixtures. 50:50 Mixtures of enantiomers are called racemic mixtures or racemates, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be converted into each other through a low energy barrier. For example, proton tautomers (i.e., proton-shifting tautomers) include tautomers by proton migration, such as keto-enol and imine-enamine isomerizations. Valence (valency) tautomers include recombination of bonding electrons.
本发明所使用的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于：与氨基基团反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐；有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括，己二酸盐、苹果酸盐、2-羟基丙酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。通过适当的碱得到的盐包括，碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠、锂、钾、钙、镁等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。"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. Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, tranbutene Diacid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactosuronate, lactate Acid, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamateate, pectic acid Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate Salt etc. 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.
本发明的“水合物”是指溶剂分子是水所形成的缔合物。"Hydrate" in the present invention refers to an association in which solvent molecules are water.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于：水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to: water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
本发明的“酯”是指含有羟基的式(I)化合物形成体内可水解的酯。这样的酯是例如在人或动物体内水解产生母体醇的药学上可接受的酯。含有羟基的式(I)化合物体内可水解的酯的基团包括，但不限于：磷酸基、乙酰氧基甲氧基、2,2-二甲基丙酰氧基甲氧基、烷酰基、苯甲酰基、苯乙酰基、烷氧基羰基、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基等。"Ester" in the present invention refers to a compound of formula (I) containing a hydroxyl group forming an ester that is hydrolyzable in vivo. Such 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.
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，例如在惰性溶剂(例如二氯甲烷中)，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。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. Particular examples of 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). In particular, 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.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类、脂肪族(C1-24)酯类、酰氧基甲基酯类、碳酸酯、氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical  Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。The term "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. In the existing invention, 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. For example, if a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent. For a complete discussion of prodrugs, please refer to the following literature: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the ACSSymposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs: Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and SJHecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51 , 2328-2345.
除非本文另有说明或者上下文清楚地有相反含义，否则本文所用的术语“一个”、“一种”、“该”以及本发明的上下文中(尤其是在权利要求书的上下文中)所使用的类似术语可以被解释为既包括单数，又包括复数。As used herein, the terms "a", "an", "the" and "the" are used in the context of the present invention (especially in the context of the claims) unless otherwise indicated herein or the context clearly contradicts the meaning. Similar terms may be construed to include both the singular and the plural.
本文所用的术语“GLP-1受体激动剂”是指能激动GLP-1受体活性的物质。The term "GLP-1 receptor agonist" as used herein refers to a substance that agonizes GLP-1 receptor activity.
一般合成过程General synthesis process
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To illustrate the present invention, examples are set forth below. However, it should be understood that the present invention is not limited to these embodiments, but only provides methods for practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如本发明所述。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, 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.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare other compounds of the invention, and that other methods for preparing compounds of the invention are considered to be within the scope of the invention. . For example, the synthesis of non-exemplary compounds according to the present invention can be successfully accomplished by one skilled in the art by modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents in addition to those described herein, or by incorporating The reaction conditions were modified with some routine modifications. In addition, the reactions disclosed in the present invention or the known reaction conditions are also recognized to be suitable for the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如安徽泽升科技有限公司，上海韶远试剂有限公司，上海迈瑞尔化学技术有限公司，上海麦克林生化科技有限公司，使用时都没有经过进一步纯化。除非其他方面表明，一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津大茂化学试剂厂，烟台江友硅胶开发有限公司和青岛海洋化工厂购买得到。The examples described below all temperatures are in degrees Celsius unless otherwise indicated. 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. Unless otherwise indicated, 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.
无水四氢呋喃，N,N-二甲基甲酰胺，1,4-二氧六环，乙腈是经过分子筛干燥得到。二氯甲烷，乙酸乙酯，石油醚，1,2-二氯乙烷和甲醇使用分析纯。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.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿均是经过干燥的。The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube over an anhydrous solvent (unless otherwise indicated). The reaction bottles are plugged with appropriate rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.
硅胶柱是使用Flash硅胶柱购于天津博纳艾杰尔科技有限公司。硅胶(300-400目)购于青岛海洋化工厂。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谱使用Bruker 500MHz核磁共振谱仪记录。1H NMR谱以CDCl3、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽的单峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数J，用赫兹(Hz)表示。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. When multiple peaks appear, the following abbreviations will be used: s (singlet, single peak), d (doublet, double peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplets), br (broadened, broad peaks), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublets), dt (doublet of triplets, double triplet). The coupling constant J is expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent G6125C四级杆HPLC-MS(色谱柱型号：XBridge BEH C18,4.6x 50mm,2.5微米,6min,流速为1mL/min。流动相：0％-95％(CH3CN)在(含0.1％甲酸的H2O:CH3CN＝90:10)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用DAD检测。The measurement conditions of low-resolution mass spectrometry (MS) data are: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6x 50mm, 2.5 micron, 6min, flow rate is 1mL/min. Mobile phase: 0% - Ratio of 95% (CH 3 CN) in (0.1% formic acid in H 2 O:CH 3 CN = 90:10) using electrospray ionization (ESI) at 210 nm/254 nm, detected with DAD.
化合物纯化使用天津博纳艾杰尔科技有限公司Cheetah Pro中压快速纯化制备色谱，在210nm/254nm下，用UV检测测。Compounds were purified using Cheetah Pro medium-pressure rapid purification and preparation chromatography of Tianjin Bona Edger Technology Co., Ltd., using UV detection at 210nm/254nm.
下面简写词的使用贯穿本发明：
PE  石油醚          EtOAc  乙酸乙酯
mg      毫克                    mmol  毫摩尔
mL      毫升                    g     克
M       摩尔/升                 rpm   转/分
μM     微摩尔/升               h     小时
DCM     二氯甲烷                MeOH  甲醇
min     分钟                    CDCl3 氘代氯仿
DMSO-d6 氘代二甲基亚砜          nM    纳摩尔/升
HEPES   4-羟乙基哌嗪乙磺酸      BSA   牛血清白蛋白
IBMX    磷酸二酯酶抑制剂        HBSS  Hank's平衡盐溶液
nL      纳升The following abbreviations are used throughout this disclosure:
PE petroleum ether EtOAc ethyl acetate
mg milligram mmol millimole
mL milliliter g grams
M mol/L rpm rpm rpm μM Micromol/L h hour
DCM dichloromethane MeOH methanol
min minutes CDCl 3 deuterated chloroform
DMSO-d 6deuterated dimethyl sulfoxide nM nanomol/L
HEPES 4-Hydroxyethylpiperazineethanesulfonic acid BSA Bovine serum albumin
IBMX Phosphodiesterase Inhibitor HBSS Hank's Balanced Salt Solution
nL nanoliter
下列反应方案描述了制备本发明化合物的步骤。环B'和环B”为含氮原子的5-6元杂环基，除非另有说明，各环B、X、R2、R6、R7、R10、R11、R12、R14、R15、Rb、n具有如本发明所述的定义。Boc为常用保护基团叔丁氧羰基。The following reaction schemes describe the steps for preparing compounds of the invention. 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.
反应方案1
Reaction scheme 1
式(9)所示的化合物可以通过该反应方案1制备得到：式(1)所示的化合物和式(2)所示的化合物反应得到式(3)所示的化合物。式(3)所示的化合物在多聚磷酸的作用下反应得到式(4)所示的化合物。式(4)所示的化合物经溴代后得到式(5)所示的化合物。式(5)所示的化合物和式(6)所示的化合物反应得到式(7)所示的化合物。式(7)所示的化合物和式(8)所示的化合物反应得到式(9)所示的化合物。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 ).
反应方案2
Reaction scheme 2
式(11)所示的化合物可以通过该反应方案2制备得到：式(10)所示的化合物经氧化得到式(11)所示的化合物。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 ).
反应方案3
Reaction scheme 3
式(19)所示的化合物可以通过该反应方案3制备得到：式(12)所示的化合物和式(13)所示的化合物反应得到式(14)所示的化合物。式(14)所示的化合物在酸性条件下反应得到式(15)所示的化合物。式(15)所示的化合物与二碳酸二叔丁酯反应得到式(16)所示的化合物。式(16)所示的化合物经还原得到式(17)所示的化合物。式(17)所示的化合物和式(11)所示的化合物反应得到式(18)所示的化合物。式(18)所示的化合物与2-氯-1,1,1-三甲氧基乙烷反应得到式(19)所示的化合物。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 ).
反应方案4
Reaction scheme 4
式(24)所示的化合物可以通过该反应方案4制备得到：式(9)所示的化合物和式(20)所示的化合物反应得到式(21)所示的化合物。式(21)所示的化合物脱N-boc得到式(22)所示的化合物。式(22)所示的化合物和式(19)所示的化合物反应得到式(23)所示的化合物。式(23)所示的化合物水解得到式(24)所示的化合物。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 ).
反应方案5
Reaction scheme 5
式(25)所示的化合物可以通过该反应方案5制备得到：式(5)所示的化合物和式(8)所示的化合物反应得到式(25)所示的化合物。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 ).
反应方案6
Reaction scheme 6
式(21)所示的化合物还可以通过该反应方案6制备得到：式(6)所示的化合物和式(26)所示的化合物反应得到式(27)所示的化合物。式(27)所示的化合物和式(25)所示的化合物反应得到式(21)所示的化合物。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 ).
反应方案7
Reaction scheme 7
式(31)所示的化合物可以通过该反应方案7制备得到：式(27)所示的化合物和式(5)所示的化合物反应得到式(28)所示的化合物。式(28)所示的化合物脱N-Boc得到式(29)所示的化合物。式(29)所示的化合物和式(19)所示的化合物反应得到式(30)所示的化合物。式(30)所示的化合物水解得到式(31)所示的化合物。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 ).
反应方案8
Reaction scheme 8
式(40)所示的化合物可以通过该反应方案8制备得到：式(6)所示的化合物和溴化苄反应得到式(32) 所示的化合物。式(32)所示的化合物和式(33)所示的化合物反应得到式(34)所示的化合物。式(34)所示的化合物脱苄基得到式(35)所示的化合物。式(35)所示的化合物和式(36)所示的化合物反应得到式(37)所示的化合物。式(37)所示的化合物脱N-Boc得到式(38)所示的化合物。式(38)所示的化合物和式(19)所示的化合物反应得到式(39)所示的化合物。式(39)所示的化合物水解得到式(40)所示的化合物。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 ).
反应方案9
Reaction scheme 9
式(42)所示的化合物可以通过该反应方案9制备得到：2-羟基乙酸甲酯和叔丁基二苯基氯硅烷反应得到式(41)所示的化合物。式(41)所示的化合物与氨气反应得到式(42)所示的化合物。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 ).
反应方案10
Reaction scheme 10
式(19)所示的化合物还可以通过该反应方案10制备得到：式(43)所示的化合物经溴代得到式(44)所示的化合物。式(44)所示的化合物和式(42)所示的化合物反应得到式(45)所示的化合物。式(45)所示的化合物经溴代反应得到式(46)所示的化合物。式(46)所示的化合物和劳森试剂反应得到式(47)所示的化合物。式(47)所示的化合物和式(48)所示的化合物反应得到式(49)所示的化合物。式(49)所示的化合物分子内成环得到式(50)所示的化合物。式(50)所示的化合物脱TBDPS保护得到式(51)所示的化合物。式(51)所示的化合物氯代得到式(19)所示的化合物。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 ).
反应方案11
Reaction Scheme 11
式(59)所示的化合物还可以通过该反应方案11制备得到：式(51)所示的化合物和式(52)所示的化合物反应得到式(53)所示的化合物。式(53)所示的化合物还原得到式(54)所示的化合物。式(54)所示的化合物氧化得到式(55)所示的化合物。式(55)所示的化合物和式(56)所示的化合物反应得到式(57)所示的化合物。式(57)所示的化合物和式(36)所示的化合物反应得到式(58)所示的化合物。式(58)所示的化合物水解得到式(59)所示的化合物。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 ).
具体实施方式Detailed ways
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are only illustrative and do not limit the present invention in any way.
实施例1(S)-2-((6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻唑并[2,3-d]咪唑-5-羧酸(化合物1)的合成
Example 1 (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 (compound 1)
步骤1：4-氯-2-(2,2-二乙氧基乙氧基)-1-甲基苯的合成Step 1: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene
将化合物5-氯-2-甲基苯酚(15g,105.2mmol)，2-溴-1,1-二乙氧基乙烷(25g,126.9mmol)和碳酸钾(29.1g,210.4mmol)加入到N,N-二甲基甲酰胺(50mL)中，氮气保护下120℃反应11h。冷却至室温，加入水(100mL)，用乙酸乙酯萃取(35mL×3)，合并有机相，用饱和食盐水(30mL)洗一次，有机相用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1％)得到浅褐色液体产物21.1g，产率77.5％。Compound 5-chloro-2-methylphenol (15g, 105.2mmol), 2-bromo-1,1-diethoxyethane (25g, 126.9mmol) and potassium carbonate (29.1g, 210.4mmol) were added to In N,N-dimethylformamide (50 mL), react at 120°C for 11 hours under nitrogen protection. Cool to room temperature, add water (100mL), extract with ethyl acetate (35mL×3), combine the organic phases, wash once with saturated brine (30mL), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent EtOAc: PE (v/v) = 1%) yielded 21.1 g of light brown liquid product with a yield of 77.5%.
1HNMR(500MHz,CDCl3)δ7.03(d,J＝7.9Hz,1H),6.84(dd,J＝7.9,2.0Hz,1H),6.81(d,J＝2.0Hz,1H), 4.84(t,J＝5.2Hz,1H),3.98(d,J＝5.2Hz,2H),3.81–3.74(m,2H),3.68–3.62(m,2H),2.18(s,3H),1.25(t,J＝7.0Hz,6H). 1 HNMR (500MHz, CDCl 3 ) δ7.03 (d, J = 7.9 Hz, 1H), 6.84 (dd, J = 7.9, 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 4.84(t,J＝5.2Hz,1H),3.98(d,J＝5.2Hz,2H),3.81–3.74(m,2H),3.68–3.62(m,2H),2.18(s,3H),1.25 (t,J＝7.0Hz,6H).
步骤2：4-氯-7-甲基苯并呋喃的合成Step 2: Synthesis of 4-chloro-7-methylbenzofuran
将化合物4-氯-2-(2,2-二乙氧基乙氧基)-1-甲基苯(21g,81.2mmol)和多聚磷酸(16.6g,202.9mmol)加入到1,2-二氯乙烷(50mL)中，氮气保护下85℃反应过夜。冷却至室温，减压除去溶剂，加入水(80mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE＝100％)得到无色液体产物9.2g，产率68.0％。Compound 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (21g, 81.2mmol) and polyphosphoric acid (16.6g, 202.9mmol) were added to 1,2- In dichloroethane (50 mL), react overnight at 85°C under nitrogen protection. Cool to room temperature, remove the solvent under reduced pressure, add water (80 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (elution (PE = 100%), 9.2 g of colorless liquid product was obtained, with a yield of 68.0%.
1HNMR(500MHz,CDCl3)δ7.63(d,J＝2.3Hz,1H),7.12(d,J＝7.9Hz,1H),7.00(d,J＝7.9Hz,1H),6.84(d,J＝2.3Hz,1H),2.48(s,3H). 1 HNMR (500MHz, CDCl 3 ) δ7.63 (d, J = 2.3Hz, 1H), 7.12 (d, J = 7.9Hz, 1H), 7.00 (d, J = 7.9Hz, 1H), 6.84 (d, J＝2.3Hz,1H),2.48(s,3H).
步骤3：7-(溴甲基)-4-氯苯并呋喃的合成Step 3: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran
将化合物4-氯-7-甲基苯并呋喃(4.1g，24.61mmol)，偶氮二异丁腈(810mg，4.92mmol)和N-溴代丁二酰亚胺(5.26g，29.53mmol)加入到1,2-二氯乙烷(30mL)中，氮气保护下75℃反应过夜。冷却至室温，加入水(50mL)，用二氯甲烷萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE＝100％)得到无色液体产物4.3g，产率71.2％。The compound 4-chloro-7-methylbenzofuran (4.1g, 24.61mmol), azobisisobutyronitrile (810mg, 4.92mmol) and N-bromosuccinimide (5.26g, 29.53mmol) Add to 1,2-dichloroethane (30 mL) and react overnight at 75°C under nitrogen protection. Cool to room temperature, add water (50mL), extract with dichloromethane (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE=100% ) to obtain 4.3g of colorless liquid product with a yield of 71.2%.
1HNMR(500MHz,CDCl3)δ7.71(s,1H),7.24–7.20(m,2H),6.89(s,1H),4.75(s,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.71(s,1H),7.24–7.20(m,2H),6.89(s,1H),4.75(s,2H).
步骤4：2-溴-6-((4-氯苯并呋喃-7-基)甲氧基)吡啶的合成Step 4: Synthesis of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine
将化合物7-(溴甲基)-4-氯苯并呋喃(600mg,2.44mmol)，2-溴-6-吡啶(467mg,2.68mmol)和碳酸钾(675mg,4.88mmol)加入到N,N-二甲基甲酰胺(6mL)中，60℃反应1.5h。冷却至室温，加入水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝8％)得到白色固体产物756mg，产率91.4％。Compound 7-(bromomethyl)-4-chlorobenzofuran (600mg, 2.44mmol), 2-bromo-6-pyridine (467mg, 2.68mmol) and potassium carbonate (675mg, 4.88mmol) were added to N,N -React in dimethylformamide (6mL) at 60°C for 1.5h. Cool to room temperature, add water (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE( v/v) = 8%) to obtain 756 mg of white solid product, with a yield of 91.4%.
1HNMR(500MHz,CDCl3)δ7.68(s,1H),7.41(td,J＝7.9,2.9Hz,1H),7.36(dd,J＝8.0,2.8Hz,1H),7.27–7.21(m,1H),7.08(dd,J＝7.5,2.9Hz,1H),6.88(s,1H),6.73(dd,J＝8.2,2.9Hz,1H),6.54(s,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.68(s,1H),7.41(td,J＝7.9,2.9Hz,1H),7.36(dd,J＝8.0,2.8Hz,1H),7.27–7.21(m ,1H),7.08(dd,J＝7.5,2.9Hz,1H),6.88(s,1H),6.73(dd,J＝8.2,2.9Hz,1H),6.54(s,2H).
步骤5：2-溴-6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶的合成Step 5: Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridine
将化合物2-溴-6-((4-氯苯并呋喃-7-基)甲氧基)吡啶(600mg，1.77mmol)和N-氟代双苯磺酰胺(670mg，2.12mmol)加入到无水四氢呋喃(30mL)中，氮气保护下-40℃冷却，加入二异丙基氨基锂的四氢呋喃溶液(2.0mol/L)(1.4mL，2.80mmol)，此温度下反应3h。加入水(50mL)，用二氯甲烷萃取(20mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝10％)得到白色固体产物211mg，产率33.4％。Compound 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (600 mg, 1.77 mmol) and N-fluorobishenylsulfonamide (670 mg, 2.12 mmol) were added to In water tetrahydrofuran (30 mL), cool to -40°C under nitrogen protection, add tetrahydrofuran solution (2.0 mol/L) of lithium diisopropylamide (1.4 mL, 2.80 mmol), and react at this temperature for 3 hours. Add water (50mL), extract with dichloromethane (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =10%) to obtain 211 mg of white solid product, with a yield of 33.4%.
1HNMR(500MHz,CDCl3)δ7.43(t,J＝7.8Hz,1H),7.33(d,J＝8.1Hz,1H),7.25(d,J＝8.5Hz,1H),7.09(d,J＝7.5Hz,1H),6.74(d,J＝8.1Hz,1H),6.01(d,J＝6.7Hz,1H),5.57(s,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.43 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.09 (d, J＝7.5Hz,1H),6.74(d,J＝8.1Hz,1H),6.01(d,J＝6.7Hz,1H),5.57(s,2H).
步骤6：5-((2,4-二甲氧苄基)氨基)-4-硝基噻吩-2-羧酸甲酯的合成Step 6: Synthesis of 5-((2,4-dimethoxybenzyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester
将化合物5-溴-4-硝基噻吩-2-羧酸甲酯(4g,15.03mmol)和碳酸钾(8.31g,60.14mmol)加入到乙腈(60mL)中，搅拌下加入2,4-二甲氧基苄胺(3.52g,21.04mmol)，室温反应3h。加入水(800mL)，析出大量固体，抽滤，滤饼用二氯甲烷(50mL)溶解，分离有机相，用无水硫酸钠干燥，减压浓缩，得到淡黄色固体产物5.2g，产率98.2％。Compound 5-bromo-4-nitrothiophene-2-carboxylic acid methyl ester (4g, 15.03mmol) and potassium carbonate (8.31g, 60.14mmol) were added to acetonitrile (60mL), and 2,4-biscarboxylic acid methyl ester was added with stirring. Methoxybenzylamine (3.52g, 21.04mmol), react at room temperature for 3h. Water (800 mL) was added to precipitate a large amount of solid, which was suction filtered. The filter cake was dissolved in methylene chloride (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.2 g of a light yellow solid product with a yield of 98.2 %.
LC-MS(ESI):[M+H]+＝353.2；LC-MS(ESI): [M+H] + =353.2;
1HNMR(500MHz,CDCl3)δ8.87(br.s,1H),7.98(s,1H),7.19(d,J＝8.2Hz,1H),6.51–6.44(m,2H),4.44(d,J＝5.7Hz,2H),3.86(s,3H),3.85(s,3H),3.81(s,3H). 1 HNMR (500MHz, CDCl 3 ) δ8.87 (br.s, 1H), 7.98 (s, 1H), 7.19 (d, J = 8.2Hz, 1H), 6.51–6.44 (m, 2H), 4.44 (d ,J＝5.7Hz,2H),3.86(s,3H),3.85(s,3H),3.81(s,3H).
步骤7：5-氨基-4-硝基苯酚-2-羧酸甲酯的合成Step 7: Synthesis of 5-amino-4-nitrophenol-2-carboxylic acid methyl ester
将化合物5-((2,4-二甲氧苄基)氨基)-4-硝基噻吩-2-羧酸甲酯(5.2g，14.76mmol)溶解在二氯甲烷(80 mL)中，搅拌下加入三氟乙酸(8mL)，室温反应过夜。减压除去溶剂，加入水(50mL)，用饱和碳酸氢钠水溶液调节pH＝8，用四氢呋喃(50mL)和乙酸乙酯(50mL)萃取，分离有机相，用无水硫酸钠干燥，减压浓缩，得到淡黄色固体产物2.9g，产率97.2％。Compound 5-((2,4-dimethoxybenzyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester (5.2g, 14.76mmol) was dissolved in dichloromethane (80 mL), add trifluoroacetic acid (8 mL) with stirring, and react at room temperature overnight. Remove the solvent under reduced pressure, add water (50 mL), adjust pH=8 with saturated sodium bicarbonate aqueous solution, extract with tetrahydrofuran (50 mL) and ethyl acetate (50 mL), separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure , 2.9g of light yellow solid product was obtained, with a yield of 97.2%.
LC-MS(ESI):[M+H]+＝203.1；LC-MS(ESI): [M+H] + =203.1;
1HNMR(500MHz,DMSO-d6)δ9.01(br.s,2H),7.75(s,1H),3.77(s,3H). 1 HNMR (500MHz, DMSO-d 6 ) δ9.01 (br.s, 2H), 7.75 (s, 1H), 3.77 (s, 3H).
步骤8：5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-羧酸甲酯的合成Step 8: Synthesis of 5-((tert-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester
将化合物5-氨基-4-硝基苯酚-2-羧酸甲酯(1.8g,8.90mmol)溶解在四氢呋喃(10mL)中，加入二碳酸二叔丁酯(4.86g,22.26mmol)和N,N-二异丙基乙胺(2.88g,22.26mmol)，60℃反应过夜。加入水(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1:8)得到淡黄色固体产物2.3g，产率85.5％。Compound 5-amino-4-nitrophenol-2-carboxylic acid methyl ester (1.8g, 8.90mmol) was dissolved in tetrahydrofuran (10mL), and di-tert-butyl dicarbonate (4.86g, 22.26mmol) and N were added. N-diisopropylethylamine (2.88g, 22.26mmol), react at 60°C overnight. Add water (50mL), extract with ethyl acetate (25mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =1:8) to obtain 2.3g of light yellow solid product, with a yield of 85.5%.
LC-MS(ESI):[M-55]+＝247.1；LC-MS(ESI): [M-55] + =247.1;
1HNMR(500MHz,CDCl3)δ10.12(s,1H),8.09(s,1H),3.89(s,3H),1.58(s,9H). 1 HNMR (500MHz, CDCl 3 ) δ10.12(s,1H),8.09(s,1H),3.89(s,3H),1.58(s,9H).
步骤9：4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-羧酸甲酯的合成Step 9: Synthesis of 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylic acid methyl ester
将化合物5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-羧酸甲酯(3.5g，11.58mmol)，铁粉(3.23g，57.89mmol)，氯化铵(1.24g，23.16mmol)加入到甲醇(60mL)和水(20mL)的混合溶剂中，40℃反应过夜。用硅藻土过滤，滤饼用甲醇洗(25mL×2)，滤液减压浓缩除去甲醇，用二氯甲烷萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝45％)得到浅褐色粘稠固体产物3.1g，产率98.3％。Compound 5-((tert-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester (3.5g, 11.58mmol), iron powder (3.23g, 57.89mmol), ammonium chloride (1.24g , 23.16 mmol) was added to a mixed solvent of methanol (60 mL) and water (20 mL), and the reaction was carried out at 40°C overnight. Filter with diatomaceous earth, wash the filter cake with methanol (25mL×2), concentrate the filtrate under reduced pressure to remove methanol, extract with dichloromethane (25mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purified by silica gel column chromatography (eluent EtOAc: PE (v/v) = 45%), 3.1 g of light brown viscous solid product was obtained, with a yield of 98.3%.
LC-MS(ESI):[M-55]+＝217.1；LC-MS(ESI): [M-55] + =217.1;
1HNMR(500MHz,DMSO-d6)δ9.64(s,1H),7.14(s,1H),4.72(s,2H),3.72(s,3H),1.48(s,9H). 1 HNMR (500MHz, DMSO-d 6 ) δ9.64(s,1H),7.14(s,1H),4.72(s,2H),3.72(s,3H),1.48(s,9H).
步骤10：(S)-5-((叔丁氧羰基)氨基)-4-((氧杂环丁烷-2-基甲基)氨基)噻吩-2-羧酸甲酯的合成Step 10 Synthesis of: (S)-5-((tert-butoxycarbonyl)amino)-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester
将化合物(S)-氧杂环丁烷-2-基甲醇(1.0g,11.35mmol)加入到二氯甲烷(25mL)，在冰浴中冷却，加入戴斯-马丁试剂(7.22g,17.03mmol)，室温反应过夜。用硅藻土过滤，滤饼用二氯甲烷洗(25mL×2)，滤液减压浓缩得到白色固体，加入EtOAc:PE(v/v)＝1:1混合溶液洗(20mL×2)，滤液减压浓缩，得白色固体产物(S)-氧杂环丁烷-2-甲醛1.06g。Compound (S)-oxetan-2-ylmethanol (1.0g, 11.35mmol) was added to dichloromethane (25mL), cooled in an ice bath, and Dess-Martin reagent (7.22g, 17.03mmol) was added ), react at room temperature overnight. Filter with diatomaceous earth, wash the filter cake with dichloromethane (25mL×2), concentrate the filtrate under reduced pressure to obtain a white solid, add EtOAc:PE (v/v)=1:1 mixed solution and wash (20mL×2), the filtrate Concentrate under reduced pressure to obtain 1.06g of white solid product (S)-oxetane-2-carbaldehyde.
将化合物4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-羧酸甲酯(260mg,0.95mmol)和(S)-氧杂环丁烷-2-甲醛(411mg,1.91mmol)加入到二氯甲烷(10mL)中，加入3滴冰醋酸，室温搅拌20min，加入三乙酰氧基硼氢化钠(443mg,2.10mmol)室温反应1h，加入水(30mL)，用二氯甲烷萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝33％)得到浅褐色液体产物177mg，产率54.1％。The compound 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylic acid methyl ester (260 mg, 0.95 mmol) and (S)-oxetane-2-carboxaldehyde (411 mg, 1.91 mmol) ) into dichloromethane (10 mL), add 3 drops of glacial acetic acid, stir at room temperature for 20 min, add sodium triacetoxyborohydride (443 mg, 2.10 mmol) and react at room temperature for 1 h, add water (30 mL), and extract with dichloromethane (10ml Yield 54.1%.
LC-MS(ESI):[M+H]+＝343.3；LC-MS(ESI): [M+H] + =343.3;
1HNMR(500MHz,CDCl3)δ7.39(s,1H),4.98–4.90(m,1H),4.77–4.70(m,1H),4.66–4.58(m,1H),3.82(s,3H),3.32–3.19(m,2H),2.73–2.64(m,1H),2.62–2.42(m,1H),1.52(s,9H). 1 HNMR(500MHz, CDCl 3 )δ7.39(s,1H),4.98–4.90(m,1H),4.77–4.70(m,1H),4.66–4.58(m,1H),3.82(s,3H) ,3.32–3.19(m,2H),2.73–2.64(m,1H),2.62–2.42(m,1H),1.52(s,9H).
步骤11：(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成Step 11: (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester Synthesis
将化合物(S)-5-((叔丁氧羰基)氨基)-4-((氧杂环丁烷-2-基甲基)氨基)噻吩-2-羧酸甲酯(980mg,2.86mmol)溶解在四氢呋喃(15mL)中，加入2-氯-1,1,1-三甲氧基乙烷(885mg,5.72mmol)和对甲苯磺酸一水合物(28mg,0.15mmol)，75℃反应2.5h。减压浓缩除去溶剂，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1:2)得到浅褐色液体产物623mg，产率72.4％。Compound (S)-5-((tert-butoxycarbonyl)amino)-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (980 mg, 2.86 mmol) Dissolve in tetrahydrofuran (15mL), add 2-chloro-1,1,1-trimethoxyethane (885mg, 5.72mmol) and p-toluenesulfonic acid monohydrate (28mg, 0.15mmol), and react at 75°C for 2.5h . The solvent was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:2) to obtain 623 mg of light brown liquid product with a yield of 72.4%.
LC-MS(ESI):[M+H]+＝301.1；LC-MS(ESI): [M+H] + =301.1;
1HNMR(500MHz,CDCl3)δ7.71(s,1H),5.22–5.16(m,1H),4.93–4.87(m,2H),4.66–4.63(m,1H),4.48 –4.39(m,2H),4.36–4.31(m,1H),3.90(s,3H),2.78–2.72(m,1H),2.45–2.38(m,1H). 1 HNMR(500MHz, CDCl 3 )δ7.71(s,1H),5.22–5.16(m,1H),4.93–4.87(m,2H),4.66–4.63(m,1H),4.48 –4.39(m,2H),4.36–4.31(m,1H),3.90(s,3H),2.78–2.72(m,1H),2.45–2.38(m,1H).
步骤12：6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯的合成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
将化合物N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(599mg,1.94mmol)，2-溴-6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶(460mg,1.29mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(106mg,0.13mmol)和碳酸钾(535mg,3.87mmol)加入到1,4-二氧六环(6mL)和水(1.5mL)的混合溶剂中，氮气保护下90℃反应2h，冷却至室温，加入水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝15％)得到无色油状产物436mg，产率73.6％。Compound N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (599mg, 1.94mmol), 2-bromo-6-((4-chloro-2-fluorobenzofuran) -7-yl)methoxy)pyridine (460mg, 1.29mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (106mg, 0.13mmol) and potassium carbonate (535 mg, 3.87 mmol) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (1.5 mL), reacted at 90°C for 2 h under nitrogen protection, cooled to room temperature, and water (50 mL) was added , extracted with ethyl acetate (15mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc: PE (v/v) = 15%) to obtain The colorless oily product was 436 mg, yield 73.6%.
LC-MS(ESI):[M+H]+＝459.3；LC-MS(ESI): [M+H] + =459.3;
1HNMR(500MHz,CDCl3)δ7.55(t,J＝7.8Hz,1H),7.31(d,J＝8.2Hz,1H),7.25(d,J＝8.2Hz,1H),6.95(d,J＝7.3Hz,1H),6.69(s,1H),6.67(d,J＝8.4Hz,1H),6.01(d,J＝6.6Hz,1H),5.62(s,2H),4.14–4.10(m,2H),3.67–3.60(m,2H),2.61–3.54(m,2H),1.49(s,9H). 1 HNMR (500MHz, CDCl 3 ) δ7.55(t,J＝7.8Hz,1H),7.31(d,J＝8.2Hz,1H),7.25(d,J＝8.2Hz,1H),6.95(d, J＝7.3Hz,1H),6.69(s,1H),6.67(d,J＝8.4Hz,1H),6.01(d,J＝6.6Hz,1H),5.62(s,2H),4.14–4.10( m,2H),3.67–3.60(m,2H),2.61–3.54(m,2H),1.49(s,9H).
步骤13：6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-1',2',3',6'-四氢-2,4'-二吡啶的合成Step 13: 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine synthesis
将化合物6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯(420mg,0.92mmol)，溶解在二氯甲烷(4mL)中，加入4mol/L氯化氢的1,4-二氧六环(3mL)溶液，室温反应30min，减压除去溶剂，加入饱和碳酸氢钠溶液调节pH＝8，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，得到浅褐色固体产物326mg，产率99.3％。Compound 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]-1'(2' H)-tert-butylcarboxylate (420mg, 0.92mmol), dissolved in dichloromethane (4mL), added 4mol/L hydrogen chloride in 1,4-dioxane (3mL) solution, reacted at room temperature for 30min, reduced pressure Remove the solvent, add saturated sodium bicarbonate solution to adjust pH = 8, extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 326 mg of light brown solid product, yield 99.3 %.
LC-MS(ESI):[M+H]+＝359.2。LC-MS (ESI): [M+H] + =359.2.
步骤14：(S)-2-((6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(170mg,0.57mmol)，6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-1',2',3',6'-四氢-2,4'-二吡啶(320mg,0.89mmol)，碘化钾(19mg,0.11mmol)和碳酸钾(235mg,1.70mmol)加入到乙腈(4mL)中，50℃反应2h。冷却至室温，加入水(30mL)，用乙酸乙酯萃取(20mL×3)，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝80％)得到淡黄色固体产物81mg，产率23.0％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 170 mg, 0.57 mmol), 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'- Dipyridine (320 mg, 0.89 mmol), potassium iodide (19 mg, 0.11 mmol) and potassium carbonate (235 mg, 1.70 mmol) were added to acetonitrile (4 mL) and reacted at 50°C for 2 hours. Cool to room temperature, add water (30mL), extract with ethyl acetate (20mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =80%) to obtain 81 mg of light yellow solid product, with a yield of 23.0%.
LC-MS(ESI):[M+H]+＝623.3。LC-MS (ESI): [M+H] + =623.3.
步骤15：(S)-2-((6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻唑并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(80mg,0.13mmol)和氢氧化锂一水合物(27mg,0.64mmol)加入到1,4-二氧六环(3mL)和水(1.5mL)的混合溶剂中，40℃反应1h。在冰浴中冷却，用系盐酸调节pH＝6，用乙酸乙酯萃取(15mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶制备板纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体产物7mg，产率9.0％。Compound (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-di Pyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid Methyl ester (80 mg, 0.13 mmol) and lithium hydroxide monohydrate (27 mg, 0.64 mmol) were added to a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), and the reaction was carried out at 40°C for 1 hour. Cool in an ice bath, adjust pH=6 with hydrochloric acid, extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify on a silica gel preparation plate (eluent MeOH: DCM (v/v) = 5%) to obtain 7 mg of white solid product, with a yield of 9.0%.
LC-MS(ESI):[M+H]+＝609.3；LC-MS(ESI): [M+H] + =609.3;
1HNMR(500MHz,CDCl3)δ7.61(s,1H),7.54(t,J＝7.6Hz,1H),7.30(d,J＝8.2Hz,1H),7.22(d,J＝8.3Hz,1H),6.94(d,J＝7.4Hz,1H),6.71–6.64(m,2H),5.99(d,J＝6.6Hz,1H),5.60(s,2H),5.16–5.09(m,1H),4.62–4.49(m,3H),4.38–4.32(m,1H),4.10–4.02(m,2H),3.48–3.42(m,2H),3.00–2.93(m,2H),2.70–2.63(m,2H),2.42–2.18(m,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.61 (s, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.30 (d, J = 8.2Hz, 1H), 7.22 (d, J = 8.3Hz, 1H),6.94(d,J＝7.4Hz,1H),6.71–6.64(m,2H),5.99(d,J＝6.6Hz,1H),5.60(s,2H),5.16–5.09(m,1H ),4.62–4.49(m,3H),4.38–4.32(m,1H),4.10–4.02(m,2H),3.48–3.42(m,2H),3.00–2.93(m,2H),2.70–2.63 (m,2H),2.42–2.18(m,2H).
实施例2(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物2)的合成
Example 2 (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 (compound 2)
步骤1：7-(溴甲基)-4-氯-2-氟苯并呋喃的合成Step 1: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran
将化合物7-(溴甲基)-4-氯苯并呋喃(3.4g,13.85mmol)和N-氟代双苯磺酰胺(5.24g,16.62mmol)加入到无水四氢呋喃(100mL)中，氮气保护下-50℃冷却，加入二异丙基氨基锂的四氢呋喃溶液(9mL,18mmol,2.0mol/L)，此温度下反应3h。加入水(300mL)，用乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE＝100％)得到白色固体产物523mg，产率14.3％。Compound 7-(bromomethyl)-4-chlorobenzofuran (3.4g, 13.85mmol) and N-fluorobishenylsulfonamide (5.24g, 16.62mmol) were added to anhydrous tetrahydrofuran (100mL), nitrogen Cool at -50°C under protection, add tetrahydrofuran solution of lithium diisopropylamide (9 mL, 18 mmol, 2.0 mol/L), and react at this temperature for 3 hours. Add water (300mL), extract with ethyl acetate (50mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE=100%) to obtain a white solid Product 523 mg, yield 14.3%.
1HNMR(500MHz,CDCl3)δ7.24–7.20(m,2H),6.01(d,J＝6.6Hz,1H),4.65(s,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.24–7.20 (m, 2H), 6.01 (d, J = 6.6Hz, 1H), 4.65 (s, 2H).
步骤2：6-羟基-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯的合成Step 2: Synthesis of 6-hydroxy-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)-carboxylic acid tert-butyl ester
化合物N-叔丁氧羰基-1,2,3,6-四氢吡啶-4-硼酸(4.0g，23.0mmol)，2-溴-6-羟基吡啶(5.2g，23.0mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(940mg,1.15mmol)和碳酸钾(6.35g,45.98mmol)加入到1,4-二氧六环(80mL)和水(20mL)的混合溶剂中，氮气保护下90℃反应2h，冷却至室温，加入水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到浅黄色固体产物5.87g，产率92.4％。Compound N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid (4.0g, 23.0mmol), 2-bromo-6-hydroxypyridine (5.2g, 23.0mmol), [1, 1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (940mg, 1.15mmol) and potassium carbonate (6.35g, 45.98mmol) were added to 1,4-dioxane (80mL) and water (20mL), react at 90°C for 2 hours under nitrogen protection, cool to room temperature, add water (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, and use anhydrous sulfuric acid The product was dried over sodium, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH: DCM (v/v) = 5%) to obtain 5.87 g of a light yellow solid product with a yield of 92.4%.
LC-MS(ESI):[M+H]+＝277.3；LC-MS(ESI): [M+H] + =277.3;
1HNMR(500MHz,DMSO-d6)δ11.18(s,1H),7.42(t,J＝8.0Hz,1H),6.47(s,1H),6.27(d,J＝8.4Hz,2H),3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H). 1 HNMR(500MHz, DMSO-d 6 )δ11.18(s,1H),7.42(t,J＝8.0Hz,1H),6.47(s,1H),6.27(d,J＝8.4Hz,2H), 3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H).
步骤3：4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
将化合物6-羟基-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯(2.0g,7.24mmol)和10％钯碳(860mg,含水量40％-60％)加入到甲醇(20mL)中，室温反应过夜。过滤除去催化剂，滤液减压浓缩，得到白色固体产物1.76g，产率87.4％。Compound 6-hydroxy-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (2.0g, 7.24mmol) and 10% palladium on carbon (860 mg, water content 40%-60%) was added to methanol (20 mL), and the reaction was carried out at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.76 g of a white solid product with a yield of 87.4%.
LC-MS(ESI):[M+H]+＝279.2；LC-MS(ESI): [M+H] + =279.2;
1HNMR(500MHz,DMSO-d6)δ11.46(s,1H),7.33(dd,J＝9.1,6.9Hz,1H),6.14(d,J＝9.0Hz,1H),5.99(s,1H),4.09–4.00(m,2H),2.80–2.64(m,2H),2.60–2.53(m,1H),1.80–1.74(m,2H),1.50–1.42(m,2H),1.40(s,9H). 1 HNMR (500MHz, DMSO-d 6 ) δ11.46(s,1H),7.33(dd,J＝9.1,6.9Hz,1H),6.14(d,J＝9.0Hz,1H),5.99(s,1H ),4.09–4.00(m,2H),2.80–2.64(m,2H),2.60–2.53(m,1H),1.80–1.74(m,2H),1.50–1.42(m,2H),1.40(s ,9H).
步骤4：4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 4: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
将化合物7-(溴甲基)-4-氯-2-氟苯并呋喃(150mg,0.57mmol)，4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯(175mg,0.63mmol)和碳酸钾(236mg,1.71mmol)加入到N,N-二甲基甲酰胺(4mL)中，60℃反应1h。冷却至室温，加入水(40mL)，用乙酸乙酯萃取(15mL×3)，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝15％)得到无色油状产物206mg，产率78.4％。Compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (150 mg, 0.57 mmol), 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester ( 175 mg, 0.63 mmol) and potassium carbonate (236 mg, 1.71 mmol) were added to N,N-dimethylformamide (4 mL), and the reaction was carried out at 60°C for 1 hour. Cool to room temperature, add water (40mL), extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =15%) to obtain 206 mg of colorless oily product with a yield of 78.4%.
LC-MS(ESI):[M+H]+＝461.3；LC-MS(ESI): [M+H] + =461.3;
1HNMR(500MHz,CDCl3)δ7.53–7.47(m,1H),7.33–7.28(m,1H),7.24–7.21(m,1H),6.74–6.70(m,1H),6.64–6.60(m,1H),6.02–5.98(m,1H),5.58(s,2H),4.29–4.15(m,2H),2.87–2.78(m,2H),2.75–2.67(m,1H),1.90–1.82(m,2H),1.74–1.64(m,2H),1.49(s,9H). 1 HNMR (500MHz, CDCl 3 ) δ7.53–7.47(m,1H),7.33–7.28(m,1H),7.24–7.21(m,1H),6.74–6.70(m,1H),6.64–6.60( m,1H),6.02–5.98(m,1H),5.58(s,2H),4.29–4.15(m,2H),2.87–2.78(m,2H),2.75–2.67(m,1H),1.90– 1.82(m,2H),1.74–1.64(m,2H),1.49(s,9H).
步骤5：2-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶的合成Step 5: Synthesis of 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine
将化合物4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(370mg,0.80mmol)，溶解在二氯甲烷(4mL)中，加入4mol/L氯化氢的1,4-二氧六环(5mL)溶液，室温反应30min，减压除去溶剂，加入饱和碳酸氢钠调节pH＝8，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，得到浅褐色固体产物277mg，产率95.6％。Compound 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (370 mg, 0.80 mmol) , dissolve in dichloromethane (4mL), add 4mol/L hydrogen chloride in 1,4-dioxane (5mL), react at room temperature for 30min, remove the solvent under reduced pressure, add saturated sodium bicarbonate to adjust pH=8, use Extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 277 mg of light brown solid product with a yield of 95.6%.
LC-MS(ESI):[M+H]+＝361.2。LC-MS (ESI): [M+H] + =361.2.
步骤6：(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(65mg,0.22mmol)，2-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶(78mg,0.22mmol)，碘化钾(8mg,0.05mmol)和碳酸钾(122mg,0.88mmol)加入到乙腈(2mL)中，50℃反应2h。冷却至室温，加入水(40mL)，用乙酸乙酯萃取(15mL×3)，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝45％)得到浅黄色固体产物76mg，产率56.3％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 65 mg, 0.22 mmol), 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (78 mg, 0.22 mmol), potassium iodide ( 8 mg, 0.05 mmol) and potassium carbonate (122 mg, 0.88 mmol) were added to acetonitrile (2 mL), and the reaction was carried out at 50°C for 2 h. Cool to room temperature, add water (40mL), extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =45%) to obtain 76 mg of light yellow solid product, with a yield of 56.3%.
LC-MS(ESI):[M+H]+＝625.3；LC-MS(ESI): [M+H] + =625.3;
步骤7：(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(72mg,0.12mmol)和氢氧化锂一水合物(48mg,1.14mmol)加入到1,4-二氧六环(3mL)和水(1.5mL)的混合溶剂中，40℃反应1.5h。在冰浴中冷却，用稀盐酸调节pH＝6，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体产物26mg，再用硅胶制备板纯化得到目标产物5mg，产率7.1％。Compound (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl (72 mg, 0.12 mmol) and lithium hydroxide monohydrate The compound (48 mg, 1.14 mmol) was added to a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), and the reaction was carried out at 40°C for 1.5 h. Cool in an ice bath, adjust pH=6 with dilute hydrochloric acid, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent MeOH :DCM (v/v) = 5%) to obtain 26 mg of a white solid product, which was then purified using a silica gel preparation plate to obtain 5 mg of the target product, with a yield of 7.1%.
LC-MS(ESI):[M+H]+＝611.4；LC-MS(ESI): [M+H] + =611.4;
1HNMR(500MHz,CDCl3)δ7.49(t,J＝7.8Hz,1H),7.40(s,1H),7.30(d,J＝8.2Hz,1H),7.20(d,J＝8.3Hz,1H),6.74(d,J＝7.3Hz,1H),6.61(d,J＝8.2Hz,1H),5.97(d,J＝6.6Hz,1H),5.56(s,2H),5.11–5.02(m,1H),4.66–4.46(m,3H),4.38–4.30(m,1H),4.14–3.99(m,2H),3.53–3.39(m,2H),2.75–2.55(m,4H),2.46–2.28(m,5H).1HNMR (500MHz, CDCl 3 ) δ7.49(t,J＝7.8Hz,1H),7.40(s,1H),7.30(d,J＝8.2Hz,1H),7.20(d,J＝8.3Hz,1H ),6.74(d,J＝7.3Hz,1H),6.61(d,J＝8.2Hz,1H),5.97(d,J＝6.6Hz,1H),5.56(s,2H),5.11–5.02(m ,1H),4.66–4.46(m,3H),4.38–4.30(m,1H),4.14–3.99(m,2H),3.53–3.39(m,2H),2.75–2.55(m,4H),2.46 –2.28(m,5H).
实施例3(S)-2-((6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻唑并[2,3-d]咪唑-5-羧酸(化合物3)的合成
Example 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-thiazolo[2,3-d]imidazole-5-carboxylic acid (compound 3 )Synthesis
步骤1：6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯的合成Step 1: 6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)- Synthesis of tert-butyl carboxylate
将化合物7-(溴甲基)-4-氯苯并呋喃(200mg,0.81mmol)，6-羟基-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯(225mg,0.81mmol)和碳酸钾(337mg,2.44mmol)加入到N,N-二甲基甲酰胺(4mL)中，60℃反应5h。冷却至室温，加入水(25mL)，用乙酸乙酯萃取(15mL×3)，有机相用饱和食盐水洗(25mL)， 用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝10％)得到无色油状产物322mg，产率90.2％。Compound 7-(bromomethyl)-4-chlorobenzofuran (200 mg, 0.81 mmol), 6-hydroxy-3',6'-dihydro-[2,4'-dipyridine]-1'(2 'H)-tert-butylcarboxylate (225mg, 0.81mmol) and potassium carbonate (337mg, 2.44mmol) were added to N,N-dimethylformamide (4mL), and reacted at 60°C for 5h. Cool to room temperature, add water (25mL), extract with ethyl acetate (15mL×3), wash the organic phase with saturated brine (25mL), Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent EtOAc: PE (v/v) = 10%) to obtain 322 mg of colorless oily product with a yield of 90.2%.
LC-MS(ESI):[M+H]+＝441.3；LC-MS(ESI): [M+H] + =441.3;
1HNMR(500MHz,CDCl3)δ7.68(d,J＝2.2Hz,1H),7.54(t,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),6.94(d,J＝7.5Hz,1H),6.89(d,J＝2.2Hz,1H),6.70–6.65(m,2H),5.70(s,2H),4.14–4.09(m,2H),3.63(t,J＝5.7Hz,2H),2.58(d,J＝6.4Hz,2H),1.49(s,9H).1HNMR (500MHz, CDCl 3 ) δ7.68(d,J＝2.2Hz,1H),7.54(t,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.22(d,J ＝8.0Hz,1H),6.94(d,J＝7.5Hz,1H),6.89(d,J＝2.2Hz,1H),6.70–6.65(m,2H),5.70(s,2H),4.14–4.09 (m,2H),3.63(t,J＝5.7Hz,2H),2.58(d,J＝6.4Hz,2H),1.49(s,9H).
步骤2：6-((4-氯苯并呋喃-7-基)甲氧基)-1',2',3',6'-四氢-2,4'-二吡啶的合成Step 2: Synthesis of 6-((4-chlorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine
将化合物6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-羧酸叔丁酯(188mg,0.43mmol)，溶解在二氯甲烷(4mL)中，加入4mol/L氯化氢的1,4-二氧六环(3mL)室温反应30min，减压除去溶剂，加入饱和碳酸氢钠调节pH＝8，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，得到浅褐色固体产物132mg，产率90.8％。Compound 6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-dipyridine]-1'(2'H)-carboxylic Dissolve tert-butyl acid ester (188 mg, 0.43 mmol) in dichloromethane (4 mL), add 4 mol/L hydrogen chloride and 1,4-dioxane (3 mL) and react at room temperature for 30 min. Remove the solvent under reduced pressure and add saturated carbonic acid. Adjust pH=8 with sodium hydrogen, extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 132 mg of light brown solid product with a yield of 90.8%.
LC-MS(ESI):[M+H]+＝341.2。LC-MS (ESI): [M+H] + =341.2.
步骤3：(S)-2-((6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(109mg,0.36mmol)，6-((4-氯苯并呋喃-7-基)甲氧基)-1',2',3',6'-四氢-2,4'-二吡啶(123mg,0.36mmol)，碘化钾(12mg,0.07mmol)和碳酸钾(150mg,1.09mmol)加入到乙腈(4mL)中，50℃反应2h。冷却至室温，加入水(40mL)，用乙酸乙酯萃取(15mL×3)，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝45％)得到浅褐色油状产物148mg，产率67.8％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 109 mg, 0.36 mmol), 6-((4-chlorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine (123 mg ,0.36mmol), potassium iodide (12mg, 0.07mmol) and potassium carbonate (150mg, 1.09mmol) were added to acetonitrile (4mL) and reacted at 50°C for 2h. Cool to room temperature, add water (40mL), extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =45%) to obtain 148 mg of light brown oily product with a yield of 67.8%.
LC-MS(ESI):[M+H]+＝605.3；LC-MS(ESI): [M+H] + =605.3;
1HNMR(500MHz,CDCl3)δ7.74(s,1H),7.66(d,J＝2.2Hz,1H),7.53(t,J＝7.8Hz,1H),7.34(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),6.93(d,J＝7.5Hz,1H),6.88(d,J＝2.2Hz,1H),6.70–6.64(m,2H),5.69(s,2H),5.18–5.13(m,1H),4.63–4.50(m,3H),4.38–4.34(m,1H),3.96–3.90(m,2H),3.89(s,3H),3.27–3.21(m,2H),2.80–2.75(m,2H),2.74–2.63(m,1H),2.60–2.55(m,2H),2.44–2.37(m,1H). 1 HNMR (500MHz, CDCl 3 ) δ7.74 (s, 1H), 7.66 (d, J = 2.2Hz, 1H), 7.53 (t, J = 7.8Hz, 1H), 7.34 (d, J = 8.0Hz, 1H),7.21(d,J＝8.0Hz,1H),6.93(d,J＝7.5Hz,1H),6.88(d,J＝2.2Hz,1H),6.70–6.64(m,2H),5.69( s,2H),5.18–5.13(m,1H),4.63–4.50(m,3H),4.38–4.34(m,1H),3.96–3.90(m,2H),3.89(s,3H),3.27– 3.21(m,2H),2.80–2.75(m,2H),2.74–2.63(m,1H),2.60–2.55(m,2H),2.44–2.37(m,1H).
步骤4：(S)-2-((6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻唑并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((6-((4-氯苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-二吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(140mg,0.23mmol)和氢氧化锂一水合物(50mg,1.19mmol)加入到1,4-二氧六环(4mL)和水(4mL)的混合溶剂中，40℃反应1h。在冰浴中冷却，用稀盐酸调节pH＝6，用乙酸乙酯萃取(15mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体产物116mg，产率79.6％。Compound (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 (140 mg ,0.23mmol) and lithium hydroxide monohydrate (50mg, 1.19mmol) were added to the mixed solvent of 1,4-dioxane (4mL) and water (4mL), and the reaction was carried out at 40°C for 1 hour. Cool in an ice bath, adjust pH=6 with dilute hydrochloric acid, extract with ethyl acetate (15mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent MeOH :DCM (v/v) = 5%) to obtain 116 mg of white solid product, with a yield of 79.6%.
LC-MS(ESI):[M+H]+＝591.4；LC-MS(ESI): [M+H] + =591.4;
1HNMR(500MHz,DMSO-d6)δ8.15(s,1H),7.83(s,1H),7.67(t,J＝7.9Hz,1H),7.42(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.09–7.02(m,2H),6.76–6.67(m,2H),5.65(s,2H),5.10–5.00(m,1H),4.71–4.61(m,1H),4.57–4.43(m,2H),4.39–4.31(m,1H),3.98–3.82(m,2H),3.24–3.14(m,2H),2.79–2.67(m,2H),2.66–2.59(m,1H),2.50–2.44(m,2H),2.39–2.31(m,1H). 1 HNMR (500MHz, DMSO-d 6 ) δ8.15 (s, 1H), 7.83 (s, 1H), 7.67 (t, J = 7.9Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.34(d,J＝8.0Hz,1H),7.09–7.02(m,2H),6.76–6.67(m,2H),5.65(s,2H),5.10–5.00(m,1H),4.71–4.61( m,1H),4.57–4.43(m,2H),4.39–4.31(m,1H),3.98–3.82(m,2H),3.24–3.14(m,2H),2.79–2.67(m,2H), 2.66–2.59(m,1H),2.50–2.44(m,2H),2.39–2.31(m,1H).
实施例4(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物4)的合成
Example 4(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 (compound 4)
步骤1：6-羟基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯的合成Step 1: Synthesis of 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester
将2-溴-6-羟基吡啶(4.00g，22.99mmol)、[1-(叔丁氧基羰基)-1,2,3,6-四氢吡啶-4-基]硼酸(5.22g,22.99mmol)、碳酸钾(6.35g,45.98mmol)和1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(0.94g,1.15mmol)加入到1,4-二氧六环(80mL)和水(20mL)的混合溶剂中。氮气保护下，加热至85℃反应3h。加入水(50mL)淬灭反应，用乙酸乙酯萃取(15mL×3)，合并有机相。无水硫酸钠干燥，减压浓缩，硅胶柱层析分离纯化(洗脱剂MeOH:DCM(v/v)＝5％)，得到浅黄色固体5.87g，产率92.4％。2-Bromo-6-hydroxypyridine (4.00g, 22.99mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (5.22g, 22.99 mmol), potassium carbonate (6.35g, 45.98mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride complex (0.94g, 1.15mmol) were added to 1 , in a mixed solvent of 4-dioxane (80mL) and water (20mL). Under nitrogen protection, heat to 85°C and react for 3 hours. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent MeOH: DCM (v/v) = 5%) to obtain 5.87 g of light yellow solid with a yield of 92.4%.
LC-MS(ESI):[M+H]+＝277.3；LC-MS(ESI): [M+H] + =277.3;
1H NMR(500MHz,DMSO-d6))δ11.18(s,1H),7.42(t,J＝8.0Hz,1H),6.47(s,1H),6.27(d,J＝8.4Hz,2H),3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H). 1 H NMR (500MHz, DMSO-d 6 )) δ11.18 (s, 1H), 7.42 (t, J = 8.0Hz, 1H), 6.47 (s, 1H), 6.27 (d, J = 8.4Hz, 2H ),3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H).
步骤2：4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 2: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
将化合物6-羟基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(2.0g，7.24mmol)，加入到甲醇(20mL)中，然后加入钯碳(10％Pd,含55％水)(0.86g,0.36mmol)。置换氢气三次后，在氢气环境下室温反应过夜。硅藻土过滤，减压除去溶剂，得到白色固体1.76g，产率87.4％。Compound 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (2.0g, 7.24mmol) was added to methanol ( 20 mL), then add palladium on carbon (10% Pd, containing 55% water) (0.86 g, 0.36 mmol). After replacing hydrogen three times, the reaction was carried out overnight at room temperature in a hydrogen environment. Filter through diatomaceous earth and remove the solvent under reduced pressure to obtain 1.76 g of white solid with a yield of 87.4%.
LC-MS(ESI):[M+H]+＝279.2；LC-MS(ESI): [M+H] + =279.2;
1H NMR(500MHz,DMSO-d6))δ11.46(s,1H),7.33(dd,J＝9.1,6.9Hz,1H),6.14(d,J＝9.1Hz,1H),5.99(s,1H),4.04(d,J＝13.1Hz,2H),2.72(s,2H),2.58－2.54(m,1H),1.78(d,J＝12.7Hz,2H),1.47(td,J＝12.5,4.2Hz,2H),1.40(s,9H). 1 H NMR (500MHz, DMSO-d 6 )) δ 11.46 (s, 1H), 7.33 (dd, J = 9.1, 6.9 Hz, 1H), 6.14 (d, J = 9.1 Hz, 1H), 5.99 (s ,1H),4.04(d,J＝13.1Hz,2H),2.72(s,2H),2.58-2.54(m,1H),1.78(d,J＝12.7Hz,2H),1.47(td,J＝ 12.5,4.2Hz,2H),1.40(s,9H).
步骤3：4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 3: Synthesis of 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
将化合物4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯(210.0mg,0.75mmol)和7-(溴甲基)-4氯苯并呋喃(203.7mg,0.83mmol)溶于N,N-二甲基甲酰胺(4.0mL)中，加入碳酸钾(312.8mg，2.26mmol)。加热至60℃反应5h。加水25mL，乙酸乙酯萃取(15mL×3)，合并有机相。有机相用饱和食盐水洗(25mL×1)，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝10％),得到无色油状液体324mg，产率97.0％。The compounds 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (210.0mg, 0.75mmol) and 7-(bromomethyl)-4chlorobenzofuran (203.7mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (4.0 mL), and potassium carbonate (312.8 mg, 2.26 mmol) was added. Heat to 60°C and react for 5 hours. Add 25 mL of water, extract with ethyl acetate (15 mL × 3), and combine the organic phases. The organic phase was washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Separate and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 10%), and obtain 324 mg of colorless oily liquid with a yield of 97.0%.
LC-MS(ESI):[M+H]+＝443.3；LC-MS(ESI): [M+H] + =443.3;
1H NMR(500MHz,CDCl3)δ7.69(d,J＝2.2Hz,1H),7.49(t,J＝7.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.22(d,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.71(d,J＝7.3Hz,1H),6.62(d,J＝8.2Hz,1H),5.66(s,2H),4.20(s,2H),2.82(t,J＝12.8Hz,2H),2.73－2.68(m,1H),1.83(d,J＝13.0Hz,2H),1.69(dd,J＝12.7,4.1Hz,2H),1.49(s,9H). 1 H NMR (500MHz, CDCl 3 ) δ7.69 (d, J = 2.2Hz, 1H), 7.49 (t, J = 7.7Hz, 1H), 7.35 (d, J = 7.9Hz, 1H), 7.22 (d ,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.71(d,J＝7.3Hz,1H),6.62(d,J＝8.2Hz,1H),5.66(s,2H ),4.20(s,2H),2.82(t,J＝12.8Hz,2H),2.73-2.68(m,1H),1.83(d,J＝13.0Hz,2H),1.69(dd,J＝12.7, 4.1Hz,2H),1.49(s,9H).
步骤4：2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶的合成Step 4: Synthesis of 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine
将化合物4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(300mg,0.68mmol)溶于二氯甲烷(5mL)，加入氯化氢的1,4-二氧六环溶液(1.7mL，4mol/L)，室温反应30min。减压浓缩，加入碳酸氢钠饱和溶液(15mL)，乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，得 到棕褐色固体200mg，产率86.1％。Compound 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.68 mmol) was dissolved in dichloromethane (5mL), add hydrogen chloride in 1,4-dioxane solution (1.7mL, 4mol/L), and react at room temperature for 30min. Concentrate under reduced pressure, add saturated sodium bicarbonate solution (15mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 200 mg of tan solid was obtained, and the yield was 86.1%.
LC-MS(ESI):[M+H]+＝343.2。LC-MS (ESI): [M+H] + =343.2.
步骤5：(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(100mg,0.27mmol)，2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶(109mg,0.32mmol)，碘化钾(9mg,0.05mmol)和碳酸钾(110mg,0.80mmol)加入到乙腈(4mL)中，50℃反应2h。冷却至室温，加水(10mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝35％)，得到棕褐色油状产物83mg，产率51.4％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 100mg, 0.27mmol), 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (109mg, 0.32mmol), potassium iodide (9mg, 0.05mmol) ) and potassium carbonate (110 mg, 0.80 mmol) were added to acetonitrile (4 mL), and the reaction was carried out at 50°C for 2 h. Cool to room temperature, add water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v /v)=35%), 83 mg of tan oily product was obtained, with a yield of 51.4%.
LC-MS(ESI):[M+H]+＝607.3；LC-MS(ESI): [M+H] + =607.3;
1HNMR(500MHz,CDCl3)δ7.75(s,1H),7.67(d,J＝2.2Hz,1H),7.49(t,J＝7.7Hz,1H),7.35(d,J＝7.9Hz,1H),7.21(d,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.72(d,J＝7.3Hz,1H),6.62(d,J＝8.2Hz,1H),5.66(s,2H),5.21–5.17(m,1H),4.61(td,J＝8.0,6.0Hz,1H),4.54(t,J＝3.6Hz,1H),4.38(dd,J＝9.2,5.9Hz,1H),3.89(s,3H),3.81(s,2H),3.49(s,1H),3.01–2.91(m,2H),2.76–2.66(m,1H),2.66–2.57(m,1H),2.49–2.39(m,1H),2.25(q,J＝12.4Hz,2H),1.88(s,2H),1.81(t,J＝12.3Hz,2H). 1 HNMR (500MHz, CDCl 3 ) δ7.75 (s, 1H), 7.67 (d, J = 2.2Hz, 1H), 7.49 (t, J = 7.7Hz, 1H), 7.35 (d, J = 7.9Hz, 1H),7.21(d,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.72(d,J＝7.3Hz,1H),6.62(d,J＝8.2Hz,1H) ,5.66(s,2H),5.21–5.17(m,1H),4.61(td,J＝8.0,6.0Hz,1H),4.54(t,J＝3.6Hz,1H),4.38(dd,J＝9.2 ,5.9Hz,1H),3.89(s,3H),3.81(s,2H),3.49(s,1H),3.01–2.91(m,2H),2.76–2.66(m,1H),2.66–2.57( m,1H),2.49–2.39(m,1H),2.25(q,J＝12.4Hz,2H),1.88(s,2H),1.81(t,J＝12.3Hz,2H).
步骤6：(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(70mg,0.12mmol)和氢氧化锂一水合物(25mg,0.60mmol)加入到1,4-二氧六环(3mL)和水(3mL)的混合溶剂中，40℃反应1h。在冰浴中冷却，用2M醋酸水溶液调节pH＝6，用乙酸乙酯萃取(15mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体产物41mg，产率60.0％。Compound (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (70 mg, 0.12 mmol) and lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added to a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL), reacted at 40°C for 1 h. Cool in an ice bath, adjust pH=6 with 2M acetic acid aqueous solution, and extract with ethyl acetate (15 mL 60.0%.
LC-MS(ESI):[M+H]+＝593.4；LC-MS(ESI): [M+H] + =593.4;
1HNMR(500MHz,CDCl3)δ7.65(s,1H),7.52–7.39(m,2H),7.33(d,J＝8.1Hz,1H),7.19(d,J＝7.9Hz,1H),6.85(s,1H),6.72(d,J＝7.2Hz,1H),6.61(d,J＝8.3Hz,1H),5.63(s,2H),5.06(s,1H),4.54–4.48(m,3H),4.33(s,1H),4.06–4.00(m,2H),3.39(d,J＝33.2Hz,2H),2.74–2.68(m,3H),2.40–2.30(m,2H),2.06–1.93(m,4H). 1 HNMR (500MHz, CDCl 3 ) δ7.65 (s, 1H), 7.52–7.39 (m, 2H), 7.33 (d, J = 8.1Hz, 1H), 7.19 (d, J = 7.9Hz, 1H), 6.85(s,1H),6.72(d,J＝7.2Hz,1H),6.61(d,J＝8.3Hz,1H),5.63(s,2H),5.06(s,1H),4.54–4.48(m ,3H),4.33(s,1H),4.06–4.00(m,2H),3.39(d,J＝33.2Hz,2H),2.74–2.68(m,3H),2.40–2.30(m,2H), 2.06–1.93(m,4H).
实施例5(S)-2-((4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物5)的合成
Example 5 (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydro Pyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 5) Synthesis
步骤1：4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成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
将2-氯-4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶(320mg,1.02mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(380mg,1.23mmol)、碳酸钾(424mg,3.07mmol)和1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(84mg,0.10mmol)加入到1,4-二氧六环(8mL)和水(2mL)的混合溶剂中。氮气保护下， 加热至95℃反应4h。加入水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相。无水硫酸钠干燥，硅藻土过滤，减压浓缩，硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝15％)，得到白色固体236mg，产率50.2％。2-Chloro-4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (320 mg, 1.02 mmol), N-Boc-1,2,5,6-tetrahydro Pinacol pyridine-4-borate (380 mg, 1.23 mmol), potassium carbonate (424 mg, 3.07 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane The complex (84 mg, 0.10 mmol) was added to a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen protection, Heat to 95°C and react for 4 hours. Water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered through diatomaceous earth, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EtOAc: PE (v/v) = 15%) to obtain 236 mg of white solid with a yield of 50.2%.
LC-MS(ESI):[M+H]+＝460.3；LC-MS(ESI): [M+H] + =460.3;
1H NMR(500MHz,CDCl3)δ8.28(d,J＝2.5Hz,1H),7.70(d,J＝2.2Hz,1H),7.36(d,J＝8.0Hz,1H),7.25(d,J＝7.8Hz,1H),7.04(d,J＝4.9Hz,1H),6.91(d,J＝2.2Hz,1H),5.81(s,2H),4.16–4.12(m,2H),3.60(t,J＝5.6Hz,2H),2.64(s,2H),1.49(s,9H). 1 H NMR (500MHz, CDCl 3 ) δ8.28(d,J＝2.5Hz,1H),7.70(d,J＝2.2Hz,1H),7.36(d,J＝8.0Hz,1H),7.25(d ,J＝7.8Hz,1H),7.04(d,J＝4.9Hz,1H),6.91(d,J＝2.2Hz,1H),5.81(s,2H),4.16–4.12(m,2H),3.60 (t,J＝5.6Hz,2H),2.64(s,2H),1.49(s,9H).
步骤2：4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟-2-(1,2,3,6-四氢吡啶-4-基)嘧啶的合成Step 2: Synthesis of 4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine
将化合物4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(220mg,0.48mmol)加入到二氯甲烷(3mL)中，然后在冰浴下加入三氟乙酸(1.53g,13.46mmol)。恢复至室温反应20min。加饱和碳酸氢钠溶液调节pH＝8，用乙酸乙酯萃取(10mL×3)。合并有机相，用无水硫酸钠干燥，过滤，减压除去溶剂，得到淡黄色固体171mg，产率99.4％。Compound 4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Tert-butyl ester (220 mg, 0.48 mmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (1.53 g, 13.46 mmol) in an ice bath. Return to room temperature and react for 20 minutes. Add saturated sodium bicarbonate solution to adjust pH=8, and extract with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 171 mg of light yellow solid with a yield of 99.4%.
LC-MS(ESI):[M+H]+＝360.1。LC-MS (ESI): [M+H] + =360.1.
步骤3：(S)-2-((4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲脂的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(85mg,0.23mmol)，4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟-2-(1,2,3,6-四氢吡啶-4-基)嘧啶(80mg,0.22mmol)，碘化钾(10mg,0.06mmol)和碳酸钾(120mg,0.87mmol)加入到乙腈(10mL)中，50℃反应2h。冷却至室温，加水(10mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝50％)，得到黄色油状产物110mg，产率79.3％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 85 mg, 0.23 mmol), 4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (80 mg, 0.22 mmol), potassium iodide (10 mg, 0.06 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added to acetonitrile (10 mL) and reacted at 50°C for 2 h. Cool to room temperature, add water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v /v)=50%), 110 mg of yellow oily product was obtained with a yield of 79.3%.
LC-MS(ESI):[M+H]+＝624.3；LC-MS(ESI): [M+H] + =624.3;
1HNMR(500MHz,CDCl3)δ8.27(d,J＝2.6Hz,1H),7.74(s,1H),7.67(d,J＝2.2Hz,1H),7.34(d,J＝8.0Hz,1H),7.24(d,J＝7.9Hz,1H),7.02(s,1H),6.90(d,J＝2.2Hz,1H),5.79(s,2H),5.21–5.09(m,1H),4.65–4.57(m,1H),4.56–4.47(m,2H),4.40–4.33(m,1H),3.94(d,J＝9.8Hz,2H),3.89(s,3H),3.27(s,2H),2.77(d,J＝6.3Hz,2H),2.72–2.55(m,3H),2.45–2.35(m,1H). 1 HNMR (500MHz, CDCl 3 ) δ8.27(d,J＝2.6Hz,1H),7.74(s,1H),7.67(d,J＝2.2Hz,1H),7.34(d,J＝8.0Hz, 1H),7.24(d,J＝7.9Hz,1H),7.02(s,1H),6.90(d,J＝2.2Hz,1H),5.79(s,2H),5.21–5.09(m,1H), 4.65–4.57(m,1H),4.56–4.47(m,2H),4.40–4.33(m,1H),3.94(d,J＝9.8Hz,2H),3.89(s,3H),3.27(s, 2H),2.77(d,J＝6.3Hz,2H),2.72–2.55(m,3H),2.45–2.35(m,1H).
步骤4：(S)-2-((4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((4-(4-((4-氯苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲脂(100mg,0.16mmol)和氢氧化锂一水合物(40mg,0.95mmol)加入到1,4-二氧六环(5mL)和水(5mL)的混合溶剂中，40℃反应1h。在冰浴中冷却，用2M醋酸水溶液调节pH＝6，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到淡黄色固体产物62mg，产率63.4％。Compound (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine -1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (100 mg, 0.16mmol) and lithium hydroxide monohydrate (40mg, 0.95mmol) were added to the mixed solvent of 1,4-dioxane (5mL) and water (5mL), and the reaction was carried out at 40°C for 1 hour. Cool in an ice bath, adjust pH=6 with 2M acetic acid aqueous solution, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) to obtain 62 mg of light yellow solid product, with a yield of 63.4%.
LC-MS(ESI):[M+H]+＝610.3；LC-MS(ESI): [M+H] + =610.3;
1HNMR(500MHz,DMSO-d6)δ8.57(s,1H),8.18(s,1H),7.70(s,1H),7.48(d,J＝8.1Hz,1H),7.39(d,J＝8.1Hz,1H),7.05(d,J＝15.6Hz,2H),5.82(s,2H),5.04(d,J＝7.9Hz,1H),4.66–4.58(m,1H),4.54–4.45(m,2H),4.38–4.33(m,1H),3.92(d,J＝13.6Hz,1H),3.84(d,J＝13.7Hz,1H),3.48–3.39(m,2H),3.26–3.22(m,2H),2.73–2.59(m,3H),2.36(t,J＝9.2Hz,1H). 1 HNMR (500MHz, DMSO-d 6 ) δ8.57(s,1H),8.18(s,1H),7.70(s,1H),7.48(d,J＝8.1Hz,1H),7.39(d,J ＝8.1Hz,1H),7.05(d,J＝15.6Hz,2H),5.82(s,2H),5.04(d,J＝7.9Hz,1H),4.66–4.58(m,1H),4.54–4.45 (m,2H),4.38–4.33(m,1H),3.92(d,J＝13.6Hz,1H),3.84(d,J＝13.7Hz,1H),3.48–3.39(m,2H),3.26– 3.22(m,2H),2.73–2.59(m,3H),2.36(t,J＝9.2Hz,1H).
实施例6(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物6)的合成
Example 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 (compound 6)
步骤1：(4-氯-2-氟苯并呋喃-7-基)乙酸甲酯的合成Step 1 Synthesis of: (4-chloro-2-fluorobenzofuran-7-yl)methyl acetate
将化合物7-(溴甲基)-4-氯-2-氟苯并呋喃(0.60g,2.28mmol)加入到N,N-二甲基甲酰胺(12mL)中，然后加入乙酸钾(1.10g,11.21mmol)。50℃反应1.5h。加入水(100mL)淬灭反应，用乙酸乙酯萃取(15mL×3)，合并有机相。有机相用饱和食盐水洗涤(15mL×3)，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝1：20)，得到淡黄色液体340mg，产率61.5％。Compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (0.60g, 2.28mmol) was added to N,N-dimethylformamide (12mL), and then potassium acetate (1.10g ,11.21mmol). Reaction at 50℃ for 1.5h. Water (100 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (15mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EtOAc:PE (v/v)=1:20) to obtain Light yellow liquid 340 mg, yield 61.5%.
步骤2：(4-氯-2-氟苯并呋喃-7-基)甲醇的合成Step 2 Synthesis of (4-chloro-2-fluorobenzofuran-7-yl)methanol
将化合物(4-氯-2-氟苯并呋喃-7-基)乙酸甲酯(340mg,1.40mmol)，加入到1,4-二氧六环(9mL)和水(3mL)的混合溶剂中，然后加入氢氧化锂一水合物(177mg,4.22mmol)。室温反应2h。加水稀释(6ml)，乙酸乙酯萃取三次(3mL×3)，合并有机相，无水硫酸钠干燥。过滤，浓缩滤液，硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝20％)，得到白色固体222mg，产率79.0％。The compound (4-chloro-2-fluorobenzofuran-7-yl)acetic acid methyl ester (340 mg, 1.40 mmol) was added to the mixed solvent of 1,4-dioxane (9 mL) and water (3 mL). , then add lithium hydroxide monohydrate (177 mg, 4.22 mmol). React at room temperature for 2 hours. Dilute with water (6 ml), extract three times with ethyl acetate (3 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and separate and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 20%) to obtain 222 mg of white solid with a yield of 79.0%.
1H NMR(500MHz,CDCl3)δ7.24(s,2H),6.00(d,J＝6.6Hz,1H),4.92(d,J＝6.1Hz,2H). 1 H NMR (500MHz, CDCl 3 ) δ7.24 (s, 2H), 6.00 (d, J = 6.6 Hz, 1H), 4.92 (d, J = 6.1 Hz, 2H).
步骤3：2-氯-4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶的合成Step 3: Synthesis of 2-chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine
将化合物(4-氯-2-氟苯并呋喃-7-基)甲醇(222mg,1.11mmol)和2,4-二氯-5-氟嘧啶(194mg,1.16mmol)溶于乙腈(10mL)中，冰浴条件下，加入碳酸铯(545mg,1.67mmol)。升至室温反应14h。硅藻土过滤，浓缩滤液。硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝10％),得到白色固体318mg，产率86.8％。Compound (4-chloro-2-fluorobenzofuran-7-yl)methanol (222 mg, 1.11 mmol) and 2,4-dichloro-5-fluoropyrimidine (194 mg, 1.16 mmol) were dissolved in acetonitrile (10 mL) , add cesium carbonate (545mg, 1.67mmol) under ice bath conditions. Warm up to room temperature and react for 14h. Filter through diatomaceous earth and concentrate the filtrate. Separate and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 10%), and obtain 318 mg of white solid with a yield of 86.8%.
LC-MS(ESI):[M+H]+＝331.1；LC-MS(ESI): [M+H] + =331.1;
1H NMR(500MHz,DMSO-d6)δ8.64(d,J＝2.6Hz,1H),7.50(d,J＝8.2Hz,1H),7.46(d,J＝8.3Hz,1H),6.55(d,J＝6.4Hz,1H),5.73(s,2H). 1 H NMR (500MHz, DMSO-d 6 ) δ8.64 (d, J = 2.6 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.55 (d,J＝6.4Hz,1H),5.73(s,2H).
步骤4：4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成Step 4: 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1( Synthesis of 2H)-tert-butylcarboxylate
将2-氯-4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶(318mg,0.96mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(357mg,1.15mmol)、碳酸钾(398mg,2.88mmol)和1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(78mg,0.10mmol)加入到1,4-二氧六环(8mL)和水(2mL)的混合溶剂中。氮气保护下，加热至95℃反应4.5h。加入水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相。无水硫酸钠干燥，硅藻土过滤，减压浓缩，硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)＝15％)，得到白色固体290mg，产率63.2％。2-Chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (318 mg, 0.96 mmol), N-Boc-1,2,5, 6-Tetrahydropyridine-4-boronic acid pinacol ester (357 mg, 1.15 mmol), potassium carbonate (398 mg, 2.88 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride ) dichloromethane complex (78 mg, 0.10 mmol) was added to the mixed solvent of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen protection, heat to 95°C and react for 4.5 hours. Water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered through diatomaceous earth, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EtOAc: PE (v/v) = 15%) to obtain 290 mg of white solid with a yield of 63.2%.
LC-MS(ESI):[M+H]+＝478.2；LC-MS(ESI): [M+H] + =478.2;
1H NMR(500MHz,CDCl3)δ8.29(d,J＝2.5Hz,1H),7.32(d,J＝8.2Hz,1H),7.26(d,J＝5.5Hz,1H),7.07(s,1H),6.03(d,J＝6.6Hz,1H),5.73(s,2H),4.15(d,J＝3.6Hz,2H),3.61(t,J＝5.8Hz,2H),2.65(s,2H),1.49(s,9H). 1 H NMR (500MHz, CDCl 3 ) δ8.29 (d, J = 2.5Hz, 1H), 7.32 (d, J = 8.2Hz, 1H), 7.26 (d, J = 5.5Hz, 1H), 7.07 (s ,1H),6.03(d,J＝6.6Hz,1H),5.73(s,2H),4.15(d,J＝3.6Hz,2H),3.61(t,J＝5.8Hz,2H),2.65(s ,2H),1.49(s,9H).
步骤5：4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟-2-(1,2,3,6-四氢吡啶-4-基)嘧啶的合成Step 5: 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl) Synthesis of pyrimidines
将化合物4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(250mg,0.52mmol)加入到二氯甲烷(4mL)中，然后在冰浴下加入三氟乙酸(1.92g,16.84mmol)。恢复至室 温反应20分钟。加饱和碳酸氢钠溶液调节pH＝8，用乙酸乙酯萃取(10mL×3)。合并有机相，用无水硫酸钠干燥，过滤，减压除去溶剂，得到淡粉色固体192mg，产率97.2％。Compound 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H )-tert-butylcarboxylate (250 mg, 0.52 mmol) was added to dichloromethane (4 mL), and then trifluoroacetic acid (1.92 g, 16.84 mmol) was added under ice bath. restore to room Warm reaction for 20 minutes. Add saturated sodium bicarbonate solution to adjust pH=8, and extract with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 192 mg of light pink solid with a yield of 97.2%.
LC-MS(ESI):[M+H]+＝378.2；LC-MS(ESI): [M+H] + =378.2;
1H NMR(500MHz,CDCl3)δ9.77(s,1H),8.30(s,1H),7.34–7.24(m,2H),7.09(s,1H),6.03(d,J＝6.4Hz,1H),5.72(s,2H),3.94(s,2H),3.43(s,2H),2.96(s,2H). 1 H NMR (500MHz, CDCl 3 ) δ9.77 (s, 1H), 8.30 (s, 1H), 7.34–7.24 (m, 2H), 7.09 (s, 1H), 6.03 (d, J = 6.4Hz, 1H),5.72(s,2H),3.94(s,2H),3.43(s,2H),2.96(s,2H).
步骤6：(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲脂的合成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
将化合物(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(120mg,0.40mmol)，4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟-2-(1,2,3,6-四氢吡啶-4-基)嘧啶(220mg,0.41mmol)，N,N-二异丙基乙胺(264mg,2.04mmol)加入到乙腈(7mL)中，60℃反应11h。冷却至室温，加水(20mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝35％)，得到黄色固体产物234mg，产率89.4％。Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 120 mg, 0.40 mmol), 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridine-4 -pyrimidine (220 mg, 0.41 mmol) and N, N-diisopropylethylamine (264 mg, 2.04 mmol) were added to acetonitrile (7 mL) and reacted at 60°C for 11 h. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v /v)=35%), 234 mg of yellow solid product was obtained, with a yield of 89.4%.
LC-MS(ESI):[M+H]+＝642.4。LC-MS (ESI): [M+H] + =642.4.
步骤7：(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲脂(234mg,0.36mmol)和氢氧化锂一水合物(77mg,1.84mmol)加入到1,4-二氧六环(6mL)和水(3mL)的混合溶剂中，40℃反应1.5h。在冰浴中冷却，用2M醋酸水溶液调节pH＝6，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体产物125mg，产率52.9％。Compound (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 methyl Lipid (234 mg, 0.36 mmol) and lithium hydroxide monohydrate (77 mg, 1.84 mmol) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (3 mL), and the reaction was carried out at 40°C for 1.5 h. Cool in an ice bath, adjust pH=6 with 2M acetic acid aqueous solution, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) to obtain 125 mg of white solid product, with a yield of 52.9%.
LC-MS(ESI):[M+H]+＝628.3；LC-MS(ESI): [M+H] + =628.3;
1HNMR(500MHz,DMSO-d6)δ8.57(s,1H),7.80(s,1H),7.50–7.40(m,2H),7.04(s,1H),6.53(d,J＝6.4Hz,1H),5.76(s,2H),5.04(d,J＝7.6Hz,1H),4.68–4.60(m,1H),4.55–4.45(m,2H),4.37–4.32(m,1H),3.93(d,J＝13.8Hz,1H),3.85(d,J＝13.7Hz,1H),3.25(br.s,2H),2.69(br.s,2H),2.66–2.60(m,1H),2.52(br.s,2H),2.40–2.31(m,1H).1HNMR (500MHz, DMSO-d 6 ) δ8.57 (s, 1H), 7.80 (s, 1H), 7.50–7.40 (m, 2H), 7.04 (s, 1H), 6.53 (d, J＝6.4Hz, 1H),5.76(s,2H),5.04(d,J＝7.6Hz,1H),4.68–4.60(m,1H),4.55–4.45(m,2H),4.37–4.32(m,1H),3.93 (d,J＝13.8Hz,1H),3.85(d,J＝13.7Hz,1H),3.25(br.s,2H),2.69(br.s,2H),2.66–2.60(m,1H), 2.52(br.s,2H),2.40–2.31(m,1H).
实施例7(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物7)的合成
Example 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 (compound 7)
步骤1：2-(苄氧基)-6-溴吡啶的合成Step 1: Synthesis of 2-(benzyloxy)-6-bromopyridine
将化合物2-溴-6-羟基吡啶(1g,5.75mmol)，苄溴(1.08g,6.32mmol)和碳酸钾(1.59g,11.49mmol)加入到10mL的N,N-二甲基甲酰胺中，60℃下反应2小时，TLC检测反应原料完全消失，停止加热，冷却至室温，加入饱和食盐水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝5％)得到无色油状产物1.12g，产率73.8％。 Compound 2-bromo-6-hydroxypyridine (1g, 5.75mmol), benzyl bromide (1.08g, 6.32mmol) and potassium carbonate (1.59g, 11.49mmol) were added to 10 mL of N,N-dimethylformamide , react at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared. Stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, and use anhydrous sodium sulfate. Dry, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent PE: EA (v/v) = 5%) to obtain 1.12 g of colorless oily product with a yield of 73.8%.
LC-MS(ESI):[M+H]+＝264.2；LC-MS(ESI): [M+H] + =264.2;
1H NMR(500MHz,CDCl3)δ7.34–7.23(m,5H),7.16(dd,J＝9.2,7.1Hz,1H),6.58(dd,J＝9.2,1.3Hz,1H),6.48(dd,J＝7.3,1.3Hz,1H),5.52(s,2H). 1 H NMR (500MHz, CDCl 3 ) δ7.34–7.23(m,5H),7.16(dd,J＝9.2,7.1Hz,1H),6.58(dd,J＝9.2,1.3Hz,1H),6.48( dd,J＝7.3,1.3Hz,1H),5.52(s,2H).
步骤2：4-(6-(苄氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯的合成Step 2: Synthesis of tert-butyl 4-(6-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate
将2-(苄氧基)-6-溴吡啶(6g,22.72mmol)，哌嗪-1-羧酸叔丁酯(8.46g,45.44mmol)，1,1'-联萘-2,2'-双二苯膦(2.83g,4.54mmol)，三(二亚苄基丙酮)二钯(2.08g,2.27mmol)，叔丁醇钾(5.1g,45.44mmol)，加入到50mL的甲苯溶液中，氮气置换三次，置于100℃下反应20分钟。TLC检测反应完全，停止加热，冷却至室温，加入饱和食盐水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝10％)得到无色油状产物7.92g，产率94.4％。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. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer Analytical purification (eluent PE: EA (v/v) = 10%) gave 7.92g of colorless oily product with a yield of 94.4%.
LC-MS(ESI):[M+H]+＝370.3LC-MS(ESI):[M+H] + =370.3
1H NMR(500MHz,CDCl3)δ7.46–7.38(m,3H),7.35(t,J＝7.6Hz,2H),7.31–7.26(m,1H),6.16(dd,J＝7.9,4.2Hz,2H),5.32(s,2H),3.55–3.46(m,8H),1.48(s,9H). 1 H NMR (500MHz, CDCl 3 ) δ7.46–7.38(m,3H),7.35(t,J＝7.6Hz,2H),7.31–7.26(m,1H),6.16(dd,J＝7.9,4.2 Hz,2H),5.32(s,2H),3.55–3.46(m,8H),1.48(s,9H).
步骤3：4-(6-羟基吡啶-2-基)哌嗪-1-羧酸叔丁酯的合成Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate
将4-(6-(苄氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(700mg,1.89mmol)，钯碳(350mg)，加入到10mL的甲醇溶液中，氢气置换三次，室温搅拌过夜。TLC检测原料反应完全，停止反应。硅藻土抽滤，滤液减压浓缩得到了棕色固体产物0.643g，产率72.8％。Add 4-(6-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.89 mmol) and palladium carbon (350 mg) to 10 mL of methanol solution, and replace with hydrogen Three times, stir at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Suction filtration was carried out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 0.643g of brown solid product with a yield of 72.8%.
LC-MS(ESI):[M+H]+＝280.2。LC-MS (ESI): [M+H] + =280.2.
步骤4：4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯的合成Step 4: Synthesis of tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
将4-(6-羟基吡啶-2-基)哌嗪-1-羧酸叔丁酯(140mg,0.5mmol)，7-(溴甲基)-4-氯苯并呋喃(122mg,0.5mmol)，碳酸钾(137mg,0.99mmol)加入到10mL的N,N-二甲基甲酰胺中，60℃下反应2小时。TLC检测反应原料完全消失，停止加热，冷却至室温，加入饱和食盐水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝5％)得到无色油状产物145mg，产率65.7％。4-(6-Hydroxypyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.5 mmol), 7-(bromomethyl)-4-chlorobenzofuran (122 mg, 0.5 mmol) , potassium carbonate (137 mg, 0.99 mmol) was added to 10 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 145 mg of colorless oily product with a yield of 65.7%.
1H NMR(500MHz,CDCl3)δ7.67(d,J＝2.3Hz,1H),7.41(t,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.16(t,J＝8.1Hz,2H),5.61(s,2H),3.51–3.38(m,8H),1.48(s,9H). 1 H NMR (500MHz, CDCl 3 ) δ7.67 (d, J = 2.3Hz, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.21 (d ,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.16(t,J＝8.1Hz,2H),5.61(s,2H),3.51–3.38(m,8H),1.48 (s,9H).
步骤5：1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪的合成Step 5: Synthesis of 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine
将4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(412mg,0.93mmol)，加入到三氟乙酸(4mL)和二氯甲烷(4mL)中，室温搅拌30分钟。TLC检测原料完全消失，停止反应。减压浓缩蒸干溶剂，用饱和的碳酸氢钠水溶液调节体系的PH至7左右，用乙酸乙酯萃取(15mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩得到了棕色的固体产物286mg，产率89.6％，直接用于下一步反应。4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (412 mg, 0.93 mmol) was added to trifluorotrifluoroethylene acetic acid (4 mL) and dichloromethane (4 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was 286 mg, yield 89.6%, and was directly used in the next reaction.
LC-MS(ESI):[M+H]+＝344.2；LC-MS(ESI): [M+H] + =344.2;
1H NMR(500MHz,CDCl3)δ7.66(d,J＝2.3Hz,1H),7.44(t,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.22(d,J＝8.0Hz,1H),6.18(d,J＝7.9Hz,1H),5.60(s,2H),3.68–3.65(m,4H),3.14–3.03(m,4H). 1 H NMR (500MHz, CDCl 3 ) δ7.66 (d, J = 2.3Hz, 1H), 7.44 (t, J = 8.0Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.22 (d ,J＝8.0Hz,1H),6.89(d,J＝2.2Hz,1H),6.22(d,J＝8.0Hz,1H),6.18(d,J＝7.9Hz,1H),5.60(s,2H ),3.68–3.65(m,4H),3.14–3.03(m,4H).
步骤6：(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪(113mg,0.33mmol)，(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(113mg，0.33mmol)，N,N-二异丙基乙胺(177mg,1.37mg)加入到10mL的乙腈溶液中，60℃反应过夜。TLC检测原料完全消失，停止加热，冷却至室温，加入饱和 食盐水(50mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝45％)得到无色油状产物139mg，产率83.5％。1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine (113 mg, 0.33 mmol), (S)-2-(chloromethyl)- 1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (113 mg, 0.33 mmol), N,N-diisopropyl Ethylamine (177 mg, 1.37 mg) was added to 10 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, and add saturated brine (50mL), extracted with ethyl acetate (10mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EA (v/v) =45%) to obtain 139 mg of colorless oily product with a yield of 83.5%.
LC-MS(ESI):[M+H]+＝608.4；LC-MS(ESI): [M+H] + =608.4;
1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.65(d,J＝2.2Hz,1H),7.40(t,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.21(d,J＝7.9Hz,1H),6.87(d,J＝2.3Hz,1H),6.15(dd,J＝8.0,3.5Hz,2H),5.59(s,2H),5.22–5.16(m,1H),4.67–4.60(m,1H),4.54–4.49(m,2H),4.41–4.35(m,1H),3.89(s,3H),3.83(d,J＝4.2Hz,2H),3.51–3.39(m,4H),2.77–2.67(m 1H),2.61–2.54(m,4H),2.48–2.39(m,1H). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (s, 1H), 7.65 (d, J = 2.2Hz, 1H), 7.40 (t, J = 8.0Hz, 1H), 7.32 (d, J = 8.0Hz ,1H),7.21(d,J＝7.9Hz,1H),6.87(d,J＝2.3Hz,1H),6.15(dd,J＝8.0,3.5Hz,2H),5.59(s,2H),5.22 –5.16(m,1H),4.67–4.60(m,1H),4.54–4.49(m,2H),4.41–4.35(m,1H),3.89(s,3H),3.83(d,J＝4.2Hz ,2H),3.51–3.39(m,4H),2.77–2.67(m 1H),2.61–2.54(m,4H),2.48–2.39(m,1H).
步骤7：(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(130mg,0.21mmol)，氢氧化锂一水合物(25.6mg,1.07mmol)加入到水(2mL)和1.4-二氧六环(6mL)的混合溶液中，40℃反应2小时。TLC检测原料完全消失，停止加热。用20％的醋酸水溶液调节体系PH至7左右，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂DCM:MeOH(v/v)＝20％)得到白色固体产物50mg，产率37.5％。(S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (130 mg, 0.21 mmol), lithium hydroxide monohydrate (25.6 mg, 1.07 mmol) was added to a mixed solution of water (2 mL) and 1.4-dioxane (6 mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 50 mg of white solid product, with a yield of 37.5%.
LC-MS(ESI):[M+H]+＝594.3；LC-MS(ESI): [M+H] + =594.3;
1H NMR(500MHz,DMSO-d6)δ8.14(d,J＝2.1Hz,1H),7.77(s,1H),7.45(t,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.04(d,J＝2.2Hz,1H),6.31(d,J＝8.1Hz,1H),6.10(d,J＝7.8Hz,1H),5.55(s,2H),5.16–5.05(m,1H),4.68–4.60(m,1H),4.57–4.46(m,2H),4.41–4.34(m,1H),3.82(d,J＝13.7Hz,1H),3.72(d,J＝13.7Hz,1H),3.43–3.41(m,4H),2.73–2.63(m,1H),2.53–2.43(m,4H),2.42–2.34(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ8.14 (d, J＝2.1Hz, 1H), 7.77 (s, 1H), 7.45 (t, J＝8.0Hz, 1H), 7.39 (d, J＝ 8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.04(d,J＝2.2Hz,1H),6.31(d,J＝8.1Hz,1H),6.10(d,J＝7.8Hz ,1H),5.55(s,2H),5.16–5.05(m,1H),4.68–4.60(m,1H),4.57–4.46(m,2H),4.41–4.34(m,1H),3.82(d ,J＝13.7Hz,1H),3.72(d,J＝13.7Hz,1H),3.43–3.41(m,4H),2.73–2.63(m,1H),2.53–2.43(m,4H),2.42– 2.34(m,1H).
实施例8(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物8)的合成
Example 8 (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 (compound 8)
步骤1：4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯的合成Step 1: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
将4-(6-羟基吡啶-2-基)哌嗪-1-羧酸叔丁酯(300mg,1.13mmol)，7-(溴甲基)-4-氯-2-氟苯并呋喃(297mg,1.13mmol)，碳酸钾(312mg,2.26mmol)，氟化钾(328mg,5.65mmol)加入到N,N-二甲基甲酰胺(10mL)中，60℃下反应2小时。TLC检测反应原料完全消失，停止加热，冷却至室温，加入饱和食盐水(50mL)，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝5％)得到无色油状产物395mg，产率75.6％。4-(6-Hydroxypyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.13 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (297 mg ,1.13mmol), potassium carbonate (312mg, 2.26mmol), and potassium fluoride (328mg, 5.65mmol) were added to N,N-dimethylformamide (10mL), and reacted at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 395 mg of colorless oily product with a yield of 75.6%.
LC-MS(ESI):[M+H]+＝462.3。LC-MS (ESI): [M+H] + =462.3.
步骤2：1-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪的合成Step 2: Synthesis of 1-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine
将4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(525mg,1.14mmol)加入到三氟乙酸(5mL)和二氯甲烷(5mL)中，室温搅拌30分钟。TLC检测原料完全消失，停止反应。减压浓缩蒸干 溶剂，用饱和的碳酸氢钠水溶液调节体系的PH至7左右，用乙酸乙酯萃取(15mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩得到了棕色的固体产物396mg，产率96.3％，直接用于下一步反应。4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (525 mg, 1.14 mmol) was added into trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrated under reduced pressure and evaporated to dryness As a solvent, use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7, extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 396 mg of a brown solid product, yielding The yield was 96.3% and was directly used in the next reaction.
LC-MS(ESI):[M+H]+＝362.2；LC-MS(ESI): [M+H] + =362.2;
1H NMR(500MHz,CDCl3)δ7.46(t,J＝8.0Hz,1H),7.30–7.26(m,1H),7.23(d,J＝8.3Hz,1H),6.25(d,J＝7.8Hz,1H),6.20(d,J＝8.0Hz,1H),6.00(d,J＝6.5Hz,1H),5.51(s,2H),3.79–3.70(m,4H),3.24–3.15(m,4H). 1 H NMR (500MHz, CDCl 3 ) δ7.46 (t, J＝8.0Hz, 1H), 7.30–7.26 (m, 1H), 7.23 (d, J＝8.3Hz, 1H), 6.25 (d, J＝ 7.8Hz,1H),6.20(d,J＝8.0Hz,1H),6.00(d,J＝6.5Hz,1H),5.51(s,2H),3.79–3.70(m,4H),3.24–3.15( m,4H).
步骤3：(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯合成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
将1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪(100mg,0.33mmol)，(S)-2-(氯甲基)-1-(氧杂环丁烷)-2-基甲基-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(123mg，0.34mmol)，N,N-二异丙基乙胺(219mg,1.69mmol)加入到10mL的乙腈溶液中，60℃反应过夜。TLC检测原料完全消失，停止加热，冷却至室温，加入饱和食盐水(50mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝45％)得到无色油状产物186mg，产率87.4％。1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine (100 mg, 0.33 mmol), (S)-2-(chloromethyl)- 1-(oxetane)-2-ylmethyl-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (123 mg, 0.34 mmol), N,N-diisopropyl Ethylamine (219 mg, 1.69 mmol) was added to 10 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 45%) yielded 186 mg of colorless oily product with a yield of 87.4%.
LC-MS(ESI):[M+H]+＝626.3；LC-MS(ESI): [M+H] + =626.3;
1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.41(t,J＝8.0Hz,1H),7.30–7.26(m,1H),7.22(d,J＝8.2Hz,1H),6.15(dd,J＝8.0,4.0Hz,2H),5.99(d,J＝6.6Hz,1H),5.52(s,2H),5.22–5.16(m,1H),4.67–4.60(m,1H),4.55–4.50(m,2H),4.41–4.35(m,1H),3.89(s,3H),3.84(d,J＝3.2Hz,2H),3.51–3.35(m,4H),2.79–2.66(m,1H),2.63–2.55(m,4H),2.44–2.38(m,1H). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (s, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.30–7.26 (m, 1H), 7.22 (d, J = 8.2Hz, 1H) ,6.15(dd,J＝8.0,4.0Hz,2H),5.99(d,J＝6.6Hz,1H),5.52(s,2H),5.22–5.16(m,1H),4.67–4.60(m,1H ),4.55–4.50(m,2H),4.41–4.35(m,1H),3.89(s,3H),3.84(d,J＝3.2Hz,2H),3.51–3.35(m,4H),2.79– 2.66(m,1H),2.63–2.55(m,4H),2.44–2.38(m,1H).
步骤4：(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(130mg,0.21mmol),氢氧化锂一水合物(25.6mg,1.07mmol)加入到2mL水和6mL1.4-二氧六环的混合溶液中，40℃反应2小时。TLC检测原料完全消失，停止加热。用20％的醋酸水溶液调节体系PH至7左右，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂DCM:MeOH(v/v)＝20％)得到白色固体产物50mg，产率37.5％。(S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (130 mg, 0.21 mmol), lithium hydroxide monohydrate (25.6 mg, 1.07 mmol) was added to a mixed solution of 2 mL water and 6 mL 1.4-dioxane, and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 50 mg of white solid product, with a yield of 37.5%.
LC-MS(ESI):[M+H]+＝612.4；LC-MS(ESI): [M+H] + =612.4;
1H NMR(500MHz,DMSO-d6)δ12.07(br.s,1H),7.82(s,1H),7.46(t,J＝7.9Hz,1H),7.39(s,2H),6.49(d,J＝6.4Hz,1H),6.32(d,J＝8.2Hz,1H),6.11(d,J＝7.8Hz,1H),5.50(s,2H),5.13–5.09(m,1H),4.72–4.59(m,1H),4.60–4.46(m,2H),4.41–4.31(m,1H),3.83(d,J＝13.6Hz,1H),3.74(d,J＝13.7Hz,1H),3.47–3.39(m,4H),2.74–2.63(m,1H),2.50–2.45(m,4H),2.43–2.33(m,1H). 1 H NMR (500MHz, DMSO-d 6 ) δ12.07 (br.s, 1H), 7.82 (s, 1H), 7.46 (t, J = 7.9Hz, 1H), 7.39 (s, 2H), 6.49 ( d,J＝6.4Hz,1H),6.32(d,J＝8.2Hz,1H),6.11(d,J＝7.8Hz,1H),5.50(s,2H),5.13–5.09(m,1H), 4.72–4.59(m,1H),4.60–4.46(m,2H),4.41–4.31(m,1H),3.83(d,J＝13.6Hz,1H),3.74(d,J＝13.7Hz,1H) ,3.47–3.39(m,4H),2.74–2.63(m,1H),2.50–2.45(m,4H),2.43–2.33(m,1H).
实施例9(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩[2,3-d]咪唑-5-羧酸(化合物9)的合成
Example 9 (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 (compound 9)
步骤1：2-((叔丁基二苯甲硅基)氧基)乙酸甲酯的合成Step 1: Synthesis of methyl 2-((tert-butyldiphenylsilyl)oxy)acetate
将化合物2-羟基乙酸甲酯(10g,111.01mmol)加入到N,N-二甲基甲酰胺(150mL)，加入咪唑(8.8 mL,130.99mmol)。在冰浴下，缓慢滴入叔丁基二苯基氯硅烷(34.5mL,133.21mmol)，0℃搅拌五个小时。减压浓缩，加入乙酸乙酯(300mL)，析出大量白色固体，过滤，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝10％)得到无色油状物35g，产率96.0％。Compound 2-glycolic acid methyl ester (10g, 111.01mmol) was added to N,N-dimethylformamide (150mL), and imidazole (8.8 mL, 130.99mmol). Under an ice bath, tert-butyldiphenylsilyl chloride (34.5 mL, 133.21 mmol) was slowly dropped into the mixture, and stirred at 0°C for five hours. Concentrate under reduced pressure, add ethyl acetate (300 mL), and precipitate a large amount of white solid, filter, and purify with silica gel column chromatography (eluent EtOAc: PE (v/v) = 10%) to obtain 35 g of colorless oil, yield 96.0%.
1HNMR(400MHz,CDCl3)δ7.63–7.60(m,4H),7.35–7.32(m,6H),4.17(s,2H),3.61(s,3H),1.02(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ7.63–7.60(m,4H),7.35–7.32(m,6H),4.17(s,2H),3.61(s,3H),1.02(s,9H).
步骤2：2-((叔丁基二苯甲硅基)氧基)乙酰胺的合成Step 2: Synthesis of 2-((tert-butyldiphenylsilyl)oxy)acetamide
将化合物2-((叔丁基二苯甲硅基)氧基)乙酸甲酯(5g,15.22mmol)溶于胺的甲醇溶液(30mL)中，50℃搅拌过夜。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝33％)得到无色油状物3g，产率62.9％。Compound 2-((tert-butyldiphenylsilyl)oxy)acetic acid methyl ester (5g, 15.22mmol) was dissolved in the methanol solution of amine (30mL), and stirred at 50°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 33%) to obtain 3 g of colorless oil with a yield of 62.9%.
1HNMR(400MHz,DMSO-d6)δ7.65–7.63(m,4H),7.49–7.43(m,7H),7.11(s,1H),3.95(s,2H),1.03(s,9H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.65–7.63(m,4H),7.49–7.43(m,7H),7.11(s,1H),3.95(s,2H),1.03(s,9H) .
步骤3：4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate
将化合物6-羟基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(500mg,1.81mmol)加入到甲醇(3mL)和乙酸乙酯(3mL)中。加入10％钯碳(100mg)在氢气的氛围下室温搅拌三个小时。用硅藻土过滤，减压浓缩，用硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝5％)得到白色固体460mg，产率91.3％。Compound 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (500 mg, 1.81 mmol) was added to methanol (3 mL) and ethyl acetate (3 mL). 10% palladium on carbon (100 mg) was added and stirred at room temperature for three hours under a hydrogen atmosphere. Filter through diatomaceous earth, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent MeOH: DCM (v/v) = 5%) to obtain 460 mg of white solid, with a yield of 91.3%.
1HNMR(400MHz,CDCl3)δ7.45–7.42(m,1H),6.45–6.42(m,1H),6.10–6.08(m,1H),4.24(s,2H),2.85(s,2H),2.73–2.69(m,1H),1.95–1.93(m,2H),1.63–1.59(m,2H),1.47(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ7.45–7.42(m,1H),6.45–6.42(m,1H),6.10–6.08(m,1H),4.24(s,2H),2.85(s,2H) ,2.73–2.69(m,1H),1.95–1.93(m,2H),1.63–1.59(m,2H),1.47(s,9H).
步骤4：4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯的合成Step 4: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
将化合物4-(6-羟基吡啶-2-基)哌啶-1-羧酸叔丁酯(400mg,1.44mmol)加入到N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(199mg,1.44mmol)和7-(溴甲基)-4-氯-2-氟苯并呋喃(416mg,1.58mmol),60℃搅拌1.5个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂乙酸乙酯:石油醚(v/v)＝1:6)得到无色油状产物540mg，产率81.5％。Compound 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.44 mmol) was added to N,N-dimethylformamide (5 mL), and potassium carbonate ( 199 mg, 1.44 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (416 mg, 1.58 mmol), stirred at 60°C for 1.5 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent: ethyl acetate:petroleum ether (v/v)=1:6) to obtain 540 mg of colorless oily product with a yield of 81.5%.
1HNMR(400MHz,CDCl3)δ7.47–7.43(m,1H),7.26–7.24(m,1H),7.19–7.15(m,1H),6.67(d,J＝7.2Hz,1H),6.57(d,J＝8Hz,1H),5.94(d,J＝6.8Hz,1H),5.52(s,2H),4.16(s,2H),2.76–2.68(m,3H),1.80–1.77(m,2H),1.64–1.60(m,2H),1.42(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ7.47–7.43(m,1H),7.26–7.24(m,1H),7.19–7.15(m,1H),6.67(d,J＝7.2Hz,1H),6.57 (d,J＝8Hz,1H),5.94(d,J＝6.8Hz,1H),5.52(s,2H),4.16(s,2H),2.76–2.68(m,3H),1.80–1.77(m ,2H),1.64–1.60(m,2H),1.42(s,9H).
步骤5：2-(4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶的合成Step 5: Synthesis of 2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine
将化合物4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(490mg,1.06mmol)加入到二氯甲烷(5mL)中，冰浴下，加入盐酸二氧六环溶液(5mL)，0℃搅拌两小时。减压浓缩，得到白色固体产物300mg并直接用于下一步反应。Compound 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (490 mg, 1.06 mmol) Add to dichloromethane (5 mL), add dioxane hydrochloride solution (5 mL) under ice bath, and stir at 0°C for two hours. Concentrate under reduced pressure to obtain 300 mg of white solid product, which was directly used in the next reaction.
LC-MS(ESI):[M+H]+＝361.2。LC-MS (ESI): [M+H] + =361.2.
步骤6：5-溴-3-氟噻吩-2-羧酸甲酯的合成Step 6: Synthesis of methyl 5-bromo-3-fluorothiophene-2-carboxylate
将化合物3-氟噻吩-2-羧酸甲酯(7.5mL,62.45mmol)加入到四氢呋喃(500mL)中。在-78℃下缓慢滴加二氯化镁(2,2,6,6-四甲基哌啶)锂盐(1N)(120mL,475.25mmol)，搅拌30min，将四溴化碳(20.7g,62.45mmol)加入到四氢呋喃(25mL)中，并将该溶液缓慢滴入到反应体系，搅拌过夜。加入HCl(0.5N)调节PH至6，减压浓缩除去四氢呋喃，加入二氯甲烷(200mL)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂石油醚:乙酸乙酯(v/v)＝25％)得到黄色固体产物9.0g，产率60.3％。Compound 3-fluorothiophene-2-carboxylic acid methyl ester (7.5 mL, 62.45 mmol) was added to tetrahydrofuran (500 mL). Slowly add magnesium dichloride (2,2,6,6-tetramethylpiperidine) lithium salt (1N) (120mL, 475.25mmol) dropwise at -78°C, stir for 30min, and add carbon tetrabromide (20.7g, 62.45 mmol) was added to tetrahydrofuran (25 mL), and the solution was slowly dropped into the reaction system, and stirred overnight. Add HCl (0.5N) to adjust the pH to 6, concentrate under reduced pressure to remove tetrahydrofuran, add dichloromethane (200 mL) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (elution Add petroleum ether: ethyl acetate (v/v) = 25%) to obtain 9.0 g of yellow solid product, with a yield of 60.3%.
1HNMR(400MHz,CDCl3)δ6.88(s,1H),3.86(s,3H). 1 HNMR (400MHz, CDCl 3 ) δ6.88 (s, 1H), 3.86 (s, 3H).
步骤7：5-(2-((叔丁基二苯甲硅基)氧基)乙酰胺)-3-氟噻吩-2-羧酸甲酯的合成Step 7: Synthesis of 5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylic acid methyl ester
将化合物5-溴-3-氟噻吩-2-羧酸甲酯(4.1g,17.15mmol)，2-((叔丁基二苯基甲硅基)氧基)乙酰胺(6.2g,18.87mmol)加入到甲苯(50mL)中，加入碳酸铯(8.44g,25.90mmol)，氮气置换三遍。加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.99g,1.72mmol)，三(二亚苄基丙酮)二钯(1.57g,1.72mmol)，氮气保护下60℃搅拌两个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝10％)得到黄色固体3.3g，产率 40.8％。The compound 5-bromo-3-fluorothiophene-2-carboxylic acid methyl ester (4.1g, 17.15mmol), 2-((tert-butyldiphenylsilyl)oxy)acetamide (6.2g, 18.87mmol) ) was added to toluene (50 mL), cesium carbonate (8.44 g, 25.90 mmol) was added, and nitrogen was substituted three times. Add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.99g, 1.72mmol) and tris(dibenzylideneacetone)dipalladium (1.57g, 1.72mmol) under nitrogen protection. Stir at 60°C for two hours. Concentrate under reduced pressure and purify with silica gel column chromatography (eluent EtOAc: PE (v/v) = 10%) to obtain 3.3g of yellow solid, yield 40.8%.
1HNMR(400MHz,CDCl3)δ9.21(s,1H),7.56–7.54(m,4H),7.44–7.42(m,2H),7.38–7.19(m,4H),6.34(s,1H),4.23(s,2H),3.79(s,3H),1.08(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ9.21(s,1H),7.56–7.54(m,4H),7.44–7.42(m,2H),7.38–7.19(m,4H),6.34(s,1H) ,4.23(s,2H),3.79(s,3H),1.08(s,9H).
步骤8：4-溴-5-(2-((叔丁基二苯基甲硅基)氧基)乙酰胺)-3-氟噻吩-2-羧酸甲酯的合成Step 8: Synthesis of methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate
将化合物5-(2-((叔丁基二苯基甲硅基)氧基)乙酰胺)-3-氟噻吩-2-羧酸甲酯(3.3g,7.0mmol)加入到四氢呋喃(20mL)中，冰浴下，缓慢加入N-溴代琥珀酰亚胺(1.62g,9.1mmol)，0℃搅拌三个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝5％)得到淡黄色固体2.6g，产率67.5％。Compound 5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylic acid methyl ester (3.3g, 7.0mmol) was added to tetrahydrofuran (20mL) medium, slowly add N-bromosuccinimide (1.62g, 9.1mmol) under an ice bath, and stir at 0°C for three hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 5%) to obtain 2.6 g of light yellow solid, with a yield of 67.5%.
1HNMR(400MHz,CDCl3)δ9.58(s,1H),7.59–7.57(m,4H),7.42–7.34(m,6H),4.23(s,2H),3.81(s,3H),1.11(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ9.58(s,1H),7.59–7.57(m,4H),7.42–7.34(m,6H),4.23(s,2H),3.81(s,3H),1.11 (s,9H).
步骤9：4-溴-5-(2-((叔丁基二苯基甲硅基)氧基)乙硫代氨基)-3-氟噻吩-2-羧酸甲酯的合成Step 9: Synthesis of 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)ethylthioamino)-3-fluorothiophene-2-carboxylic acid methyl ester
将化合物4-溴-5-(2-((叔丁基二苯基甲硅基)氧基)乙酰胺)-3-氟噻吩-2-羧酸甲酯(1.3g,2.36mmol)加入到1,4-二氧六环(10mL)，加入劳森试剂(2.39g,5.9mmol)，110℃搅拌过夜。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝9％)得到黄色固体1.2g，产率89.7％。Compound 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylic acid methyl ester (1.3g, 2.36mmol) was added to 1,4-dioxane (10 mL), add Lawson's reagent (2.39 g, 5.9 mmol), and stir at 110°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 9%) to obtain 1.2 g of yellow solid, with a yield of 89.7%.
1HNMR(400MHz,CDCl3)δ11.18(s,1H),7.60–7.57(m,4H),7.43–7.33(m,6H),4.52(s,2H),3.83(s,3H),1.12(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ11.18(s,1H),7.60–7.57(m,4H),7.43–7.33(m,6H),4.52(s,2H),3.83(s,3H),1.12 (s,9H).
步骤10：(S,Z)-4-溴-5-((2-((叔丁基二苯基甲硅基)氧基)-1-((氧杂环丁烷-2-基甲基)氨基)亚乙基)氨基)-3-氟噻吩-2-羧酸甲酯的合成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
将化合物4-溴-5-(2-((叔丁基二苯基甲硅基)氧基)乙硫代氨基)-3-氟噻吩-2-羧酸甲酯(1.3g,2.29mmol)加入到N,N-二甲基甲酰胺(15mL)中。加入醋酸银(780mg,4.67mmol)，氮气置换三次，室温搅拌过夜。减压浓缩，加入乙酸乙酯(10mL)和水(10mL)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝17％)得到黄色固体600mg，产率42.2％。Compound 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)ethylthioamino)-3-fluorothiophene-2-carboxylic acid methyl ester (1.3g, 2.29mmol) Add to N,N-dimethylformamide (15 mL). Add silver acetate (780 mg, 4.67 mmol), replace with nitrogen three times, and stir at room temperature overnight. Concentrate under reduced pressure, add ethyl acetate (10 mL) and water (10 mL) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) ) = 17%) to obtain 600 mg of yellow solid, with a yield of 42.2%.
1HNMR(400MHz,CDCl3)δ7.63(br t,J＝5.65Hz,4H),7.52–7.39(m,6H),6.95(s,1H),5.17–5.05(m,1H),4.78–4.68(m,1H),4.53(dt,J＝9.22,5.93Hz,1H),4.45–4.31(m,2H),3.88–3.77(m,4H),3.66–3.56(m,1H),2.78–2.67(m,1H),2.66–2.55(m,1H),1.10(s,9H). 1 HNMR (400MHz, CDCl 3 ) δ7.63 (br t, J = 5.65Hz, 4H), 7.52–7.39 (m, 6H), 6.95 (s, 1H), 5.17–5.05 (m, 1H), 4.78– 4.68(m,1H),4.53(dt,J＝9.22,5.93Hz,1H),4.45–4.31(m,2H),3.88–3.77(m,4H),3.66–3.56(m,1H),2.78– 2.67(m,1H),2.66–2.55(m,1H),1.10(s,9H).
步骤11：(S)-2-(((叔丁基二苯基甲硅基)氧基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物甲基(S,Z)-4-溴-5-((2-((叔丁基二苯基甲硅基)氧基)-1-((氧杂环丁烷-2-基甲基)氨基)亚乙基)氨基)-3-氟噻吩-2-羧酸甲酯(600mg,0.97mmol)加入到乙腈(8mL)中，加入N,N-二甲基乙二胺(0.2mL,1.37mmol)，加入碘化亚铜(200mg,0.63mmol)在氮气保护下85℃搅拌过夜。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝25％)得到无色油状产物250mg，产率47.9％。The compound methyl (S,Z)-4-bromo-5-((2-((tert-butyldiphenylsilyl)oxy)-1-((oxetan-2-ylmethyl) (base)amino)ethylene)amino)-3-fluorothiophene-2-carboxylic acid methyl ester (600mg, 0.97mmol) was added to acetonitrile (8mL), and N,N-dimethylethylenediamine (0.2mL ,1.37mmol), add copper iodide (200mg, 0.63mmol) and stir at 85°C overnight under nitrogen protection. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 25%) to obtain 250 mg of colorless oily product with a yield of 47.9%.
LC-MS(ESI):[M+H]+＝539.3。LC-MS (ESI): [M+H] + =539.3.
步骤12：(S)-6-氟-2-(羟甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成Step 12: (S)-6-fluoro-2-(hydroxymethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Synthesis of methyl carboxylate
将化合物(S)-2-(((叔丁基二苯基甲硅基)氧基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(230mg,0.43mmol)加入到四氢呋喃(5mL)中，加入四丁基氟化铵(168mg,0.64mmol)室温搅拌两个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝33％)得到白色固体产物100mg，产率78％。Compound (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H- Thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (230 mg, 0.43 mmol) was added to tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (168 mg, 0.64 mmol) was added and stirred at room temperature for two hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 33%) to obtain 100 mg of white solid product, with a yield of 78%.
LC-MS(ESI):[M+H]+＝301.3。LC-MS (ESI): [M+H] + =301.3.
步骤13：(S)-2-(氯甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成Step 13: (S)-2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Synthesis of methyl carboxylate
将化合物(S)-6-氟-2-(羟甲基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(30mg,0.1mmol)加入到二氯甲烷(2mL)中。加入三乙胺(20mg,0.2mmol)置于0℃搅拌五分钟。加入甲基磺酰 氯(17mg,0.15mmol)冰浴搅拌1.5个小时。加入水(2mL)和二氯甲烷(2mL)萃取，合并有机相，用无水硫酸钠干燥，得到白色固体35mg，并直接用于下一步反应。Compound (S)-6-fluoro-2-(hydroxymethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic Methyl acid ester (30 mg, 0.1 mmol) was added to dichloromethane (2 mL). Add triethylamine (20 mg, 0.2 mmol) and stir at 0°C for five minutes. Add methylsulfonyl Chlorine (17 mg, 0.15 mmol) was stirred in ice bath for 1.5 hours. Water (2 mL) and dichloromethane (2 mL) were added for extraction, the organic phases were combined, and dried over anhydrous sodium sulfate to obtain 35 mg of white solid, which was directly used in the next reaction.
步骤14：(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(35mg,0.11mmol)加入乙腈(2mL)中，加入碳酸钾(45mg,0.33mmol)和碘化钾(4mg,0.02mmol)。加入2-(4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶(43mg,0.12mmol)，50℃搅拌两个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝50％)得到无色油状产物38mg，产率53.8％。Compound (S)-2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic Methyl acid ester (35 mg, 0.11 mmol) was added to acetonitrile (2 mL), potassium carbonate (45 mg, 0.33 mmol) and potassium iodide (4 mg, 0.02 mmol) were added. 2-(4-Chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (43 mg, 0.12 mmol) was added and stirred at 50°C for two hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 50%) to obtain 38 mg of colorless oily product with a yield of 53.8%.
LC-MS(ESI):[M+H]+＝643.3。LC-MS (ESI): [M+H] + =643.3.
步骤15：(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(28mg,0.04mmol)加入到1,4-二氧六环(0.2mL)和水(0.2mL)中，加入氢氧化锂(6mg,0.25mmol)，40℃搅拌六个小时。加入醋酸(0.5mL)。减压浓缩，用Prep-HPLC(乙腈:水＝60％)纯化，得到白色固体20.4mg，产率74.5％。Compound (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (28 mg, 0.04 mmol) was added to 1 , add lithium hydroxide (6 mg, 0.25 mmol) to 4-dioxane (0.2 mL) and water (0.2 mL), and stir at 40°C for six hours. Acetic acid (0.5 mL) was added. Concentrate under reduced pressure and purify using Prep-HPLC (acetonitrile: water = 60%) to obtain 20.4 mg of white solid with a yield of 74.5%.
LC-MS(ESI):[M+H]+＝629.3；LC-MS(ESI): [M+H] + =629.3;
1HNMR(400MHz,DMSO-d6)δ7.65–7.61(m,1H),7.44–7.38(m,2H),6.87(d,J＝7.2Hz,1H),6.69(d,J＝8Hz,1H),6.51(d,J＝6.4Hz,1H),5.56(s,2H),5.08–5.06(m,1H),4.6–4.38(m,4H),3.83–3.69(m,2H),2.97–2.86(m,2H),2.75–2.7(m,1H),2.57–2.55(m,1H),2.45–2.42(m,1H),2.21–2.11(m,2H),1.75–1.65(m,4H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.65–7.61(m,1H),7.44–7.38(m,2H),6.87(d,J＝7.2Hz,1H),6.69(d,J＝8Hz, 1H),6.51(d,J＝6.4Hz,1H),5.56(s,2H),5.08–5.06(m,1H),4.6–4.38(m,4H),3.83–3.69(m,2H),2.97 –2.86(m,2H),2.75–2.7(m,1H),2.57–2.55(m,1H),2.45–2.42(m,1H),2.21–2.11(m,2H),1.75–1.65(m, 4H).
实施例10(S)-2-((6-((4-4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物10)的合成
Example 10 (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 (compound 10)
步骤1：(S)-2-((6-((4-4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(42mg,0.13mmol)加入乙腈(2mL)中，加入碳酸钾(55mg,0.4mmol)和碘化钾(4mg,0.02mmol)。加入6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-1',2',3',6'-四氢-2,4'-联吡啶(52mg,0.14mmol)，50℃搅拌两个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝75％)得到淡黄色固体产物56mg，产率66.3％。Compound (S)-2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic Methyl acid ester (42 mg, 0.13 mmol) was added to acetonitrile (2 mL), potassium carbonate (55 mg, 0.4 mmol) and potassium iodide (4 mg, 0.02 mmol) were added. Add 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (52 mg, 0.14mmol), stir at 50°C for two hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 75%) to obtain 56 mg of light yellow solid product with a yield of 66.3%.
1HNMR(400MHz,DMSO-d6)δ7.70(t,J＝7.8Hz,1H),7.44–7.39(m,2H),7.09(d,J＝7.2Hz,1H),6.76(d,J＝8.4Hz,1H),6.71(s,1H),6.53(d,J＝6.4Hz,1H),5.69(s,2H),5.04–5.02(m,1H),4.63–4.37(m,4H),3.98–3.85(m,2H),3.83(s,3H),3.33–3.21(m,4H),2.72–2.69(m,3H),2.42–2.39(1H). 1 HNMR(400MHz, DMSO-d 6 )δ7.70(t,J＝7.8Hz,1H),7.44–7.39(m,2H),7.09(d,J＝7.2Hz,1H),6.76(d,J ＝8.4Hz,1H),6.71(s,1H),6.53(d,J＝6.4Hz,1H),5.69(s,2H),5.04–5.02(m,1H),4.63–4.37(m,4H) ,3.98–3.85(m,2H),3.83(s,3H),3.33–3.21(m,4H),2.72–2.69(m,3H),2.42–2.39(1H).
步骤2：(S)-2-((6-((4-4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((6-((4-4-氯-2-氟苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-6-氟-1- (氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(46mg,0.07mmol)加入到1,4-二氧六环(1.0mL)和水(0.2mL)中。加入氢氧化锂(11mg,0.46mmol)，40℃搅拌六个小时。加入醋酸(0.5mL)，减压浓缩，用Prep-HPLC(乙腈:水＝60％)纯化，得到白色固体26.3mg，产率58.5％。Compound (S)-2-((6-((4-4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-Bipyridyl]-1'(2'H)-yl)methyl)-6-fluoro-1- (Oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (46 mg, 0.07 mmol) was added to 1,4-dioxane ( 1.0 mL) and water (0.2 mL). Lithium hydroxide (11 mg, 0.46 mmol) was added and stirred at 40°C for six hours. Acetic acid (0.5 mL) was added, concentrated under reduced pressure, and purified by Prep-HPLC (acetonitrile: water = 60%) to obtain 26.3 mg of white solid with a yield of 58.5%.
LC-MS(ESI):[M+H]+＝627.3；LC-MS(ESI): [M+H] + =627.3;
1HNMR(400MHz,DMSO-d6)δ7.69(t,J＝7.8Hz,1H),7.44–7.38(m,2H),7.08(d,J＝7.6Hz,1H),6.74(d,J＝8Hz,1H),6.70(s,1H),6.52(d,J＝6.8Hz,1H),5.59(s,2H),5.02–5.01(m,1H),4.61–4.36(m,4H),3.96–3.83(m,2H),3.2–3.15(m,2H),2.72–2.69(m,3H),2.52–2.49(m,2H),2.41–2.35(m,1H). 1 HNMR(400MHz, DMSO-d 6 ) δ7.69(t,J＝7.8Hz,1H),7.44–7.38(m,2H),7.08(d,J＝7.6Hz,1H),6.74(d,J ＝8Hz,1H),6.70(s,1H),6.52(d,J＝6.8Hz,1H),5.59(s,2H),5.02–5.01(m,1H),4.61–4.36(m,4H), 3.96–3.83(m,2H),3.2–3.15(m,2H),2.72–2.69(m,3H),2.52–2.49(m,2H),2.41–2.35(m,1H).
实施例11(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-2-氟苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物11)的合成
Example 11 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (compound 11)
步骤1：2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸甲酯的合成Step 1: Synthesis of methyl 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
将化合物6-溴-2-((甲氧基甲基)氧)吡啶(419mg,1.92mmol)和2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯(470mg,1.60mmol)加入1,4-二氧六环(10mL)和水(2.5mL)中，加入碳酸钾(663mg,4.80mmol)和二氯(1,1'-二(二苯基膦)二茂铁)钯(58mg,0.08mmol)，在氮气保护下升温至85℃搅拌过夜。反应液冷却至室温，过滤后减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝1:10)，得到淡黄色固体产物320mg，产率65.6％。Compound 6-bromo-2-((methoxymethyl)oxy)pyridine (419 mg, 1.92 mmol) and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)methyl acetate (470mg, 1.60mmol) was added to 1,4-dioxane (10mL) and water (2.5mL), and carbonic acid was added Potassium (663 mg, 4.80 mmol) and dichloro(1,1'-bis(diphenylphosphine)ferrocene)palladium (58 mg, 0.08 mmol) were heated to 85°C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v/v) = 1:10) to obtain 320 mg of a light yellow solid product with a yield of 65.6%.
1HNMR(400MHz,DMSO-d6)δ7.92–7.79(m,3H),7.66(d,J＝7.6Hz,1H),7.46(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),5.61(s,2H),3.80(s,2H),3.65(s,3H),3.45(s,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.92–7.79(m,3H),7.66(d,J＝7.6Hz,1H),7.46(t,J＝8.0Hz,1H),6.87(d,J =8.0Hz,1H),5.61(s,2H),3.80(s,2H),3.65(s,3H),3.45(s,3H).
步骤2：2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙烷-1-醇的合成Step 2: Synthesis of 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethane-1-ol
将化合物2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸甲酯(320mg,1.05mmol)加入四氢呋喃(10mL)中，冰浴冷却至0℃。加入四氢铝锂(150mg,3.95mmol)，冰浴反应2小时。加入水(2mL)淬灭反应，硅藻土过滤，滤饼用二氯甲烷(20mL)洗涤。滤液减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝1:10)，得到淡黄色油状产物190mg，产率68.4％。Compound 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate methyl ester (320 mg, 1.05 mmol) was added to tetrahydrofuran (10 mL), and cooled in an ice bath to 0℃. Lithium aluminum tetrahydride (150 mg, 3.95 mmol) was added, and the reaction was carried out in ice bath for 2 hours. Water (2 mL) was added to quench the reaction, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE:EA (v/v)=1:10) to obtain 190 mg of light yellow oily product with a yield of 68.4%.
1HNMR(400MHz,DMSO-d6)δ7.88–7.76(m,3H),7.64(d,J＝7.6Hz,1H),7.42(t,J＝8.0Hz,1H),6.85(d,J＝8.0Hz,1H),5.60(s,2H),4.76(t,J＝5.2Hz,1H),3.64(dd,J＝12.4,6.8Hz,2H),3.45(s,3H),2.81(t,J＝6.8Hz,2H). 1 HNMR(400MHz, DMSO-d 6 )δ7.88–7.76(m,3H),7.64(d,J＝7.6Hz,1H),7.42(t,J＝8.0Hz,1H),6.85(d,J ＝8.0Hz,1H),5.60(s,2H),4.76(t,J＝5.2Hz,1H),3.64(dd,J＝12.4,6.8Hz,2H),3.45(s,3H),2.81(t ,J＝6.8Hz,2H).
步骤3：2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛的合成Step 3: Synthesis of 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde
将化合物2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙-1-醇(190mg,0.69mmol)加入二氯甲烷(10mL)中，冰浴冷却至0℃。加入戴斯马丁氧化剂(872mg,2.06mmol)，在氮气保护下0℃反应2小时。用硅藻土过滤，减压浓缩，用硅胶柱层析纯化(洗脱剂PE:EA(v/v)＝1:5)，得到黄色油状产物40mg，产率21.2％。Compound 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (190 mg, 0.69 mmol) was added to dichloromethane (10 mL) , cool to 0℃ in ice bath. Desmartin oxidant (872 mg, 2.06 mmol) was added, and the reaction was carried out at 0°C for 2 hours under nitrogen protection. Filter through diatomaceous earth, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent PE: EA (v/v) = 1:5) to obtain 40 mg of yellow oily product with a yield of 21.2%.
1HNMR(400MHz,DMSO-d6)δ9.73(s,1H),7.95–7.84(m,3H),7.67(d,J＝7.4Hz,1H),7.42(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),5.60(s,2H),3.92(s,2H),3.44(s,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ9.73 (s, 1H), 7.95–7.84 (m, 3H), 7.67 (d, J = 7.4Hz, 1H), 7.42 (t, J = 8.0Hz, 1H ),6.87(d,J=8.0Hz,1H),5.60(s,2H),3.92(s,2H),3.44(s,3H).
步骤4：(S)-2-(2-氟-4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸 甲酯的合成Step 4: (S)-2-(2-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno [2,3-d]imidazole-5-carboxylic acid Synthesis of methyl ester
将化合物2-(2-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛(390mg,1.42mmol)，(S)-5-氨基-4-((氧杂环丁烷-2-基甲基)氨基)噻吩-2-羧酸甲酯(412mg,1.70mmol)，加入醋酸(5mL)中，氮气保护下升温至60℃反应8小时。减压浓缩，用硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝1:20)，得到棕色固体产物123mg，产率17.4％。Compound 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (390 mg, 1.42 mmol), (S)-5-amino-4- ((Oxetan-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (412 mg, 1.70 mmol) was added to acetic acid (5 mL), and the temperature was raised to 60°C under nitrogen protection for 8 hours. Concentrate under reduced pressure and purify using silica gel column chromatography (eluent MeOH:DCM (v/v) = 1:20) to obtain 123 mg of brown solid product with a yield of 17.4%.
LC-MS(ESI):[M+H]+＝454.4。LC-MS (ESI): [M+H] + =454.4.
步骤5：2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-2-氟苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(2-氟-4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(110mg,0.24mmol)加入N,N-二甲基甲酰胺(10mL)中。加入7-(溴甲基)-4-氯-2-氟-1-苯并呋喃(64mg,0.24mmol)和碳酸钾(101mg,0.73mmol)，反应液氮气保护下升温至60℃反应2小时。减压浓缩，用硅胶柱层析纯化(洗脱剂MeOH:DCM(v/v)＝1:20)，得到黄色固体产物51mg，产率33.1％。Compound (S)-2-(2-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[ Methyl 2,3-d]imidazole-5-carboxylate (110 mg, 0.24 mmol) was added to N,N-dimethylformamide (10 mL). Add 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (64mg, 0.24mmol) and potassium carbonate (101mg, 0.73mmol), and heat the reaction liquid to 60°C under nitrogen protection for 2 hours. . Concentrate under reduced pressure and purify by silica gel column chromatography (eluent MeOH:DCM (v/v)=1:20) to obtain 51 mg of yellow solid product with a yield of 33.1%.
1HNMR(400MHz,DMSO-d6)δ7.95(s,1H),7.87–7.78(m,3H),7.63(d,J＝7.4Hz,1H),7.47(d,J＝8.0Hz,1H),7.42–7.35(m,2H),6.90(d,J＝8.0Hz,1H),6.53(d,J＝6.4Hz,1H),5.71(s,2H),5.03–4.98(m,1H),4.66–4.58(m,1H),4.54–4.44(m,2H),4.41–4.29(m,3H),3.82(s,3H),2.71–2.65(m,1H),2.35–2.31(m,1H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.95 (s, 1H), 7.87–7.78 (m, 3H), 7.63 (d, J = 7.4Hz, 1H), 7.47 (d, J = 8.0Hz, 1H ),7.42–7.35(m,2H),6.90(d,J＝8.0Hz,1H),6.53(d,J＝6.4Hz,1H),5.71(s,2H),5.03–4.98(m,1H) ,4.66–4.58(m,1H),4.54–4.44(m,2H),4.41–4.29(m,3H),3.82(s,3H),2.71–2.65(m,1H),2.35–2.31(m, 1H).
步骤6：(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-2-氟苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩[2,3-d]咪唑-5-羧酸的合成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
将化合物2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-2-氟苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(51mg,0.08mmol)加入1,4-二氧六环(2mL)和水(0.5mL)中，加入氢氧化锂(17mg,0.41mmol)。反应液在氮气保护下升温至40℃搅拌2小时。冷却至室温，用醋酸调节PH值至6～7。减压浓缩，用Prep-HPLC纯化(洗脱剂CH3CN:H2O(v/v)＝0～50％)，得到白色固体产物30mg，产率60.1％。Compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxa Cyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (51 mg, 0.08 mmol) was added to 1,4-dioxane (2 mL) and water (0.5 mL), add lithium hydroxide (17 mg, 0.41 mmol). The reaction solution was heated to 40°C under nitrogen protection and stirred for 2 hours. Cool to room temperature and adjust the pH value to 6-7 with acetic acid. Concentrate under reduced pressure and purify by Prep-HPLC (eluent CH 3 CN:H 2 O (v/v) = 0-50%) to obtain 30 mg of white solid product with a yield of 60.1%.
LC-MS(ESI):[M+H]+＝622.2；LC-MS(ESI): [M+H] + =622.2;
1HNMR(400MHz,DMSO-d6)δ12.68(br.s,1H),7.83(dd,J＝8.8,5.6Hz,4H),7.63(d,J＝7.2Hz,1H),7.47(d,J＝8.0Hz,1H),7.39(dd,J＝16.4,8.1Hz,2H),6.89(d,J＝8.0Hz,1H),6.53(d,J＝6.4Hz,1H),5.71(s,2H),5.04–4.98(m,1H),4.65–4.58(m,1H),4.52–4.47(m,2H),4.41–4.28(m,3H),2.69–4.52(m,1H),2.38–2.31(m,1H). 1 HNMR (400MHz, DMSO-d 6 ) δ12.68(br.s,1H),7.83(dd,J＝8.8,5.6Hz,4H),7.63(d,J＝7.2Hz,1H),7.47(d ,J＝8.0Hz,1H),7.39(dd,J＝16.4,8.1Hz,2H),6.89(d,J＝8.0Hz,1H),6.53(d,J＝6.4Hz,1H),5.71(s ,2H),5.04–4.98(m,1H),4.65–4.58(m,1H),4.52–4.47(m,2H),4.41–4.28(m,3H),2.69–4.52(m,1H),2.38 –2.31(m,1H).
实施例12(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物12)的合成
Example 12 (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 (compound 12)
步骤1：2-溴-6-(甲氧基甲氧基)吡啶的合成Step 1: Synthesis of 2-bromo-6-(methoxymethoxy)pyridine
将化合物6-溴吡啶-2-醇(25g,143.7mmol)加入二氯甲烷(250mL)中，加入三乙胺(100.0mL,431.0 mmol)，冰浴搅拌十分钟。加入溴(甲氧基)甲烷(36.0g,287.4mmol)，室温搅拌两小时。加入水(50mL)，用二氯甲烷(50mL×3)萃取，合并有机相，有机相使用饱和食盐水洗一次，无水硫酸钠干燥后，减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1:20)得到无色油状产物11.1g，产率35.5％。Compound 6-bromopyridin-2-ol (25g, 143.7mmol) was added to dichloromethane (250mL), and triethylamine (100.0mL, 431.0 mmol), stir in ice bath for ten minutes. Add bromo(methoxy)methane (36.0g, 287.4mmol) and stir at room temperature for two hours. Add water (50 mL), extract with dichloromethane (50 mL EtOAc:PE (v/v)=1:20) to obtain 11.1g of colorless oily product with a yield of 35.5%.
1HNMR(400MHz,DMSO-d6)δ7.72(d,J＝7.8Hz,1H),7.28(d,J＝7.3Hz,1H),6.93(d,J＝7.9Hz,1H),5.42(s,2H),3.42(s,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.72(d,J＝7.8Hz,1H),7.28(d,J＝7.3Hz,1H),6.93(d,J＝7.9Hz,1H),5.42( s,2H),3.42(s,3H).
步骤2：2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸甲酯的合成Step 2: Synthesis of methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
将化合物2-溴-6-(甲氧基甲氧基)吡啶(3.0g,13.7mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸甲酯(4.54g,16.5mmol)加入到1,4-二氧六环(32mL)和水(8mL)中。加入碳酸钾(5.67g,41.1mmol)，用氮气置换三次，加入1,1'-双二苯基膦二茂铁二氯化钯(0.3g,0.41mmol)，氮气置换三次，85℃搅拌过夜。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1:12)得到无色油状产物2.2g，产率55.7％。Compound 2-bromo-6-(methoxymethoxy)pyridine (3.0g, 13.7mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-di Methyl oxaborolan-2-yl)phenyl)acetate (4.54 g, 16.5 mmol) was added to 1,4-dioxane (32 mL) and water (8 mL). Add potassium carbonate (5.67g, 41.1mmol), replace it with nitrogen three times, add 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (0.3g, 0.41mmol), replace it with nitrogen three times, and stir at 85°C overnight. . Concentrate under reduced pressure and purify using silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:12) to obtain 2.2 g of colorless oily product with a yield of 55.7%.
1HNMR(400MHz,CDCl3)δ7.90(d,J＝8.3Hz,2H),7.60(t,J＝7.8Hz,1H),7.30(dd,J＝7.6,6.7Hz,3H),6.68(d,J＝8.1Hz,1H),5.58(s,2H),3.63(s,3H),3.61(s,2H),3.49(s,3H). 1 HNMR (400MHz, CDCl 3 ) δ7.90 (d, J = 8.3Hz, 2H), 7.60 (t, J = 7.8Hz, 1H), 7.30 (dd, J = 7.6, 6.7Hz, 3H), 6.68 ( d,J＝8.1Hz,1H),5.58(s,2H),3.63(s,3H),3.61(s,2H),3.49(s,3H).
步骤3：2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙-1-醇的合成Step 3: Synthesis of 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol
将化合物2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸甲酯(2.2g,7.7mmol)加入四氢呋喃(20mL)中，0℃搅拌五分钟。加入四氢铝锂(0.87g,23.0mmol)，0℃搅拌两小时。加入水(10mL)淬灭，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相使用饱和食盐水洗一次，无水硫酸钠干燥后，减压浓缩，用硅胶柱层析进行纯化(洗脱剂EtOAc:PE(v/v)＝1:5)得无色油状产物1.45g，产率72.5％。Compound 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate methyl ester (2.2g, 7.7mmol) was added to tetrahydrofuran (20mL), and stirred at 0°C for five minutes. Lithium aluminum tetrahydride (0.87g, 23.0mmol) was added and stirred at 0°C for two hours. Add water (10 mL) to quench, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography ( The eluent (EtOAc:PE (v/v)=1:5) gave 1.45g of colorless oily product with a yield of 72.5%.
LC-MS(ESI):[M+H]+＝260.3。LC-MS (ESI): [M+H] + =260.3.
步骤4：2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛的合成Step 4: Synthesis of 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde
将化合物2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙-1-醇(1.45g,5.6mmol)加入到二氯甲烷(20mL)中，加入戴斯马丁试剂(3.7g,8.6mmol)冰浴搅拌1小时，析出大量固体。加入饱和碳酸氢钠(5mL)，过滤后减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝1:8)得无色油状产物750mg，产率52.4％。Compound 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (1.45g, 5.6mmol) was added to dichloromethane (20mL), and Dessmartin's reagent (3.7g, 8.6mmol) was stirred in an ice bath for 1 hour, and a large amount of solid precipitated. Saturated sodium bicarbonate (5 mL) was added, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:8) to obtain 750 mg of colorless oily product with a yield of 52.4%.
LC-MS(ESI):[M+H]+＝258.3。LC-MS (ESI): [M+H] + =258.3.
步骤5：(S)-2-(4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成Step 5: (S)-2-(4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3 -D] Synthesis of imidazole-5-carboxylic acid methyl ester
将化合物2-(4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛(600mg,2.33mmol)、(S)-5-氨基-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸甲酯(860mg,3.38mmol)加入醋酸(20mL)中，60℃搅拌5小时。减压浓缩，用硅胶柱层析纯化(洗脱剂DCM:MeOH(v/v)＝20:1)得到浅褐色固体产物200mg，产率20.0％。Compound 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (600mg, 2.33mmol), (S)-5-amino-4-(oxa Cyclbut-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (860 mg, 3.38 mmol) was added to acetic acid (20 mL), and stirred at 60°C for 5 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 200 mg of light brown solid product with a yield of 20.0%.
LC-MS(ESI):[M+H]+＝436.4；LC-MS(ESI): [M+H] + =436.4;
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),7.92(s,1H),7.73(d,J＝8.1Hz,2H),7.52(dd,J＝8.8,7.1Hz,1H),7.39(d,J＝8.3Hz,2H),6.66(d,J＝5.6Hz,1H),6.36(d,J＝8.9Hz,1H),4.96–4.86(m,1H),4.62–4.51(m,1H),4.47(s,2H),4.35(s,3H),3.82(s,3H),2.66–2.58(m,1H),2.31–2.24(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.62 (s, 1H), 7.92 (s, 1H), 7.73 (d, J = 8.1Hz, 2H), 7.52 (dd, J = 8.8, 7.1Hz, 1H),7.39(d,J＝8.3Hz,2H),6.66(d,J＝5.6Hz,1H),6.36(d,J＝8.9Hz,1H),4.96–4.86(m,1H),4.62– 4.51(m,1H),4.47(s,2H),4.35(s,3H),3.82(s,3H),2.66–2.58(m,1H),2.31–2.24(m,1H).
步骤6：(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸甲酯(110mg,0.25mmol)、7-(溴甲基)-4-氯-2-氟-1-苯并呋喃(87.0mg,0.32mmol)加入N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(135mg,0.75mmol)，60℃搅拌一小时。加入水(10mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，有机相使用饱和食盐水洗一次，无水硫酸钠干燥，用硅胶柱层析纯化(洗脱剂DCM:MeOH(v/v)＝10:1)得到白色固体产物65mg，产率39.5％。 Compound (S)-2-(4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3- d] Imidazole-5-carboxylic acid methyl ester (110 mg, 0.25 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (87.0 mg, 0.32 mmol) were added to N, N- To dimethylformamide (5 mL), potassium carbonate (135 mg, 0.75 mmol) was added, and the mixture was stirred at 60°C for one hour. Add water (10 mL), extract with ethyl acetate (15 mL /v)=10:1) 65 mg of white solid product was obtained with a yield of 39.5%.
LC-MS(ESI):[M+H]+＝618.4；LC-MS(ESI): [M+H] + =618.4;
1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝8.3Hz,2H),7.92(s,1H),7.80(t,J＝7.8Hz,1H),7.56(d,J＝7.4Hz,1H),7.47(d,J＝8.2Hz,1H),7.39(dd,J＝10.6,8.3Hz,3H),6.84(d,J＝8.1Hz,1H),6.53(d,J＝6.4Hz,1H),5.69(s,2H),4.95–4.88(m,1H),4.63–4.51(m,1H),4.50–4.41(m,2H),4.38–4.31(m,3H),3.82(s,3H),2.61(dd,J＝11.8,5.6Hz,1H),2.33–2.24(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.99 (d, J＝8.3Hz, 2H), 7.92 (s, 1H), 7.80 (t, J＝7.8Hz, 1H), 7.56 (d, J＝ 7.4Hz,1H),7.47(d,J＝8.2Hz,1H),7.39(dd,J＝10.6,8.3Hz,3H),6.84(d,J＝8.1Hz,1H),6.53(d,J＝ 6.4Hz,1H),5.69(s,2H),4.95–4.88(m,1H),4.63–4.51(m,1H),4.50–4.41(m,2H),4.38–4.31(m,3H),3.82 (s,3H),2.61(dd,J＝11.8,5.6Hz,1H),2.33–2.24(m,1H).
步骤7：(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(65mg,0.1mmol)溶解在二氧六环(4mL)和水(1mL)中。加入氢氧化锂(12mg,0.50mmol)，室温搅拌2小时。用醋酸调节PH为6～7，减压浓缩，用prep-HPLC(洗脱剂CH3CN:H2O(v/v)＝50％)纯化得白色固体产物33.6mg，产率52.9％。Compound (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxa Methyl cyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (65 mg, 0.1 mmol) was dissolved in dioxane (4 mL) and water (1 mL) middle. Lithium hydroxide (12 mg, 0.50 mmol) was added and stirred at room temperature for 2 hours. Adjust the pH to 6-7 with acetic acid, concentrate under reduced pressure, and purify with prep-HPLC (eluent CH 3 CN: H 2 O (v/v) = 50%) to obtain 33.6 mg of white solid product with a yield of 52.9%.
LC-MS(ESI):[M+H]+＝604.2；LC-MS(ESI): [M+H] + =604.2;
1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.99(d,J＝8.3Hz,2H),7.86–7.73(m,2H),7.56(d,J＝7.5Hz,1H),7.47(d,J＝8.2Hz,1H),7.39(dd,J＝11.3,8.4Hz,3H),6.84(d,J＝8.2Hz,1H),6.53(d,J＝6.4Hz,1H),5.69(s,2H),4.98–4.85(m,1H),4.59–4.47(m,1H),4.49–4.39(m,2H),4.37–4.29(m,3H),2.66–2.55(m,1H),2.33–2.21(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.90 (s, 1H), 7.99 (d, J = 8.3Hz, 2H), 7.86–7.73 (m, 2H), 7.56 (d, J = 7.5Hz, 1H),7.47(d,J＝8.2Hz,1H),7.39(dd,J＝11.3,8.4Hz,3H),6.84(d,J＝8.2Hz,1H),6.53(d,J＝6.4Hz, 1H),5.69(s,2H),4.98–4.85(m,1H),4.59–4.47(m,1H),4.49–4.39(m,2H),4.37–4.29(m,3H),2.66–2.55( m,1H),2.33–2.21(m,1H).
实施例13(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物13)的合成
Example 13 (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 (compound 13)
步骤1：(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(氯甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(42mg,0.13mmol)加入乙腈(2mL)中，加入碳酸钾(55mg,0.4mmol)和碘化钾(4mg,0.02mmol)。加入4-(4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟-2-(1,2,3,6-四氢吡啶-4-基)嘧啶(55mg,0.15mmol)，50℃搅拌两个小时。减压浓缩，用硅胶柱层析纯化(洗脱剂EtOAc:PE(v/v)＝75％)得到淡黄色固体产物63.4mg，产率72.9％。Compound (S)-2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic Methyl acid ester (42 mg, 0.13 mmol) was added to acetonitrile (2 mL), potassium carbonate (55 mg, 0.4 mmol) and potassium iodide (4 mg, 0.02 mmol) were added. Add 4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (55 mg ,0.15mmol), stir at 50°C for two hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc: PE (v/v) = 75%) to obtain 63.4 mg of light yellow solid product with a yield of 72.9%.
LC-MS(ESI):[M+H]+＝660.2；LC-MS(ESI): [M+H] + =660.2;
1HNMR(400MHz,DMSO-d6)δ8.22(d,J＝2.4Hz,1H),7.26–7.18(m 2H),6.99(s,1H),5.96(d,J＝6.8Hz,1H),5.65(s,2H),5.08–5.06(m,1H),4.58–4.53(m,2H),4.35–4.32(m,1H),3.93(s,1H),3.83(s,3H),3.23–3.22(m,1H),2.74–2.61(m,4H),2.39–2.38(m,1H),1.98(s,2H),1.21–1.19(m,2H). 1 HNMR (400MHz, DMSO-d 6 ) δ8.22 (d, J＝2.4Hz, 1H), 7.26–7.18 (m 2H), 6.99 (s, 1H), 5.96 (d, J＝6.8Hz, 1H) ,5.65(s,2H),5.08–5.06(m,1H),4.58–4.53(m,2H),4.35–4.32(m,1H),3.93(s,1H),3.83(s,3H),3.23 –3.22(m,1H),2.74–2.61(m,4H),2.39–2.38(m,1H),1.98(s,2H),1.21–1.19(m,2H).
步骤2：(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸的合成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
将化合物(S)-2-((4-(4-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-5-氟嘧啶-2-基)-3,6-二氢吡啶-1(2H)-基)甲基)-6-氟-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(54mg,0.08mmol)加入到1,4-二氧六环 (1.0mL)和水(0.2mL)中。加入氢氧化锂(10mg,0.42mmol)，40℃搅拌两个小时。加入醋酸(0.2mL)，减压浓缩，用Prep-HPLC(乙腈:水＝50％)纯化，得到白色固体30mg，产率56.8％。Compound (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-5 -Methyl carboxylate (54 mg, 0.08 mmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL). Lithium hydroxide (10 mg, 0.42 mmol) was added and stirred at 40°C for two hours. Acetic acid (0.2 mL) was added, concentrated under reduced pressure, and purified by Prep-HPLC (acetonitrile: water = 50%) to obtain 30 mg of white solid with a yield of 56.8%.
LC-MS(ESI):[M+H]+＝646.2；LC-MS(ESI): [M+H] + =646.2;
1HNMR(400MHz,DMSO-d6)δ13.22(s,1H),8.59(d,J＝2.8Hz,1H),7.50–7.43(m,2H),7.05(s,1H),6.55(d,J＝6.4Hz,1H),5.77(s,2H),5.02–4.99(m,1H),4.59–4.36(m,4H),3.96–3.83(m,2H),3.32–3.24(m,2H),2.71–2.43(m,6H). 1 HNMR (400MHz, DMSO-d 6 ) δ13.22 (s, 1H), 8.59 (d, J = 2.8Hz, 1H), 7.50–7.43 (m, 2H), 7.05 (s, 1H), 6.55 (d ,J＝6.4Hz,1H),5.77(s,2H),5.02–4.99(m,1H),4.59–4.36(m,4H),3.96–3.83(m,2H),3.32–3.24(m,2H ),2.71–2.43(m,6H).
实施例14(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-3-氟苄基)-1-(氧杂环丁烷-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸(化合物14)的合成
Example 14 (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (compound 14)
步骤1：2-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸乙酯的合成Step 1: Ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate synthesis
将化合物2-(4-溴-3-氟苯基)乙酸乙酯(3.5g,13.41mmol)，联硼酸频那醇酯(3.74g,14.75mmol)，1,1'-双二苯基膦二茂铁二氯化钯(0.29g,0.40mmol)，醋酸钾(3.95g,40.22mmol)加入到1,4-二氧六环(100mL)中，反应液在90℃下搅拌3小时。过滤反应液，减压下浓缩，得黑色油状液体，直接投入下一步反应。Compound 2-(4-bromo-3-fluorophenyl)ethyl acetate (3.5g, 13.41mmol), pinacol diborate (3.74g, 14.75mmol), 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride (0.29g, 0.40mmol) and potassium acetate (3.95g, 40.22mmol) were added to 1,4-dioxane (100mL), and the reaction solution was stirred at 90°C for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a black oily liquid, which was directly put into the next reaction step.
LC-MS(ESI):[M+H]+＝309.2。LC-MS (ESI): [M+H] + =309.2.
步骤2：2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸乙酯的合成Step 2: Synthesis of ethyl 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate
将化合物2-溴-6-(甲氧基甲氧基)吡啶(3g,13.76mmol)，2-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酸乙酯(5.69g,9.24mmol)，1,1'-双二苯基膦二茂铁二氯化钯(0.02g,0.03mmol)，碳酸钾(0.15g,1.10mmol)加入到1,4-二氧六环(100mL)和水(25mL)中。反应液于85℃下搅拌过夜。将反应液过滤，减压浓缩，用硅胶柱层析纯化(洗脱剂:PE:EA(v/v)＝5:1)，得到无色油状液体产物1.8g,产率41.0％。The compound 2-bromo-6-(methoxymethoxy)pyridine (3g, 13.76mmol), 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)ethyl acetate (5.69g, 9.24mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (0.02g, 0.03 mmol), potassium carbonate (0.15g, 1.10mmol) was added to 1,4-dioxane (100mL) and water (25mL). The reaction solution was stirred at 85°C overnight. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v/v) = 5:1) to obtain 1.8 g of colorless oily liquid product with a yield of 41.0%.
LC-MS(ESI):[M+1]+＝320.2；LC-MS(ESI): [M+1] + =320.2;
1HNMR(400MHz,DMSO-d6)δ8.01–7.81(m,2H),7.51–7.43(m,1H),7.31–7.20(m,2H),6.95–6.84(m,1H),5.57(s,2H),4.16–4.07(q,J＝7.2Hz,2H),3.77(s,2H),3.44(s,3H),1.21(t,J＝7.2Hz,3H). 1 HNMR (400MHz, DMSO-d 6 ) δ8.01–7.81(m,2H),7.51–7.43(m,1H),7.31–7.20(m,2H),6.95–6.84(m,1H),5.57( s,2H),4.16–4.07(q,J＝7.2Hz,2H),3.77(s,2H),3.44(s,3H),1.21(t,J＝7.2Hz,3H).
步骤3：2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙-1-醇的合成Step 3: Synthesis of 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol
将化合物2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙酸乙酯(1.75g,5.48mmol)加入到四氢呋喃(50mL)中，冰浴下缓慢加入氢化铝锂(0.62g,16.44mmol)，继续搅拌2小时。冰浴下缓慢滴加水(5mL)淬灭反应，用乙酸乙酯萃取(100mL×3)，无水硫酸钠干燥，用硅胶柱层析纯化(洗脱剂:PE:EA(v/v)＝3:1)，得到淡绿色固体产物910mg,产率59.9％。Compound 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate ethyl ester (1.75g, 5.48mmol) was added to tetrahydrofuran (50mL) and iced. Lithium aluminum hydride (0.62g, 16.44mmol) was slowly added under the bath, and stirring was continued for 2 hours. Water (5 mL) was slowly added dropwise in an ice bath to quench the reaction, extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE: EA (v/v) = 3:1), 910 mg of light green solid product was obtained, with a yield of 59.9%.
LC-MS(ESI):[M+H]+＝278.2；LC-MS(ESI): [M+H] + =278.2;
1HNMR(400MHz,DMSO-d6)δ7.93–7.80(m,2H),7.47–7.41(m,1H),7.24–7.16(m,2H),6.90–6.82(m,1H),5.56(s,2H),4.71(t,J＝4.0Hz,1H),3.70–3.63(m,2H),3.44(s,3H),2.79(t,J＝8.0Hz,2H). 1 HNMR (400MHz, DMSO-d 6 ) δ7.93–7.80(m,2H),7.47–7.41(m,1H),7.24–7.16(m,2H),6.90–6.82(m,1H),5.56( s,2H),4.71(t,J＝4.0Hz,1H),3.70–3.63(m,2H),3.44(s,3H),2.79(t,J＝8.0Hz,2H).
步骤4:2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛的合成 Step 4: Synthesis of 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde
将化合物2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙-1-醇(0.80g,2.88mmol)加入到二氯甲烷(70mL)中，冰浴下缓慢加入戴斯-马丁氧化剂(2.45g,5.77mmol)，并继续搅拌3小时。加入饱和碳酸氢钠溶液至溶液pH＝8，用二氯甲烷萃取(30ml×3)，无水硫酸钠干燥，用硅胶柱层析纯化(洗脱剂:PE:EA(v/v)＝5:1)，得到淡黄色油状液体410mg，产率51.6％。Compound 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (0.80g, 2.88mmol) was added to dichloromethane (70mL ), slowly add Dess-Martin oxidant (2.45g, 5.77mmol) under ice bath, and continue stirring for 3 hours. Add saturated sodium bicarbonate solution until the solution pH=8, extract with dichloromethane (30ml×3), dry with anhydrous sodium sulfate, and purify with silica gel column chromatography (eluent: PE:EA (v/v)=5 :1), 410 mg of light yellow oily liquid was obtained, with a yield of 51.6%.
LC-MS(ESI):[M+H]+＝276.2。LC-MS (ESI): [M+H] + =276.2.
步骤5:(S)-2-(3-氟-4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物2-(3-氟-4-(6-(甲氧基甲氧基)吡啶-2-基)苯基)乙醛(380mg,1.38mmol)，(S)-5-氨基-4-((氧杂环丁烷-2-基甲基)氨基)噻吩-2-羧酸甲酯(401mg,1.66mmol)加入到醋酸(10mL)中。反应液于60℃下搅拌4小时。减压浓缩，用硅胶柱层析纯化(洗脱剂:DCM:MeOH(v/v)＝20:1)，得到棕色固体产物105mg，产率16.8％。Compound 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (380 mg, 1.38 mmol), (S)-5-amino-4- ((Oxetan-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (401 mg, 1.66 mmol) was added to acetic acid (10 mL). The reaction solution was stirred at 60°C for 4 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent: DCM:MeOH (v/v) = 20:1) to obtain 105 mg of brown solid product with a yield of 16.8%.
LC-MS(ESI):[M+H]+＝454.2；1HNMR(400MHz,DMSO-d6)δ11.71(s,1H),7.95(s,1H),7.64–7.45(m,2H),7.37–7.18(m,2H),6.55–6.33(m,2H),5.01–4.90(m,1H),4.67–4.28(m,5H),3.82(s,3H),2.72–2.57(m,1H),2.37–2.23(m,1H),1.95–1.87(m,1H).LC-MS(ESI): [M+H] + =454.2; 1 HNMR (400MHz, DMSO-d 6 ) δ11.71 (s, 1H), 7.95 (s, 1H), 7.64–7.45 (m, 2H) ,7.37–7.18(m,2H),6.55–6.33(m,2H),5.01–4.90(m,1H),4.67–4.28(m,5H),3.82(s,3H),2.72–2.57(m, 1H),2.37–2.23(m,1H),1.95–1.87(m,1H).
步骤6:(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-3-氟苄基)-1-(氧杂环丁烷-2基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯的合成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
将化合物(S)-2-(3-氟-4-(6-羟基吡啶-2-基)苄基)-1-(氧杂环丁烷-2基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(105mg,0.23mmol)，7-(溴甲基)-4-氯-2-氟-1-苯并呋喃(61mg,0.23mmol)，碳酸钾(96mg,0.69mmol)加入到N,N-二甲基甲酰胺(5mL)中，60℃下搅拌3小时。减压浓缩，用硅胶柱层析纯化(洗脱剂:PE:EA(v/v)＝1:1)，得到棕色固体产物35mg，产率23.8％。Compound (S)-2-(3-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2ylmethyl)-1H-thieno[2 ,3-d]imidazole-5-carboxylic acid methyl ester (105mg, 0.23mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (61mg, 0.23mmol), potassium carbonate (96 mg, 0.69 mmol) was added to N,N-dimethylformamide (5 mL), and stirred at 60°C for 3 hours. Concentrate under reduced pressure and purify using silica gel column chromatography (eluent: PE:EA (v/v) = 1:1) to obtain 35 mg of brown solid product with a yield of 23.8%.
LC-MS(ESI):[M+H]+＝636.1。LC-MS (ESI): [M+H] + =636.1.
步骤7:2-((4-(6-(((4-氯-2-氟-1-苯并呋喃-7-基)甲基)氧基)吡啶-2-基)-3-氟苯基)甲基)-1-(((2S)-氧杂环丁烷-2-基)甲基)噻吩基[2,3-d]咪唑-5-羧酸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
将化合物(S)-2-(4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)-3-氟苄基)-1-(氧杂环丁烷-2基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸甲酯(35mg,0.06mmol)，氢氧化锂(7mg,0.29mmol)加入到1,4-二氧六环(2mL)和水(0.5mL)中，40℃下搅拌2小时。在冰浴下滴加醋酸至pH＝6，减压浓缩，用Pre-HPLC(洗脱剂:ACN:H2O(v/v)＝90％)纯化，得到白色固体产物7.7mg，产率22.5％。Compound (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)-1 -(oxetane-2ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (35mg, 0.06mmol), lithium hydroxide (7mg, 0.29mmol) was added into 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 40°C for 2 hours. Add acetic acid dropwise under an ice bath until pH=6, concentrate under reduced pressure, and purify with Pre-HPLC (eluent: ACN:H 2 O (v/v) = 90%) to obtain 7.7 mg of white solid product, yield 22.5%.
LC-MS(ESI):[M+H]+＝622.1；LC-MS(ESI): [M+H] + =622.1;
1HNMR(400MHz,DMSO-d6)δ12.95(s,1H),7.93–7.78(m,3H),7.51–7.36(m,3H),7.33–7.18(m,2H),6.90(d,J＝8.0Hz,1H),6.52(d,J＝8.0Hz,1H),5.65(s,2H),5.00–4.91(m,1H),4.62–4.53(m,1H)，4.51–4.42(m,2H)，4.40–4.29(m,3H)，2.71–2.58(m,1H)，2.36–2.23(m,1H). 1 HNMR(400MHz, DMSO-d 6 )δ12.95(s,1H),7.93–7.78(m,3H),7.51–7.36(m,3H),7.33–7.18(m,2H),6.90(d, J＝8.0Hz,1H),6.52(d,J＝8.0Hz,1H),5.65(s,2H),5.00–4.91(m,1H),4.62–4.53(m,1H),4.51–4.42(m ,2H), 4.40–4.29(m,3H), 2.71–2.58(m,1H), 2.36–2.23(m,1H).
实验例1体外细胞活性测试Experimental Example 1 In vitro cell activity test
1.材料1.Materials
(1)细胞株(1)Cell line
该细胞由上海药明康德新药开发有限公司构建，见下表1。The cells were constructed by Shanghai WuXi AppTec New Drug Development Co., Ltd., as shown in Table 1 below.
表1
Table 1
(2)试剂见下表2。 (2) See Table 2 below for reagents.
表2
Table 2
(3)仪器见下表3。(3) Instruments are shown in Table 3 below.
表3
table 3
(4)化合物信息(4)Compound information
用DMSO将化合物配制为100μM或10μM的工作浓度化合物溶液。做10个点4倍稀释(稀释后最高浓度为1000nM或100nM)，自动移液工作站完成稀释。Prepare compounds in DMSO to a working concentration compound solution of 100 μM or 10 μM. Make 10 points of 4-fold dilution (the highest concentration after dilution is 1000nM or 100nM), and the automatic pipetting workstation completes the dilution.
2.方法2.Method
(1)实验材料(1) Experimental materials
实验缓冲液见下表4。The experimental buffer is shown in Table 4 below.
表4
Table 4
检测试剂制备的终浓度见下表5。The final concentration of the detection reagent preparation is shown in Table 5 below.
表5
table 5
(2)实验方法 (2) Experimental methods
(a)配制化合物板：(a) Prepare compound plate:
待测化合物做10个点4倍稀释，起始浓度为100μM，自动移液工作站完成稀释The compound to be tested is diluted 10 times 4 times, with a starting concentration of 100 μM, and the automatic pipetting workstation completes the dilution.
(b)转移化合物：(b) Transfer compound:
(i)使用液体处理仪转移100nL 100x化合物至384孔板。(i) Use a liquid handler to transfer 100 nL of 100x compound to a 384-well plate.
(ii)将384孔板在1000rpm离心5秒。(ii) Centrifuge the 384-well plate at 1000 rpm for 5 seconds.
(c)细胞悬液的制备(c) Preparation of cell suspension
(i)将一支高表达hGLP-1R的HEK293细胞冻存管迅速置于37℃温水中解冻。(i) Quickly thaw a cryovial of HEK293 cells that highly express hGLP-1R in warm water at 37°C.
(ii)将细胞悬液转移至15mL离心管中，用10mL HBSS轻柔冲洗。(ii) Transfer the cell suspension to a 15mL centrifuge tube and rinse gently with 10mL HBSS.
(iii)将离心管在1000rpm室温离心1分钟。(iii) Centrifuge the tube at 1000 rpm for 1 minute at room temperature.
(iv)弃去上清。(iv) Discard the supernatant.
(v)再用10ml HBSS轻柔冲洗，离心沉降细胞，最后用实验缓冲液重悬细胞。(v) Wash gently with 10ml HBSS, centrifuge to sediment the cells, and finally resuspend the cells in experimental buffer.
(vi)利用细胞计数仪测量细胞密度与活度。(vi) Use a cell counter to measure cell density and activity.
(vii)用实验缓冲液将GLP-1R细胞浓度稀释至1.0*105/mL。(vii) Dilute the GLP-1R cell concentration to 1.0*10 5 /mL with experimental buffer.
(viii)在384孔板中转入10μL稀释好的细胞悬液。(viii) Transfer 10 μL of diluted cell suspension into a 384-well plate.
(ix)室温孵育30分钟。(ix) Incubate at room temperature for 30 minutes.
(d)检测：(d) Testing:
(i)在384孔板空孔中加入10μL 800nM梯度稀释好的cAMP标准品。(i) Add 10 μL of 800 nM gradient diluted cAMP standard into the empty wells of the 384-well plate.
(ii)加入10μL cAMP检测试剂。(ii) Add 10μL cAMP detection reagent.
(iii)室温孵育60分钟后，在酶标仪读数。(iii) After incubating at room temperature for 60 minutes, read on a microplate reader.
结果参见表1，表1为本发明部分实施例提供的化合物的激动作用(EC50)。The results are shown in Table 1. Table 1 shows the agonistic effects (EC 50 ) of the compounds provided in some examples of the present invention.
表1.本发明部分实施例提供的化合物的激动作用实验结果
Table 1. Experimental results of agonistic effects of compounds provided in some examples of the present invention
结果与讨论：本发明的化合物表现出较优的对GLP-1受体的激动能力。Results and Discussion: The compounds of the present invention showed superior agonistic ability on GLP-1 receptors.
实验例2：本发明化合物小鼠药代动力学研究Experimental Example 2: Study on the pharmacokinetics of the compound of the present invention in mice
1、实验材料1. Experimental materials
C57BL/6小鼠：雄性，6-8周龄，体重20-30克，购自维通利华(北京)实验动物科技有限公司。C57BL/6 mice: male, 6-8 weeks old, weighing 20-30 grams, purchased from Vitong Lever (Beijing) Experimental Animal Technology Co., Ltd.
试剂：色谱级乙腈购自于Thermo Fisher Scientific公司，色谱级甲酸购自于迪科马公司，实验用水为超纯水，其余试剂均为市售分析纯。 Reagents: 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.
仪器：AB LCMS-5500串联质谱仪Instrument: AB LCMS-5500 tandem mass spectrometer
2、实验方法2. Experimental methods
称取化合物溶于10％DMSO/5％Kolliphor-EL/85％HP-β-CD(20％)或其它适当体系中，制剂均呈澄清溶液，小鼠静脉或灌胃给药，于给药后5min、15min、30min、1h、2h、4h、6h、8h、24h采集血样。将每个PK采样点采全血30μL至EDTA-K2抗凝采血管中30min内于4℃离心取血浆。离心前全血样品置于湿冰上。所有采集的血浆样品保存在干冰上或冷冻保存中直至分析检测。Weigh the compound and dissolve it in 10% DMSO/5% Kolliphor-EL/85% HP-β-CD (20%) or other appropriate systems. The preparations are in the form of clear solutions. The mice are administered intravenously or intragastrically. Blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h later. Collect 30 μL 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.
称取约1mg的化合物溶解于DMSO中，涡旋并超声，获得1mg/mL标准储备溶液。将标准储备溶液用50％乙腈水溶液稀释，得到浓度为5、10、20、50、100、500、1000、5000和10000ng/mL的标准工作溶液。用相同的稀释方法制备浓度为10、20、500和8000ng/mL的质控工作液。3μL浓度为(5、10、20、50、100、500、1000、5000和10000ng/mL)的标准工作液加入30μL空白C57BL/6小鼠血浆中，获得总体积为33μL，浓度为0.5-1000ng/mL(0.5、1、2、5、10、50、100、500、1000ng/mL)的标准曲线样品。浓度为(1ng/ml(低-1)和2ng/ml(低-2)、50ng/ml(中)、800ng/ml(高))的质控样品另外配置。Weigh about 1 mg of the compound and dissolve it in DMSO, vortex and sonicate to obtain a 1 mg/mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile aqueous solution to obtain standard working solutions with concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL. Use the same dilution method to prepare quality control working solutions with concentrations of 10, 20, 500 and 8000ng/mL. 3 μL of standard working solution with concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL) was added to 30 μL of blank C57BL/6 mouse plasma to obtain a total volume of 33 μL and a concentration of 0.5-1000ng. /mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000ng/mL) standard curve samples. Quality control samples with concentrations of (1ng/ml (low-1), 2ng/ml (low-2), 50ng/ml (medium), and 800ng/ml (high)) are separately prepared.
33μL标准样品、33μL质控样品或33μL未知样品(30μL血浆和3μL空白溶液)加入200μL含内标(地塞米松)的乙腈沉淀蛋白。然后样品涡旋30秒，在4000g，4℃下离心15分钟后，取上清用水稀释3倍，10μL上清稀释液注入LC-MS/MS系统进行定量分析，检测条件如下：Add 200 μL of acetonitrile containing internal standard (dexamethasone) to precipitate protein to 33 μL of standard sample, 33 μL of quality control sample, or 33 μL of unknown sample (30 μL of plasma and 3 μL of blank solution). Then the sample was vortexed for 30 seconds, centrifuged at 4000g and 4°C for 15 minutes, the supernatant was diluted 3 times with water, and 10 μL of the supernatant dilution was injected into the LC-MS/MS system for quantitative analysis. The detection conditions are as follows:
色谱柱:Raptor Biphenyl 2.7μm 2.1×50mmColumn: Raptor Biphenyl 2.7μm 2.1×50mm
流动相:溶液A:100％水(0.1％甲酸)；溶液B:95％乙腈(0.1％甲酸，5％水)，按下表进行梯度洗脱。
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.
3、数据处理3. Data processing
使用Phoenix TM软件的非房室模型进行药代动力学数据分析。Using Phoenix TM The software's noncompartmental model performs pharmacokinetic data analysis.
结果与讨论：本发明化合物在小鼠口服吸收较好，具有较高的暴露量和生物利用度。Results and discussion: The compound of the present invention is well absorbed orally in mice, with high exposure and bioavailability.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。 In the description of this specification, reference 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.

Claims (12)

  1. 一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvent of a compound represented by formula (I) compounds, metabolites, pharmaceutically acceptable salts or prodrugs,
    其中：in:
    X为N或CR16；X is N or CR 16 ;
    Y为O或S；Y is O or S;
    R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基、C1-6烷氨基、C1-6卤代烷氧基或-C1-6亚烷基-C1-6烷氧基；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;
    R3为H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基或-C1-6亚烷基-R15，所述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基和-C1-6亚烷基-R15可独立任选地被1、2或3个R3a取代；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 ;
    R15为C3-6环烷基、3-8元杂环基或5-10元杂芳基；R 15 is C 3-6 cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl;
    R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基或3-6元杂环基，所述C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基和3-6元杂环基可独立任选地被1、2或3个R3b取代；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 ;
    R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氨基、C3-6环烷基或3-6元杂环基；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;
    R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    环B为5-6元杂环基、苯基或5-6元杂芳基；Ring B is a 5-6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl;
    各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基或C1-6烷基，所述C1-6烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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为0、1、2、3、4、5、6、7或8。n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  2. 根据权利要求1所示的化合物，其具有式(II)、式(III)、式(IV)或式(V)所示结构：
    The compound according to claim 1, which has a structure represented by formula (II), formula (III), formula (IV) or formula (V):
  3. 根据权利要求1或2所述的化合物，其中R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3羟基烷基、C1-3氨基烷基、C1-3烷氧基、C1-3烷氨基、C1-3卤代烷氧基或-C1-3亚烷基-C1-3烷氧基；The compound according to claim 1 or 2, wherein R 2 is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, 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;
    R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基或C1-3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基或C1-3烷基，所述C1-3烷基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代。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.
  4. 根据权利要求1-3任意一项所述的化合物，其中R2为氢、氘、F、Cl、Br、I、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、羟基甲基、羟基乙基、氨甲基、氨乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、N-甲氨基、N-乙氨基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、-CH2OCH3、-CH2OCH2CH3、-CH2CH2OCH3或-CH2CH2OCH2CH3；The compound according to any one of claims 1-3, wherein R2 is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, Isopropyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , hydroxymethyl, hydroxyethyl, aminomethyl, amino Ethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -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 or -CH 2 CH 2 OCH 2 CH 3 ;
    R4、R5、R8和R9各自独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    各Rb独立地为H、D、F、Cl、Br、I、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代；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;
    R6、R7、R10、R11、R12、R13、R14和R16各自独立地为H、D、F、Cl、Br、I、羟基、氰基、硝基、甲基、乙基、正丙基或异丙基，所述甲基、乙基、正丙基和异丙基可独立任选地被1、2或3个F、Cl、Br、I、羟基、氰基、氨基或硝基取代。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.
  5. 根据权利要求1-4任意一项所述的化合物，其中R3为H、C1-3烷基、C2-3烯基、C2-3炔基、C3-6环烷基、3-6元杂环基或-C1-3亚烷基-R15，所述C1-3烷基、C2-3烯基、C2-3炔基、C3-6环烷基、3-6元杂环基和-C1-3亚 烷基-R15可独立任选地被1、2或3个R3a取代；The compound according to any one of claims 1-4, wherein R 3 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 sub- Alkyl-R 15 may be independently optionally substituted by 1, 2 or 3 R 3a ;
    R15为C3-6环烷基、3-6元杂环基或5-10元杂芳基；R 15 is C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;
    R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C3-6环烷基或5-6元杂环基，所述C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C3-6环烷基和5-6元杂环基可独立任选地被1、2或3个R3b取代；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 ;
    R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、C5-6环烷基或5-6元杂环基。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.
  6. 根据权利要求1-5任意一项所述的化合物，其中R3为H、甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基或-CH2R15，所述甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、乙炔基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基和-CH2R15可独立任选地被1、2或3个R3a取代；The compound according to any one of claims 1-5, wherein R3 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1- Propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or -CH 2 R 15 , The methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and -CH 2 R 15 can be independently optionally substituted by 1, 2 or 3 R 3a ;
    R15为环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、 R 15 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, morpholinyl,
    R3a为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基，所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基可独立任选地被1、2或3个R3b取代；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, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl and morpholinyl can be independently optionally substituted by 1, 2 or 3 R 3b ;
    R3b为D、F、Cl、Br、I、CN、羟基、氧代、氨基、硝基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、N-甲氨基、N-乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基。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 .
  7. 根据权利要求1-6任意一项所述的化合物，其中R3为H、 The compound according to any one of claims 1-6, wherein R 3 is H,
  8. 根据权利要求1-7任意一项所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的 盐或它的前药：

    The compound according to any one of claims 1 to 7, which is a compound with one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxidation compound of a compound with one of the following structures substances, hydrates, solvates, metabolites, pharmaceutically acceptable Salt or its prodrug:

  9. 一种药物组合物，包含权利要求1-8任意一项所述的化合物；所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。A pharmaceutical composition comprising the compound of any one of claims 1 to 8; the pharmaceutical composition optionally further comprises pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof.
  10. 权利要求1-8任意一项所述的化合物或者权利要求9所述的药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻患者GLP-1受体激动剂介导的疾病。The use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of medicines for preventing, treating or alleviating GLP-1 receptor agonist-mediated symptoms in patients disease.
  11. 根据权利要求10所述的用途，其中，所述GLP-1受体激动剂介导的疾病为糖尿病、非酒精性脂肪肝 病或肥胖。The use according to claim 10, wherein the disease mediated by the GLP-1 receptor agonist is diabetes, non-alcoholic fatty liver disease disease or obesity.
  12. 根据权利要求11所述的用途，其中，所述糖尿病为I型糖尿病、II型糖尿病、妊娠糖尿病、特发性I型糖尿病、早发型II型糖尿病、青年人的成年型糖尿病、青少年发作的非典型糖尿病、营养不良相关性糖尿病或成人隐匿性自身免疫性糖尿病。 The use according to claim 11, wherein the diabetes is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, adult-onset diabetes of the young, adolescent-onset SARS. Type 2 diabetes, malnutrition-related diabetes, or latent autoimmune diabetes in adults.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020263695A1 (en) * 2019-06-28 2020-12-30 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
WO2021081207A1 (en) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Glp-1r modulating compounds
WO2021112538A1 (en) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Glp-1 receptor agonist
CN113480534A (en) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 Benzimidazole or azabenzimidazole-6-carboxylic acid compounds and application thereof
CN113853371A (en) * 2019-04-12 2021-12-28 上海齐鲁锐格医药研发有限公司 GLP-1R agonists and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113853371A (en) * 2019-04-12 2021-12-28 上海齐鲁锐格医药研发有限公司 GLP-1R agonists and uses thereof
WO2020263695A1 (en) * 2019-06-28 2020-12-30 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
WO2021081207A1 (en) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Glp-1r modulating compounds
WO2021112538A1 (en) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Glp-1 receptor agonist
CN113480534A (en) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 Benzimidazole or azabenzimidazole-6-carboxylic acid compounds and application thereof

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