WO2022068772A1 - Benzimidazole derivative, and preparation method therefor, and medical use thereof - Google Patents

Benzimidazole derivative, and preparation method therefor, and medical use thereof Download PDF

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Publication number
WO2022068772A1
WO2022068772A1 PCT/CN2021/120978 CN2021120978W WO2022068772A1 WO 2022068772 A1 WO2022068772 A1 WO 2022068772A1 CN 2021120978 W CN2021120978 W CN 2021120978W WO 2022068772 A1 WO2022068772 A1 WO 2022068772A1
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Prior art keywords
methyl
mmol
oxetan
benzo
ylmethyl
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PCT/CN2021/120978
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French (fr)
Chinese (zh)
Inventor
吴俊军
陆银锁
肖瑛
周鹏
滕耀辉
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深圳信立泰药业股份有限公司
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Priority to CN202180030750.1A priority Critical patent/CN115515956B/en
Publication of WO2022068772A1 publication Critical patent/WO2022068772A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of chemical medicine, and provides a series of agonists of glucagon-like peptide-1 receptor (GLP-1R).
  • GLP-1R glucagon-like peptide-1 receptor
  • the present invention also relates to pharmaceutical compositions containing these compounds and the use of the compounds in medicines for treating diseases such as diabetes.
  • Diabetes affects millions of people worldwide and is considered one of the major threats to human mortality in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. Worldwide, the socioeconomic burden of diabetes is high.
  • Type I diabetes is characterized by insulin deficiency, mainly caused by autoimmune-mediated destruction of islet beta cells
  • type II diabetes is characterized by abnormal insulin secretion and consequent insulin resistance.
  • To prevent ketoacidosis patients with type 1 diabetes must take exogenous insulin to survive.
  • type II diabetics are not as dependent on exogenous insulin as type I diabetics, they may require exogenous insulin to control blood sugar levels.
  • GLP-1 Glucagon-like peptide-1
  • GLP-1R GLP-1 receptor
  • GLP-1R GLP-1 receptor
  • GLP-1 receptor agonist is a new type of hypoglycemic drug, which can not only effectively control blood sugar level without causing hypoglycemia, but also increase satiety, delay gastric emptying, suppress appetite and reduce fat. Accumulation, etc., effectively reduce body weight and achieve the purpose of weight loss.
  • GLP-1 receptor agonist-based polypeptide drugs liraglutide, exenatide, semaglutide, etc. have been applied to obese type II diabetic patients and simple obesity or overweight patients, all showing Significantly reduce body weight, but often accompanied by nausea, vomiting and other gastrointestinal adverse reactions.
  • Oral non-peptide drugs have always been tried by research institutions for the treatment of type II diabetes and weight loss.
  • the glucagon-like peptide-1 receptor small molecule drugs are limited. 's discovery.
  • the present invention aims to discover new non-polypeptide GLP-1 receptor agonists, especially new compounds with good biological properties that can be safely applied to the human body, and the present invention also provides for prevention and/or The tools needed to treat GLP-1 related diseases, especially diabetes related diseases.
  • the invention provides a series of benzimidazole derivatives, their preparation method and their application in medicine.
  • the present invention provides compounds of formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein all variables are as defined herein.
  • GLP-1 R glucagon-like peptide 1 receptor
  • the present invention realizes through the following technical solutions:
  • A is selected from 8-10-membered fused aromatic rings
  • R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
  • n 0, 1, 2 or 3;
  • W is O or NH
  • R 2 is selected from hydrogen, halogen, cyano
  • R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
  • q 0, 1, 2;
  • XL is selected from N- CH2 , CHCH2 , or cyclopropyl
  • Y is CH or NH
  • R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituents of -C 0-1 alkylene-OR O and -N(R N ) 2 , wherein the alkylene and cycloalkyl groups can be independently selected from 0 to 2 when the valence allows Substituent from 0 to 2 F atoms or substituted with 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O and -N(R N ) 2 base substitution;
  • R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
  • R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
  • alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
  • Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
  • each R N is independently H or -C 1-3 alkyl
  • Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
  • R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
  • R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
  • A is selected from 8-10-membered fused aromatic rings
  • R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
  • n 0, 1, 2 or 3;
  • W is O or NH
  • R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
  • q 0, 1, 2;
  • XL is selected from N- CH2 , CHCH2 , or cyclopropyl
  • Y is CH or N
  • R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituent substitution of -C 0-1 alkylene-OR O or -N(R N ) 2 , and the alkylene and cycloalkyl groups described therein may be independently replaced by 0 to 2 when the valence allows Substituents selected from 0 to 2 F atoms or through 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O or -N(R N ) 2 Substituent substitution;
  • R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
  • R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
  • alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
  • Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
  • each R N is independently H or -C 1-3 alkyl
  • Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
  • R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
  • R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
  • the alkyl group refers to a branched, unbranched and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms, preferably an alkyl group selected from C 1-6 , the C 1 -6
  • the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl , 2-methylbutyl, tert-amyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl base, 1,2-dimethylbutyl, 1-ethylbutyl.
  • the alkoxy group refers to an alkyl ether radical, preferably from a C 1-6 alkoxy group, and the C 1-6 alkoxy group is selected from methoxy, ethyl Oxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-amyloxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy group, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy.
  • the alkoxyalkyl group means that one or more hydrogen atoms of the alkyl group are substituted by an alkoxy group, preferably an alkyl group selected from C 1-4 alkoxy C 1-4 , and further selected from Methoxymethyl, Methoxyethyl, Methoxypropyl, Methoxybutyl, Ethoxymethyl, Ethoxyethyl, Ethoxypropyl, Ethoxybutyl, Propoxymethyl, Propoxyethyl, Propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, etc.
  • the halogen is selected from fluorine, chlorine, bromine and iodine
  • haloalkyl means that one or more hydrogen atoms of an alkyl group are replaced by halogen
  • haloalkoxy means that one or more hydrogen atoms of an alkoxy group are replaced by halogen
  • hydroxyalkyl means that more than one hydrogen atom of an alkyl group is replaced by a hydroxyl group
  • heterocycloalkyl means that more than one hydrogen atom of an alkyl group is replaced by a heterocyclic ring
  • cycloalkanemethylene means that one or more hydrogen atoms of an alkyl group are replaced by a heterocyclic ring. Cycloalkane substitution.
  • the fused aromatic ring is selected from naphthalene or a fused aromatic heterocyclic ring
  • the fused aromatic heterocyclic ring refers to an aromatic ring or a heteroaromatic ring and a heteroaromatic ring fused
  • the heteroaromatic ring is fused.
  • the heteroatom on the aromatic ring is selected from nitrogen, oxygen and sulfur, and the heteroatom is one or more.
  • the fused aromatic heterocycle is selected from indazole, quinoline, isoquinoline, quinoxaline, indole, isoindole, cinnoline, quinazoline, phthalazine, purine, Naphthyridine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole , benzotriazine, benzimidazole, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine, pyrazinotriazine, pyrimidopyrazole, pyrimidazole, pyrimidotriazole, pyrimidotriazine azine, pyrimidopyridazine, pyridazine, pyrida
  • the naphthyridine is selected from The pyridoimidazole is selected from The pyrazinimidazole is selected from The pyrazinotriazole is selected from The pyrimidopyrazole is selected from The pyrimimidazole is selected from The pyrimidotriazole is selected from The pyridazinimidazole is selected from The pyridazinotriazole is selected from The triazineimidazole is selected from The pyridopyridazine is selected from The pyridopyrazole is selected from The pyridopyrimidine is selected from The pyridotriazine is selected from The pyrimidotriazine is selected from
  • the heterocycle of the heterocycloalkyl is selected from 4- to 10-membered heterocycles, and the 4- to 10-membered heterocycles are selected from
  • the aryl group is selected from phenyl; the heteroaryl group is selected from the 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group is selected from
  • the "alkylene group” means that the alkyl group can be independently substituted by 0 to 2 substituents when the valence allows.
  • the "heterocycle” refers to a saturated or unsaturated heterocycle containing one or more heteroatoms (nitrogen, oxygen, sulfur);
  • the "aromatic ring” is a Refers to a benzene ring;
  • the "heteroaromatic ring” refers to a heterocyclic ring with a closed conjugated system of 4n+2 ⁇ electrons, such as furan, thiophene, tetrahydropyrrole, dihydropyrazole, imidazole, thiazole, isotope Thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, piperidine, piperazine, pyridazine, pyrazine, triazine, pyrimidine, morpholine or pyridine, etc.; the multiple refers to two, three one, or four.
  • the cycloalkane is selected from C 3-6 cycloalkane, and the C 3-6 cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the A is selected from
  • the compound or its stereoisomer, tautomer and pharmaceutically acceptable salt wherein: the A is selected from
  • R 1 is selected from hydrogen, cyano, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxyethyl, difluoromethyl, trifluoromethyl, oxetan-3-yl , fluorine, chlorine, 2,2-difluoroethyl, 2-fluoroethyl, trifluoroethyl, cyanomethyl, cyclopropylmethyl, 2-methoxy-2-oxoethyl, oxygen Hetidine-3-ylmethyl,
  • R 2 is hydrogen
  • R 3 is methyl
  • R 4 is oxetan-2-ylmethyl
  • XL is selected from N- CH2 , CHCH2 , or cyclopropyl
  • W is O
  • Y is CH or N
  • Z 1 is CH or N
  • Z 2 is CH, CF or N
  • Z 3 is CH, CF or N.
  • the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the pharmaceutically acceptable salt refers to the preparation of a compound with a pharmaceutically acceptable acid or base.
  • more than one hydrogen atom of the compound is substituted with the isotope deuterium.
  • Another object of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt and more than one pharmaceutically acceptable compound thereof a.
  • Another object of the present invention is to provide the compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, in the preparation of pharmaceutical use for the preparation of treatment of GLP-1 related diseases , in particular, relates to the pharmaceutical use of diabetes-related diseases.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound of the present invention having a specified substituent and a pharmaceutically acceptable acid or base.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the atoms of the molecules of the compounds of the present invention are isotopes, and the isotope derivatization can usually prolong the half-life, reduce the clearance rate, stabilize the metabolism and improve the activity in vivo. Also, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (sum of protons and neutrons).
  • isotopes included in the compounds of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
  • radioisotopes that emit radiation as they decay such as 3 H or 14 C, are useful in the topological examination of pharmaceutical formulations or compounds in vivo. Stable isotopes neither decay or change with their amount nor are they radioactive, so they are safe to use.
  • the isotopes can be converted according to general methods by substituting the reagents used in the synthesis with reagents containing the corresponding isotopes.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • one or more hydrogen atoms of the compounds of the present invention are substituted by the isotope deuterium ( 2 H).
  • the compounds of the present invention After deuteration, the compounds of the present invention have the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.
  • the preparation methods of the isotopic derivatives generally include: a phase transfer catalysis method.
  • a preferred deuteration method employs a phase transfer catalyst (eg, tetraalkylammonium salts, NBu4HSO4 ) .
  • the methylene protons of diphenylmethane compounds are exchanged using a phase transfer catalyst, resulting in higher ratios than with deuterated silanes (eg, triethyldeuterated silane) or with Lewis acids such as trichloro in the presence of an acid (eg, methanesulfonic acid) Aluminium is reduced with sodium deuteroborate to introduce higher deuterium.
  • pharmaceutically acceptable carrier refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient
  • representative carriers include water, oil , vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like.
  • Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
  • HPLC High performance liquid chromatography
  • CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Yinlong HSGF 254 or GF 254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.17mm ⁇ 0.23mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
  • Reagents LDA-lithium diisopropylamide, THF-tetrahydrofuran, TEA-triethylamine, Dioxane-1,4-dioxane, BH3-borane, EDCl-1-ethyl-( 3 -dimethylamine) aminopropyl)carbodiimide hydrochloride, HOBT-1-hydroxybenzotriazole, DIPEA-N,N-diisopropylethylamine, DMF-N,N-dimethylformamide, K 2CO3 - potassium carbonate, DMSO-dimethylsulfoxide, EtOH -ethanol, NaH-sodium hydride, toluene-toluene, rt-room temperature, PdCl2 (dppf)-[1,1'-bis(diphenylphosphine) base)ferrocene]palladium dichloride, Pd(OAc)2-palladium acetate,
  • abs refers to absolute configuration, absolute configuration.
  • Step A Synthesis of tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
  • tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (150.3 mg, 0.5 mmol), (1-methyl-1H-indazol-6-yl) Methanol (98.3 mg, 0.6 mmol), cesium carbonate (260.2 mg, 0.8 mmol) were dissolved in dry dioxane (10 mL) and protected by nitrogen replacement three times.
  • Tridibenzylideneacetone dipalladium (22.4 mg, 25.1 micromoles) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (12.2 mg, 25.3 micromoles) were then added and again flushed with nitrogen Replace three protections. The temperature was raised to 90 degrees Celsius and the reaction was refluxed overnight.
  • reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure.
  • the mixture was diluted with water (50 mL), the aqueous layer was extracted with ethyl acetate (30 mL ⁇ L), washed with saturated brine (50 mL ⁇ L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Step B Synthesis of 1-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
  • tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (120.4 mg, 284.1 Micromolar) was dissolved in 4 mol per liter of ethyl acetate solution of hydrochloric acid (10 ml), stirred for 1 hour, and gradually a white solid was precipitated.
  • Step C Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester
  • reaction solution was diluted with water (80 mL), the aqueous layer was extracted with ethyl acetate (50 mL ⁇ L), washed with saturated brine (50 mL ⁇ L), and then dried over anhydrous sodium sulfate. , and finally concentrated under reduced pressure.
  • Step D Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step B (S)-Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate
  • Step C Synthesis of 1-((4-(methoxycarbonyl)-2-(((S)-oxetan-2-ylmethyl)amino)phenyl)carbamoyl)-6-azaspiro [2.5]octane-6-carboxylate tert-butyl ester
  • reaction solution was diluted with ethyl acetate (150 mL), washed with water (30 mL ⁇ L), washed with saturated brine (30 mL ⁇ L), then dried with anhydrous sodium sulfate, and finally reduced pressure concentrate.
  • Step D Synthesis of 2-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate methyl ester
  • reaction solution was cooled to room temperature, diluted with water (100 mL), the aqueous layer was extracted with ethyl acetate (50 mL ⁇ L), the organic layers were combined, and then washed with saturated aqueous sodium carbonate (50 mL). ⁇ liters), washed with saturated brine (50 ml ⁇ liters), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Step E Synthesis of 1-((S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole -6-Carboxylic acid methyl ester
  • Step F Synthesis of 1-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl)-1H-indazole
  • Step G Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step H Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5.
  • Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL ⁇ L), the organic layers were combined, washed with saturated brine (25 mL ⁇ L), then dried over anhydrous sodium sulfate, and finally reduced pressure concentrate.
  • Methyl 2-methyl-2H-indazole-6-carboxylate (300.0 mg, 1.6 mmol) was dissolved in dry tetrahydrofuran (10 mL) solution under ice-bath conditions and nitrogen purged three times. Under nitrogen, lithium aluminum tetrahydride (121.6 mg, 3.2 mmol) was added in portions.
  • reaction solution was continued to stir for 1 hour under ice bath conditions. After the reaction was completed, 1N aqueous sodium hydroxide solution was added dropwise to quench the reaction. After stirring for 15 minutes, it was filtered through celite. The obtained filtrate was diluted with ethyl acetate (150 mL), washed with water (30 mL ⁇ L), saturated brine (30 mL ⁇ L), and then washed with anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure.
  • Step B Synthesis of 2-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-2H-indazole
  • Step C Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step D Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5.
  • Water (30 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (50 mL ⁇ L), the organic phases were combined and washed with saturated brine (25 mL ⁇ L), then dried over anhydrous sodium sulfate, and finally reduced pressure concentrate.
  • Step A Synthesis of 1-methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-1H-indazole
  • Step B Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step C Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5.
  • Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL ⁇ L), washed with saturated brine (25 mL ⁇ L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Methyl 2-methyl-2H-indazole-5-carboxylic acid methyl ester (300.0 mg, 1.6 mmol) was dissolved in dry tetrahydrofuran (10 mL) solution under ice-bath conditions and nitrogen purged three times. Under nitrogen, lithium aluminum tetrahydride (121.6 mg, 3.2 mmol) was added in portions. The resulting reaction solution was further stirred for 1 hour under ice bath conditions.
  • Step B Synthesis of 2-methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-2H-indazole
  • Step C Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)piperidin-2-yl)-6-nitrogen Heterospiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step D Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5.
  • Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL ⁇ L), washed with saturated brine (25 mL ⁇ L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Step B Synthesis of (S)-2-methyl-4-(2-(((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine-1- tert-butyl formate
  • Step C Synthesis of (S)-1-methyl-6-((((4-(3-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)methyl)-1H-indazole
  • Step D Synthesis of 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine -1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step E Synthesis of 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine -1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[ 2.5] Octan-1-yl)-1-((((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester
  • Imidazo[1,2-a]pyridin-6-ylmethanol (23mg, 0.155mmol) was dissolved in 5ml of anhydrous N,N-dimethylformamide, and 60% sodium hydride (10mg, 0.25 mmol) was stirred for 10 minutes and then 1-((((S)-oxetan-2-yl)methyl)-2-(6-(6-(3,5,6-trifluoropyridine- 2-yl)-6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (75 mg, 0.155 mmol) in 3 mL of N,N-dicarbonate The methylformamide solution was continued to react for 2 hours at zero degrees Celsius.
  • Step B Synthesis of 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • the reaction was completed, diluted with water, then extracted with dichloromethane (20 mL ⁇ L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL ⁇ L), then dried with anhydrous sodium sulfate, and finally reduced.
  • Step B Synthesis of 2-(-6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)methoxy)pyrimidin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step C Synthesis of 2-(-6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)methoxy)pyrimidin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step B Synthesis of 4-(4-Fluoro-3-hydroxyphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate tert-butyl ester
  • Step C Synthesis of tert-butyl 4-(4-fluoro-3-hydroxyphenyl)piperidine-1-carboxylate
  • Step D Synthesis of tert-butyl 4-(4-fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidine-1-carboxylate
  • tert-butyl 4-(4-fluoro-3-hydroxyphenyl)piperidine-1-carboxylate (396.8 mg, 1.3 mmol) and 6-(bromomethyl)-1-methyl-1H -Indazole (438.7 mg, 1.9 mmol) was dissolved in N,N-dimethylformamide (4 mL) and anhydrous potassium carbonate (542.1 mg, 3.9 mmol) was added. The reaction solution was stirred at room temperature for 6 hours.
  • Step E Synthesis of 6-((2-Fluoro-5-(piperidin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole
  • Step F Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl ) methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • reaction solution was reacted at room temperature for 6 hours, diluted with ethyl acetate (150 mL), washed with water (30 mL ⁇ 2 times), saturated brine (30 mL ⁇ 1 time), and then washed with anhydrous sodium sulfate It was dried and finally concentrated under reduced pressure.
  • Step G Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl ) methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of tert-butyl 4-(6-(((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
  • tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate 150.0 mg, 0.50 mmol
  • (2-methylquinolin-6-yl)methanol 130.0 mg , 0.75 mmol
  • cesium carbonate 326.0 mg, 1.00 mmol
  • dioxane 5.0 mL
  • 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl 47.0 mg, 0.1 mmol
  • tris(dibenzylideneacetone)dipalladium 46.0 mg, 0.05 mmol
  • Step B Synthesis of 2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
  • tert-butyl 4-(6-(((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (67.0 mg, 0.15 mmol)
  • Dioxane hydrochloric acid solution (1.00 mmol/mL, 5 mL) was added, and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of (S)-2-(((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step D Synthesis of (S)-2-((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-2-((4-(6-(((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step B Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • diisopropyl azodicarboxylate 130 mg, 0.65 mmol
  • triphenylphosphine 1500 mg, 5.24 mmol
  • 1-methyl-1H-indazol-5-yl 300 mg, 1.85 mmol
  • 5-bromo-2-fluorophenol 386 mg, 2.04 mmol
  • Step B Synthesis of 4-(4-fluoro-3-((1-methyl-1H-indazol-5-yl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxyl tert-butyl acid
  • Step C Synthesis of 5-((2-Fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole
  • Step D Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1Hindazol-5-ylmethoxy)phenyl)-3,6-dihydropyridine- 1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • Step E Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-3,6-di Hydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • reaction solution was diluted with 10 ml of ethyl acetate, poured into water, the pH of the aqueous phase was adjusted to neutrality with saturated ammonium chloride solution, the organic layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid .
  • Step F Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step B Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • the reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL ⁇ L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution.
  • Step A Synthesis of tert-butyl 4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate
  • Step B Synthesis of 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
  • Step C Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinoline-6-methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 2-methylbenzo[d]oxazole-6-carboxylate
  • Methyl 2-methylbenzo[d]oxazole-6-carboxylate 120 mg, 0.67 mmol was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at minus 20 degrees Celsius, lithium aluminum tetrahydrogen (38 mg, 1.0 mmol) was added to the reaction solution, stirred at minus 20 degrees Celsius for 30 minutes, and monitored by LC-MS until the reaction was complete.
  • Step C Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step D Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Dichloromethane (30.0 mL) was added to the reaction solution to dilute, saturated ammonium chloride solution (5.0 mL) was added, the layers were separated, the aqueous phase was extracted three times with dichloromethane (20.0 mL ⁇ 3 times), the organic phases were combined, Dry over sodium sulfate, filter, and concentrate under reduced pressure.
  • Step A Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step B Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • the reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL ⁇ L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL ⁇ L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography.
  • the separation conditions were as follows, column: Agilent 5 Prep-C18 100mm ⁇ 30mm 5 ⁇ M; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 8% acetonitrile at 5.10 minutes come out; detection wavelength: 254nm.
  • Step A Synthesis of (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step B Synthesis of (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • the reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step B Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step B Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of a mixture of methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate
  • methyl 1H-benzo[d]imidazole-5-carboxylate (0.95 g, 5.40 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (0.3 g) was added in portions under nitrogen protection. , 7.60 mmol), stirred for 20 minutes, then slowly added iodomethane (1.53 g, 1.08 mmol) dropwise, heated to 25 degrees Celsius, and stirred for 1 hour.
  • Methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (0.77 g, 4.05 mmol) was dissolved in tetrahydrofuran (10 mL) at zero degrees Celsius, hydrogenated in portions under nitrogen Lithium aluminum (0.77 g, 20.25 mmol), stirred for 1 hour.
  • Step C Synthesis of (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step C Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((quinolin-6-ylmethyl)amino)pyridin-2-yl )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step C Synthesis of (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Methyl 1-methyl-1H-indazole-6-carboxylate (110 mg, 0.56 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring at 0°C for 15 min, deuterated lithium aluminum hydride (42 mg, 1.0 mmol) was added to the reaction solution, stirred at zero degrees Celsius for 30 minutes, and monitored by LC-MS until the reaction was complete.
  • Step B Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy-D2)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step A Synthesis of methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate
  • Methyl 3-bromo-1H-indazole-6-carboxylate (2.50 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (30.0 mL) and potassium carbonate (2.76 g, 20.0 mmol) was added. mol), iodomethane (0.8 mL, 12.0 mmol) was added to the reaction solution, and after stirring at room temperature for 18 hours, TLC was monitored until the reaction was complete.
  • Step B Synthesis of methyl 3-cyclopropyl-1-methyl-1H-indazole-6-carboxylate
  • Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate 500 mg, 1.86 mmol was dissolved in 1,4-dioxane (20.0 mL) and water (5.0 mL) , followed by cyclopropylboronic acid (300 mg, 3.49 mmol), potassium carbonate (550 mg, 3.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (150 mg, 0.20 mmol) was added to the reaction solution, and after nitrogen protection, stirred at 100 degrees Celsius for 16 hours, and monitored by LC-MS until the reaction was complete.
  • Step D Synthesis of (S)-2-((4-(6-((3-cyclopropyl-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step A Synthesis of methyl 5-fluoro-2-methyl-2H-indazole-6-carboxylate
  • Methyl 5-fluoro-1H-indazole-6-carboxylate 150 mg, 0.77 mmol
  • cesium carbonate 503 mg, 1.54 mmol
  • iodomethane 0.5 mL
  • Methyl 5-fluoro-2-methyl-2H-indazole-6-carboxylate (55 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (50 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour.
  • Step C (S)-2-((4-(6-((5-Fluoro-2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 5-fluoro-1H-indazole-6-carboxylate
  • Step B Synthesis of methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate
  • Methyl 5-fluoro-1H-indazole-6-carboxylate 150 mg, 0.77 mmol
  • cesium carbonate 503 mg, 1.54 mmol
  • iodomethane 0.5 mL
  • Methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate (95 mg, 0.46 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (87 mg, 2.28 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour.
  • Step D (S)-2-((4-(6-((5-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1-acetyl-5-fluoro-1H-indazole-6-carboxylate
  • Methyl 5-amino-2-fluoro-4-methylbenzoate (1.83 g, 10 mmol) was dissolved in chloroform (50 mL), cooled to zero degrees Celsius under an ice bath, and acetic anhydride (2.36 mL) was added dropwise , the reaction temperature was raised to room temperature and stirred for 1 hour, then potassium acetate (0.29 g) and isoamyl nitrite (2.69 mL) were added, and the reaction temperature was raised to 70 degrees Celsius and refluxed for 5 hours.
  • Step B Synthesis of 1-(5-Fluoro-6-(hydroxymethyl)-1H-indazol-1-yl)ethan-1-one
  • Methyl 1-acetyl-5-fluoro-1H-indazole-6-carboxylate 100 mg, 0.42 mmol was dissolved in tetrahydrofuran (2 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (80 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for half an hour.
  • Step C Synthesis of (S)-2-((4-(6-((5-fluoro-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and (S)-2-((4-(6-(((5-fluoro) -2H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d]Imidazole-6-carboxylic acid
  • Step A Synthesis of quinoline-5-methanol
  • quinoline-5-carbaldehyde 100 mg, 0.64 mmol was dissolved in methanol (2 mL), and under nitrogen protection, sodium borohydride (49 mg, 1.28 mmol) was added, and the mixture was stirred for 1 hour.
  • Step B Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step C Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate
  • Methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate (220.0 mg, 0.9 mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature, and tetrahydrofuran was added under ice bath conditions. Lithium aluminum hydride (71.4 mg, 1.9 mmol), reacted for 1.0 hour.
  • Step C Synthesis of (S)-2-((4-(6-((2-(2-(2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((2-(2-(2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • the reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (20 mL ⁇ L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL ⁇ L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography.
  • Step B Synthesis of tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
  • Step C Synthesis of 1-methyl-6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
  • tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (90 mg, 0.21 mmol) was dissolved in 10 ml of methanol solvent, 3 ml of 4M/L hydrochloric acid dioxane solution was added under ice bath, and the reaction was carried out at room temperature for 2 hours.
  • Step D Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step E Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate tert-butyl acid
  • Step C Synthesis of (S)-1-methyl-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
  • Step D Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine -1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step E Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine -1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1-(2-methoxyethyl)-1H-indazole-6-carboxylate and methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate ester
  • Methyl 1-(2-methoxyethyl)-1H-indazole-6-carboxylate (300.0 mg, 1.3 mmol) was dissolved in tetrahydrofuran (8.0 mL) at room temperature, and tetrahydrofuran was added under ice bath conditions. Lithium aluminum hydride (97.2 mg, 2.6 mmol), reacted for 1.0 hour.
  • Step C Synthesis of (S)-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((1-(2-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • the reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL ⁇ L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL ⁇ L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography.
  • Step A Synthesis of methyl 1-isopropyl-1H-indazole-6-carboxylate
  • Methyl 1H-indazole-6-carboxylate (1.0 g, 5.60 mmol) and cesium carbonate (3.6 g, 11.2 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature , and then iodoisopropane (1.0 g, 6.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 h.
  • methyl 1-isopropyl-1H-indazole-6-carboxylate 600 mg, 2.75 mmol was dissolved in tetrahydrofuran (15 mL), cooled to zero degrees Celsius in an ice bath, and tetrahydrofuran was added.
  • Aluminum lithium 500 mg, 13.76 mmol was stirred at room temperature for 0.5 h.
  • Step C (S)-2-((4-(6-((1-isopropyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • isoquinoline-5-carbaldehyde 100 mg, 0.64 mmol was dissolved in methanol (2 mL), sodium borohydride (49 mg, 1.28 mmol) was added under nitrogen protection, and the mixture was stirred for 1 hour.
  • Step B Synthesis of (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step C Synthesis of (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Methyl 1H-indazole-6-carboxylate 200 mg, 1.14 mmol
  • 2-iodopropane 388 mg, 2.28 mmol
  • potassium carbonate 304 mg, 2.28 mmol
  • Step C Synthesis of (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1-(difluoromethyl)-1H-indazole-6-carboxylate
  • methyl 1H-indazole-6-carboxylate 500.0 mg, 2.82 mmol was added to acetonitrile (28.0 mL), followed by ethyl 2-bromo-2,2-difluoroacetate (690.2 mg). , 3.42 mmol), potassium hydroxide (314.6 mg, 5.63 mmol), under the protection of N 2 , at 60 degrees Celsius for 16.0 hours.
  • Step C Synthesis of (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of 1-(oxetan-3-yl)-1H-indazole-6-carboxylate methyl ester
  • Step C Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H-indone azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H-indone azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1,3-dimethyl-1H-indazole-6-carboxylate
  • Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate 500 mg, 1.86 mmol was dissolved in 1,4-dioxane (20.0 mL) and water (5.0 mL) , followed by 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborolane (440 mg, 3.49 mmol), potassium carbonate (550 mg, 3.99 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.20 mmol) was added to the reaction solution, followed by nitrogen protection, stirred at 100 degrees Celsius for 16 hours, and monitored by LC-MS until the reaction is complete.
  • Methyl 1,3-dimethyl-1H-indazole-6-carboxylate 200 mg, 0.98 mmol was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at zero degrees Celsius, lithium aluminum hydride ( 38 mg, 1.0 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
  • Step C Synthesis of (S)-2-((4-(6-((1,3-Dimethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step A Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step B Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1-((3-methyloxetan-3-yl)methyl)-1H-indazole-6-carboxylate
  • Methyl 1H-indazole-6-carboxylate 200 mg, 1.14 mmol
  • 3-(bromomethyl)-3-methyloxetane 225 mg, 1.36 mmol
  • potassium carbonate 304 mg, 2.28 mmol
  • Step B Synthesis of 1-((3-Methyloxetan-3-yl)methyl)-1H-indazole-6-methanol
  • Step C Synthesis of (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methan oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
  • Butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenoneacetone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius , stir for 1 hour.
  • Step D Synthesis of (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methan Oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • 2,5-Difluoro-4-nitrobenzoic acid (1.2 g, 6.0 mmol) was dissolved in 4.0 M potassium hydroxide solution (20.0 mL), stirred at room temperature for 16 hours, and monitored by LC-MS until the reaction was complete.
  • Step B Synthesis of methyl 2-fluoro-5-hydroxy-4-nitrobenzoate
  • Step C Synthesis of methyl 4-amino-2-fluoro-5-hydroxybenzoate
  • Methyl 2-fluoro-5-hydroxy-4-nitrobenzoate (340 mg, 1.60 mmol) was dissolved in methanol (10.0 mL), saturated ammonium chloride solution (4.0 mL) and reducing iron powder ( 560 mg, 10.0 mmol) was added to the reaction solution, stirred at room temperature for 16 hours, and monitored by LC-MS until the reaction was complete.
  • Step D Synthesis of methyl 5-fluoro-2-methylbenzo[d]oxazole-6-carboxylate
  • Methyl 4-amino-2-fluoro-5-hydroxybenzoate (200 mg, 1.1 mmol) was dissolved in triethyl orthoacetate (3.0 mL), stirred at 100 degrees Celsius for 3 hours, and the reaction was monitored by LC-MS completely.
  • Methyl 5-fluoro-2-methylbenzo[d]oxazole-6-carboxylate 210 mg, 1.0 mmol was dissolved in tetrahydrofuran (10.0 mL), and after stirring at 0°C for 15 minutes, the hydrogenated Lithium aluminum (76 mg, 2.0 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
  • Step F Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL ⁇ 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step G Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinoxalin-6-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Step A Synthesis of methyl 1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylate
  • Step B Synthesis of 1-(6-(hydroxymethyl)-1H-indazol-1-yl)-2-methylpropan-2-ol
  • Step C Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
  • Step D Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

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Abstract

A compound related to formula (I), a preparation method therefor, and the use thereof in medicine. Specifically, provided are a compound related to formula (I) or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof. The compounds are agonists of glucagon-like peptide-1 receptors (GLP-1R). The present invention also relates to a pharmaceutical composition comprising the compounds and the use of the compounds in drugs for treating diseases such as diabetes.

Description

一种苯并咪唑类衍生物及其制备方法和医药用途A kind of benzimidazole derivative and its preparation method and medical use 技术领域technical field
本发明属于化学药物技术领域，提供了一系列的胰高血糖样肽-1受体(GLP-1R)的激动剂。本发明还涉及包含这些化合物的药物组合物以及使用该化合物治疗糖尿病等疾病的药物中的用途。The invention belongs to the technical field of chemical medicine, and provides a series of agonists of glucagon-like peptide-1 receptor (GLP-1R). The present invention also relates to pharmaceutical compositions containing these compounds and the use of the compounds in medicines for treating diseases such as diabetes.
背景技术Background technique
糖尿病影响全世界数百万人，被认为是21世纪人类死亡的主要威胁之一。随着时间推移，不被控制的糖尿病能损坏身体系统，包括心脏、血管、眼、肾和神经。在全世界范围，糖尿病的社会经济负担很沉重。Diabetes affects millions of people worldwide and is considered one of the major threats to human mortality in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. Worldwide, the socioeconomic burden of diabetes is high.
有两种主要类型的糖尿病，命名为I型和II型，其中II型糖尿病(T2DM)占全世界所有糖尿病的超过90％。I型糖尿病特征为胰岛素缺乏，主要由自身免疫介导的胰岛β细胞破坏引起，II型糖尿病特征为胰岛素分泌异常和随之而来的胰岛素耐受。为预防引起酮酸中毒，患有I型糖尿病的患者必须摄取外源胰岛素以存活。尽管II型糖尿病患者不像I型糖尿病患者那样依赖于外源胰岛素，他们可能需要外源胰岛素以控制血糖水平。There are two main types of diabetes, designated Type I and Type II, with Type II diabetes (T2DM) accounting for over 90% of all diabetes worldwide. Type I diabetes is characterized by insulin deficiency, mainly caused by autoimmune-mediated destruction of islet beta cells, and type II diabetes is characterized by abnormal insulin secretion and consequent insulin resistance. To prevent ketoacidosis, patients with type 1 diabetes must take exogenous insulin to survive. Although type II diabetics are not as dependent on exogenous insulin as type I diabetics, they may require exogenous insulin to control blood sugar levels.
胰高血糖素样肽-1(GLP-1)是肠促胰素的一种，由肠道上皮L细胞分泌，通过与其受体结合发挥生理效应。GLP-1受体(GLP-1R)属于G蛋白耦联受体亚家族，当GLP-1与GLP-1受体相结合后，引发一系列的生物学效应。有研究表明，GLP-1是以葡萄糖依赖的方式促进胰岛素分泌，即当人体内血糖浓度升高时，GLP-1刺激胰岛细胞，增加胰岛素分泌，降低血糖。GLP-1受体激动剂是一种新型的降糖药物，既可在不引起低血糖的情况下，有效控制血糖水平；又可通过增加饱腹感、延缓胃排空、抑制食欲及减少脂肪堆积等，有效减轻体质量，达到减肥的目的。Glucagon-like peptide-1 (GLP-1), a type of incretin, is secreted by intestinal epithelial L cells and exerts physiological effects by binding to its receptors. GLP-1 receptor (GLP-1R) belongs to the subfamily of G protein-coupled receptors. When GLP-1 binds to GLP-1 receptor, a series of biological effects are triggered. Studies have shown that GLP-1 promotes insulin secretion in a glucose-dependent manner, that is, when the blood glucose concentration in the human body increases, GLP-1 stimulates pancreatic islet cells, increases insulin secretion, and lowers blood sugar. GLP-1 receptor agonist is a new type of hypoglycemic drug, which can not only effectively control blood sugar level without causing hypoglycemia, but also increase satiety, delay gastric emptying, suppress appetite and reduce fat. Accumulation, etc., effectively reduce body weight and achieve the purpose of weight loss.
目前，以GLP-1受体激动剂为基础的多肽类药物利拉鲁肽、艾塞那肽、索马鲁肽等已经应用于肥胖的II型糖尿病患者以及单纯肥胖或超重患者，均显示出明显地减轻体质量作用，但常伴有恶心、呕吐等胃肠道不良反应。口服非多肽类药物一直是研究机构尝试用于治疗II型糖尿病及减肥的药物，但由于小分子难以模拟受体与多肽的相互作用，限制了胰高血糖素样肽-1受体小分子药物的发现。At present, GLP-1 receptor agonist-based polypeptide drugs liraglutide, exenatide, semaglutide, etc. have been applied to obese type II diabetic patients and simple obesity or overweight patients, all showing Significantly reduce body weight, but often accompanied by nausea, vomiting and other gastrointestinal adverse reactions. Oral non-peptide drugs have always been tried by research institutions for the treatment of type II diabetes and weight loss. However, due to the difficulty of small molecules to simulate the interaction between receptors and peptides, the glucagon-like peptide-1 receptor small molecule drugs are limited. 's discovery.
目前公开非多肽类GLP-1受体激动剂的专利申请有WO2009/111700、WO2010/114824、WO2011/114271、WO2013/090454、WO2018/056453、WO2018/109607、WO2019239319、WO2019239371、WO2020103815等。其中，目前仅有vTv公司的TTP-273和辉瑞公司的PF-06882961进入了临床二期研究。Currently, there are WO2009/111700, WO2010/114824, WO2011/114271, WO2013/090454, WO2018/056453, WO2018/109607, WO2019239319, WO2019239371, WO20201038 and so on patent applications disclosing non-polypeptide GLP-1 receptor agonists. Among them, currently only TTP-273 from vTv and PF-06882961 from Pfizer have entered the Phase II clinical study.
因此，本发明意在发现新的非多肽类GLP-1受体激动剂、特别是具有良好的生物性能、能够被安全地应用到人体中的新化合物，本发明也提供用于预防和/或治疗涉及GLP-1相关疾病、特别是糖尿病相关疾病的所需工具。Therefore, the present invention aims to discover new non-polypeptide GLP-1 receptor agonists, especially new compounds with good biological properties that can be safely applied to the human body, and the present invention also provides for prevention and/or The tools needed to treat GLP-1 related diseases, especially diabetes related diseases.
发明内容SUMMARY OF THE INVENTION
本发明提供了一系列的苯并咪唑类衍生物、其制备方法及其在医药上的应用。The invention provides a series of benzimidazole derivatives, their preparation method and their application in medicine.
具体而言，本发明提供式(I)的化合物或其立体异构体、互变异构体、药学上可接受的盐，其中所有变量如本文所定义。In particular, the present invention provides compounds of formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein all variables are as defined herein.
Figure PCTCN2021120978-appb-000001
Figure PCTCN2021120978-appb-000001
这些化合物是胰高血糖素样肽1受体(GLP-1 R)的激动剂。本发明还涉及包含这些化合物的药物组合物以及使用该化合物治疗糖尿病等疾病的药物中的用途。These compounds are agonists of the glucagon-like peptide 1 receptor (GLP-1 R). The present invention also relates to pharmaceutical compositions containing these compounds and the use of the compounds in medicines for treating diseases such as diabetes.
具体的，本发明通过以下技术方案来实现：Specifically, the present invention realizes through the following technical solutions:
式(I)的化合物：Compounds of formula (I):
Figure PCTCN2021120978-appb-000002
Figure PCTCN2021120978-appb-000002
或其立体异构体、互变异构体、药学上可接受的盐，其中：or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
A选自8～10元稠芳环；A is selected from 8-10-membered fused aromatic rings;
R 1选自氢、卤素、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、1个或多个R 7取代的烷基、1个或多个R 8取代的芳基和杂芳基； R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
m为0、1、2或3；m is 0, 1, 2 or 3;
W为O或NH；W is O or NH;
R 2选自氢、卤素、氰基； R 2 is selected from hydrogen, halogen, cyano;
R 3选自氟、羟基、氰基、C 1-3烷基、OC 1-3烷基、C 3-4环烷基、或2个R 3一起环化成C 3-4螺环烷基，其中C 1-3烷基和OC 1-3烷基、环烷基或螺环烷基在化合价容许时可经0～3个氟原子或经0～1个羟基取代； R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
q为0、1、2；q is 0, 1, 2;
X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
Y为CH或NH；Y is CH or NH;
R 4为-C 1-3烷基、-C 0-3亚烷基-C 3-6环烷基、-C 0-3亚烷基-R 5或-C 1-3亚烷基-R 6，其中所述的烷基在化合价容许时可经0至3个独立地选自0至3个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O和-N(R N) 2的取代基取代，其中所述的亚烷基和环烷基在化合价容许时可独立地经0至2个独立地选自0至2个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O和-N(R N) 2的取代基取代； R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituents of -C 0-1 alkylene-OR O and -N(R N ) 2 , wherein the alkylene and cycloalkyl groups can be independently selected from 0 to 2 when the valence allows Substituent from 0 to 2 F atoms or substituted with 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O and -N(R N ) 2 base substitution;
R 5为4至6元杂环烷基，其中该杂环烷基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
0至1个氧代(＝O)，0 to 1 oxo (=O),
0至1个-CN，0 to 1 -CN,
0至2个F原子，或0 to 2 F atoms, or
0至2个独立地选自-C 1-3烷基和-OC 1-3烷基的取代基，其中C 1-3烷基和OC 1-3烷基的烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 substituents independently selected from -C 1-3 alkyl and -OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be modified by the valence permitting. Substituted with 0 to 3 substituents independently selected from:
0至3个F原子，0 to 3 F atoms,
0至1个-CN，或0 to 1 -CN, or
0至1个-OR O； 0 to 1 -OR O ;
R 6为5至6元杂芳基，其中该杂芳基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
0至2个卤素，0 to 2 halogens,
0至1个选自-OR O和-N(R N) 2的取代基，或 0 to 1 substituent selected from -OR O and -N(R N ) 2 , or
0至2个-C 1-3烷基，其中该烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 -C 1-3 alkyl groups, wherein the alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
0至3个F原子，或0 to 3 F atoms, or
0至1个-OR O； 0 to 1 -OR O ;
各R O独立地为H或-C 1-3烷基，其中C 1-3烷基可经0至3个F原子取代； Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
各R N独立地为H或-C 1-3烷基； each R N is independently H or -C 1-3 alkyl;
Z 1、Z 2和Z 3各自独立地为-CR Z或N，各R Z独立地为H、F、Cl或-CH 3； Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
R 7选自卤素、氰基、羟基、环烷基、杂环烷基、砜基； R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
R 8选自卤素、氰基、烷基、卤代烷基，烷氧基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、砜基。 R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
作为本发明的一种优选方案，所述化合物或其立体异构体、互变异构体、药学上可接受的盐如式(II) 所示：As a preferred solution of the present invention, the compound or its stereoisomer, tautomer, and pharmaceutically acceptable salt are shown in formula (II):
Figure PCTCN2021120978-appb-000003
其中：
Figure PCTCN2021120978-appb-000003
in:
A选自8～10元稠芳环；A is selected from 8-10-membered fused aromatic rings;
R 1选自氢、卤素、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、1个或多个R 7取代的烷基、1个或多个R 8取代的芳基和杂芳基； R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
m为0、1、2或3；m is 0, 1, 2 or 3;
W为O或NH；W is O or NH;
R 3选自氟、羟基、氰基、C 1-3烷基、OC 1-3烷基、C 3-4环烷基、或2个R 3一起环化成C 3-4螺环烷基，其中C 1-3烷基和OC 1-3烷基、环烷基或螺环烷基在化合价容许时可经0～3个氟原子或经0～1个羟基取代； R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
q为0、1、2；q is 0, 1, 2;
X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
Y为CH或N；Y is CH or N;
R 4为-C 1-3烷基、-C 0-3亚烷基-C 3-6环烷基、-C 0-3亚烷基-R 5或-C 1-3亚烷基-R 6，其中所述的烷基在化合价容许时可经0至3个独立地选自0至3个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代，及其中所述的亚烷基和环烷基在化合价容许时可独立地经0至2个独立地选自0至2个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代； R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituent substitution of -C 0-1 alkylene-OR O or -N(R N ) 2 , and the alkylene and cycloalkyl groups described therein may be independently replaced by 0 to 2 when the valence allows Substituents selected from 0 to 2 F atoms or through 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O or -N(R N ) 2 Substituent substitution;
R 5为4至6元杂环烷基，其中该杂环烷基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
0至1个氧代(＝O)，0 to 1 oxo (=O),
0至1个-CN，0 to 1 -CN,
0至2个F原子，或0 to 2 F atoms, or
0至2个独立地选自-C 1-3烷基或-OC 1-3烷基的取代基，其中C 1-3烷基和OC 1-3烷基的烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 substituents independently selected from -C 1-3 alkyl or -OC 1-3 alkyl, wherein the alkyl of C 1-3 and OC 1-3 alkyl may be modified by valence when allowed. Substituted with 0 to 3 substituents independently selected from:
0至3个F原子，0 to 3 F atoms,
0至1个-CN，或0 to 1 -CN, or
0至1个-OR O； 0 to 1 -OR O ;
R 6为5至6元杂芳基，其中该杂芳基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
0至2个卤素，0 to 2 halogens,
0至1个选自-OR O和-N(R N) 2的取代基，或 0 to 1 substituent selected from -OR O and -N(R N ) 2 , or
0至2个-C 1-3烷基，其中该烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 -C 1-3 alkyl groups, wherein the alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
0至3个F原子，或0 to 3 F atoms, or
0至1个-OR O； 0 to 1 -OR O ;
各R O独立地为H或-C 1-3烷基，其中C 1-3烷基可经0至3个F原子取代； Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
各R N独立地为H或-C 1-3烷基； each R N is independently H or -C 1-3 alkyl;
Z 1、Z 2和Z 3各自独立地为-CR Z或N，各R Z独立地为H、F、Cl或-CH 3； Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
R 7选自卤素、氰基、羟基、环烷基、杂环烷基、砜基； R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
R 8选自卤素、氰基、烷基、卤代烷基，烷氧基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、砜基。 R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
作为本发明的一种优选方案，所述烷基是指包含指定数量的碳原子的分支的、不分支的和环状的饱和烃链，优选自C 1-6的烷基，所述C 1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1,2-二甲基丙基、异戊基、新戊基、正己基，异己基，仲己基，叔己基，新己基，2-甲基戊基，1，2-二甲基丁基，1-乙基丁基。 As a preferred embodiment of the present invention, the alkyl group refers to a branched, unbranched and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms, preferably an alkyl group selected from C 1-6 , the C 1 -6 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl , 2-methylbutyl, tert-amyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl base, 1,2-dimethylbutyl, 1-ethylbutyl.
作为本发明的一种优选方案，所述烷氧基是指烷基醚自由基，优选自C 1-6的烷氧基，所述C 1-6的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1,2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基，异己氧基，仲己氧基，叔己氧基，新己氧基，2-甲基戊氧基，1，2-二甲基丁氧基，1-乙基丁氧基。 As a preferred solution of the present invention, the alkoxy group refers to an alkyl ether radical, preferably from a C 1-6 alkoxy group, and the C 1-6 alkoxy group is selected from methoxy, ethyl Oxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-amyloxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy group, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy.
作为本发明的一种优选方案，所述烷氧烷基是指烷基一个以上的氢原子被烷氧基取代，优选自C 1-4的烷氧C 1-4的烷基，进一步选自甲氧甲基、甲氧乙基、甲氧丙基、甲氧丁基、乙氧甲基、乙氧乙基、乙氧丙基、乙氧丁基、丙氧甲基、丙氧乙基、丙氧丙基、丙氧丁基、丁氧甲基、丁氧乙基、丁氧丙基、丁氧丁基等。 As a preferred embodiment of the present invention, the alkoxyalkyl group means that one or more hydrogen atoms of the alkyl group are substituted by an alkoxy group, preferably an alkyl group selected from C 1-4 alkoxy C 1-4 , and further selected from Methoxymethyl, Methoxyethyl, Methoxypropyl, Methoxybutyl, Ethoxymethyl, Ethoxyethyl, Ethoxypropyl, Ethoxybutyl, Propoxymethyl, Propoxyethyl, Propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, etc.
作为本发明的一种优选方案，所述卤素选自氟、氯、溴、碘，卤代烷基指烷基一个以上的氢原子被卤素取代，卤代烷氧基指烷氧基一个以上的氢原子被卤素取代，羟烷基指烷基一个以上的氢原子被羟基取代，杂环烷基是指烷基一个以上的氢原子被杂环取代，环烷亚甲基是指烷基一个以上的氢原子被环烷取代。As a preferred solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine, haloalkyl means that one or more hydrogen atoms of an alkyl group are replaced by halogen, and haloalkoxy means that one or more hydrogen atoms of an alkoxy group are replaced by halogen Substituted, hydroxyalkyl means that more than one hydrogen atom of an alkyl group is replaced by a hydroxyl group, heterocycloalkyl means that more than one hydrogen atom of an alkyl group is replaced by a heterocyclic ring, and cycloalkanemethylene means that one or more hydrogen atoms of an alkyl group are replaced by a heterocyclic ring. Cycloalkane substitution.
作为本发明的一种优选方案，所述所述稠芳环选自萘或者稠芳杂环，所述稠芳杂环指芳环或杂芳环与杂芳环稠合而成，所述杂芳环上的杂原子选自氮、氧、硫，所述杂原子为一个或者多个。As a preferred solution of the present invention, the fused aromatic ring is selected from naphthalene or a fused aromatic heterocyclic ring, the fused aromatic heterocyclic ring refers to an aromatic ring or a heteroaromatic ring and a heteroaromatic ring fused, and the heteroaromatic ring is fused. The heteroatom on the aromatic ring is selected from nitrogen, oxygen and sulfur, and the heteroatom is one or more.
作为本发明的一种优选方案，所述稠芳杂环选自吲唑、喹啉、异喹啉、喹喔啉、吲哚、异吲哚、噌啉、喹唑啉、酞嗪、嘌呤、萘啶、蝶啶、苯并呋喃、苯并噻吩、苯并噁唑、苯并噻唑、苯并异噁唑、苯并异噻唑、苯并噁二唑、苯并噻二唑、苯并三唑、苯并三嗪、苯并咪唑、吡嗪并吡唑、吡嗪并嘧啶、吡嗪并哒嗪、吡嗪并三嗪、嘧啶并吡唑、嘧啶并咪唑、嘧啶并三唑、嘧啶并三嗪、嘧啶并哒嗪、哒嗪并咪唑、哒嗪并吡唑、哒嗪并三唑、哒嗪并三嗪、三嗪并咪唑、三嗪并吡唑、三嗪并三唑、吡啶并噁唑、吡啶并噻唑、吡啶并异噁唑、吡啶并异噻唑、吡啶并噁二唑、吡啶并噻二唑、吡啶并呋喃、吡啶并吡咯、吡嗪并噁唑、吡嗪并噻唑、吡嗪并异噁唑、吡嗪并异噻唑、吡嗪并噁二唑、吡嗪并噻二唑、吡嗪并呋喃、吡嗪并吡咯、嘧啶并噁唑、嘧啶并噻唑、嘧啶并异噁唑、嘧啶并异噻唑、嘧啶并噁二唑、嘧啶并噻二唑、嘧啶并呋喃、嘧啶并吡咯、哒嗪并噁唑、哒嗪并噻唑、哒嗪并异噁唑、哒嗪并异噻唑、哒嗪并噁二唑、哒嗪并噻二唑、哒嗪并呋喃、哒嗪并吡咯、三嗪并噁唑、三嗪并噻唑、三嗪并异噁唑、三嗪并异噻唑、三嗪并噁二唑、三嗪并噻二唑、三嗪并呋喃、三嗪并吡咯。其中所述萘啶选自
Figure PCTCN2021120978-appb-000004
Figure PCTCN2021120978-appb-000005
所述吡啶并咪唑选自
Figure PCTCN2021120978-appb-000006
Figure PCTCN2021120978-appb-000007
所述吡嗪并咪唑选自
Figure PCTCN2021120978-appb-000008
所述吡嗪并三唑选自
Figure PCTCN2021120978-appb-000009
所述嘧啶并吡唑选自
Figure PCTCN2021120978-appb-000010
所述嘧啶并咪唑选自
Figure PCTCN2021120978-appb-000011
所述嘧啶并三唑选自
Figure PCTCN2021120978-appb-000012
所述哒嗪并咪唑选自
Figure PCTCN2021120978-appb-000013
所述哒嗪并三唑选自
Figure PCTCN2021120978-appb-000014
所述三嗪并咪唑选自
Figure PCTCN2021120978-appb-000015
所述吡啶并哒嗪选自
Figure PCTCN2021120978-appb-000016
所述吡啶并吡唑选自
Figure PCTCN2021120978-appb-000017
Figure PCTCN2021120978-appb-000018
所述吡啶并嘧啶选自
Figure PCTCN2021120978-appb-000019
所述吡啶并三嗪选自
Figure PCTCN2021120978-appb-000020
Figure PCTCN2021120978-appb-000021
所述嘧啶并三嗪选自
Figure PCTCN2021120978-appb-000022
As a preferred embodiment of the present invention, the fused aromatic heterocycle is selected from indazole, quinoline, isoquinoline, quinoxaline, indole, isoindole, cinnoline, quinazoline, phthalazine, purine, Naphthyridine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole , benzotriazine, benzimidazole, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine, pyrazinotriazine, pyrimidopyrazole, pyrimidazole, pyrimidotriazole, pyrimidotriazine azine, pyrimidopyridazine, pyridazinimidazole, pyridazinopyrazole, pyridazinotriazole, pyridazinotriazine, triazinimidazole, triazinopyrazole, triazinotriazole, pyridooxane azoles, pyridothiazoles, pyridoisoxazoles, pyridoisothiazoles, pyridooxadiazoles, pyridothiadiazoles, pyridofurans, pyridopyrroles, pyrazinooxazoles, pyrazinothiazoles, pyrazine isooxazole, pyrazinoisothiazole, pyrazinooxadiazole, pyrazinothiadiazole, pyrazinofuran, pyrazinopyrrole, pyrimidoxazole, pyrimidothiazole, pyrimidoisoxazole, Pyrimidoisothiazoles, Pyrimidooxadiazoles, Pyrimidothiadiazoles, Pyrimidofurans, Pyrimidopyrroles, Pyridazinoxazoles, Pyridazinothiazoles, Pyridazinoisoxazoles, Pyridazinoisothiazoles, Pyridazinoisothiazoles azinooxadiazoles, pyridazinothiadiazoles, pyridazinofurans, pyridazinopyrroles, triazinoxazoles, triazinothiazoles, triazinoisoxazoles, triazinoisothiazoles, triazinos Oxadiazoles, triazinothiadiazoles, triazinofurans, triazinopyrroles. wherein the naphthyridine is selected from
Figure PCTCN2021120978-appb-000004
Figure PCTCN2021120978-appb-000005
The pyridoimidazole is selected from
Figure PCTCN2021120978-appb-000006
Figure PCTCN2021120978-appb-000007
The pyrazinimidazole is selected from
Figure PCTCN2021120978-appb-000008
The pyrazinotriazole is selected from
Figure PCTCN2021120978-appb-000009
The pyrimidopyrazole is selected from
Figure PCTCN2021120978-appb-000010
The pyrimimidazole is selected from
Figure PCTCN2021120978-appb-000011
The pyrimidotriazole is selected from
Figure PCTCN2021120978-appb-000012
The pyridazinimidazole is selected from
Figure PCTCN2021120978-appb-000013
The pyridazinotriazole is selected from
Figure PCTCN2021120978-appb-000014
The triazineimidazole is selected from
Figure PCTCN2021120978-appb-000015
The pyridopyridazine is selected from
Figure PCTCN2021120978-appb-000016
The pyridopyrazole is selected from
Figure PCTCN2021120978-appb-000017
Figure PCTCN2021120978-appb-000018
The pyridopyrimidine is selected from
Figure PCTCN2021120978-appb-000019
The pyridotriazine is selected from
Figure PCTCN2021120978-appb-000020
Figure PCTCN2021120978-appb-000021
The pyrimidotriazine is selected from
Figure PCTCN2021120978-appb-000022
作为本发明的一种优选方案，所述杂环烷基的杂环选自4至10元杂环，所述4至10元杂环选自
Figure PCTCN2021120978-appb-000023
Figure PCTCN2021120978-appb-000024
所述芳基选自苯基；所述杂芳基选自5至12元杂芳基，所述5至12元杂芳基选自
Figure PCTCN2021120978-appb-000025
Figure PCTCN2021120978-appb-000026
As a preferred embodiment of the present invention, the heterocycle of the heterocycloalkyl is selected from 4- to 10-membered heterocycles, and the 4- to 10-membered heterocycles are selected from
Figure PCTCN2021120978-appb-000023
Figure PCTCN2021120978-appb-000024
The aryl group is selected from phenyl; the heteroaryl group is selected from the 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group is selected from
Figure PCTCN2021120978-appb-000025
Figure PCTCN2021120978-appb-000026
作为本发明的一种优选方案，所述的“亚烷基”，是指烷基在化合价容许时可独立地经0至2个独立地被取代基取代。As a preferred embodiment of the present invention, the "alkylene group" means that the alkyl group can be independently substituted by 0 to 2 substituents when the valence allows.
作为本发明的一种优选方案，所述的“杂环”，是指含一个或多个杂原子(氮、氧、硫)的饱和或不饱和杂环；所述的“芳环”，是指苯环；所述的“杂芳环”，是指具有4n+2个π电子的闭合共轭体系的杂环，如呋喃、噻吩、四氢吡咯、二氢吡唑、咪唑、噻唑、异噻唑、噻二唑、噁唑、噁二唑、异噁唑、哌啶、哌嗪、哒嗪、吡嗪、三嗪、嘧啶、吗啉或吡啶等；所述多个是指两个、三个、或四个。As a preferred embodiment of the present invention, the "heterocycle" refers to a saturated or unsaturated heterocycle containing one or more heteroatoms (nitrogen, oxygen, sulfur); the "aromatic ring" is a Refers to a benzene ring; the "heteroaromatic ring" refers to a heterocyclic ring with a closed conjugated system of 4n+2 π electrons, such as furan, thiophene, tetrahydropyrrole, dihydropyrazole, imidazole, thiazole, isotope Thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, piperidine, piperazine, pyridazine, pyrazine, triazine, pyrimidine, morpholine or pyridine, etc.; the multiple refers to two, three one, or four.
作为本发明的一种优选方案，所述环烷选自C 3-6的环烷，C 3-6的环烷选自环丙基、环丁基、环戊基、环己基。 As a preferred solution of the present invention, the cycloalkane is selected from C 3-6 cycloalkane, and the C 3-6 cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
作为本发明的一种优选方案，所述A选自
Figure PCTCN2021120978-appb-000027
Figure PCTCN2021120978-appb-000028
Figure PCTCN2021120978-appb-000029
As a preferred solution of the present invention, the A is selected from
Figure PCTCN2021120978-appb-000027
Figure PCTCN2021120978-appb-000028
Figure PCTCN2021120978-appb-000029
作为本发明的一种优选方案，所述化合物或其立体异构体、互变异构体、药学上可接受的盐，其中：所述A选自
Figure PCTCN2021120978-appb-000030
Figure PCTCN2021120978-appb-000031
As a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer and pharmaceutically acceptable salt, wherein: the A is selected from
Figure PCTCN2021120978-appb-000030
Figure PCTCN2021120978-appb-000031
R 1选自氢、氰基、甲基、乙基、异丙基、环丙基、甲氧基、甲氧乙基、二氟甲基、三氟甲基、氧杂环丁-3-基、氟、氯、2，2-二氟乙基、2-氟乙基、三氟乙基、氰基甲基、环丙基甲基、2-甲氧基-2-氧代乙基、氧杂环丁-3-基甲基、
Figure PCTCN2021120978-appb-000032
R 1 is selected from hydrogen, cyano, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxyethyl, difluoromethyl, trifluoromethyl, oxetan-3-yl , fluorine, chlorine, 2,2-difluoroethyl, 2-fluoroethyl, trifluoroethyl, cyanomethyl, cyclopropylmethyl, 2-methoxy-2-oxoethyl, oxygen Hetidine-3-ylmethyl,
Figure PCTCN2021120978-appb-000032
R 2为氢； R 2 is hydrogen;
R 3为甲基； R 3 is methyl;
R 4为氧杂环丁-2-基甲基； R 4 is oxetan-2-ylmethyl;
X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
W为O；W is O;
Y为CH或N；Y is CH or N;
Z 1为CH或N； Z 1 is CH or N;
Z 2为CH、CF或N； Z 2 is CH, CF or N;
Z 3为CH、CF或N。 Z 3 is CH, CF or N.
作为本发明的一种优选方案，所述化合物或其药学上可接受的盐，选自以下化合物：As a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:
Figure PCTCN2021120978-appb-000033
Figure PCTCN2021120978-appb-000033
Figure PCTCN2021120978-appb-000034
Figure PCTCN2021120978-appb-000034
Figure PCTCN2021120978-appb-000035
Figure PCTCN2021120978-appb-000035
Figure PCTCN2021120978-appb-000036
Figure PCTCN2021120978-appb-000036
Figure PCTCN2021120978-appb-000037
Figure PCTCN2021120978-appb-000037
Figure PCTCN2021120978-appb-000038
Figure PCTCN2021120978-appb-000038
Figure PCTCN2021120978-appb-000039
Figure PCTCN2021120978-appb-000039
作为本发明的一种优选方案，所述药学上可接受的盐是指化合物与药学上可接受的酸或碱制备。As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to the preparation of a compound with a pharmaceutically acceptable acid or base.
作为本发明的一种优选方案，所述化合物的一个以上的氢原子上被同位素氘取代。As a preferred solution of the present invention, more than one hydrogen atom of the compound is substituted with the isotope deuterium.
本发明另一目的提供了一种药物组合物，包括前述的式(I)的化合物，或其立体异构体、互变异构体、药学上可接受的盐和一种以上药学上可接受的载体。Another object of the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt and more than one pharmaceutically acceptable compound thereof a.
本发明另一目的在于提供所述的式(I)的化合物，或其立体异构体、互变异构体、药学上可接受的盐在制备用于制备治疗GLP-1相关疾病的药物用途，具体地，涉及糖尿病相关疾病的药物用途。Another object of the present invention is to provide the compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, in the preparation of pharmaceutical use for the preparation of treatment of GLP-1 related diseases , in particular, relates to the pharmaceutical use of diabetes-related diseases.
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与药学上可接受的酸或碱制备。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound of the present invention having a specified substituent and a pharmaceutically acceptable acid or base.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
本发明化合物分子的原子是同位素，通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且，包括一个实施方案，其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子，其分别包括 2H、 3H、 13C、 14C、 15N、 17O、 18O、 31P、 32P、 35S、 18F、 36Cl。特别的是，随其衰退而发射辐射的放射性同位素例如 3H或 14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化，也不具有放射性，因此其可以安全使用。当构成本发明化合物分子的原子是同位素时，通过用包含相应同位素的试剂替代合成中所用的试剂，可以根据通用方法转化同位素。 The atoms of the molecules of the compounds of the present invention are isotopes, and the isotope derivatization can usually prolong the half-life, reduce the clearance rate, stabilize the metabolism and improve the activity in vivo. Also, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioisotopes that emit radiation as they decay, such as 3 H or 14 C, are useful in the topological examination of pharmaceutical formulations or compounds in vivo. Stable isotopes neither decay or change with their amount nor are they radioactive, so they are safe to use. When the atoms making up the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by substituting the reagents used in the synthesis with reagents containing the corresponding isotopes.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
进一步地，本发明的化合物一个或多个氢原子上被同位素氘( 2H)取代，本发明化合物氘代后，具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。 Further, one or more hydrogen atoms of the compounds of the present invention are substituted by the isotope deuterium ( 2 H). After deuteration, the compounds of the present invention have the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.
所述同位素衍生物的制备方法通常包括：相转移催化方法。例如，优选的氘化方法采用相转移催化剂(例如，四烷基铵盐，NBu 4HSO 4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子，导致比在酸(例如，甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。 The preparation methods of the isotopic derivatives generally include: a phase transfer catalysis method. For example, a preferred deuteration method employs a phase transfer catalyst (eg, tetraalkylammonium salts, NBu4HSO4 ) . The methylene protons of diphenylmethane compounds are exchanged using a phase transfer catalyst, resulting in higher ratios than with deuterated silanes (eg, triethyldeuterated silane) or with Lewis acids such as trichloro in the presence of an acid (eg, methanesulfonic acid) Aluminium is reduced with sodium deuteroborate to introduce higher deuterium.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、 洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient, and representative carriers include water, oil , vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the target disorder, disease or condition.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
Figure PCTCN2021120978-appb-000040
表示连接键。
Figure PCTCN2021120978-appb-000040
Represents a connection key.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
具体实施方式Detailed ways
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。The present invention will be further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto.
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-III核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structures of compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). The measurement of NMR was performed by Bruker AVANCE-III nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
MS的测定用ISQ EC质谱仪(生产商：Thermo,型号：ISQ EC)。The MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
高效液相色谱法(HPLC)分析使用Thermo U3000 HPLC DAD高效液相色谱仪和Agilent 1260高效液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD high performance liquid chromatograph and an Agilent 1260 high performance liquid chromatograph.
CombiFlash快速制备仪使用CombiFlash Rf+LUMEN(TELEDYNE ISCO)。CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
薄层层析硅胶板使用烟台银龙HSGF 254或GF 254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.17mm～0.23mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。 The thin layer chromatography silica gel plate uses Yantai Yinlong HSGF 254 or GF 254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.17mm ~ 0.23mm, and the size of the TLC separation and purification products is 0.4mm～0.5mm.
硅胶柱色谱法一般使用乳山上邦硅胶100～200目硅胶为载体。Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
试剂：LDA-二异丙基氨基锂，THF-四氢呋喃，TEA-三乙胺，Dioxane-1，4-二氧六环，BH 3-硼烷，EDCl-1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，HOBT-1-羟基苯并三唑，DIPEA-N,N-二异丙基乙胺，DMF-N,N-二甲基甲酰胺，K 2CO 3-碳酸钾，DMSO-二甲基亚砜，EtOH-乙醇，NaH-氢化钠，toluene-甲苯，r.t.-室温，PdCl 2(dppf)-[1,1'-双(二苯基膦基)二茂铁]二氯化钯，Pd(OAc)2-乙酸钯，PhMe-甲苯，HCl-dioxane-盐酸的二氧六环，NaCO 3-碳酸钠，MeOH-甲醇，DCE-二氯乙烷，NCS-N-氯代丁二酰亚胺，TfOH-三氟甲磺酸，TFA-三氟乙酸，AcOH-乙酸，(CH2O)n多聚甲醛，CDI-N,N'-羰基二咪唑，LAH-氢化铝锂，PPA-多聚磷酸，TsOH-甲苯磺酸，NBS-N-溴代丁二酰亚胺，BPO-过氧苯甲酰。 Reagents: LDA-lithium diisopropylamide, THF-tetrahydrofuran, TEA-triethylamine, Dioxane-1,4-dioxane, BH3-borane, EDCl-1-ethyl-( 3 -dimethylamine) aminopropyl)carbodiimide hydrochloride, HOBT-1-hydroxybenzotriazole, DIPEA-N,N-diisopropylethylamine, DMF-N,N-dimethylformamide, K 2CO3 - potassium carbonate, DMSO-dimethylsulfoxide, EtOH -ethanol, NaH-sodium hydride, toluene-toluene, rt-room temperature, PdCl2 (dppf)-[1,1'-bis(diphenylphosphine) base)ferrocene]palladium dichloride, Pd(OAc)2-palladium acetate, PhMe-toluene, HCl-dioxane-hydrochloric acid, dioxane, NaCO3 -sodium carbonate, MeOH-methanol, DCE-dichloroethane Alkane, NCS-N-chlorosuccinimide, TfOH-trifluoromethanesulfonic acid, TFA-trifluoroacetic acid, AcOH-acetic acid, (CH2O)n paraformaldehyde, CDI-N,N'-carbonyldiimidazole , LAH-lithium aluminum hydride, PPA-polyphosphoric acid, TsOH-toluenesulfonic acid, NBS-N-bromosuccinimide, BPO-benzoyl peroxide.
abs是指absolute configuration，绝对构型。abs refers to absolute configuration, absolute configuration.
实施例1Example 1
合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-Methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000041
Figure PCTCN2021120978-appb-000041
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000042
Figure PCTCN2021120978-appb-000042
室温下，将4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(150.3毫克，0.5毫摩尔)、(1-甲基-1H-吲唑-6-基)甲醇(98.3毫克，0.6毫摩尔)、碳酸铯(260.2毫克，0.8毫摩尔)溶解在无水二氧六环(10毫升)中，并用氮气置换三次保护。随后加入三二亚苄基丙酮二钯(22.4毫克，25.1微摩尔)和2-二环己基磷-2,4,6-三异丙基联苯(12.2毫克，25.3微摩尔)并再次用氮气置换三次保护。并将温度升到90摄氏度回流反应过夜。At room temperature, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (150.3 mg, 0.5 mmol), (1-methyl-1H-indazol-6-yl) Methanol (98.3 mg, 0.6 mmol), cesium carbonate (260.2 mg, 0.8 mmol) were dissolved in dry dioxane (10 mL) and protected by nitrogen replacement three times. Tridibenzylideneacetone dipalladium (22.4 mg, 25.1 micromoles) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (12.2 mg, 25.3 micromoles) were then added and again flushed with nitrogen Replace three protections. The temperature was raised to 90 degrees Celsius and the reaction was refluxed overnight.
待反应完全后，反应液用硅藻土过滤，所得滤液进行减压浓缩。将混合物用水(50毫升)稀释，将水层用乙酸乙酯(30毫升×升次)萃取，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝6/1)得到120.3毫克黄色油状物4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(收率：56.3％)LC-MS:RT＝2.90min,[M+Na] +＝445.19。 After the reaction was completed, the reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The mixture was diluted with water (50 mL), the aqueous layer was extracted with ethyl acetate (30 mL×L), washed with saturated brine (50 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=6/1) to obtain 120.3 mg of 4-(6-((1-methyl-1H-indazole-6-) as a yellow oily substance yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (yield: 56.3%) LC-MS: RT=2.90 min, [M+Na] + =445.19.
步骤B：合成1-甲基-6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑Step B: Synthesis of 1-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000043
Figure PCTCN2021120978-appb-000043
室温下，将4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(120.4毫克，284.1微摩尔)溶解于4摩尔每升的盐酸乙酸乙酯溶液(10毫升)中，搅拌1小时，逐渐有白色固体析出。At room temperature, tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (120.4 mg, 284.1 Micromolar) was dissolved in 4 mol per liter of ethyl acetate solution of hydrochloric acid (10 ml), stirred for 1 hour, and gradually a white solid was precipitated.
待反应完全后，将反应液减压浓缩，混合物用水(50毫升)稀释，滴入饱和碳酸钠水溶液将混合液调至碱性，将水层用乙酸乙酯(25毫升×升次)萃取，饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到90.2毫克黄色油状物1-甲基-6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑，无需纯化，直接用于下步反应。LC-MS:RT＝3.38min,[M+H] +＝323.18。 After the reaction was completed, the reaction solution was concentrated under reduced pressure, the mixture was diluted with water (50 mL), and the mixture was adjusted to alkaline by adding dropwise saturated aqueous sodium carbonate solution, and the aqueous layer was extracted with ethyl acetate (25 mL×L), Washed with saturated brine (25 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 90.2 mg of 1-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indazole was obtained as a yellow oil which was used without purification next reaction. LC-MS: RT=3.38 min, [M+H] + =323.18.
步骤C：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester
Figure PCTCN2021120978-appb-000044
Figure PCTCN2021120978-appb-000044
在室温下，将化合物1-甲基-6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑(90.3毫克，244.7微摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80.2毫克，269.2微摩尔)和碳酸钾(170.5毫克，1.2毫摩尔)溶解在乙腈(10毫升)中，在50摄氏度反应16小时。Compound 1-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indazole (90.3 mg, 244.7 μmol) was added to the compound at room temperature ), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80.2 mg, 269.2 μm mol) and potassium carbonate (170.5 mg, 1.2 mmol) were dissolved in acetonitrile (10 mL) and reacted at 50°C for 16 hours.
待反应完全后，反应液中加入水(80毫升)稀释，水层用乙酸乙酯(50毫升×升次)萃取，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1到二氯甲烷/甲醇＝10/1)，得到154毫克淡黄色固体(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：78.2％.)。LC-MS:RT＝2.22min,[M+H] +＝581.26。 After the reaction was completed, the reaction solution was diluted with water (80 mL), the aqueous layer was extracted with ethyl acetate (50 mL×L), washed with saturated brine (50 mL×L), and then dried over anhydrous sodium sulfate. , and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=10/1) to obtain 154 mg of pale yellow solid (S)-2-(( 4-(6-((1-Methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 78.2%.). LC-MS: RT=2.22 min, [M+H] + =581.26.
步骤D：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000045
Figure PCTCN2021120978-appb-000045
在室温下，将化合物(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(154.5毫克，265.4微摩尔)，溶解在四氢呋喃(10毫升)和水(3毫升)溶液中并加入氢氧化钠(32.6毫克，1.3毫摩尔)，在室温下反应48小时。反应完全后，往反应液中逐滴滴加1N的柠檬酸水溶液，直到溶液的pH到5为止，加入水(50毫升)稀释，水层用乙酸乙酯(25毫升×升次)萃取，饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用反相HPLC(流动相：水/乙腈＝90/10到5/95)进行进一步的纯化，冻干得到124.2毫克白色固体(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：82.5％)。LC-MS:RT＝3.79min,[M+H] +＝567.26。 1H NMR(400MHz,DMSO-d 6)δ8.29(d,J＝7.9Hz,1H),8.03(s,1H),7.84(d,J＝8.5Hz,1H),7.75(d,J＝6.3Hz,2H),7.67–7.61(m,2H),7.25(d,J＝8.5Hz,1H),6.88(d,J＝7.3Hz,1H),6.70(d,J＝8.2Hz,1H),5.52–5.48(m,2H),5.15(q,J＝7.7Hz,1H),4.81(dd,J＝15.4,7.1Hz,1H),4.68(d,J＝14.9Hz,1H),4.47(q,J＝7.3Hz,1H),4.38(d,J＝7.7Hz,1H),4.05(q,J＝7.1Hz,1H),3.97(d,J＝10.6Hz,5H),3.80(d,J＝13.6Hz,1H),3.04(d,J＝11.2Hz,1H),2.90(d,J＝11.0Hz,1H),2.77–2.59(m,3H),2.45(d,J＝9.1Hz,1H),2.24(dt,J＝30.8,10.7Hz,3H)。 Compound (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- (154.5 mg, 265.4 μmol), dissolved in tetrahydrofuran (10 ml) and water (3 ml), sodium hydroxide (32.6 mg, 1.3 mmol) was added, and the reaction was carried out at room temperature for 48 hours. After the reaction was completed, 1N aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5, water (50 mL) was added to dilute, and the aqueous layer was extracted with ethyl acetate (25 mL×L), saturated Washed with brine (25 mL×L), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was further purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 124.2 mg of white solid (S)-2-((4-(6-(( 1-Methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (yield: 82.5%). LC-MS: RT=3.79 min, [M+H] + =567.26. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J=7.9 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.75 (d, J= 6.3Hz, 2H), 7.67–7.61 (m, 2H), 7.25 (d, J=8.5Hz, 1H), 6.88 (d, J=7.3Hz, 1H), 6.70 (d, J=8.2Hz, 1H) ,5.52–5.48(m,2H),5.15(q,J＝7.7Hz,1H),4.81(dd,J＝15.4,7.1Hz,1H),4.68(d,J＝14.9Hz,1H),4.47( q,J＝7.3Hz,1H),4.38(d,J＝7.7Hz,1H),4.05(q,J＝7.1Hz,1H),3.97(d,J＝10.6Hz,5H),3.80(d, J=13.6Hz, 1H), 3.04 (d, J=11.2Hz, 1H), 2.90 (d, J=11.0Hz, 1H), 2.77–2.59 (m, 3H), 2.45 (d, J=9.1Hz, 1H), 2.24 (dt, J=30.8, 10.7Hz, 3H).
实施例2Example 2
合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5 ]Octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000046
Figure PCTCN2021120978-appb-000046
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯Step A: Synthesis of (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate
Figure PCTCN2021120978-appb-000047
Figure PCTCN2021120978-appb-000047
室温下，将三乙胺(2.3克，22.5毫摩尔)及3-氟-4-硝基苯甲酸甲酯(1.4克，7.0毫摩尔)，添加至THF(10ml)中的(S)-2-(氨基甲基)氧杂环丁(618.0毫克，7.0毫摩尔)的溶液中，将混合物在室温下搅拌过夜。Triethylamine (2.3 g, 22.5 mmol) and methyl 3-fluoro-4-nitrobenzoate (1.4 g, 7.0 mmol) were added to (S)-2 in THF (10 ml) at room temperature -(aminomethyl)oxetine (618.0 mg, 7.0 mmol), and the mixture was stirred at room temperature overnight.
反应结束后，将混合物在减压下浓缩，加入水(100毫升)稀释，用乙酸乙酯(50毫升×3次)萃取，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)，得到1.5克黄色固体(S)-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(收率：81.0％)。LC-MS:RT＝2.30min,[M+H] +＝267.25。 1H NMR(400MHz,CDCl 3)δ8.41(s,1H),8.27(dd,J＝9.0,1.7Hz,1H),7.67(d,J＝1.8Hz,1H),7.31–7.28(m,1H),5.26–5.15(m,1H),4.79(q,J＝7.3,6.8Hz,1H),4.67(dtd,J＝7.7,6.1,1.6Hz,1H),3.98(d,J＝1.8Hz,3H),3.67(t,J＝5.2Hz,2H),2.88–2.75(m,1H),2.72–2.61(m,1H)。 After the reaction, the mixture was concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (50 mL×3 times), washed with saturated brine (50 mL×L times), and then washed with anhydrous sulfuric acid. It was dried over sodium and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 1.5 g of yellow solid (S)-4-nitro-3-((oxetine-2 -ylmethyl)amino)methyl benzoate (yield: 81.0%). LC-MS: RT=2.30 min, [M+H] + =267.25. 1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (s, 1H), 8.27 (dd, J=9.0, 1.7 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.31-7.28 (m, 1H), 5.26–5.15 (m, 1H), 4.79 (q, J=7.3, 6.8Hz, 1H), 4.67 (dtd, J=7.7, 6.1, 1.6Hz, 1H), 3.98 (d, J=1.8Hz) , 3H), 3.67 (t, J=5.2Hz, 2H), 2.88–2.75 (m, 1H), 2.72–2.61 (m, 1H).
步骤B：(S)-4-氨基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯Step B: (S)-Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate
Figure PCTCN2021120978-appb-000048
Figure PCTCN2021120978-appb-000048
室温下，将(S)-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(1.5克，5.7毫摩尔)溶解在乙酸乙酯(50毫升)中，随后加入10％的钯碳(225.0毫克)。用氢气球置换三次，并在室温下反应过夜。Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (1.5 g, 5.7 mmol) was dissolved in ethyl acetate (50 mL) at room temperature ) followed by the addition of 10% palladium on carbon (225.0 mg). Replaced with hydrogen balloon three times and reacted overnight at room temperature.
待反应完全后，用硅藻土过滤，随后滤液减压浓缩得到1.37克黄色油状物(S)-4-氨基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯，无需进一步纯化直接投入下一步。LC-MS:RT＝2.30min,[M+H] +＝237.16。 1H NMR(400MHz,CDCl 3)δ7.51(d,J＝8.1Hz,1H),7.40(s,1H),6.71(d,J＝8.0Hz,1H),5.13(dd,J＝7.0,3.6Hz,1H),4.77(q,J＝7.4Hz,1H),4.69–4.61(m,1H),3.89(s,3H),3.47(dd,J＝12.8,6.6Hz,1H),3.38(dd,J＝12.8,3.5Hz,1H),2.79(dt,J＝10.8,7.6Hz,1H),2.66–2.56(m,1H)。 After the reaction was completed, filter through celite, and then the filtrate was concentrated under reduced pressure to obtain 1.37 g of yellow oil (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester The ester was carried directly to the next step without further purification. LC-MS: RT=2.30 min, [M+H] + =237.16. 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 5.13 (dd, J=7.0, 3.6Hz, 1H), 4.77 (q, J=7.4Hz, 1H), 4.69–4.61 (m, 1H), 3.89 (s, 3H), 3.47 (dd, J=12.8, 6.6Hz, 1H), 3.38 ( dd, J=12.8, 3.5 Hz, 1H), 2.79 (dt, J=10.8, 7.6 Hz, 1H), 2.66–2.56 (m, 1H).
步骤C：合成1-((4-(甲氧羰基)-2-(((S)-氧杂环丁-2-基甲基)氨基)苯基)氨基甲酰基)-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯Step C: Synthesis of 1-((4-(methoxycarbonyl)-2-(((S)-oxetan-2-ylmethyl)amino)phenyl)carbamoyl)-6-azaspiro [2.5]octane-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000049
Figure PCTCN2021120978-appb-000049
室温下，将6-[(叔丁氧基)羰基]-6-氮杂螺[2.5]辛烷-1-羧酸(2.0克，7.8毫摩尔)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(3.0克，7.8毫摩尔)、N,N-二异丙基乙胺(2.6毫升，15.6摩尔)溶解于N,N-二甲基甲酰胺溶液(25毫升)中，室温反应0.5小时后，加入(S)-4-氨基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(1.8克，7.8毫摩尔)，继续反应24小时。At room temperature, 6-[(tert-butoxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylic acid (2.0 g, 7.8 mmol), 2-(7-azabenzotri azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.0 g, 7.8 mmol), N,N-diisopropylethylamine (2.6 mL, 15.6 mol) were dissolved in (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid was added to the N,N-dimethylformamide solution (25 mL) after reaction at room temperature for 0.5 hours. Methyl ester (1.8 g, 7.8 mmol), and the reaction was continued for 24 hours.
待反应完全后，将反应液用乙酸乙酯(150毫升)稀释，用水(30毫升×升次)洗涤，饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得到2.8克黄色油状物1-((4-(甲氧羰基)-2-(((S)-氧杂环丁-2-基甲基)氨基)苯基)氨基甲酰基)-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯(收率：75.6％)。LC-MS:RT＝3.09min,[M+Na] +＝496.37。 After the reaction was completed, the reaction solution was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), washed with saturated brine (30 mL×L), then dried with anhydrous sodium sulfate, and finally reduced pressure concentrate. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 2.8 g of yellow oily substance 1-((4-(methoxycarbonyl)-2-(((S) -oxetan-2-ylmethyl)amino)phenyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (yield: 75.6%). LC-MS: RT=3.09 min, [M+Na] + =496.37.
步骤D：合成2-(6-(叔丁氧羰基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step D: Synthesis of 2-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000050
Figure PCTCN2021120978-appb-000050
室温下，将1-((4-(甲氧羰基)-2-(((S)-氧杂环丁-2-基甲基)氨基)苯基)氨基甲酰基)-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯(2.8克，5.9毫摩尔)加入到二甲苯(30毫升)中，并加入醋酸(2.5毫升)。将温度升到110摄氏度反应2小时。At room temperature, 1-((4-(methoxycarbonyl)-2-(((S)-oxetan-2-ylmethyl)amino)phenyl)carbamoyl)-6-azaspiro [2.5] Octane-6-carboxylate tert-butyl ester (2.8 g, 5.9 mmol) was added to xylene (30 mL) and acetic acid (2.5 mL). The temperature was raised to 110 degrees Celsius and the reaction was carried out for 2 hours.
待反应完全后，将反应液冷却至室温，以水(100毫升)稀释，将水层用乙酸乙酯(50毫升×升次)萃取，将有机层合并，然后用饱和碳酸钠水溶液(50毫升×升次)洗涤，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到2.7g黄色油状物2-(6-(叔丁氧羰基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。无需纯化，直接用于下步反应。LC-MS:RT＝3.90min,[M+H] +＝456.30。 After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (100 mL), the aqueous layer was extracted with ethyl acetate (50 mL×L), the organic layers were combined, and then washed with saturated aqueous sodium carbonate (50 mL). × liters), washed with saturated brine (50 ml × liters), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 2.7g of yellow oil was obtained 2-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethane yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. Without purification, it was directly used in the next step. LC-MS: RT=3.90 min, [M+H] + =456.30.
步骤E：合成1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of 1-((S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole -6-Carboxylic acid methyl ester
Figure PCTCN2021120978-appb-000051
Figure PCTCN2021120978-appb-000051
室温下，将2-(6-(叔丁氧羰基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(2.7克，5.9毫摩尔)溶解在二氯甲烷(15毫升)中，并加入三氟乙酸(4.5毫升)。室温反应2小时。待反应完全后，将混合物以50毫升水稀释，滴入饱和碳酸钠水溶液将混合液调至碱性，将水层用乙酸乙酯(100毫升×升次)萃取，将有几层合并，并用饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到1.9克黄色油状物1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯。无需纯化，直接用于下步反应。LC-MS:RT＝1.80min,[M+H] +＝ 356.30。 At room temperature, 2-(6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl) Methyl -1H-benzo[d]imidazole-6-carboxylate (2.7 g, 5.9 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (4.5 mL) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with 50 mL of water, and the mixture was adjusted to alkaline by adding dropwise saturated aqueous sodium carbonate solution, the aqueous layer was extracted with ethyl acetate (100 mL×L), several layers were combined, and mixed with Washed with saturated brine (25 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 1.9 g of yellow oil were obtained 1-((S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d ] Methyl imidazole-6-carboxylate. Without purification, it was directly used in the next step. LC-MS: RT = 1.80 min, [M+H] + = 356.30.
步骤F：合成1-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基)-1H-吲唑Step F: Synthesis of 1-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000052
Figure PCTCN2021120978-appb-000052
室温下，将(1-甲基-1H-吲唑-6-基)甲醇(645.0毫克，4.0毫摩尔)、四氟吡啶(1.2克，8.0毫摩尔)、碳酸钾(1.6克，11.9毫摩尔)溶解加入到N-甲基吡咯烷酮(10毫升)中。将温度升到110摄氏度反应24小时。At room temperature, combine (1-methyl-1H-indazol-6-yl)methanol (645.0 mg, 4.0 mmol), tetrafluoropyridine (1.2 g, 8.0 mmol), potassium carbonate (1.6 g, 11.9 mmol) ) was dissolved in N-methylpyrrolidone (10 mL). The temperature was raised to 110 degrees Celsius and the reaction was carried out for 24 hours.
待反应完全后，反应液用硅藻土过滤，所得滤液进行减压浓缩。将混合物用乙酸乙酯(150毫升)稀释，用水(30毫升×升次)洗涤，饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到352.2毫克黄色固体1-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基)-1H-吲唑(收率：27.8％)。LC-MS:RT＝3.52min,[M+H] +＝294.11。 After the reaction was completed, the reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The mixture was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), saturated brine (30 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 352.2 mg of yellow solid 1-methyl-6-(((3,5,6-trifluoropyridine- 2-yl)oxy)methyl)-1H-indazole (yield: 27.8%). LC-MS: RT=3.52 min, [M+H] + =294.11.
步骤G：合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step G: Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000053
Figure PCTCN2021120978-appb-000053
室温下，将1-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基)-1H-吲唑(133.0毫克，452.2微摩尔)、1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(180.5毫克，506.4微摩尔)及碳酸钾(130.2毫克，0.9毫摩尔)溶解加入到N,N-二甲基甲酰胺(8毫升)中。并将温度升到100摄氏度反应6小时。待反应完全后，将混合物用乙酸乙酯(150毫升)稀释，用水(30毫升×升次)洗涤，饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1到二氯甲烷/甲醇＝10/1)得到160.2毫克黄色油状物2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：56.3％)。LC-MS:RT＝2.90min,[M+H] +＝629.24。 At room temperature, 1-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl)-1H-indazole (133.0 mg, 452.2 μmol), 1- ((S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylate methyl The ester (180.5 mg, 506.4 μmol) and potassium carbonate (130.2 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (8 mL). And the temperature was raised to 100 degrees Celsius for 6 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), washed with saturated brine (30 mL×L), then dried over anhydrous sodium sulfate, and finally reduced in pressure. concentrate. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=10/1) to obtain 160.2 mg of yellow oily substance 2-(6-(3,5 -Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1 -((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 56.3%). LC-MS: RT=2.90 min, [M+H] + =629.24.
步骤H：合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step H: Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000054
Figure PCTCN2021120978-appb-000054
在室温下，将化合物2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(160.0毫克，254.6微摩尔)溶解在四氢呋喃(6毫升)、乙醇(2毫升)和水(2毫升)溶液中并加入氢氧化钠(101.8毫克，2.5毫摩尔)，在室温下反应24小时。反应完全后，往反应液中逐滴滴加1N的柠檬酸水溶液，直到溶液的pH到5为止。加入水(50毫升)稀释，水层用乙酸乙酯(25毫升×升次)萃取，合并有机层，并用饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用反相HPLC(流动相：水/乙腈＝90/10到5/95)进行进一步的纯化，冻干得到20.0毫克白色固体(S)-2-((4-(6-((4-氰基-2-氟苄基)氨基)吡啶-2-基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：12.1％)。LC-MS:RT＝2.34min,[M+H] +＝615.45。 At room temperature, compound 2-(6-(3,5-difluoro-6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)-6- Azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (160.0 mg, 254.6 μmol) was dissolved in a solution of tetrahydrofuran (6 mL), ethanol (2 mL) and water (2 mL) and sodium hydroxide (101.8 mg, 2.5 mmol) was added to react at room temperature for 24 hours. After the reaction was completed, 1N aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5. Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL×L), the organic layers were combined, washed with saturated brine (25 mL×L), then dried over anhydrous sodium sulfate, and finally reduced pressure concentrate. The resulting residue was further purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 20.0 mg of white solid (S)-2-((4-(6-(( 4-cyano-2-fluorobenzyl)amino)pyridin-2-yl)piperidin-1-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylic acid (yield: 12.1%). LC-MS: RT=2.34 min, [M+H] + =615.45.
实施例3Example 3
合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂 环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5 ]Octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000055
Figure PCTCN2021120978-appb-000055
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-甲基-2H-吲唑-6-基)甲醇Step A: Synthesis of (2-methyl-2H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000056
Figure PCTCN2021120978-appb-000056
冰浴条件下，将2-甲基-2H-吲唑-6-羧酸甲酯(300.0毫克，1.6毫摩尔)溶解在干燥的四氢呋喃(10毫升)溶液中，氮气置换三次。在氮气保护下，分批加入四氢铝锂(121.6毫克，3.2毫摩尔)。Methyl 2-methyl-2H-indazole-6-carboxylate (300.0 mg, 1.6 mmol) was dissolved in dry tetrahydrofuran (10 mL) solution under ice-bath conditions and nitrogen purged three times. Under nitrogen, lithium aluminum tetrahydride (121.6 mg, 3.2 mmol) was added in portions.
所得反应液在冰浴条件下继续搅拌反应1小时，待反应完全后，逐滴加入1N氢氧化钠水溶液淬灭反应。搅拌15分钟后，用硅藻土过滤，所得滤液用乙酸乙酯(150毫升)稀释，并用水(30毫升×升次)洗涤，饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到204.3mg毫克白色固体(2-甲基-2H-吲唑-6-基)甲醇(收率：82.2％)。LC-MS:RT＝1.15min,[M+H] +＝163.19。 The obtained reaction solution was continued to stir for 1 hour under ice bath conditions. After the reaction was completed, 1N aqueous sodium hydroxide solution was added dropwise to quench the reaction. After stirring for 15 minutes, it was filtered through celite. The obtained filtrate was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), saturated brine (30 mL×L), and then washed with anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1) to obtain 204.3 mg of white solid (2-methyl-2H-indazol-6-yl)methanol (yield 204.3 mg). : 82.2%). LC-MS: RT=1.15 min, [M+H] + =163.19.
步骤B：合成2-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基-2H-吲唑Step B: Synthesis of 2-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-2H-indazole
Figure PCTCN2021120978-appb-000057
Figure PCTCN2021120978-appb-000057
室温下，将(2-甲基-2H-吲唑-6-基)甲醇(322.2毫克，2.0毫摩尔)、四氟吡啶(0.6克，6.0毫摩尔)、碳酸钾(830.3毫克，6.0毫摩尔)溶解加入到N-甲基吡咯烷酮(10毫升)中。将温度升到110摄氏度反应24小时。待反应完全后，将混合物用水(30毫升)稀释，将水层用乙酸乙酯(50毫升×升次)萃取，合并有机相并用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到300毫克黄色固体2-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基-2H-吲唑(收率：48.9％)。LC-MS:RT＝2.90min,[M+H] +＝294.04。 At room temperature, combine (2-methyl-2H-indazol-6-yl)methanol (322.2 mg, 2.0 mmol), tetrafluoropyridine (0.6 g, 6.0 mmol), potassium carbonate (830.3 mg, 6.0 mmol) ) was dissolved in N-methylpyrrolidone (10 mL). The temperature was raised to 110 degrees Celsius and the reaction was carried out for 24 hours. After the reaction was completed, the mixture was diluted with water (30 mL), the aqueous layer was extracted with ethyl acetate (50 mL×L), the organic phases were combined and washed with saturated brine (30 mL×L), and then anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 300 mg of yellow solid 2-methyl-6-(((3,5,6-trifluoropyridine- 2-yl)oxy)methyl-2H-indazole (yield: 48.9%). LC-MS: RT=2.90 min, [M+H] + =294.04.
步骤C：合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000058
Figure PCTCN2021120978-appb-000058
室温下，将2-甲基-6-(((3,5,6-三氟吡啶-2-基)氧基)甲基)-1H-吲唑(133.0毫克，452.2微摩尔)、1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(180.5毫克，506.4微摩尔)及碳酸钾(130毫克，0.9毫摩尔)溶解加入到N,N-二甲基甲酰胺(8毫升)中。并将温度升到100摄氏度反应6小时。At room temperature, 2-methyl-6-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl)-1H-indazole (133.0 mg, 452.2 μmol), 1- ((S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylate methyl The ester (180.5 mg, 506.4 μmol) and potassium carbonate (130 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (8 mL). And the temperature was raised to 100 degrees Celsius for 6 hours.
待反应完全后，将混合物用水(20毫升)稀释，将水层用乙酸乙酯(30毫升×升次)萃取，合并有机层并用饱和食盐水(15毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1到二氯甲烷/甲醇＝10/1)得到160.2毫克黄色油状物2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：56.3％)。LC-MS:RT＝2.48min,[M+H] +＝629.45 After the reaction was completed, the mixture was diluted with water (20 mL), the aqueous layer was extracted with ethyl acetate (30 mL×L), the organic layers were combined and washed with saturated brine (15 mL×L), and then anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=10/1) to obtain 160.2 mg of yellow oily substance 2-(6-(3,5 -Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1 -((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 56.3%). LC-MS: RT=2.48min, [M+H] + =629.45
步骤D：合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000059
Figure PCTCN2021120978-appb-000059
在室温下，将化合物2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(160.0毫克，254.6微摩尔)，溶解在四氢呋喃(6毫升)乙醇(2毫升)和水(2毫升)溶液中并加入氢氧化钠(101.8毫克，2.5毫摩尔)，在室温下反应24小时。At room temperature, compound 2-(6-(3,5-difluoro-6-((2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6- Azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (160.0 mg, 254.6 μmol), was dissolved in a solution of tetrahydrofuran (6 mL) ethanol (2 mL) and water (2 mL) and sodium hydroxide (101.8 mg, 2.5 mmol) was added and reacted at room temperature for 24 hours.
反应完全后，往反应液中逐滴滴加1N的柠檬酸水溶液，直到溶液的pH到5为止。加入水(30毫升)稀释，水层用乙酸乙酯(50毫升×升次)萃取，合并有机相并用饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用反相HPLC(流动相：水/乙腈＝90/10到5/95)进行进一步的纯化，冻干得到65.5毫克白色固体2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：41.8％)。LC-MS:RT＝3.98min,[M+H] +＝615.38。 After the reaction was completed, 1N aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5. Water (30 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (50 mL×L), the organic phases were combined and washed with saturated brine (25 mL×L), then dried over anhydrous sodium sulfate, and finally reduced pressure concentrate. The resulting residue was further purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 65.5 mg of white solid 2-(6-(3,5-difluoro-6- ((2-Methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1-((S)- Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 41.8%). LC-MS: RT=3.98 min, [M+H] + =615.38.
实施例4Example 4
合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(6-(3,5-difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5 ]Octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000060
Figure PCTCN2021120978-appb-000060
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-1H-吲唑Step A: Synthesis of 1-methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-1H-indazole
Figure PCTCN2021120978-appb-000061
Figure PCTCN2021120978-appb-000061
室温下，将(1-甲基-1H-吲唑-5-基)甲醇(322.0毫克，2.0毫摩尔)、四氟吡啶(0.6克，6.0毫摩尔)、碳酸钾(830.0毫克，6.0毫摩尔)溶解加入到N-甲基吡咯烷酮(10毫升)中。将温度升到110摄氏度反应24小时。At room temperature, combine (1-methyl-1H-indazol-5-yl)methanol (322.0 mg, 2.0 mmol), tetrafluoropyridine (0.6 g, 6.0 mmol), potassium carbonate (830.0 mg, 6.0 mmol) ) was dissolved in N-methylpyrrolidone (10 mL). The temperature was raised to 110 degrees Celsius and the reaction was carried out for 24 hours.
待反应完全后，反应液用硅藻土过滤，所得滤液进行减压浓缩。将混合物用乙酸乙酯(150毫升)稀释，用水(30毫升×升次)洗涤，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到300.5毫克黄色固体1-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-1H-吲唑(收率：48.9％)。LC-MS:RT＝3.48min,[M+H] +＝294.11。, After the reaction was completed, the reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The mixture was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), saturated brine (50 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 300.5 mg of yellow solid 1-methyl-5-(((3,5,6-trifluoropyridine- 2-yl)oxy)methyl-1H-indazole (yield: 48.9%). LC-MS: RT=3.48 min, [M+H] + =294.11.,
步骤B：合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step B: Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000062
Figure PCTCN2021120978-appb-000062
室温下，将1-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-1H-吲唑(133.0毫克，452.2微摩尔)、1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(180.5毫克，506.4微摩尔)及碳酸钾(130毫克，0.9毫摩尔)溶解加入到N,N-二甲基甲酰胺(8毫升)中。并将温度升到100摄氏 度反应6小时。1-Methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-1H-indazole (133.0 mg, 452.2 μmol), 1-( (S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (180.5 mg, 506.4 μmol) and potassium carbonate (130 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (8 mL), and the temperature was raised to 100 degrees Celsius for 6 hours.
待反应完全后，将混合物用水(20毫升)稀释，将水层用乙酸乙酯(30毫升×升次)萃取，合并有机层并用饱和食盐水(15毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1到二氯甲烷/甲醇＝10/1)得到160.3毫克黄色油状物2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：56.3％)。LC-MS:RT＝2.73min,[M+H] +＝629.65。 After the reaction was completed, the mixture was diluted with water (20 mL), the aqueous layer was extracted with ethyl acetate (30 mL×L), the organic layers were combined and washed with saturated brine (15 mL×L), and then anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=10/1) to obtain 160.3 mg of yellow oily substance 2-(6-(3,5 -Difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1 -((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 56.3%). LC-MS: RT=2.73 min, [M+H] + =629.65.
步骤C：合成2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of 2-(6-(3,5-Difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000063
Figure PCTCN2021120978-appb-000063
在室温下，将化合物2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(120毫克，191微摩尔)，溶解在四氢呋喃(6毫升)乙醇(2毫升)和水(2毫升)溶液中并加入氢氧化钠(101.8毫克，1.9毫摩尔)，在室温下反应24小时。At room temperature, compound 2-(6-(3,5-difluoro-6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6- Azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (120 mg, 191 μmol), was dissolved in a solution of tetrahydrofuran (6 mL) ethanol (2 mL) and water (2 mL) and sodium hydroxide (101.8 mg, 1.9 mmol) was added to react at room temperature for 24 hours.
反应完全后，往反应液中逐滴滴加1N的柠檬酸水溶液，直到溶液的pH到5为止。加入水(50毫升)稀释，水层用乙酸乙酯(25毫升×升次)萃取，饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用反相HPLC(流动相：水/乙腈＝90/10到5/95)进行进一步的纯化，冻干得到33.5毫克白色固体2-(6-(3,5-二氟-6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30.3％)。LC-MS:RT＝4.20min,[M+H] +＝615.38。 After the reaction was completed, 1N aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5. Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL×L), washed with saturated brine (25 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was further purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 33.5 mg of white solid 2-(6-(3,5-difluoro-6- ((1-Methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1-((S)- Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 30.3%). LC-MS: RT=4.20 min, [M+H] + =615.38.
实施例5Example 5
合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)pyridin-2-yl)-6-azaspiro[2.5 ]Octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000064
Figure PCTCN2021120978-appb-000064
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-甲基-2H-吲唑-5-基)甲醇Step A: Synthesis of (2-methyl-2H-indazol-5-yl)methanol
Figure PCTCN2021120978-appb-000065
Figure PCTCN2021120978-appb-000065
冰浴条件下，将甲基2-甲基-2H-吲唑-5-甲酸甲酯(300.0毫克，1.6毫摩尔)溶解在干燥的四氢呋喃(10毫升)溶液中，氮气置换三次。在氮气保护下，分批加入四氢铝锂(121.6毫克，3.2毫摩尔)。所得反应液在冰浴条件下继续搅拌反应1小时。Methyl 2-methyl-2H-indazole-5-carboxylic acid methyl ester (300.0 mg, 1.6 mmol) was dissolved in dry tetrahydrofuran (10 mL) solution under ice-bath conditions and nitrogen purged three times. Under nitrogen, lithium aluminum tetrahydride (121.6 mg, 3.2 mmol) was added in portions. The resulting reaction solution was further stirred for 1 hour under ice bath conditions.
待反应完全后，逐滴加入1N氢氧化钠水溶液淬灭反应。搅拌15分钟后，用硅藻土过滤，所得滤液用乙酸乙酯(150毫升)稀释，并用水(30毫升×升次)洗涤，饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到204.3毫克白色固体(2-甲基-2H-吲唑-5-基)甲醇(收率：82.2％)。LC-MS:RT＝1.15min,[M+H] +＝163.19。 After the reaction was complete, 1N aqueous sodium hydroxide solution was added dropwise to quench the reaction. After stirring for 15 minutes, it was filtered through celite. The obtained filtrate was diluted with ethyl acetate (150 mL), washed with water (30 mL×L), saturated brine (30 mL×L), and then washed with anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 204.3 mg of white solid (2-methyl-2H-indazol-5-yl)methanol (yield: 82.2%). LC-MS: RT=1.15 min, [M+H] + =163.19.
步骤B：合成2-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-2H-吲唑Step B: Synthesis of 2-methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-2H-indazole
Figure PCTCN2021120978-appb-000066
Figure PCTCN2021120978-appb-000066
室温下，将(2-甲基-2H-吲唑-5-基)甲醇(310.5毫克，2.0毫摩尔)、四氟吡啶(0.6克，6.0毫摩尔)、碳酸钾(830.5毫克，6.0毫摩尔)溶解加入到N-甲基吡咯烷酮(10毫升)中。将温度升到110摄氏度反应24小时。At room temperature, combine (2-methyl-2H-indazol-5-yl)methanol (310.5 mg, 2.0 mmol), tetrafluoropyridine (0.6 g, 6.0 mmol), potassium carbonate (830.5 mg, 6.0 mmol) ) was dissolved in N-methylpyrrolidone (10 mL). The temperature was raised to 110 degrees Celsius and the reaction was carried out for 24 hours.
待反应完全后，反应液用硅藻土过滤，所得滤液进行减压浓缩。将混合物用水(100毫升)稀释，将水层用乙酸乙酯(50毫升×升次)萃取，饱和食盐水(50毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到300.3毫克黄色固体2-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-2H-吲唑(收率：48.9％)。LC-MS:RT＝2.87min,[M+H] +＝293.98。 After the reaction was completed, the reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure. The mixture was diluted with water (100 mL), the aqueous layer was extracted with ethyl acetate (50 mL×L), washed with saturated brine (50 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 300.3 mg of yellow solid 2-methyl-5-(((3,5,6-trifluoropyridine- 2-yl)oxy)methyl-2H-indazole (yield: 48.9%). LC-MS: RT=2.87 min, [M+H] + =293.98.
步骤C：合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)哌啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)piperidin-2-yl)-6-nitrogen Heterospiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000067
Figure PCTCN2021120978-appb-000067
室温下，将2-甲基-5-(((3,5,6-三氟吡啶-2-基)氧基)甲基-2H-吲唑(133.0毫克，452.2微摩尔)、1-((S)-氧杂环丁-2-基甲基)-2-(6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(180.5毫克，506.4微摩尔)及碳酸钾(130毫克，0.9毫摩尔)溶解加入到N,N-二甲基甲酰胺(8毫升)中。并将温度升到100摄氏度反应6小时。2-Methyl-5-(((3,5,6-trifluoropyridin-2-yl)oxy)methyl-2H-indazole (133.0 mg, 452.2 μmol), 1-( (S)-oxetan-2-ylmethyl)-2-(6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (180.5 mg, 506.4 μmol) and potassium carbonate (130 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (8 mL), and the temperature was raised to 100 degrees Celsius for 6 hours.
待反应完全后，将混合物用水(20毫升)稀释，将水层用乙酸乙酯(10毫升×升次)萃取，饱和食盐水(15毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1到二氯甲烷/甲醇＝10/1)得到160mg毫克黄色油状物2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)哌啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：56.3％)。LC-MS:RT＝2.32min,[M+Na] +＝629.45 After the reaction was completed, the mixture was diluted with water (20 mL), the aqueous layer was extracted with ethyl acetate (10 mL×L), washed with saturated brine (15 mL×L), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=10/1) to obtain 160 mg of yellow oily substance 2-(6-(3,5 -Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)piperidin-2-yl)-6-azaspiro[2.5]octan-1-yl)- 1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 56.3%). LC-MS: RT=2.32min, [M+Na] + =629.45
步骤D：合成2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of 2-(6-(3,5-Difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)pyridin-2-yl)-6-aza Spiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000068
Figure PCTCN2021120978-appb-000068
在室温下，将化合物2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)哌啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(138.0毫克，219.6微摩尔)，溶解在四氢呋喃(6毫升)、乙醇(2毫升)和水(2毫升)溶液中并加入氢氧化钠(88.0毫克，2.2毫摩尔)，在室温下反应24小时。反应完全后，往反应液中逐滴滴加1N的柠檬酸水溶液，直到溶液的pH到5为止。加入水(50毫升)稀释，水层用乙酸乙酯(25毫升×升次)萃取，饱和食盐水(25毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用反相HPLC(流动相：水/乙腈＝90/10到5/95)进行进一步的纯化，冻干得到56.0毫克白色固体2-(6-(3,5-二氟-6-((2-甲基-2H-吲唑-5-基)甲氧基)哌啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：41.5％)。LC-MS:RT＝3.87min,[M+H] +＝615.17。 At room temperature, compound 2-(6-(3,5-difluoro-6-((2-methyl-2H-indazol-5-yl)methoxy)piperidin-2-yl)-6 -Azaspiro[2.5]octan-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 138.0 mg, 219.6 μmol), was dissolved in a solution of tetrahydrofuran (6 mL), ethanol (2 mL) and water (2 mL) and sodium hydroxide (88.0 mg, 2.2 mmol) was added and reacted at room temperature for 24 hours. After the reaction was completed, 1N aqueous citric acid solution was added dropwise to the reaction solution until the pH of the solution reached 5. Water (50 mL) was added to dilute, the aqueous layer was extracted with ethyl acetate (25 mL×L), washed with saturated brine (25 mL×L), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was further purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 56.0 mg of white solid 2-(6-(3,5-difluoro-6- ((2-Methyl-2H-indazol-5-yl)methoxy)piperidin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1-((S) -oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 41.5%). LC-MS: RT=3.87 min, [M+H] + =615.17.
实施例6Example 6
合成2-((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl )methyl)-1-((((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000069
Figure PCTCN2021120978-appb-000069
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-4-(2-氯嘧啶-4-基)-2-甲基哌嗪-1-羧酸叔丁酯Step A: Synthesis of (S)-tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylpiperazine-1-carboxylate
Figure PCTCN2021120978-appb-000070
Figure PCTCN2021120978-appb-000070
将2,4-二氯嘧啶(1.70g,11.40mmol)和(S)-2-甲基哌嗪-1-羧酸叔丁酯(2.50g,12.53mmol)溶解于20毫升无水二氯甲烷中，加入三乙胺(2.29g,22.8mmol)于30摄氏度下反应4小时。反应结束，反应液减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)，得到2.80克淡黄色固体(S)-4-(2-氯嘧啶-4-基)-2-甲基哌嗪-1-羧酸叔丁酯(收率：80.2％)。LC-MS:RT＝2.01min,[M-H] -＝313.21。 2,4-Dichloropyrimidine (1.70 g, 11.40 mmol) and (S)-2-methylpiperazine-1-carboxylate tert-butyl ester (2.50 g, 12.53 mmol) were dissolved in 20 mL of anhydrous dichloromethane In the solution, triethylamine (2.29 g, 22.8 mmol) was added to react at 30 degrees Celsius for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 2.80 g of pale yellow solid (S)-4-(2-chloro) Pyrimidine-4-yl)-2-methylpiperazine-1-carboxylate tert-butyl ester (yield: 80.2%). LC-MS: RT=2.01 min, [MH] − = 313.21.
步骤B:合成(S)-2-甲基-4-(2-(((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-甲酸叔丁酯Step B: Synthesis of (S)-2-methyl-4-(2-(((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine-1- tert-butyl formate
Figure PCTCN2021120978-appb-000071
Figure PCTCN2021120978-appb-000071
将(1-甲基-1H-吲唑-6-基)甲醇(200mg,1.23mmol)溶解于5毫升无水四氢呋喃中，零摄氏度下加入60％氢化钠(73.8mg,1.85mmol)搅拌反应20分钟后加入(S)-4-(2-氯嘧啶-4-基)-2-甲基哌嗪-1-羧酸叔丁酯(385mg,1.23mmol)的3毫升四氢呋喃溶液于室温下继续反应4小时。反应结束，加饱和氯化铵淬灭，混合液用乙酸乙酯(50毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝3/1)，得到400豪克淡黄色固体(S)-2-甲基-4-(2-(((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-甲酸叔丁酯(收率：74.3％)。LC-MS:RT＝1.73min,[M-H] -＝439.29。 (1-methyl-1H-indazol-6-yl)methanol (200mg, 1.23mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, 60% sodium hydride (73.8mg, 1.85mmol) was added at zero degrees Celsius and the reaction was stirred for 20 After minutes, a solution of (S)-4-(2-chloropyrimidin-4-yl)-2-methylpiperazine-1-carboxylate tert-butyl ester (385 mg, 1.23 mmol) in 3 mL of tetrahydrofuran was added to continue the reaction at room temperature 4 hours. The reaction was completed, quenched by adding saturated ammonium chloride, the mixture was extracted with ethyl acetate (50 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (20 mL×L), and then washed with anhydrous After drying over sodium sulfate, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/1) to obtain 400 mg of pale yellow solid (S)-2-methyl- 4-(2-(((1-Methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (yield: 74.3%). LC - MS: RT = 1.73 min, [MH] - = 439.29.
步骤C：合成(S)-1-甲基-6-((((4-(3-甲基哌嗪-1-基)嘧啶-2-基)氧基)甲基)-1H-吲唑Step C: Synthesis of (S)-1-methyl-6-((((4-(3-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000072
Figure PCTCN2021120978-appb-000072
将(S)-2-甲基-4-(2-(((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-甲酸叔丁酯(400mg,0.911mmol)溶解于10毫升无水二氯甲烷中，加入三氟乙酸(519mg,4.55mmol)于室温下反应2小时。反应结束，反应液减压浓缩所得340毫克(S)-1-甲基-6-((((4-(3-甲基哌嗪-1-基)嘧啶-2-基)氧基)甲基)-1H-吲唑粗品，直接用于下一步。LC-MS:RT＝0.24min,[M-H] -＝339.29。 (S)-2-methyl-4-(2-(((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester (400mg, 0.911mmol) was dissolved in 10 milliliters of anhydrous dichloromethane, and trifluoroacetic acid (519mg, 4.55mmol) was added to react at room temperature for 2 hours. The reaction was completed, and the reaction solution was concentrated under reduced pressure for 340 mg (S)- Crude 1-methyl-6-((((4-(3-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)methyl)-1H-indazole was used directly in the next step. LC-MS: RT = 0.24 min, [MH] − = 339.29.
步骤D：合成2-(((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step D: Synthesis of 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine -1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000073
Figure PCTCN2021120978-appb-000073
将(S)-1-甲基-6-((((4-(3-甲基哌嗪-1-基)嘧啶-2-基)氧基)甲基)-1H-吲唑(200mg,0.589mmol)和(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(174mg,0.589mmol)溶解于8毫升无水乙腈中，加入碳酸钾(203mg,1.47mmol)于50摄氏度下反应2小时。(S)-1-methyl-6-((((4-(3-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)methyl)-1H-indazole (200 mg, 0.589 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (174 mg, 0.589 mmol) was dissolved in 8 mL of anhydrous acetonitrile, potassium carbonate (203 mg, 1.47 mmol) was added to react at 50 degrees Celsius for 2 hours.
反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得210豪克淡黄色固体2-(((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(粗品)。LC-MS:RT＝1.66min,[M-H] -＝597.36。 After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 210 mg of pale yellow solid 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidine- 4-yl)piperazin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Methyl ester (crude). LC-MS: RT=1.66 min, [MH] − = 597.36.
步骤E：合成2-(((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine -1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000074
Figure PCTCN2021120978-appb-000074
将2-(((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(100mg,0.167mmol)溶解于5毫升四氢呋喃/水(4/1)中，零摄氏度下加入氢氧化锂(35.2mg,0.837mmol)和1毫升乙醇，零摄氏度下反应20分钟。反应结束，加水稀释，然后用二氯甲烷(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得粗品经prep-TLC(乙酸乙酯/乙醇＝20/1)分离纯化得52毫克白色固体2-((S)-2-甲基-4-(2-((1-甲基-1H-吲唑-6-基)甲氧基)嘧啶-4-基)哌嗪-1-基)甲基)-1-((((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸。 1H NMR(500MHz,DMSO)δ8.21(s,1H),8.01(dd,2H),7.79(dd,1H),7.72(d,1H),7.67(s,1H),7.59(d,1H),7.19(dd,1H),6.48(d,1H),5.40(s,2H),5.12–5.18(m,1H),4.66–4.76(m,2H),4.43–4.51(m,1H),4.24–4.33(m,2H),4.02(s,3H),3.79–3.99(m,2H),3.67(d,1H),3.21-3.25(m,1H),3.03-3.08(m,1H),2.63–2.71(m,3H),2.25–2.40(m,2H),1.09(d,3H).LC-MS:RT＝1.58min,[M+H] +＝583.35。 2-(((S)-2-methyl-4-(2-((1-methyl-1H-indazol-6-yl)methoxy)pyrimidin-4-yl)piperazine-1- yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.167 mmol) was dissolved in 5 In milliliter tetrahydrofuran/water (4/1), lithium hydroxide (35.2 mg, 0.837 mmol) and 1 ml of ethanol were added at zero degrees Celsius, and the reaction was carried out at zero degrees Celsius for 20 minutes. The reaction was completed, diluted with water, then extracted with dichloromethane (20 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), then dried with anhydrous sodium sulfate, and finally reduced. The crude product was concentrated under pressure to obtain 52 mg of white solid 2-((S)-2-methyl-4-(2-((1-methyl- 1H-Indazol-6-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid. 1 H NMR (500MHz, DMSO) δ 8.21(s, 1H), 8.01(dd, 2H), 7.79(dd, 1H), 7.72(d ,1H),7.67(s,1H),7.59(d,1H),7.19(dd,1H),6.48(d,1H),5.40(s,2H),5.12–5.18(m,1H),4.66– 4.76 (m, 2H), 4.43–4.51 (m, 1H), 4.24–4.33 (m, 2H), 4.02 (s, 3H), 3.79–3.99 (m, 2H), 3.67 (d, 1H), 3.21- 3.25(m,1H),3.03-3.08(m,1H),2.63-2.71(m,3H),2.25-2.40(m,2H),1.09(d,3H).LC-MS:RT=1.58min, [M+H] + =583.35.
实施例7Example 7
合成2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[2.5]octane -1-yl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000075
Figure PCTCN2021120978-appb-000075
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step A: Synthesis of 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[ 2.5] Octan-1-yl)-1-((((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester
Figure PCTCN2021120978-appb-000076
Figure PCTCN2021120978-appb-000076
将咪唑并[1,2-a]吡啶-6-基甲醇(23mg,0.155mmol)溶解于5毫升无水N,N-二甲基甲酰胺中，零摄氏度下加入60％氢化钠(10mg,0.25mmol)搅拌反应10分钟后加入1-((((S)-氧杂环丁-2-基)甲基)-2-(6-(6-(3,5,6-三氟吡啶-2-基)-6-氮杂螺[2.5]辛烷-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(75mg,0.155mmol)的3毫升N,N-二 甲基甲酰胺溶液于零摄氏度下继续反应2小时。反应结束，加饱和氯化铵淬灭，混合液用乙酸乙酯(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得80.0毫克淡黄色固体2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-(((S)-氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：85.1％)。LC-MS:RT＝1.75min,[M+H] +＝615.33。 Imidazo[1,2-a]pyridin-6-ylmethanol (23mg, 0.155mmol) was dissolved in 5ml of anhydrous N,N-dimethylformamide, and 60% sodium hydride (10mg, 0.25 mmol) was stirred for 10 minutes and then 1-((((S)-oxetan-2-yl)methyl)-2-(6-(6-(3,5,6-trifluoropyridine- 2-yl)-6-azaspiro[2.5]octan-1-yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (75 mg, 0.155 mmol) in 3 mL of N,N-dicarbonate The methylformamide solution was continued to react for 2 hours at zero degrees Celsius. After the reaction was completed, saturated ammonium chloride was added for quenching, the mixed solution was extracted with ethyl acetate (20 ml × liter), the organic phases were combined, and the organic phase was first used with saturated common salt Washed with water (20 mL×L), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 80.0 mg of pale yellow solid 2-(6-(3,5-difluoro-6-(imidazo[1, 2-a]Pyridin-6-methoxy)pyridin-2-yl)-6-azaspiro[2.5]oct-1-yl)-1-(((S)-oxetan-2-yl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 85.1%). LC-MS: RT=1.75 min, [M+H] + =615.33.
步骤B：合成2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000077
Figure PCTCN2021120978-appb-000077
将2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80mg,0.131mmol)溶解于5毫升四氢呋喃/水(4/1)中，零摄氏度下加入氢氧化锂(27.5mg,0.655mmol)和1毫升乙醇，零摄氏度下反应20分钟。反应结束，加水稀释，然后用二氯甲烷(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得粗品经prep-TLC(乙酸乙酯/乙醇＝20/1)分离纯化得22毫克白色固体2-(6-(3,5-二氟-6-(咪唑并[1,2-a]吡啶-6-甲氧基)吡啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸。 1H NMR(500MHz,DMSO)δ8.61(s,1H),8.16(d,1H),7.87(s,1H),7.72–7.78(m,2H),7.53–7.56(m,3H),7.25–7.27(m,1H),5.34(d,2H),5.04–5.09(m,1H),4.65–4.75(m,1H),4.50–4.63(m,1H),4.40–4.47(m,1H),4.23–4.32(m,1H),3.57–3.64(m,1H),3.19–3.25(m,3H),2.66–2.71(m,1H),2.37–2.43(m,2H),1.77–1.84(m,1H),1.46–1.61(m,4H),1.14–1.16(m,1H).LC-MS:RT＝1.61min,[M+H] +＝601.30。 2-(6-(3,5-Difluoro-6-(imidazo[1,2-a]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[2.5]octane -1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (80 mg, 0.131 mmol) was dissolved in 5 mL In tetrahydrofuran/water (4/1), lithium hydroxide (27.5 mg, 0.655 mmol) and 1 ml of ethanol were added at zero degrees Celsius, and the reaction was carried out at zero degrees Celsius for 20 minutes. The reaction was completed, diluted with water, then extracted with dichloromethane (20 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), then dried with anhydrous sodium sulfate, and finally reduced. The crude product was concentrated under pressure to obtain the crude product, which was separated and purified by prep-TLC (ethyl acetate/ethanol=20/1) to obtain 22 mg of white solid 2-(6-(3,5-difluoro-6-(imidazo[1,2-a) ]pyridine-6-methoxy)pyridin-2-yl)-6-azaspiro[2.5]oct-1-yl)-1-((S)-oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid. 1 H NMR (500MHz, DMSO)δ8.61(s,1H),8.16(d,1H),7.87(s,1H),7.72-7.78(m,2H),7.53-7.56(m,3H),7.25 –7.27(m,1H), 5.34(d,2H), 5.04–5.09(m,1H), 4.65–4.75(m,1H), 4.50–4.63(m,1H), 4.40–4.47(m,1H) ,4.23–4.32(m,1H),3.57–3.64(m,1H),3.19–3.25(m,3H),2.66–2.71(m,1H),2.37–2.43(m,2H),1.77–1.84( m, 1H), 1.46-1.61 (m, 4H), 1.14-1.16 (m, 1H). LC-MS: RT=1.61 min, [M+H] + =601.30.
实施例8Example 8
合成2-(-6-(5-氟-4-((1-甲基-1H-吲唑-5-基)甲氧基)嘧啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of 2-(-6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)methoxy)pyrimidin-2-yl)-6-azaspiro[2.5]octane -1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000078
Figure PCTCN2021120978-appb-000078
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-(((2-氯-5-氟嘧啶-4-基)氧基)甲基)-1-甲基-1H-吲唑Step A: Synthesis of 5-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000079
Figure PCTCN2021120978-appb-000079
室温下，将(1-甲基-1H-吲唑-5-基)甲醇(750毫克，4.63毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，冰浴下冷却至零摄氏度。加入氢化钠(111毫克4.63毫摩尔)搅拌0.5小时，再加入2,4-二氯-5-氟嘧啶(768毫克，4.63毫摩尔)。冰浴下反应2小时。(1-Methyl-1H-indazol-5-yl)methanol (750 mg, 4.63 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature and cooled to zero degrees Celsius. Sodium hydride (111 mg, 4.63 mmol) was added and stirred for 0.5 h, followed by 2,4-dichloro-5-fluoropyrimidine (768 mg, 4.63 mmol). The reaction was carried out in an ice bath for 2 hours.
反应结束后，加入饱和食盐水淬灭反应，混合液用乙酸乙酯萃取(20毫升×3次)，合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得 到850毫克淡黄色油状液体5-(((2-氯-5-氟嘧啶-4-基)氧基)甲基)-1-甲基-1H-吲唑(收率：63％)。LC-MS:RT＝1.98min,[M+H] +＝293.16。 After the reaction was completed, saturated brine was added to quench the reaction, the mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the obtained crude product was subjected to silica gel column chromatography Purification (eluent: ethyl acetate/n-hexane=1/1) gave 850 mg of 5-(((2-chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-1 as a pale yellow oily liquid -Methyl-1H-indazole (yield: 63%). LC-MS: RT=1.98 min, [M+H] + =293.16.
步骤B：合成2-(-6-(5-氟-4-((1-甲基-1H-吲唑-5-基)甲氧基)嘧啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step B: Synthesis of 2-(-6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)methoxy)pyrimidin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000080
Figure PCTCN2021120978-appb-000080
室温下，将5-(((2-氯-5-氟嘧啶-4-基)氧基)甲基)-1-甲基-1H-吲唑(200毫克，0.68毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，加入三乙胺(1毫升)，再加入1-((S)-氧杂环丁-2-基)甲基)-2-(6-氮杂螺[2.5]-辛-1-基)-1H-苯并[d]咪唑-6-羧酸甲酯(243毫克，0.68毫摩尔)。反应温度升高到90摄氏度搅拌4小时。5-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-1-methyl-1H-indazole (200 mg, 0.68 mmol) was dissolved in N at room temperature, To N-dimethylformamide (5 mL) was added triethylamine (1 mL) followed by 1-((S)-oxetan-2-yl)methyl)-2-(6-nitrogen Heterospiro[2.5]-oct-1-yl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (243 mg, 0.68 mmol). The reaction temperature was raised to 90°C and stirred for 4 hours.
反应结束后，加入饱和食盐水淬灭反应，混合液用乙酸乙酯萃取(20毫升×3次)，合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到144毫克白色固体2-(6-(5-氟-4-((1-甲基-1H-吲唑-5-基)甲氧基)嘧啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：34％),利用Chiraloel CD手性柱(正己烷/异丙醇＝6/4)拆分先后得到73毫克中间体A和43毫克中间体B。After the reaction was completed, saturated brine was added to quench the reaction, the mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the obtained crude product was subjected to silica gel column chromatography Purification (eluent: ethyl acetate/n-hexane=1/1) gave 144 mg of white solid 2-(6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)) Methoxy)pyrimidin-2-yl)-6-azaspiro[2.5]oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (yield: 34%), using Chiraloel CD chiral column (n-hexane/isopropanol=6/4) to obtain 73 mg of intermediate A and 43 mg of intermediate successively B.
中间体A，HPLC:RT＝26.59min；LC-MS:RT＝1.99min,[M+H] +＝612.35。 Intermediate A, HPLC: RT=26.59 min; LC-MS: RT=1.99 min, [M+H] + =612.35.
中间体B，HPLC:RT＝30.11min；LC-MS:RT＝1.99min,[M+H] +＝612.35。 Intermediate B, HPLC: RT=30.11 min; LC-MS: RT=1.99 min, [M+H] + =612.35.
步骤C：合成2-(-6-(5-氟-4-((1-甲基-1H-吲唑-5-基)甲氧基)嘧啶-2-基)-6-氮杂螺[2.5]辛-1-基)-1-((S)-氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of 2-(-6-(5-fluoro-4-((1-methyl-1H-indazol-5-yl)methoxy)pyrimidin-2-yl)-6-azaspiro[ 2.5]Oct-1-yl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000081
Figure PCTCN2021120978-appb-000081
室温下，将中间体A(73毫克0.12毫摩尔)溶于混合溶剂(7毫升，四氢呋喃/甲醇/水＝5/1/1)中，加入氢氧化锂(50毫克，1.2毫摩尔)。反应温度升高到40摄氏度搅拌3小时。反应结束后，加入饱和氯化铵淬灭反应，混合液用乙酸乙酯萃取(10毫升×2次)，再用混合溶剂萃取(10毫升×2次，二氯甲烷/甲醇＝30/1)合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)得到33毫克白色固体实施例8A化合物(收率：46％)。LC-MS:RT＝1.85min,[M+H] +＝598.31。 Intermediate A (73 mg, 0.12 mmol) was dissolved in a mixed solvent (7 mL, tetrahydrofuran/methanol/water=5/1/1) at room temperature, and lithium hydroxide (50 mg, 1.2 mmol) was added. The reaction temperature was raised to 40°C and stirred for 3 hours. After the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×2 times), and then extracted with a mixed solvent (10 mL×2 times, dichloromethane/methanol=30/1) The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to obtain 33 mg of the compound of Example 8A as a white solid (acquired). rate: 46%). LC-MS: RT=1.85 min, [M+H] + =598.31.
室温下，将中间体B(43毫克0.12毫摩尔)溶于混合溶剂(7毫升，四氢呋喃/甲醇/水＝5/1/1)中，加入氢氧化锂(50毫克，1.2毫摩尔)。反应温度升高到40摄氏度搅拌3小时。反应结束后，加入饱和氯化 铵淬灭反应，混合液用乙酸乙酯萃取(10毫升×2次)，再用混合溶剂萃取(10毫升×2次，二氯甲烷/甲醇＝30/1)合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)得到29毫克实施例8B化合物(收率：69％)。LC-MS:RT＝1.86min,[M+H] +＝598.29。 Intermediate B (43 mg, 0.12 mmol) was dissolved in a mixed solvent (7 mL, tetrahydrofuran/methanol/water=5/1/1) at room temperature, and lithium hydroxide (50 mg, 1.2 mmol) was added. The reaction temperature was raised to 40°C and stirred for 3 hours. After the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×2 times), and then extracted with a mixed solvent (10 mL×2 times, dichloromethane/methanol=30/1) The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to obtain 29 mg of the compound of Example 8B (yield: 1/20). 69%). LC-MS: RT=1.86 min, [M+H] + =598.29.
实施例9Example 9
合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000082
Figure PCTCN2021120978-appb-000082
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-(溴甲基)-1-甲基-1H-吲唑Step A: Synthesis of 6-(bromomethyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000083
Figure PCTCN2021120978-appb-000083
冰浴条件下，将(1-甲基-1H-吲唑6-基)甲醇(200.0毫克,1.2毫摩尔)和三苯基磷(483.4毫克，1.8毫摩尔)溶解在干燥的四氢呋喃溶液(6毫升)中，随后加入四溴化碳(596.9毫克，1.8毫摩尔)。反应液随后在室温下继续搅拌反应2小时，待反应完全后，过滤除去三苯基氧磷，所得滤液减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得到161.3毫克无色油状物6-(溴甲基)-1-甲基-1H-吲唑(收率：57.9％)。LC-MS:RT＝2.65min,[M+H] +＝225.04。 (1-Methyl-1H-indazol 6-yl)methanol (200.0 mg, 1.2 mmol) and triphenylphosphine (483.4 mg, 1.8 mmol) were dissolved in dry tetrahydrofuran solution (6 mL) followed by carbon tetrabromide (596.9 mg, 1.8 mmol). The reaction solution was subsequently stirred at room temperature for 2 hours. After the reaction was complete, triphenylphosphine oxide was removed by filtration, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate). ester = 10/1) to obtain 161.3 mg of 6-(bromomethyl)-1-methyl-1H-indazole as a colorless oil (yield: 57.9%). LC-MS: RT=2.65 min, [M+H] + =225.04.
步骤B：合成4-(4-氟-3-羟基苯基)-3,6-二氢哌啶-1(2H)-羧酸叔丁酯Step B: Synthesis of 4-(4-Fluoro-3-hydroxyphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000084
Figure PCTCN2021120978-appb-000084
室温下，将4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-3,6-二氢哌啶啶-1(2H)-羧酸叔丁酯(728.2毫克,2.3毫摩尔)，5-溴-2-氟苯酚(300.0毫克，1.5毫摩尔)，碳酸铯(1.4克,，4.5毫摩尔)溶解在二氧六环(10毫升)溶液中。随后用氮气置换三次，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73.2毫克，0.1毫摩尔)，再用氮气置换三次。在氮气保护下，反应液在90摄氏度下反应过夜。At room temperature, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropiperidine-1(2H)- tert-Butyl carboxylate (728.2 mg, 2.3 mmol), 5-bromo-2-fluorophenol (300.0 mg, 1.5 mmol), cesium carbonate (1.4 g, 4.5 mmol) were dissolved in dioxane (10 ml) solution. This was followed by three flushes with nitrogen and the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73.2 mg, 0.1 mmol), followed by three flushes with nitrogen. Under nitrogen protection, the reaction solution was reacted at 90 degrees Celsius overnight.
待反应完全后，过滤除去固体，所得滤液用乙酸乙酯(100毫升)稀释溶解，加入水(30毫升×2)洗涤，饱和食盐水(30毫升×1)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得到414.3毫克淡黄色油状物4-(4-氟-3-羟基苯基)-3,6-二氢哌啶-1(2H)-羧酸叔丁酯(收率：89.8％)。LC-MS:RT＝3.27min,[M- tBu] +＝238.19。 After the reaction was completed, the solid was removed by filtration. The obtained filtrate was diluted and dissolved with ethyl acetate (100 mL), washed with water (30 mL×2), washed with saturated brine (30 mL×1), and then dried with anhydrous sodium sulfate. , and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 414.3 mg of 4-(4-fluoro-3-hydroxyphenyl)-3,6 as a pale yellow oily substance -Dihydropiperidine-1(2H)-carboxylate tert-butyl ester (yield: 89.8%). LC-MS: RT=3.27 min, [M-tBu] + = 238.19 .
步骤C：合成4-(4-氟-3-羟基苯基)哌啶-1-羧酸叔丁酯Step C: Synthesis of tert-butyl 4-(4-fluoro-3-hydroxyphenyl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000085
Figure PCTCN2021120978-appb-000085
室温下，将4-(4-氟-3-羟基苯基)-3,6-二氢哌啶-1(2H)-羧酸叔丁酯(414.3毫克，1.4毫摩尔)溶解在乙酸乙酯(15毫升)中，加入二氧化铂(22.7毫克，0.1毫摩尔)。以上反应液在氢气氛围条件下反应过夜。待反应完全后，用硅藻土进行过滤，所得滤液减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得到396.8毫克无色油状物4-(4-氟-3-羟基苯基)哌啶-1-羧酸叔丁酯(收率：95.7％)。LC-MS:RT＝3.29min,[M- tBu] +＝240.04。 4-(4-Fluoro-3-hydroxyphenyl)-3,6-dihydropiperidine-1(2H)-carboxylate tert-butyl ester (414.3 mg, 1.4 mmol) was dissolved in ethyl acetate at room temperature (15 mL), platinum dioxide (22.7 mg, 0.1 mmol) was added. The above reaction solution was reacted overnight under hydrogen atmosphere. After the reaction was completed, it was filtered through celite, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 396.8 mg of colorless oil tert-butyl 4-(4-fluoro-3-hydroxyphenyl)piperidine-1-carboxylate (yield: 95.7%). LC-MS: RT=3.29 min, [M-tBu] + = 240.04 .
步骤D:合成4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-羧酸叔丁酯Step D: Synthesis of tert-butyl 4-(4-fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000086
Figure PCTCN2021120978-appb-000086
室温下，将4-(4-氟-3-羟基苯基)哌啶-1-羧酸叔丁酯(396.8毫克，1.3毫摩尔)和6-(溴甲基)-1-甲基-1H-吲唑(438.7毫克，1.9毫摩尔)溶解在N,N-二甲基甲酰胺(4毫升)中，并加入无水碳酸钾(542.1毫克，3.9毫摩尔)。该反应液在室温下反应搅拌6小时，待反应完全后，用乙酸乙酯(150毫升)稀释，并用水(30毫升×2次)洗涤，饱和食盐水(30毫升×1次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得到394.8毫克淡黄色油状物4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-羧酸叔丁酯(收率：66.8％)。LC-MS:RT＝2.77min,[M-Boc] +＝340.18。 At room temperature, tert-butyl 4-(4-fluoro-3-hydroxyphenyl)piperidine-1-carboxylate (396.8 mg, 1.3 mmol) and 6-(bromomethyl)-1-methyl-1H -Indazole (438.7 mg, 1.9 mmol) was dissolved in N,N-dimethylformamide (4 mL) and anhydrous potassium carbonate (542.1 mg, 3.9 mmol) was added. The reaction solution was stirred at room temperature for 6 hours. After the reaction was completed, it was diluted with ethyl acetate (150 mL), washed with water (30 mL×2 times), and washed with saturated brine (30 mL×1 time), then It was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 394.8 mg of 4-(4-fluoro-3-((1-methyl-1H) as a pale yellow oily substance -Indazol-6-yl)methoxy)phenyl)piperidine-1-carboxylate tert-butyl ester (yield: 66.8%). LC-MS: RT=2.77 min, [M-Boc] + =340.18.
步骤E：合成6-((2-氟-5-(哌啶-4-基)苯氧基)甲基)-1-甲基-1H-吲唑Step E: Synthesis of 6-((2-Fluoro-5-(piperidin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000087
Figure PCTCN2021120978-appb-000087
室温下，将4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-羧酸叔丁酯(394.8毫克，0.9毫摩尔)溶解在30％三氟乙酸/二氯甲烷(5毫升)溶液中。在室温下反应2小时，待反应完全后，减压浓缩得到295.3毫克淡黄色油状物6-((2-氟-5-(哌啶-4-基)苯氧基)甲基)-1-甲基-1H-吲唑(收率：95.8％)。LC-MS:RT＝1.57min,[M+H] +＝340.18。 At room temperature, tert-butyl 4-(4-fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidine-1-carboxylate (394.8 mg, 0.9 mmol) in 30% trifluoroacetic acid/dichloromethane (5 mL). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, concentrated under reduced pressure to obtain 295.3 mg of pale yellow oily substance 6-((2-fluoro-5-(piperidin-4-yl)phenoxy)methyl)-1- Methyl-1H-indazole (yield: 95.8%). LC-MS: RT=1.57 min, [M+H] + =340.18.
步骤F：合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step F: Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl ) methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000088
Figure PCTCN2021120978-appb-000088
室温下，将6-((2-氟-5-(哌啶-4-基)苯氧基)甲基)-1-甲基-1H-吲唑(165.3毫克，0.5毫摩尔)和(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(176.8毫克，0.6毫摩尔)溶解在N,N-二甲基甲酰胺(4毫升)溶液中，随后加入无水碳酸钾(208.5毫克，1.5毫摩尔)。该反应液在室温下反应6小时后，加入乙酸乙酯(150毫升)稀释，并用水(30毫升×2次)洗涤，饱和食盐水(30毫升×1次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝15/1)，得到180.2毫克淡黄色油状物(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：62.5％)。LC-MS:RT＝2.32min,[M+H] +＝598.29。 At room temperature, 6-((2-fluoro-5-(piperidin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole (165.3 mg, 0.5 mmol) and (S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (176.8 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (4 mL) solution, followed by anhydrous potassium carbonate (208.5 mg, 1.5 mmol). The reaction solution was reacted at room temperature for 6 hours, diluted with ethyl acetate (150 mL), washed with water (30 mL×2 times), saturated brine (30 mL×1 time), and then washed with anhydrous sodium sulfate It was dried and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1) to obtain 180.2 mg of (S)-2-((4-(4-fluoro-3-() as a pale yellow oily substance. (1-Methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzene and [d]imidazole-6-carboxylic acid methyl ester (yield: 62.5%). LC-MS: RT=2.32 min, [M+H] + =598.29.
步骤G：合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step G: Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl ) methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000089
Figure PCTCN2021120978-appb-000089
室温下，将(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(180.2毫克，0.3毫摩尔)溶解在四氢呋喃/水/乙醇＝3：1：1(8毫升)混合溶剂中，随后加入氢氧化钠(120.0毫克，3毫摩尔)。该反应液在室温下搅拌反应过夜，待反应完全后，在冰浴条件下，用1M的柠檬酸水溶液调节溶液pH到3-4。随后加入乙酸乙酯(150毫升)稀释，并用水(30毫升×2次)洗涤，饱和食盐水(30毫升×1次)洗涤，然后用无水硫酸钠干燥，最后减压 浓缩。所得残余物反相HPLC(流动相：水/乙腈＝90/10到5/95)进行纯化，冻干得到94.3毫克白色固体(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-6-基)甲氧基)苯基)哌啶-1-基)甲基-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：52.3％)。LC-MS:RT＝1.84min,[M+H] +＝584.28。 At room temperature, (S)-2-((4-(4-fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl ) methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (180.2 mg, 0.3 mmol) was dissolved in tetrahydrofuran/water/ethanol= 3:1:1 (8 ml) mixed solvent, then sodium hydroxide (120.0 mg, 3 mmol) was added. The reaction solution was stirred at room temperature and reacted overnight. After the reaction was completed, under ice bath conditions, 1 M citric acid aqueous solution to adjust the pH of the solution to 3-4. Then add ethyl acetate (150 mL) to dilute, and wash with water (30 mL × 2 times), saturated brine (30 mL × 1 time), and then wash with anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC (mobile phase: water/acetonitrile = 90/10 to 5/95) and lyophilized to give 94.3 mg of white solid (S)-2-((4 -(4-Fluoro-3-((1-methyl-1H-indazol-6-yl)methoxy)phenyl)piperidin-1-yl)methyl-1-(oxetan-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 52.3%). LC-MS: RT=1.84 min, [M+H] + =584.28.
实施例10Example 10
合成(S)-2-((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000090
Figure PCTCN2021120978-appb-000090
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6-(((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(6-(((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000091
Figure PCTCN2021120978-appb-000091
室温下，将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(150.0毫克，0.50毫摩尔)、(2-甲基喹啉-6-基)甲醇(130.0毫克，0.75毫摩尔)和碳酸铯(326.0毫克，1.00毫摩尔)加入二氧六环(5.0毫升)中，再依次加入2-二环己基磷-2,4,6-三异丙基联苯(47.0毫克，0.1毫摩尔)、三(二亚苄基丙酮)二钯(46.0毫克，0.05毫摩尔)，N 2保护下，95摄氏度反应3.0小时。 At room temperature, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (150.0 mg, 0.50 mmol), (2-methylquinolin-6-yl)methanol (130.0 mg , 0.75 mmol) and cesium carbonate (326.0 mg, 1.00 mmol) were added to dioxane (5.0 mL), followed by 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl ( 47.0 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (46.0 mg, 0.05 mmol), under N2 protection, react at 95 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1)，得到67.0毫克淡黄色固体4-(6-(((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：31.0％)。LC-MS:RT＝1.93min,[M+H] +＝434.27。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (30 mL×L), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×L), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1) to obtain 67.0 mg of pale yellow solid 4-(6-(((2-methylquinolin-6-yl )methoxy)pyridin-2-yl)piperidine-1-carboxylate tert-butyl ester (yield: 31.0%). LC-MS: RT=1.93 min, [M+H] + =434.27.
步骤B：合成2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉Step B: Synthesis of 2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
Figure PCTCN2021120978-appb-000092
Figure PCTCN2021120978-appb-000092
室温下，将4-(6-(((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(67.0毫克，0.15毫摩尔)加入二氧六环的盐酸溶液(1.00毫摩尔/毫升，5毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(6-(((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (67.0 mg, 0.15 mmol) Dioxane hydrochloric acid solution (1.00 mmol/mL, 5 mL) was added, and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
反应结束，减压浓缩。得到50.0毫克乳白色固体2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(收率：97.4％)直接用于下步反应。LC-MS:RT＝1.52min,[M+H] +＝334.22。 After the reaction was completed, it was concentrated under reduced pressure. 50.0 mg of milky white solid was obtained. 2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (yield: 97.4%) was used directly next reaction. LC-MS: RT=1.52 min, [M+H] + =334.22.
步骤C：合成(S)-2-(((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of (S)-2-(((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000093
Figure PCTCN2021120978-appb-000093
室温下，将2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(50.0毫克，0.15毫摩尔)、(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(44.1毫克，0.15毫摩尔)和碳酸铯(48.9毫克，0.15毫摩尔)加入N,N-二甲基甲酰胺(10.0毫升)中，最后加入N,N-二异丙基乙胺，N 2保护下，50摄氏度 反应4.0小时。 2-Methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (50.0 mg, 0.15 mmol), (S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (44.1 mg, 0.15 mmol) and carbonic acid Cesium (48.9 mg, 0.15 mmol) was added to N,N-dimethylformamide (10.0 mL), and finally N,N-diisopropylethylamine was added, and the reaction was carried out at 50 degrees Celsius for 4.0 hours under the protection of N 2 .
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到70.0毫克淡黄色固体(S)-2-(((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：79.0％)。LC-MS:RT＝1.65min,[M+H] +＝592.23。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 70.0 mg pale yellow solid (S)-2-(((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (yield: 79.0%). LC-MS: RT=1.65 min, [M+H] + =592.23.
步骤D：合成(S)-2-((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000094
Figure PCTCN2021120978-appb-000094
室温下，向含有(S)-2-(((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(70.0毫克，0.12毫摩尔)的四氢呋喃(3.0毫升)中滴加氢氧化锂(20.0毫克，0.48毫摩尔)水溶液(1.0毫升)，最后加入(1.0毫升)的甲醇，室温下反应1.0小时。At room temperature, the solution containing (S)-2-(((4-(6-((2-methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (70.0 mg, 0.12 mmol) in tetrahydrofuran (3.0 mL) was added dropwise Lithium hydroxide (20.0 mg, 0.48 mmol) aqueous solution (1.0 mL), and finally methanol (1.0 mL) was added, and the reaction was carried out at room temperature for 1.0 h.
反应结束，加水淬灭，用氯化铵水溶液(0.5摩尔/升)调pH至6，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相先用氯化铵水溶液(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝10：1)得到56.0毫克淡黄色固体(S)-2-((4-(6-((2-甲基喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：80.0％)。LC-MS:RT＝1.57min,[M+H] +＝578.32。 1H NMR(500MHz,DMSO)δ8.28(dd,J＝1.5,0.6Hz,1H),8.18(d,J＝8.4Hz,1H),7.99(d,J＝1.6Hz,1H),7.90(d,J＝8.7Hz,1H),7.82(dd,J＝8.4,1.6Hz,1H),7.78(dd,J＝8.7,2.0Hz,1H),7.69–7.65(m,1H),7.64–7.62(m,1H),7.33(d,J＝8.4Hz,1H),6.87(d,J＝7.1Hz,1H),6.72(dd,J＝8.2,0.6Hz,1H),5.53(d,J＝1.8Hz,2H),5.12(qd,J＝7.6,3.1Hz,1H),4.81(dd,J＝15.2,7.2Hz,1H),4.67(dd,J＝15.2,2.9Hz,1H),4.50–4.43(m,1H),4.37(dt,J＝9.0,5.8Hz,1H),3.96(d,J＝13.7Hz,1H),3.79(d,J＝13.5Hz,1H),3.01(d,J＝13.0Hz,2H),2.87(d,J＝12.2Hz,1H),2.74–2.65(m,1H),2.63(s,3H),2.48–2.40(m,1H),2.28–2.15(m,2H),1.86–1.66(m,4H)。 After the reaction was completed, water was added to quench, and the pH was adjusted to 6 with an aqueous ammonium chloride solution (0.5 mol/L). (30 mL×L), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10: 1) to obtain 56.0 mg of pale yellow solid (S)-2- ((4-(6-((2-Methylquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 80.0%). LC-MS: RT=1.57 min, [M+H] + =578.32. 1 H NMR (500MHz, DMSO) δ 8.28 (dd, J=1.5, 0.6Hz, 1H), 8.18 (d, J=8.4Hz, 1H), 7.99 (d, J=1.6Hz, 1H), 7.90 ( d, J=8.7Hz, 1H), 7.82 (dd, J=8.4, 1.6Hz, 1H), 7.78 (dd, J=8.7, 2.0Hz, 1H), 7.69–7.65 (m, 1H), 7.64–7.62 (m,1H),7.33(d,J=8.4Hz,1H),6.87(d,J=7.1Hz,1H),6.72(dd,J=8.2,0.6Hz,1H),5.53(d,J= 1.8Hz, 2H), 5.12 (qd, J=7.6, 3.1Hz, 1H), 4.81 (dd, J=15.2, 7.2Hz, 1H), 4.67 (dd, J=15.2, 2.9Hz, 1H), 4.50– 4.43(m,1H),4.37(dt,J=9.0,5.8Hz,1H),3.96(d,J=13.7Hz,1H),3.79(d,J=13.5Hz,1H),3.01(d,J ＝13.0Hz, 2H), 2.87(d, J＝12.2Hz, 1H), 2.74-2.65(m, 1H), 2.63(s, 3H), 2.48-2.40(m, 1H), 2.28-2.15(m, 2H), 1.86–1.66 (m, 4H).
实施例11Example 11
合成(S)-2-((4-(6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000095
Figure PCTCN2021120978-appb-000095
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000096
Figure PCTCN2021120978-appb-000096
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克,0.20毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(1-甲基-1H-吲唑-5-基)甲醇(40毫克,0.24毫摩尔),叔丁醇钠(66毫克,0.4毫摩尔),1,1'-联萘-2,2'-双二苯膦(39毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(27毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌2小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.20 mmol) was dissolved in 1,4-dioxane (10.0 mL), and (1-methyl-1H-indazole- 5-yl)methanol (40 mg, 0.24 mmol), sodium tert-butoxide (66 mg, 0.4 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (39 mg, 0.040 mmol) mol) and tris(dibenzylideneacetone)dipalladium (27 mg, 0.020 mmol) were added to the reaction flask, and after nitrogen protection, stirred at 100 degrees Celsius for 2 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到80毫克黄色固体(S)-2-((4-(6-(((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：64.5％)。LC-MS：RT＝1.83min,[M+H] +＝623.19。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 80 mg of yellow solid (S)-2-((4-(6-((((1-methyl- 1H-Indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] tert-butyl imidazole-6-carboxylate (yield: 64.5%). LC-MS: RT=1.83 min, [M+H] + =623.19.
步骤B：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000097
Figure PCTCN2021120978-appb-000097
将(S)-2-((4-(6-(((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.13毫摩尔)溶于二氯甲烷(7.5毫升)中,然后将三氟乙酸(0.5毫升)加入反应液中,室温搅拌2小时后,LC-MS监测至反应完全。(S)-2-((4-(6-(((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.13 mmol) in dichloromethane (7.5 mL) Then, trifluoroacetic acid (0.5 mL) was added to the reaction solution, and after stirring at room temperature for 2 hours, LC-MS was monitored until the reaction was complete.
反应液室温室温旋干,粗品用乙酸乙酯(1.0毫升)溶解,然后缓慢滴加到正己烷(15.0毫升)中,析出大量黄色固体,过滤,滤饼用正己烷(15.0毫升)洗涤三次,收集滤饼得到30毫克黄色固体(S)-2-((4-(6-((1-甲基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：41.1％)。LC-MS：RT＝1.72min,[M+H] +＝567.33。 1H NMR(500MHz,DMSO-d6)：δ12.72(s,1H),8.28(d,J＝1.0Hz,1H),8.02(s,1H),7.84(s,1H),7.81(dd,J＝8.4,1.5Hz,1H),7.69–7.58(m,3H),7.50(dd,J＝8.7,1.4Hz,1H),6.86(d,J＝7.3Hz,1H),6.65(d,J＝8.1Hz,1H),5.45(d,J＝2.4Hz,2H),5.13(dd,J＝7.2,2.7Hz,1H),4.81(dd,J＝15.3,7.2Hz,1H),4.67(dd,J＝15.1,2.7Hz,1H),4.51–4.29(m,2H),4.13–3.91(m,4H),3.80(d,J＝13.5Hz,1H),3.03(d,J＝11.8Hz,1H),2.88(d,J＝10.8Hz,1H),2.79–2.58(m,2H),2.49–2.41(m,1H),2.29–2.15(m,2H),1.87–1.67(m,4H)。 The reaction solution was spin-dried at room temperature, the crude product was dissolved in ethyl acetate (1.0 mL), and then slowly added dropwise to n-hexane (15.0 mL), a large amount of yellow solid was precipitated, filtered, and the filter cake was washed three times with n-hexane (15.0 mL), The filter cake was collected to give 30 mg of yellow solid (S)-2-((4-(6-((1-methyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 41.1%). LC-MS: RT=1.72 min, [M+H] + =567.33. 1 H NMR (500MHz, DMSO-d6): δ 12.72 (s, 1H), 8.28 (d, J=1.0 Hz, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.81 (dd, J=8.4,1.5Hz,1H),7.69–7.58(m,3H),7.50(dd,J=8.7,1.4Hz,1H),6.86(d,J=7.3Hz,1H),6.65(d,J ＝8.1Hz,1H),5.45(d,J＝2.4Hz,2H),5.13(dd,J＝7.2,2.7Hz,1H),4.81(dd,J＝15.3,7.2Hz,1H),4.67(dd , J=15.1, 2.7Hz, 1H), 4.51–4.29 (m, 2H), 4.13–3.91 (m, 4H), 3.80 (d, J=13.5Hz, 1H), 3.03 (d, J=11.8Hz, 1H), 2.88(d, J=10.8Hz, 1H), 2.79–2.58 (m, 2H), 2.49–2.41 (m, 1H), 2.29–2.15 (m, 2H), 1.87–1.67 (m, 4H) .
实施例12Example 12
合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000098
Figure PCTCN2021120978-appb-000098
具体合成路线如下：The specific synthetic route is as follows:
步骤A:合成5-((5-溴-2-氟苯氧)甲基)-1-甲基-1H-吲唑Step A: Synthesis of 5-((5-bromo-2-fluorophenoxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000099
Figure PCTCN2021120978-appb-000099
冰浴下，将偶氮二羧酸二异丙酯(130毫克，0.65毫摩尔)和三苯基磷(1500毫克，5.24毫摩尔)加入到10毫升干燥的四氢呋喃溶剂中，冰浴下搅拌10分钟后，再分别加入(1-甲基-1H-吲唑-5-基)甲醇(300毫克，1.85毫摩尔)和5-溴-2-氟苯酚(386毫克，2.04毫摩尔)，加毕，室温反应10小时。Under ice bath, diisopropyl azodicarboxylate (130 mg, 0.65 mmol) and triphenylphosphine (1500 mg, 5.24 mmol) were added to 10 mL of dry tetrahydrofuran solvent, and stirred for 10 under ice bath. After min, (1-methyl-1H-indazol-5-yl)methanol (300 mg, 1.85 mmol) and 5-bromo-2-fluorophenol (386 mg, 2.04 mmol) were added separately, and the addition was complete. , and react at room temperature for 10 hours.
反应结束后，加入20毫升乙酸乙酯萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝10/1)，得310毫克白色固体5-((5-溴-2-氟苯氧)甲基)-1-甲基-1H-吲唑(收率：50.2％)。LC-MS：RT＝2.01min，[M-H] -＝333.10。 After the reaction, 20 ml of ethyl acetate was added for extraction, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (n-hexane/ethyl acetate=10/1) to obtain 310 mg of white solid 5-((5-bromo-2-fluorophenoxy)methyl)-1-methyl-1H-indazole ( Yield: 50.2%). LC-MS: RT = 2.01 min, [MH] − = 333.10.
步骤B:合成4-(4-氟-3-((1-甲基-1H-吲唑-5-基)加氧)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯Step B: Synthesis of 4-(4-fluoro-3-((1-methyl-1H-indazol-5-yl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxyl tert-butyl acid
Figure PCTCN2021120978-appb-000100
Figure PCTCN2021120978-appb-000100
室温下，将中间体5-((5-溴-2-氟苯氧)甲基)-1-甲基-1H-吲唑(450毫克，1.35毫摩尔)以及N-叔丁氧羰基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(500毫克，1.62毫摩尔)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(98.5毫克，0.135毫摩尔)，碳酸钠(280毫克，2.70毫摩尔)加入至10毫升二氧六环/水(4/1)的混合溶液中，N 2保护下升温至100摄氏度反应2小时。 At room temperature, the intermediate 5-((5-bromo-2-fluorophenoxy)methyl)-1-methyl-1H-indazole (450 mg, 1.35 mmol) and N-tert-butoxycarbonyl-1 ,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (500 mg, 1.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 98.5 mg, 0.135 mmol), sodium carbonate (280 mg, 2.70 mmol) were added to 10 ml of a mixed solution of dioxane/water (4/1), and the temperature was raised to 100 degrees Celsius under the protection of N 2 for 2 hours.
反应结束后，蒸干反应液，乙酸乙酯萃取，萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝10/1)，得310毫克白色固体4-(4-氟-3-((1-甲基-1H-吲唑-5-基)加氧)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(收率：50.2％)。LC-MS：RT＝2.21min，[M-55] -＝382.21。 After the reaction, the reaction solution was evaporated to dryness, extracted with ethyl acetate, extracted, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (n-hexane/ethyl acetate = 10/1) to give 310 mg of white solid 4-(4-fluoro-3-((1-methyl-1H-indazol-5-yl)oxygenated) Phenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (yield: 50.2%). LC-MS: RT = 2.21 min, [M-55] − = 382.21.
步骤C:合成5-((2-氟-5-(1,2,3,6-四氢吡啶-4-基)苯氧)甲基)-1-甲基-1H-吲唑Step C: Synthesis of 5-((2-Fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000101
Figure PCTCN2021120978-appb-000101
室温下，将中间体4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(35毫克，0.08毫摩尔)溶于10mL甲醇中，冰浴下加入5毫升4M/L的盐酸二氧六环溶液，室温反应2小时。At room temperature, the intermediate 4-(4-fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-3,6-dihydropyridine-1(2H )-tert-butyl formate (35 mg, 0.08 mmol) was dissolved in 10 mL of methanol, 5 mL of 4M/L hydrochloric acid dioxane solution was added under ice bath, and the reaction was carried out at room temperature for 2 hours.
反应结束后，蒸干反应液得28毫克白色固体5-((2-氟-5-(1,2,3,6-四氢吡啶-4-基)苯氧)甲基)-1-甲基-1H-吲唑(收率：93.6％)。LC-MS：RT＝1.66min，[M+H] +＝338.22。 After the reaction, the reaction solution was evaporated to dryness to obtain 28 mg of white solid 5-((2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy)methyl)-1-methyl yl-1H-indazole (yield: 93.6%). LC-MS: RT=1.66 min, [M+H] + =338.22.
步骤D：合成(S)-2-((4-(4-氟-3-((1-甲基-1H吲唑-5-基甲氧)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step D: Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1Hindazol-5-ylmethoxy)phenyl)-3,6-dihydropyridine- 1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000102
Figure PCTCN2021120978-appb-000102
室温下，将中间体5-((2-氟-5-(1,2,3,6-四氢吡啶-4-基)苯氧)甲基)-1-甲基-1H-吲唑(114毫克，0.31毫摩尔)以及甲基(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(90毫克，0.31毫摩尔)碳酸铯(200毫克，0.62毫摩尔)加入至10毫升DMF溶液中，升温至60摄氏度反应2小时。At room temperature, the intermediate 5-((2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)phenoxy)methyl)-1-methyl-1H-indazole ( 114 mg, 0.31 mmol) and methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (90 mg, 0.31 mmol) cesium carbonate (200 mg, 0.62 mmol) was added to 10 mL of DMF solution, and the temperature was raised to 60 degrees Celsius to react for 2 hours.
反应结束后，将反应液倒入冰水，析出固体，抽滤，水洗滤饼得93毫克白色产品(S)-2-((4-(4-氟-3-((1-甲基-1H吲唑-5-基甲氧)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：51.4％)。LC-MS：RT＝1.77min，[M+H] +＝596.33。 After the reaction was completed, the reaction solution was poured into ice water, the solid was precipitated, suction filtered, and the filter cake was washed with water to obtain 93 mg of white product (S)-2-((4-(4-fluoro-3-((1-methyl- 1Hindazol-5-ylmethoxy)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Methyl benzo[d]imidazole-6-carboxylate (yield: 51.4%). LC-MS: RT=1.77 min, [M+H] + =596.33.
步骤E：合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-3,6-di Hydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000103
Figure PCTCN2021120978-appb-000103
室温下，将(S)-2-((4-(4-氟-3-((1-甲基-1H吲唑-5-基甲氧)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(50毫克，0.084毫摩尔)和氢氧化锂(20.16毫克，0.84毫摩尔)加入至11毫升混合溶剂中(THF/MeOH/H 2O＝5/5/1)，室温反应4小时。 At room temperature, (S)-2-((4-(4-fluoro-3-((1-methyl-1Hindazol-5-ylmethoxy)phenyl)-3,6-dihydropyridine- 1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (50 mg, 0.084 mmol) and Lithium hydroxide (20.16 mg, 0.84 mmol) was added to 11 mL of mixed solvent (THF/MeOH/H 2 O=5/5/1), and the reaction was carried out at room temperature for 4 hours.
反应结束后，将反应液用10毫升乙酸乙酯稀释，倒入水中，用饱和氯化铵溶液调节水相pH至中性，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝30/1)，得30毫克白 色固体(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)-3,6-二氢吡啶-1-(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：61.5％)。LC-MS：RT＝1.72min，[M+H] +＝582.31。 After the reaction, the reaction solution was diluted with 10 ml of ethyl acetate, poured into water, the pH of the aqueous phase was adjusted to neutrality with saturated ammonium chloride solution, the organic layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid . Purified by column chromatography (dichloromethane/methanol=30/1) to give 30 mg of white solid (S)-2-((4-(4-fluoro-3-((1-methyl-1H-indazole- 5-yl)methoxy)phenyl)-3,6-dihydropyridin-1-(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene and [d]imidazole-6-carboxylic acid (yield: 61.5%). LC-MS: RT=1.72 min, [M+H] + =582.31.
步骤F:合成(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(4-Fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000104
Figure PCTCN2021120978-appb-000104
室温下，将甲基(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(50毫克，0.086毫摩尔)溶于10毫升甲醇溶剂中，加入10％的Pd/C(5毫克)，H 2作用下，40摄氏度反应4小时。 At room temperature, methyl(S)-2-((4-(4-fluoro-3-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-3,6 -Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.086 mm mol) was dissolved in 10 ml of methanol solvent, 10% Pd/C (5 mg) was added, and the reaction was carried out at 40 degrees Celsius for 4 hours under the action of H 2 .
反应结束后，抽滤，蒸干滤液得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝30/1)，得20毫克白色固体(S)-2-((4-(4-氟-3-((1-甲基-1H-吲唑-5-基)甲氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：39.8％)。LC-MS：RT＝1.73min，[M+H] +＝584.32。 After the reaction was completed, suction filtration, and the filtrate was evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=30/1) to give 20 mg of white solid (S)-2-((4-(4-fluoro-3-((1-methyl-1H-indazole- 5-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Yield: 39.8%). LC-MS: RT=1.73 min, [M+H] + =584.32.
实施例13Example 13
合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000105
Figure PCTCN2021120978-appb-000105
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000106
Figure PCTCN2021120978-appb-000106
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100.0毫克，0.20毫摩尔)、咪唑并[1,2-a]吡啶-7-基甲醇(30.0毫克，0.20毫摩尔)和叔丁醇钠(40.0毫克，0.4毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(25.0毫克，0.04毫摩尔)、三(二亚苄基丙酮)二钯(18.3毫克，0.02毫摩尔)，N 2保护下，100摄氏度反应3.0小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-methyl)- 1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (100.0 mg, 0.20 mmol), imidazo[1,2-a]pyridin-7-ylmethanol (30.0 mg, 0.20 mmol) and tert-butyl Sodium butoxide (40.0 mg, 0.4 mmol) was added to dioxane (10.0 mL) followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (25.0 mg, 0.04 mmol) , tris(dibenzylideneacetone)dipalladium (18.3 mg, 0.02 mmol), under the protection of N 2 , reacted at 100 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到50.0毫克淡黄色固体(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：41.0％)。LC-MS:RT＝1.63min,[M+H] +＝609.40。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 50.0 mg pale yellow solid (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 41.0%). LC-MS: RT=1.63 min, [M+H] + =609.40.
步骤B：合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000107
Figure PCTCN2021120978-appb-000107
室温下，向含有(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50.0毫克，0.08毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0 毫升)，室温下反应6.0小时。at room temperature, to a compound containing (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50.0 mg, 0.08 mmol) in dichloromethane (8.0 mL) ) was added dropwise trifluoroacetic acid (1.0 mL), and the reaction was carried out at room temperature for 6.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相先用氯化铵水溶液(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝10：1)得到35.0毫克淡黄色固体(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：77.3％)。LC-MS:RT＝1.53min,[M+H] +＝553.34。 The reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL×L), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10: 1) to obtain 35.0 mg of pale yellow solid (S)-2- ((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 77.3%). LC-MS: RT=1.53 min, [M+H] + =553.34.
实施例14Example 14
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000108
Figure PCTCN2021120978-appb-000108
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000109
Figure PCTCN2021120978-appb-000109
室温下，将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(150.0毫克，0.5毫摩尔)、喹啉-6基甲醇(150.0毫克，1.0毫摩尔)和碳酸铯(326.0毫克，1.0毫摩尔)加入二氧六环(10.0毫升)中，再依次加入2-二环己基磷-2,4,6-三异丙基联苯(46.0毫克，0.1毫摩尔)、三(二亚苄基丙酮)二钯(46.0毫克，0.1毫摩尔)，N 2保护下，95摄氏度反应12小时。 At room temperature, combine tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (150.0 mg, 0.5 mmol), quinolin-6ylmethanol (150.0 mg, 1.0 mmol) and carbonic acid Cesium (326.0 mg, 1.0 mmol) was added to dioxane (10.0 mL) followed by 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (46.0 mg, 0.1 mmol) , tris(dibenzylideneacetone)dipalladium (46.0 mg, 0.1 mmol), under N 2 protection, react at 95 degrees Celsius for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(15毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(10毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)，得到153.0毫克淡黄色固体4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：72.1％)。LC-MS:RT＝2.14min,[M+H] +＝420.28。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (15 mL×L), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×L), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 153.0 mg of pale yellow solid 4-(6-(quinolin-6-ylmethoxy)pyridine- 2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 72.1%). LC-MS: RT=2.14 min, [M+H] + =420.28.
步骤B：合成6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉Step B: Synthesis of 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
Figure PCTCN2021120978-appb-000110
Figure PCTCN2021120978-appb-000110
25摄氏度下，将4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(153.0毫克，0.3毫摩尔)溶于二氧六环(2.0毫升)中，零摄氏度下滴加盐酸的二氧六环溶液(8.0毫升，4.0摩尔每升)，N 2保护下，25度反应1小时。 Dissolve tert-butyl 4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate (153.0 mg, 0.3 mmol) in dioxane at 25°C (2.0 mL), a solution of hydrochloric acid in dioxane (8.0 mL, 4.0 mol per liter) was added dropwise at zero degrees Celsius, and the reaction was carried out at 25 degrees for 1 hour under the protection of N 2 .
反应结束，减压浓缩。得到143.0毫克淡黄色固体6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉盐酸盐。无需纯化，直接用于下一步反应。LC-MS:RT＝1.52min,[M+H] +＝320.24 After the reaction was completed, it was concentrated under reduced pressure. 143.0 mg of 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline hydrochloride was obtained as a pale yellow solid. It was used in the next reaction without purification. .LC-MS: RT=1.52min, [M+H] + =320.24
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-6-甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinoline-6-methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000111
Figure PCTCN2021120978-appb-000111
室温下，将6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉盐酸盐(143.0毫克，0.4毫摩尔)，N,N-二异丙基乙胺(0.3毫升)溶于N,N-二甲基甲酰胺(3.0毫升)中，搅拌10分钟后，加入碳酸铯(247.7毫克，0.7毫摩尔)和(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(130.0毫克，0.4毫摩尔)，N 2保护下，50摄氏度反应12小时。 At room temperature, 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline hydrochloride (143.0 mg, 0.4 mmol), N,N - Diisopropylethylamine (0.3 mL) was dissolved in N,N-dimethylformamide (3.0 mL), and after stirring for 10 min, cesium carbonate (247.7 mg, 0.7 mmol) and (S)-2 were added -(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (130.0 mg, 0.4 mmol), N2 protected at 50 degrees Celsius for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(10毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝12/1)得到90.0毫克淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-6-甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(收率：38.2％)。LC-MS:RT＝1.82min,[M+H] +＝620.39 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (10 mL×L). The organic phases were combined, washed with saturated brine (10 mL×L), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=12/1) to obtain 90.0 mg pale yellow solid (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinoline-6-methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 38.2%). LC-MS: RT=1.82 min, [M+H] + = 620.39
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-6-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000112
Figure PCTCN2021120978-appb-000112
零摄氏度下，向(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-6-甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(70.0毫克，0.1毫摩尔)的二氯甲烷(2.0毫升)中滴加三氟乙酸(0.4毫升)，滴加完毕，25摄氏度下反应3小时。At zero degrees Celsius, to (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinoline-6-methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (70.0 mg, 0.1 mmol) in dichloromethane (2.0 mL) was added dropwise trifluoroacetic acid (0.4 ml), the dropwise addition was completed, and the reaction was carried out at 25 degrees Celsius for 3 hours.
反应结束后，室温下旋干溶剂，TLC分离(二氯甲烷/甲醇＝10/1)得到7.12毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：12.6％)。LC-MS:RT＝1.63min,[M+H]+＝564.35。After the reaction was completed, the solvent was spin-dried at room temperature, and separated by TLC (dichloromethane/methanol=10/1) to obtain 7.12 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-( (4-(6-(Quinolin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield : 12.6%). LC-MS: RT=1.63 min, [M+H]+=564.35.
实施例15Example 15
合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000113
Figure PCTCN2021120978-appb-000113
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-甲基苯并[d]噁唑-6-羧酸甲酯Step A: Synthesis of methyl 2-methylbenzo[d]oxazole-6-carboxylate
Figure PCTCN2021120978-appb-000114
Figure PCTCN2021120978-appb-000114
将2-甲基苯并[d]噁唑-6-羧酸(120毫克,0.68毫摩尔)溶于甲醇(5.0毫升)中,氮气保护后,零摄氏度下将草酰氯(0.1毫升,1.3毫摩尔)缓慢滴加入反应瓶中,室温搅拌1小时。2-Methylbenzo[d]oxazole-6-carboxylic acid (120 mg, 0.68 mmol) was dissolved in methanol (5.0 mL), and oxalyl chloride (0.1 mL, 1.3 mmol) was added under nitrogen protection at zero degrees Celsius. mol) was slowly added dropwise to the reaction flask and stirred at room temperature for 1 hour.
向反应液加碳酸氢钠溶液(5.0毫升),混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物即产物粗品,得到120毫克黄色固体2-甲基苯并[d]噁唑-6-羧酸甲酯(收率：91.5％)。LCMS：RT＝1.82min,[M+H] +＝192.13。 Sodium bicarbonate solution (5.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20.0 mL×3 times), the organic phases were combined, and the organic phase was washed with saturated brine (15.0 mL×3 times), anhydrous sodium sulfate Dry and concentrate under reduced pressure. The obtained residue was the crude product, and 120 mg of methyl 2-methylbenzo[d]oxazole-6-carboxylate was obtained as a yellow solid (yield: 91.5%). LCMS: RT=1.82 min, [M+H] + =192.13.
步骤B：合成(2-甲基苯并[d]噁唑-6-基)甲醇Step B: Synthesis of (2-methylbenzo[d]oxazol-6-yl)methanol
Figure PCTCN2021120978-appb-000115
Figure PCTCN2021120978-appb-000115
将2-甲基苯并[d]噁唑-6-羧酸甲酯(120毫克,0.67毫摩尔)溶于四氢呋喃(10.0毫升)中,零下20摄氏度下搅拌15分钟后，将四氢锂铝(38毫克,1.0毫摩尔)加入反应液中,零下20摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 2-methylbenzo[d]oxazole-6-carboxylate (120 mg, 0.67 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at minus 20 degrees Celsius, lithium aluminum tetrahydrogen (38 mg, 1.0 mmol) was added to the reaction solution, stirred at minus 20 degrees Celsius for 30 minutes, and monitored by LC-MS until the reaction was complete.
向反应液加水(2.0毫升)，析出大量白色固体，向反应液中加无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物即产物粗品，经硅胶柱层析纯化得到50毫克黄色固体(2-甲基苯并[d]噁唑-6-基)甲醇(收率：45.8％)。LC-MS：RT＝1.50min,[M+H] +＝164.11。 Water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue, the crude product, was purified by silica gel column chromatography to obtain 50 mg of yellow solid (2-methylbenzo[d]oxazol-6-yl)methanol (yield: 45.8%). LC-MS: RT=1.50 min, [M+H] + =164.11.
步骤C：合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000116
Figure PCTCN2021120978-appb-000116
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.16毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(2-甲基苯并[d]噁唑-6-基)甲醇(29毫克,0.20毫摩尔),叔丁醇钠(30毫克,0.32毫摩尔),1,1'-联萘-2,2'-双二苯膦(26毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌2小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (10.0 mL), and (2-methylbenzo[d]oxa oxazol-6-yl)methanol (29 mg, 0.20 mmol), sodium tert-butoxide (30 mg, 0.32 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26 mg, 0.040 mmol) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.020 mmol) were added to the reaction flask. After nitrogen protection, the mixture was stirred at 100 degrees Celsius for 2 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到50毫克黄色固体(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：51.5％)。LC-MS：RT＝1.86min,[M+H] +＝624.39。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 50 mg of yellow solid (S)-2-((4-(6-((2-methylbenzoic acid) [d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-yl)methyl)-1H-benzene and [d]imidazole-6-carboxylate tert-butyl ester (yield: 51.5%). LC-MS: RT=1.86 min, [M+H] + =624.39.
步骤D：合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000117
Figure PCTCN2021120978-appb-000117
将(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50毫克,0.080毫摩尔)溶于甲醇(5.0毫升)中,然后将氢氧化钾的水溶液(2N,2.0毫升)加入反应液中,50摄氏度搅拌3小时。(S)-2-((4-(6-((2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan (50 mg, 0.080 mmol) in methanol (5.0 mL) , and then an aqueous solution of potassium hydroxide (2N, 2.0 mL) was added to the reaction solution and stirred at 50°C for 3 hours.
向反应液中加二氯甲烷(30.0毫升)稀释，加饱和氯化铵溶液(5.0毫升),分液，水相用二氯甲烷(20.0毫升×3次)萃取三次，合并有机相，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到9毫克黄色固体(S)-2-((4-(6-((2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：20.0％)。LC-MS：RT＝1.72min,[M+H] +＝568.26。 1H NMR(500MHz,DMSO-d6)：δ12.68(s,1H),8.29(s,1H),7.82(dd,J＝8.4,1.5Hz,1H),7.75(s,1H),7.69–7.62(m,3H),7.45(dd,J＝8.1,1.3Hz,1H),6.88(d,J＝7.3Hz,1H),6.69(d,J＝8.1Hz,1H),5.47(s,2H),5.18–5.09(m,1H),4.82(dd,J＝15.2,7.2Hz,1H),4.69(dd,J＝15.2,2.6Hz,1H),4.52–4.35(m,2H),3.03(d,J＝14.0Hz,3H),2.88(d,J＝11.1Hz,1H),2.79–2.61(m,2H),2.60(s,3H),2.50–2.41(m,1H),2.24(dt,J＝21.3,10.2Hz,2H),1.92–1.68(m,4H)。 Dichloromethane (30.0 mL) was added to the reaction solution to dilute, saturated ammonium chloride solution (5.0 mL) was added, the layers were separated, the aqueous phase was extracted three times with dichloromethane (20.0 mL×3 times), the organic phases were combined, Dry over sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 9 mg of yellow solid (S)-2-((4-(6-((2-methylbenzoic acid) [d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Imidazole-6-carboxylic acid (yield: 20.0%). LC-MS: RT=1.72 min, [M+H] + =568.26. 1 H NMR (500 MHz, DMSO-d6): δ 12.68 (s, 1H), 8.29 (s, 1H), 7.82 (dd, J=8.4, 1.5 Hz, 1H), 7.75 (s, 1H), 7.69– 7.62(m, 3H), 7.45(dd, J=8.1, 1.3Hz, 1H), 6.88(d, J=7.3Hz, 1H), 6.69(d, J=8.1Hz, 1H), 5.47(s, 2H ), 5.18–5.09 (m, 1H), 4.82 (dd, J=15.2, 7.2Hz, 1H), 4.69 (dd, J=15.2, 2.6Hz, 1H), 4.52–4.35 (m, 2H), 3.03 ( d, J=14.0Hz, 3H), 2.88 (d, J=11.1Hz, 1H), 2.79–2.61 (m, 2H), 2.60 (s, 3H), 2.50–2.41 (m, 1H), 2.24 (dt , J = 21.3, 10.2 Hz, 2H), 1.92–1.68 (m, 4H).
实施例16Example 16
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000118
Figure PCTCN2021120978-appb-000118
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000119
Figure PCTCN2021120978-appb-000119
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100.0毫克，0.20毫摩尔)、喹啉-4-基甲醇(31.8毫克，0.20毫摩尔)和叔丁醇钠(40.0毫克，0.4毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(25.0毫克，0.04毫摩尔)、三(二亚苄基丙酮)二钯(18.3毫克，0.02毫摩尔)，N 2保护下，100摄氏度反应3.0小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (100.0 mg, 0.20 mmol), quinolin-4-ylmethanol (31.8 mg, 0.20 mmol) and sodium tert-butoxide (40.0 mg, 0.4 mmol) was added to dioxane (10.0 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (25.0 mg, 0.04 mmol), tris(dibenzylidene) acetone) dipalladium (18.3 mg, 0.02 mmol), under N 2 protection, reacted at 100 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到24.0毫克淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：19.3％)。LCMS:RT＝1.79min,[M+H] +＝620.39。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 24.0 mg pale yellow solid (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl) )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 19.3%). LCMS: RT=1.79 min, [M+H] + = 620.39.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-4-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000120
Figure PCTCN2021120978-appb-000120
室温下，向含有(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50.0毫克，0.08毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应1.0小时。at room temperature, to a compound containing (S)-2-((4-(6-(imidazo[1,2-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50.0 mg, 0.08 mmol) in dichloromethane (8.0 mL) ) was added dropwise trifluoroacetic acid (1.0 mL), and the reaction was carried out at room temperature for 1.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相先用氯化铵水溶液(30毫升×升次)洗涤，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由8％乙腈在5.10分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得5.11毫克淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：27.5％)。LC-MS:RT＝1.63min,[M+H] +＝564.33。 The reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL×L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 8% acetonitrile at 5.10 minutes come out; detection wavelength: 254nm. After purification, lyophilized at low temperature to obtain 5.11 mg of pale yellow solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-4-ylmethoxy) )pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 27.5%). LC-MS: RT=1.63 min, [M+H] + =564.33.
实施例17Example 17
合成(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000121
Figure PCTCN2021120978-appb-000121
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000122
Figure PCTCN2021120978-appb-000122
将5-(氨基甲基)吲哚(28毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，瞬速升温至100摄氏度,搅拌1小时。5-(Aminomethyl)indole (28 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl) - tert-butyl 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindeneacetone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was rapidly increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯34毫克(收率：29.6％)。LC-MS：RT＝1.66min,[M+H] +＝607.39。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, and then saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A white solid (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester 34 mg (yield: 29.6%). LC-MS: RT=1.66 min, [M+H] + =607.39.
步骤B：合成(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000123
Figure PCTCN2021120978-appb-000123
将(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(34毫克，0.06毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，室温下搅拌3小时。(S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (34 mg, 0.06 mmol), dissolved in mixed solvent (2 mL, dichloromethane/ Trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at room temperature for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到6毫克白色固体(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：18.5％)。LC-MS：RT＝1.57min,[M+H] +＝551.38。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC preparative instrument to obtain 6 mg of white solid (S)-2-((4-(6-(((1H-indol-5-yl)methyl)amino)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 18.5%). LC-MS: RT=1.57 min, [M+H] + =551.38.
实施例18Example 18
合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000124
Figure PCTCN2021120978-appb-000124
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000125
Figure PCTCN2021120978-appb-000125
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.16毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将咪唑并[1,2-a]吡啶-6-基甲醇(29毫克,0.20毫摩尔),叔丁醇钠(30毫克,0.32毫摩尔),1,1'-联萘-2,2'-双二苯膦(26毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌2小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (10.0 mL) and the imidazo[1,2-a]pyridine- 6-ylmethanol (29 mg, 0.20 mmol), sodium tert-butoxide (30 mg, 0.32 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26 mg, 0.040 mmol) ) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.020 mmol) were added to the reaction flask, and after nitrogen protection, stirred at 100 degrees Celsius for 2 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到50毫克黄色固体叔丁基(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：51.5％)。LC-MS：RT＝1.63min,[M+H] +＝609.37。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20/1) to obtain 50 mg of tert-butyl(S)-2-((4-(6-(imidazo[1) as a yellow solid. ,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Imidazole-6-carboxylic acid (yield: 51.5%). LC-MS: RT=1.63 min, [M+H] + =609.37.
步骤B：合成(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000126
Figure PCTCN2021120978-appb-000126
将(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50毫克,0.080毫摩尔)溶于二氯甲烷(3.0毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌2小时后,LC-MS监测至反应完全。(S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50 mg, 0.080 mmol) was dissolved in dichloromethane (3.0 mL), Then trifluoroacetic acid (0.4 mL) was added to the reaction solution, and after stirring at room temperature for 2 hours, LC-MS was monitored until the reaction was complete.
反应液室温室温旋干,粗品经高效液相制备仪分离纯化得到8毫克黄色液体(S)-2-((4-(6-(咪唑并[1,2-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：18.2％)。LC-MS：RT＝1.52min,[M+H] +＝553.31。 The reaction solution was spin-dried at room temperature, and the crude product was separated and purified by HPLC to obtain 8 mg of yellow liquid (S)-2-((4-(6-(imidazo[1,2-a]pyridin-6-ylmethyl) oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (received rate: 18.2%). LC-MS: RT=1.52 min, [M+H] + =553.31.
实施例19Example 19
合成(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000127
Figure PCTCN2021120978-appb-000127
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000128
Figure PCTCN2021120978-appb-000128
室温下，将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)、(1-乙基-1H-吲唑-5-基)甲醇(34毫克，0.2毫摩尔)、三(二亚苄基丙酮)二钯(18.3毫克，0.02毫摩尔)、1,1'-联萘-2,2'-双二苯膦(19.9毫克，0.032毫摩尔)和叔丁醇钠(30.7毫克，0.32毫摩尔)加入到10毫升干燥的二氧六环溶液中，N 2保护下100摄氏度反应2小时。 At room temperature, (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol), (1-ethyl-1H-indazol-5-yl)methanol (34 mg, 0.2 mmol), Tris(dibenzylideneacetone)dipalladium (18.3 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (19.9 mg, 0.032 mmol) and sodium tert-butoxide ( 30.7 mg, 0.32 mmol) was added to 10 mL of dry dioxane solution and reacted at 100 °C for 2 h under N2 protection.
反应结束后，加入20毫升乙酸乙酯，萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得60毫克白色固体(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：66.8％)。LC-MS：RT＝1.86min，[M+H] +＝637.42. After the reaction, 20 ml of ethyl acetate was added, extracted, and the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 60 mg of white solid (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert. Butyl ester (yield: 66.8%). LC-MS: RT=1.86 min, [M+H] + =637.42.
步骤B:合成(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000129
Figure PCTCN2021120978-appb-000129
室温下，将中间体(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.094毫摩尔)溶于6毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。At room temperature, the intermediate (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.094 mmol) in 6 mL of To the methyl chloride solution, 0.5 ml of trifluoroacetic acid was added dropwise under an ice bath. The reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得25毫克白色固体(S)-2-((4-(6-((1-乙基-1H-吲唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：45.7％)。LC-MS：RT＝1.70min，[M+H] +＝581.35。 After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 25 mg of white solid (S)-2-((4-(6-((1-ethyl-1H-indazol-5-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 45.7%). LC-MS: RT=1.70 min, [M+H] + =581.35.
实施例20Example 20
合成(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000130
Figure PCTCN2021120978-appb-000130
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-甲基-1H-苯并[d]咪唑-5-羧酸甲酯和1-甲基-1H-苯并[d]咪唑-6-羧酸甲酯的混合物Step A: Synthesis of a mixture of methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate
Figure PCTCN2021120978-appb-000131
Figure PCTCN2021120978-appb-000131
零摄氏度下，将1H-苯并[d]咪唑-5-羧酸甲酯(0.95克,5.40毫摩尔),溶于四氢呋喃(10毫升)中，氮气保护下，分批加入氢化钠(0.3克，7.60毫摩尔)，搅拌20分钟，随后缓慢滴加碘甲烷(1.53克，1.08毫摩尔)，升至25摄氏度，搅拌1小时。At zero degrees Celsius, methyl 1H-benzo[d]imidazole-5-carboxylate (0.95 g, 5.40 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (0.3 g) was added in portions under nitrogen protection. , 7.60 mmol), stirred for 20 minutes, then slowly added iodomethane (1.53 g, 1.08 mmol) dropwise, heated to 25 degrees Celsius, and stirred for 1 hour.
反应结束后，冰浴下缓慢加入饱和氯化铵溶液，调节pH至中性，减压浓缩除去四氢呋喃，水相部分用乙酸乙酯(30毫升×3次)萃取，合并有机相，然后用饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)，得白色固体1-甲基-1H-苯并[d]咪唑-5-羧酸甲酯0.77克(收率：75.0％)。LC-MS：RT＝1.15min,[M+H] +＝191.12。 After the reaction, saturated ammonium chloride solution was slowly added under ice bath, adjusted to neutral pH, concentrated under reduced pressure to remove tetrahydrofuran, the aqueous part was extracted with ethyl acetate (30 ml × 3 times), the organic phases were combined, and then saturated Washed with brine (30 mL×3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/2) to obtain a white solid 1-Methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 0.77 g (yield: 75.0%). LC-MS: RT=1.15 min, [M+H] + =191.12.
步骤B：合成(1-甲基-1H-苯并[d]咪唑-5-基)甲醇Step B: Synthesis of (1-methyl-1H-benzo[d]imidazol-5-yl)methanol
Figure PCTCN2021120978-appb-000132
Figure PCTCN2021120978-appb-000132
零摄氏度下，将1-甲基-1H-苯并[d]咪唑-5-羧酸甲酯(0.77克，4.05毫摩尔)溶于四氢呋喃(10毫升)中，氮气保护下，分批加入氢化锂铝(0.77克，20.25毫摩尔),搅拌1小时。Methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (0.77 g, 4.05 mmol) was dissolved in tetrahydrofuran (10 mL) at zero degrees Celsius, hydrogenated in portions under nitrogen Lithium aluminum (0.77 g, 20.25 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.75毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(30毫升×3次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得白色固体(1-甲基-1H-苯并[d]咪唑-5-基)甲醇556毫克(收率：84.7％)。LC-MS：RT＝0.26min,[M+H] +＝163.13。 After the reaction, sodium hydroxide solution (5%, 0.75 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (30 ml × 3 times, dichloromethane/methanol) = 10/1), the organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: two Chloromethane/methanol=10/1). A white solid (1-methyl-1H-benzo[d]imidazol-5-yl)methanol 556 mg was obtained (yield: 84.7%). LC-MS: RT=0.26 min, [M+H] + =163.13.
步骤C：合成(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000133
Figure PCTCN2021120978-appb-000133
将(1-甲基-1H-苯并[d]咪唑-5-基)甲醇(31毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。(1-Methyl-1H-benzo[d]imidazol-5-yl)methanol (31 mg, 0.19 mmol), (S)-2-((((4-(6-chloropyridin-2-yl) )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol ) was dissolved in 1,4-dioxane (1 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene) (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯63毫克(收率：53.2％)。LC-MS：RT＝1.72min,[M+H] +＝623.39。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, and then saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidine-1 was obtained -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 63 mg (yield: 53.2%). LC-MS: RT=1.72 min, [M+H] + =623.39.
步骤D：合成(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000134
Figure PCTCN2021120978-appb-000134
将(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(63毫克，0.10毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (63 mg, 0.10 mmol), dissolved in mixed solvent ( 2 ml, dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到36毫克白色固体(S)-2-((4-(6-((1-甲基-1H-苯并[d]咪唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：59.4％)。LC-MS：RT＝1.55min,[M+H] +＝567.32。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 36 mg of white solid (S)-2-((4-(6-((1-methyl-1H-benzo[d]imidazol-5-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 59.4%). LC-MS: RT=1.55 min, [M+H] + =567.32.
实施例21Example 21
合成(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000135
Figure PCTCN2021120978-appb-000135
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(1-乙基-1H-吲唑-6-基)羧酸甲酯Step A: Synthesis of Methyl (1-ethyl-1H-indazol-6-yl)carboxylate
Figure PCTCN2021120978-appb-000136
Figure PCTCN2021120978-appb-000136
将1H-吲唑-6-羧酸甲酯(200毫克，1.14毫摩尔),碘乙烷溶于甲醇(4毫升)中，加入碳酸钾(304毫克，2.28毫摩尔)，加毕，氮气保护下，快速升温至回流,搅拌12小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.14 mmol), iodoethane was dissolved in methanol (4 mL), potassium carbonate (304 mg, 2.28 mmol) was added, and the addition was complete, under nitrogen protection The temperature was rapidly raised to reflux and stirred for 12 hours.
反应结束后，冷却至室温，减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体(1-乙基-1H-吲唑-6-基)羧酸甲酯105毫克(收率：45.1％)。LC-MS：RT＝1.90min,[M+H] +＝205.16。 After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, 30 ml of ethyl acetate was added to the reaction solution, washed with saturated brine (20 ml × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4). 105 mg of methyl (1-ethyl-1H-indazol-6-yl)carboxylate was obtained as a yellow solid (yield: 45.1%). LC-MS: RT=1.90 min, [M+H] + =205.16.
步骤B：合成(1-乙基-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-ethyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000137
Figure PCTCN2021120978-appb-000137
零摄氏度下，(1-乙基-1H-吲唑-6-基)羧酸甲酯105毫克，0.51毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，分批加入氢化锂铝(78毫克，2.05毫摩尔),搅拌1小时。At zero degrees Celsius, methyl (1-ethyl-1H-indazol-6-yl)carboxylate 105 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride ( 78 mg, 2.05 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.2毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×3次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(1-乙基-1H-吲唑-6-基)甲醇86毫克(收率：95.8％)。LC-MS：RT＝1.73min,[M+H] +＝177.12。 After the reaction, sodium hydroxide solution (5%, 0.2 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × 3 times, dichloromethane/methanol) = 10/1) rinsed, combined the organic phases, then washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained white solid was directly used in the next reaction to obtain (1-ethyl acetate) yl-1H-indazol-6-yl)methanol 86 mg (yield: 95.8%). LC-MS: RT=1.73 min, [M+H] + =177.12.
步骤C：合成(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000138
Figure PCTCN2021120978-appb-000138
将(1-乙基-1H-吲唑-6-基)甲醇(34毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，快速升温至100摄氏度搅拌1小时。Mix (1-ethyl-1H-indazol-6-yl)methanol (34 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1 ,4-dioxane (1 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone) Dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol) were added, and the temperature was rapidly increased to 100 degrees Celsius and stirred for 1 hour under nitrogen protection.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯69毫克(收率：57.1％)。LC-MS：RT＝1.86min,[M+H] +＝637.42。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, and then saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan was obtained yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 69 mg (yield: 57.1%). LC-MS: RT=1.86 min, [M+H] + =637.42.
步骤D：合成(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000139
Figure PCTCN2021120978-appb-000139
将(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(69毫克，0.11毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (69 mg, 0.11 mmol), dissolved in mixed solvent (3 mL, di Chloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到45毫克白色固体(S)-2-((4-(6-((1-乙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：70.4％)。LC-MS：RT＝1.72min,[M+H] +＝581.36。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 45 mg of white solid (S)-2-((4-(6-((1-ethyl-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 70.4 %). LC-MS: RT=1.72 min, [M+H] + =581.36.
实施例22Example 22
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((喹啉-6-基甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((quinolin-6-ylmethyl)amino)pyridin-2-yl)piperidine -1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000140
Figure PCTCN2021120978-appb-000140
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((喹啉-6-基甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step A: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((quinolin-6-ylmethyl)amino)pyridin-2-yl )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000141
Figure PCTCN2021120978-appb-000141
将喹啉-6基甲胺(19毫克，0.12毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.12毫摩尔)，钯催化剂(6毫克，0.006毫摩尔)，1,1'-联萘-2,2'-双二苯膦(37毫克，0.06毫摩尔)和叔丁醇钠(23毫克，0.24毫摩尔)溶于二氧六环(20毫升)中，温度升高到100摄氏度搅拌5个小时。The quinolin-6ylmethanamine (19 mg, 0.12 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.12 mmol), palladium catalyst (6 mg, 0.006 mmol), 1,1'-Binaphthalene-2,2'-bisdiphenylphosphine (37 mg, 0.06 mmol) and sodium tert-butoxide (23 mg, 0.24 mmol) were dissolved in dioxane (20 mL), The temperature was raised to 100°C and stirred for 5 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相制备得到5.89毫克白色固体合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((喹啉-6-基甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：9％)。LC-MS:RT＝1.46min,[M+H] +＝563.34。 After the reaction was completed, suction filtration with diatomaceous earth, washed with dichloromethane and concentrated the organic phase, the obtained crude product was prepared by high-performance liquid phase to obtain 5.89 mg of white solid synthesis (S)-1-(oxetan-2-ylmethyl) yl)-2-((4-(6-((quinolin-6-ylmethyl)amino)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole -6-carboxylic acid (yield: 9%). LC-MS: RT=1.46 min, [M+H] + =563.34.
实施例23Example 23
合成(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000142
Figure PCTCN2021120978-appb-000142
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-乙基-2H-吲唑-6-基)羧酸甲酯Step A: Synthesis of Methyl (2-ethyl-2H-indazol-6-yl)carboxylate
Figure PCTCN2021120978-appb-000143
Figure PCTCN2021120978-appb-000143
将1H-吲唑-6-羧酸甲酯(200毫克，1.14毫摩尔),碘乙烷溶于甲醇(4毫升)中，加入碳酸钾(304毫克，2.28毫摩尔)，加毕，氮气保护下，快速升温至回流,搅拌12小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.14 mmol), iodoethane was dissolved in methanol (4 mL), potassium carbonate (304 mg, 2.28 mmol) was added, the addition was complete, nitrogen protection The temperature was rapidly raised to reflux and stirred for 12 hours.
反应结束后，冷却至室温，减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体(2-乙基-2H-吲唑-6-基)羧酸甲酯51毫克(收率：22.9％)。LC-MS：RT＝1.82min,[M+H] +＝205.14。 After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, 30 ml of ethyl acetate was added to the reaction solution, washed with saturated brine (20 ml × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4). 51 mg of methyl (2-ethyl-2H-indazol-6-yl)carboxylate was obtained as a yellow solid (yield: 22.9%). LC-MS: RT=1.82 min, [M+H] + =205.14.
步骤B：合成(2-乙基-2H-吲唑-6-基)甲醇Step B: Synthesis of (2-ethyl-2H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000144
Figure PCTCN2021120978-appb-000144
零摄氏度下，将(2-乙基-2H-吲唑-6-基)羧酸甲酯51毫克，0.25毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，加入氢化锂铝(38毫克，1.00毫摩尔),搅拌1小时。At zero degrees Celsius, methyl (2-ethyl-2H-indazol-6-yl)carboxylate 51 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (38 mL) was added under nitrogen protection. mg, 1.00 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.1毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×3次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(2-乙基-2H-吲唑-6-基)甲醇42毫克(收率：95.5％)。LC-MS：RT＝1.72min,[M+H] +＝177.11。 After the reaction, sodium hydroxide solution (5%, 0.1 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × 3 times, dichloromethane/methanol) = 10/1) rinsed, combined the organic phases, then washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained white solid was directly used in the next reaction to obtain (2-ethyl acetate) yl-2H-indazol-6-yl)methanol 42 mg (yield: 95.5%). LC-MS: RT=1.72 min, [M+H] + =177.11.
步骤C：合成(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000145
Figure PCTCN2021120978-appb-000145
将(2-乙基-2H-吲唑-6-基)甲醇(34毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，快速升温至100摄氏度搅拌1小时。Mix (2-ethyl-2H-indazol-6-yl)methanol (34 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1 ,4-dioxane (1 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone) Dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol) were added, and the temperature was rapidly increased to 100 degrees Celsius and stirred for 1 hour under nitrogen protection.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯63毫克(收率：52.1％)。LC-MS：RT＝1.86min,[M+H] +＝637.42。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×3 times), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan was obtained yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 63 mg (yield: 52.1%). LC-MS: RT=1.86 min, [M+H] + =637.42.
步骤D：(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000146
Figure PCTCN2021120978-appb-000146
将(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(69毫克，0.11毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (69 mg, 0.11 mmol), dissolved in mixed solvent (3 mL, di Chloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到38毫克白色固体(S)-2-((4-(6-((2-乙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：65.5％)。LC-MS：RT＝1.72min,[M+H] +＝581.36。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 38 mg of white solid (S)-2-((4-(6-((2-ethyl-2H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 65.5 %). LC-MS: RT=1.72 min, [M+H] + =581.36.
实施例24Example 24
合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基-D2)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-Methyl-1H-indazol-6-yl)methoxy-D2)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000147
Figure PCTCN2021120978-appb-000147
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(1-甲基-1H-吲唑-6-基)甲烷-D2醇Step A: Synthesis of (1-methyl-1H-indazol-6-yl)methane-D2 alcohol
Figure PCTCN2021120978-appb-000148
Figure PCTCN2021120978-appb-000148
将1-甲基-1H-吲唑-6-羧酸甲酯(110毫克,0.56毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后，将氘代氢化锂铝(42毫克,1.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 1-methyl-1H-indazole-6-carboxylate (110 mg, 0.56 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring at 0°C for 15 min, deuterated lithium aluminum hydride (42 mg, 1.0 mmol) was added to the reaction solution, stirred at zero degrees Celsius for 30 minutes, and monitored by LC-MS until the reaction was complete.
向反应液加水(2.0毫升)，析出大量白色固体，向反应液中加无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物即产物粗品，经硅胶柱层析纯化得到90毫克白色固体(1-甲基-1H-吲唑-6-基)甲烷-D2醇(收率：97.2％)。LC-MS：RT＝1.56min,[M+H] +＝165.13。 Water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue, the crude product, was purified by silica gel column chromatography to obtain 90 mg of white solid (1-methyl-1H-indazol-6-yl)methane-D2 alcohol (yield: 97.2%). LC-MS: RT=1.56 min, [M+H] + =165.13.
步骤B：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基-D2)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy-D2)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000149
Figure PCTCN2021120978-appb-000149
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.16毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(1-甲基-1H-吲唑-6-基)甲烷-D2醇(50毫克,0.32毫摩尔),叔丁醇钠(31毫克,0.32毫摩尔),1,1'-联萘-2,2'-双二苯膦(30毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(22毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌2小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (10.0 mL) and (1-methyl-1H-indazole- 6-yl)methane-D2 alcohol (50 mg, 0.32 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (30 mg , 0.040 mmol) and tris(dibenzylideneacetone)dipalladium (22 mg, 0.020 mmol) were added to the reaction flask, under nitrogen protection, stirred at 100 degrees Celsius for 2 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到17毫克黄色固体(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基-D2)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：18.8％)。LC-MS：RT＝1.70min,[M+H] +＝569.31。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 17 mg of yellow solid (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy-D2 )pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 18.8%). LC-MS: RT=1.70 min, [M+H] + =569.31.
实施例25Example 25
合成(S)-2-((4-(6-((3-环丙基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Cyclopropyl-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000150
Figure PCTCN2021120978-appb-000150
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-溴-1-甲基-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000151
Figure PCTCN2021120978-appb-000151
将3-溴-1H-吲唑-6-羧酸甲酯(2.50克,10.0毫摩尔)溶于N,N-二甲基甲酰胺(30.0毫升)中,加碳酸钾(2.76克,20.0毫摩尔)，碘甲烷(0.8毫升,12.0毫摩尔)加入反应液中,室温搅拌18小时后,TLC监测至反应完全。Methyl 3-bromo-1H-indazole-6-carboxylate (2.50 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (30.0 mL) and potassium carbonate (2.76 g, 20.0 mmol) was added. mol), iodomethane (0.8 mL, 12.0 mmol) was added to the reaction solution, and after stirring at room temperature for 18 hours, TLC was monitored until the reaction was complete.
向反应液加水(30.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩，所得残余物经硅胶柱层析纯化得到1.5克黄色固体3-溴-1-甲基-1H-吲唑-6-羧酸甲酯(收率：55.7％)。Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL × 3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. After concentration, the obtained residue was purified by silica gel column chromatography to obtain 1.5 g of methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate as a yellow solid (yield: 55.7%).
步骤B：合成3-环丙基-1-甲基-1H-吲唑-6-羧酸甲酯Step B: Synthesis of methyl 3-cyclopropyl-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000152
Figure PCTCN2021120978-appb-000152
将3-溴-1-甲基-1H-吲唑-6-羧酸甲酯(500毫克,1.86毫摩尔)溶于1,4-二氧六环(20.0毫升)和水(5.0毫升)中，依次将环丙基硼酸(300毫克,3.49毫摩尔)，碳酸钾(550毫克,3.99毫摩尔)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(150毫克,0.20毫摩尔)加入反应液中,氮气保护后，100摄氏度下搅拌16小时,LC-MS监测至反应完全。Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (500 mg, 1.86 mmol) was dissolved in 1,4-dioxane (20.0 mL) and water (5.0 mL) , followed by cyclopropylboronic acid (300 mg, 3.49 mmol), potassium carbonate (550 mg, 3.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (150 mg, 0.20 mmol) was added to the reaction solution, and after nitrogen protection, stirred at 100 degrees Celsius for 16 hours, and monitored by LC-MS until the reaction was complete.
向反应液加水(20.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到200毫克白色固体3-环丙基-1-甲基-1H-吲唑-6-羧酸甲酯(收率：46.5％)。LC-MS：RT＝1.98min,[M+H] +＝231.18。 Water (20.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. concentrate. The obtained residue was purified by silica gel column chromatography to obtain 200 mg of methyl 3-cyclopropyl-1-methyl-1H-indazole-6-carboxylate as a white solid (yield: 46.5%). LC-MS: RT=1.98 min, [M+H] + =231.18.
步骤C：合成(3-环丙基-1-甲基-1H-吲唑-6-基)甲醇Step C: Synthesis of (3-cyclopropyl-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000153
Figure PCTCN2021120978-appb-000153
将3-环丙基-1-甲基-1H-吲唑-6-羧酸甲酯(200毫克,0.87毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后,将氢化锂铝(38毫克,1.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。3-Cyclopropyl-1-methyl-1H-indazole-6-carboxylic acid methyl ester (200 mg, 0.87 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at zero degrees Celsius, the hydrogenated Lithium aluminum (38 mg, 1.0 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
向反应液加水(2.0毫升)，析出大量白色固体，向反应液中加无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物经硅胶柱层析纯化得到80毫克白色固体(3-环丙基-1-甲基-1H-吲唑-6-基)甲醇(收率：45.7％)。LC-MS：RT＝1.72min,[M+H] +＝203.17。 Water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of white solid (3-cyclopropyl-1-methyl-1H-indazol-6-yl)methanol (yield: 45.7%). LC-MS: RT=1.72 min, [M+H] + =203.17.
步骤D：合成(S)-2-((4-(6-((3-环丙基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((3-cyclopropyl-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000154
Figure PCTCN2021120978-appb-000154
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(95毫克,0.20毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(3-环丙基-1-甲基-1H-吲唑-6-基)甲醇(80毫克,0.40毫摩尔),叔丁醇钠(40毫克,0.40毫摩尔),1,1'-联萘-2,2'-双二苯膦(26毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌3小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (95 mg, 0.20 mmol) was dissolved in 1,4-dioxane (10.0 mL), (3-cyclopropyl-1-methyl) -1H-Indazol-6-yl)methanol (80 mg, 0.40 mmol), sodium tert-butoxide (40 mg, 0.40 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26 mg, 0.040 mmol) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.020 mmol) were added to the reaction flask. After nitrogen protection, the mixture was stirred at 100 degrees Celsius for 3 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到10毫克白色固体(S)-2-((4-(6-((3-环丙基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：8.3％)。LC-MS：RT＝1.77min,[M+H] +＝607.41。 1H NMR(500MHz,DMSO)δ12.93(s,1H),8.36(s,1H),7.89(d,J＝8.2Hz,1H),7.79(d,J＝8.3Hz,1H),7.74(d,J＝8.3Hz,1H),7.70–7.60(m,2H),7.18(d,J＝8.4Hz,1H),6.90(d,J＝6.8Hz,1H),6.73(d,J＝8.2Hz,1H),5.49(s,2H),5.05(d,J＝5.5Hz,1H),4.81(dd,J＝15.4,6.8Hz,2H),4.67(d,J＝13.4Hz,1H),4.48(d,J＝6.0Hz,1H),4.33(dd,J＝14.7,5.9Hz,1H),3.91(m,5H),3.75(s,1H),2.93(s,1H),2.72(s,1H),2.33(s,1H),2.23(ddd,J＝13.3,8.4,5.1Hz,2H),2.08(m,4H),1.07–0.83(m,6H)。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 10 mg of white solid (S)-2-((4-(6-((3-cyclopropyl-1-methyl-1H-indazol-6-yl) )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Yield: 8.3%). LC-MS: RT=1.77 min, [M+H] + =607.41. 1 H NMR(500MHz, DMSO)δ12.93(s,1H),8.36(s,1H),7.89(d,J=8.2Hz,1H),7.79(d,J=8.3Hz,1H),7.74( d, J=8.3Hz, 1H), 7.70–7.60 (m, 2H), 7.18 (d, J=8.4Hz, 1H), 6.90 (d, J=6.8Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 5.49(s, 2H), 5.05(d, J＝5.5Hz, 1H), 4.81(dd, J＝15.4, 6.8Hz, 2H), 4.67(d, J＝13.4Hz, 1H), 4.48(d,J＝6.0Hz,1H),4.33(dd,J＝14.7,5.9Hz,1H),3.91(m,5H),3.75(s,1H),2.93(s,1H),2.72(s , 1H), 2.33 (s, 1H), 2.23 (ddd, J=13.3, 8.4, 5.1 Hz, 2H), 2.08 (m, 4H), 1.07–0.83 (m, 6H).
实施例26Example 26
合成(S)-2-((4-(6-((5-氟-2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲 基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-fluoro-2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000155
Figure PCTCN2021120978-appb-000155
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-氟-2-甲基-2H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 5-fluoro-2-methyl-2H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000156
Figure PCTCN2021120978-appb-000156
室温下，将5-氟-1H-吲唑-6-羧酸甲酯(150毫克，0.77毫摩尔)和碳酸铯(503毫克，1.54毫摩尔)溶于N,N-二甲基甲酰胺(2毫升)中，再加入碘甲烷(0.5毫升)，在室温下搅拌0.5小时。Methyl 5-fluoro-1H-indazole-6-carboxylate (150 mg, 0.77 mmol) and cesium carbonate (503 mg, 1.54 mmol) were dissolved in N,N-dimethylformamide ( 2 mL), iodomethane (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到95毫克白色固体5-氟-1-甲基-1H-吲唑-6-羧酸甲酯和40毫克白色固体5-氟-2-甲基-2H-吲唑-6-羧酸甲酯(收率：25％)。LC-MS:RT＝1.82min,[M+H] +＝209.11。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane = 1/3) to give 95 mg of methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate as a white solid and 40 mg of 5-fluoro-2-methyl-2H-indazole as a white solid -6-Carboxylic acid methyl ester (yield: 25%). LC-MS: RT=1.82 min, [M+H] + =209.11.
步骤B：合成(5-氟-2-甲基-2H-吲唑-6基)-甲醇Step B: Synthesis of (5-fluoro-2-methyl-2H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000157
Figure PCTCN2021120978-appb-000157
室温下，将5-氟-2-甲基-2H-吲唑-6-羧酸甲酯(55毫克，0.26毫摩尔)溶于四氢呋喃(2毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(50毫克，1.32毫摩尔)，在室温下搅拌0.5小时。Methyl 5-fluoro-2-methyl-2H-indazole-6-carboxylate (55 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (50 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到36毫克白色固体(5-氟-2-甲基-2H-吲唑-6基)-甲醇(收率：77％)。LC-MS:RT＝1.54min,[M] +＝181.10。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (20 mL) was added to wash the organic phase twice with water and dried over anhydrous sodium sulfate, filtered and concentrated to obtain 36 mg of white solid (5-fluoro-2- Methyl-2H-indazol-6yl)-methanol (yield: 77%). LC-MS: RT=1.54 min, [M] + =181.10.
步骤C：(S)-2-((4-(6-((5-氟-2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: (S)-2-((4-(6-((5-Fluoro-2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000158
Figure PCTCN2021120978-appb-000158
将(5-氟-2-甲基-2H-吲唑-6基)-甲醇(36毫克，0.20毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(99毫克，0.20毫摩尔)，钯催化剂(9毫克)，1,1’-联萘-2,2’-双二苯膦(12毫克)和叔丁醇钠(38毫克，0.40毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌2个小时。(5-Fluoro-2-methyl-2H-indazol-6yl)-methanol (36 mg, 0.20 mmol), (S)-2-(chloromethyl)-1-(oxetine- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (99 mg, 0.20 mmol), palladium catalyst (9 mg), 1,1'-binaphthalene-2,2 '-Bisdiphenylphosphine (12 mg) and sodium tert-butoxide (38 mg, 0.40 mmol) were dissolved in dioxane (10 mL) and the temperature was raised to 100°C with stirring for 2 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相纯化得到7.53毫克白色固体(S)-2-((4-(6-((5-氟-2-甲基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：6％)。LC-MS:RT＝1.73min,[M+H] +＝585.35。 After the reaction was completed, suction filtration with celite, washed with dichloromethane and concentrated the organic phase, the obtained crude product was purified by high performance liquid phase to obtain 7.53 mg of white solid (S)-2-((4-(6-((5- Fluoro-2-methyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylic acid (yield: 6%). LC-MS: RT=1.73 min, [M+H] + =585.35.
实施例27Example 27
合成(S)-2-((4-(6-((5-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲 基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000159
Figure PCTCN2021120978-appb-000159
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-氟-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 5-fluoro-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000160
Figure PCTCN2021120978-appb-000160
将1-乙酰基-5-氟-1H-吲唑-6-羧酸甲酯(200毫克，0.85毫摩尔)溶于甲醇(15毫升)中，然后滴加浓盐酸(3毫升)，反应温度升高到80摄氏度搅拌5个小时。1-Acetyl-5-fluoro-1H-indazole-6-carboxylic acid methyl ester (200 mg, 0.85 mmol) was dissolved in methanol (15 mL), then concentrated hydrochloric acid (3 mL) was added dropwise, the reaction temperature Raised to 80°C and stirred for 5 hours.
反应结束后，直接浓缩得到150毫克白色固体5-氟-1H-吲唑-6-羧酸甲酯(收率：91％)。LC-MS:RT＝1.73min,[M+H] +＝195.12。 After the reaction was completed, it was directly concentrated to obtain 150 mg of methyl 5-fluoro-1H-indazole-6-carboxylate as a white solid (yield: 91%). LC-MS: RT=1.73 min, [M+H] + =195.12.
步骤B：合成5-氟-1-甲基-1H-吲唑-6-羧酸甲酯Step B: Synthesis of methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000161
Figure PCTCN2021120978-appb-000161
室温下，将5-氟-1H-吲唑-6-羧酸甲酯(150毫克，0.77毫摩尔)和碳酸铯(503毫克，1.54毫摩尔)溶于N,N-二甲基甲酰胺(2毫升)中，再加入碘甲烷(0.5毫升)，在室温下搅拌0.5小时。Methyl 5-fluoro-1H-indazole-6-carboxylate (150 mg, 0.77 mmol) and cesium carbonate (503 mg, 1.54 mmol) were dissolved in N,N-dimethylformamide ( 2 mL), iodomethane (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到95毫克白色固体5-氟-1-甲基-1H-吲唑-6-羧酸甲酯(收率：59％)。LC-MS:RT＝1.82min,[M+H] +＝209.11。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/3) to obtain 95 mg of methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate as a white solid (yield: 59%). LC-MS: RT=1.82 min, [M+H] + =209.11.
步骤C：合成(5-氟-1-甲基-1H-吲唑-6基)-甲醇Step C: Synthesis of (5-fluoro-1-methyl-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000162
Figure PCTCN2021120978-appb-000162
室温下，将5-氟-1-甲基-1H-吲唑-6-羧酸甲酯(95毫克，0.46毫摩尔)溶于四氢呋喃(3毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(87毫克，2.28毫摩尔)，在室温下搅拌0.5小时。Methyl 5-fluoro-1-methyl-1H-indazole-6-carboxylate (95 mg, 0.46 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (87 mg, 2.28 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到74毫克白色固体(5-氟-1-甲基-1H-吲唑-6基)-甲醇(收率：90％)。LC-MS:RT＝1.61min,[M+H] +＝181.11。 After the reaction, saturated sodium chloride was added to quench the reaction, ethyl acetate (20 mL) was added, and the organic phase was washed twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 74 mg of white solid (5-fluoro-1- Methyl-1H-indazol-6yl)-methanol (yield: 90%). LC-MS: RT=1.61 min, [M+H] + =181.11.
步骤D：(S)-2-((4-(6-((5-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: (S)-2-((4-(6-((5-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000163
Figure PCTCN2021120978-appb-000163
将(5-氟-1-甲基-1H-吲唑-6基)-甲醇(74毫克，0.41毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(203毫克，0.41毫摩尔)，钯催化剂(18毫克)，1,1’-联萘-2,2’-双二苯膦(25毫克)和叔丁醇钠(79毫克，0.82毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌2个小时。(5-Fluoro-1-methyl-1H-indazol-6yl)-methanol (74 mg, 0.41 mmol), (S)-2-(chloromethyl)-1-(oxetine- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (203 mg, 0.41 mmol), palladium catalyst (18 mg), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (25 mg) and sodium tert-butoxide (79 mg, 0.82 mmol) were dissolved in dioxane (10 mL) and the temperature was raised to 100°C with stirring for 2 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相纯化得到19.54毫克白色固体(S)-2-((4-(6-((5-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：8％)。LC-MS:RT＝1.73min,[M+H] +＝585.35。 After completion of the reaction, suction filtration with diatomaceous earth, washing with dichloromethane and then concentrating the organic phase, the obtained crude product was purified by high performance liquid phase to obtain 19.54 mg of white solid (S)-2-(((4-(6-((5- Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylic acid (yield: 8%). LC-MS: RT=1.73 min, [M+H] + =585.35.
实施例28和实施例29Example 28 and Example 29
合成(S)-2-((4-(6-((5-氟-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸和(S)-2-((4-(6-((5-氟-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and (S)-2-((4-(6-((5-fluoro-2H- Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000164
Figure PCTCN2021120978-appb-000164
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-乙酰基-5-氟-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-acetyl-5-fluoro-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000165
Figure PCTCN2021120978-appb-000165
将5-氨基-2-氟-4-甲基苯甲酸甲酯(1.83克，10毫摩尔)溶于氯仿(50毫升)中，冰浴下冷却至零摄氏度，滴加乙酸酐(2.36毫升)，反应温度升至室温搅拌1个小时，然后再加入醋酸钾(0.29克)和亚硝酸异戊酯(2.69毫升)，反应温度升至70摄氏度回流5个小时。Methyl 5-amino-2-fluoro-4-methylbenzoate (1.83 g, 10 mmol) was dissolved in chloroform (50 mL), cooled to zero degrees Celsius under an ice bath, and acetic anhydride (2.36 mL) was added dropwise , the reaction temperature was raised to room temperature and stirred for 1 hour, then potassium acetate (0.29 g) and isoamyl nitrite (2.69 mL) were added, and the reaction temperature was raised to 70 degrees Celsius and refluxed for 5 hours.
反应结束后，用饱和碳酸氢钠淬灭，用二氯甲烷(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)纯化得到300毫克淡黄色固体1-乙酰基-5-氟-1H-吲唑-6-羧酸甲酯(收率：13％)。LC-MS:RT＝1.72min,[M] +＝236.14。 After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted with dichloromethane (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane). alkane=1/2) and purified to obtain 300 mg of methyl 1-acetyl-5-fluoro-1H-indazole-6-carboxylate as a pale yellow solid (yield: 13%). LC-MS: RT=1.72 min, [M] + =236.14.
步骤B：合成1-(5-氟-6-(羟甲基)-1H-吲唑-1-基)乙-1-酮Step B: Synthesis of 1-(5-Fluoro-6-(hydroxymethyl)-1H-indazol-1-yl)ethan-1-one
Figure PCTCN2021120978-appb-000166
Figure PCTCN2021120978-appb-000166
室温下，将1-乙酰基-5-氟-1H-吲唑-6-羧酸甲酯(100毫克，0.42毫摩尔)溶于四氢呋喃(2毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(80毫克，2.1毫摩尔)，在室温下搅拌半个小时。Methyl 1-acetyl-5-fluoro-1H-indazole-6-carboxylate (100 mg, 0.42 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, Lithium aluminum tetrahydride (80 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到50毫克白色固体5-氟-6-(羟甲基)-1H-吲唑(收率：57％)。LC-MS:RT＝1.55min,[M] +＝208.16。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (20 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 50 mg of white solid 5-fluoro-6-( Hydroxymethyl)-1H-indazole (yield: 57%). LC-MS: RT=1.55 min, [M] + =208.16.
步骤C：合成(S)-2-((4-(6-((5-氟-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸和(S)-2-((4-(6-((5-氟-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧 杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-((5-fluoro-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and (S)-2-((4-(6-(((5-fluoro) -2H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d]Imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000167
Figure PCTCN2021120978-appb-000167
将5-氟-6-(羟甲基)-1H-吲唑(50毫克，0.24毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(119毫克，0.24毫摩尔)，钯催化剂(11毫克)，1,1’-联萘-2,2’-双二苯膦(15毫克)和叔丁醇钠(46毫克，0.48毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌2个小时。5-Fluoro-6-(hydroxymethyl)-1H-indazole (50 mg, 0.24 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl) yl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (119 mg, 0.24 mmol), palladium catalyst (11 mg), 1,1'-binaphthalene-2,2'-bisdidi Phenylphosphine (15 mg) and sodium tert-butoxide (46 mg, 0.48 mmol) were dissolved in dioxane and the temperature was raised to 100°C and stirred for 2 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相纯化，分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由5％乙腈在5.10分钟洗脱出来；检测波长：254nm。先后得到2.40毫克白色固体(S)-2-((4-(6-((5-氟-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(实施例28)(收率：2％)和5.35毫克白色固体(S)-2-((4-(6-((5-氟-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(实施例29)(收率：4％)。After the reaction was completed, suction filtration with diatomaceous earth, washed with dichloromethane and concentrated the organic phase, the obtained crude product was purified by high performance liquid phase, and the separation conditions were as follows, chromatographic column: Agilent 5 Prep-C18 100mm × 30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: elution from 5% acetonitrile at 5.10 min; detection wavelength: 254 nm. 2.40 mg of white solid (S)-2-((4-(6-((5-fluoro-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl was obtained successively )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 28) (yield: 2%) and 5.35 mg of white solid (S)-2-((4-(6-((5-Fluoro-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 29) (yield: 4%).
实施例28：HPLC：RT＝4.98min；LC-MS:RT＝1.68min,[M+H] +＝571.29。 Example 28: HPLC: RT=4.98 min; LC-MS: RT=1.68 min, [M+H] + =571.29.
实施例29：HPLC：RT＝6.32min；LC-MS:RT＝1.68min,[M+H] +＝571.28。 Example 29: HPLC: RT=6.32 min; LC-MS: RT=1.68 min, [M+H] + =571.28.
实施例30Example 30
合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000168
Figure PCTCN2021120978-appb-000168
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成喹啉-5-甲醇Step A: Synthesis of quinoline-5-methanol
Figure PCTCN2021120978-appb-000169
Figure PCTCN2021120978-appb-000169
零摄氏度下，喹啉-5-甲醛(100毫克，0.64毫摩尔)溶于甲醇(2毫升)中，氮气保护下，加入硼氢化钠(49毫克，1.28毫摩尔),搅拌1小时。At zero degrees Celsius, quinoline-5-carbaldehyde (100 mg, 0.64 mmol) was dissolved in methanol (2 mL), and under nitrogen protection, sodium borohydride (49 mg, 1.28 mmol) was added, and the mixture was stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加水(2毫升)，反应液加入乙酸乙酯(30毫升)稀释，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得喹啉-5-甲醇89毫克(收率：87.5％)。LC-MS：RT＝0.33min,[M+H] +＝160.13。 After the reaction, water (2 mL) was slowly added dropwise under an ice bath, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. After concentration, the obtained white solid was directly used in the next reaction to obtain 89 mg of quinoline-5-methanol (yield: 87.5%). LC-MS: RT=0.33 min, [M+H] + =160.13.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000170
Figure PCTCN2021120978-appb-000170
将喹啉-5-甲醇(30毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，快速升温至100摄氏度,搅拌1小时。The quinoline-5-methanol (30 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL ), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone)dipalladium (15 mg, 0.016 mmol) , Sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was rapidly increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯92毫克(收率：92.9％)。LC-MS：RT＝1.81min,[M+H] +＝620.36。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×3 times), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 92 mg (yield: 92.9%). LC-MS: RT=1.81 min, [M+H ] + = 620.36.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000171
Figure PCTCN2021120978-appb-000171
将(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(92毫克，0.15毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-5-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (92 mg, 0.15 mmol), dissolved in mixed solvent (2 mL, dichloromethane/trifluoroacetic acid=6 /1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到46毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：54.5％)。LC-MS：RT＝1.63min,[M+H] +＝564.31。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by high-performance liquid chromatography to obtain 46 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinoline- 5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 54.5%). LC-MS: RT =1.63min, [M+H] + =564.31.
实施例31Example 31
合成(S)-2-((4-(6-((2-(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000172
Figure PCTCN2021120978-appb-000172
具体合成路线如下：The specific synthetic route is as follows:
步骤A:合成2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000173
Figure PCTCN2021120978-appb-000173
室温下，将1H-吲唑-6-羧酸甲酯(1.5克，8.5毫摩尔)、1-溴-2-甲氧基乙烷(1.7克，12.7毫摩尔)和碳酸钾(2.3克，17.0毫摩尔)加入N,N-二甲基甲酰胺(15.0毫升)中，25摄氏度反应12小时。At room temperature, methyl 1H-indazole-6-carboxylate (1.5 g, 8.5 mmol), 1-bromo-2-methoxyethane (1.7 g, 12.7 mmol) and potassium carbonate (2.3 g, 17.0 mmol) was added to N,N-dimethylformamide (15.0 mL) and reacted at 25 degrees Celsius for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到394.0毫克淡油状液体2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯(收率：19.7％)。LC-MS:RT＝1.77min,[M+H] +＝235.16。 1H NMR(500MHz,DMSO-d 6)δ8.48(s,1H),8.29(d,J＝0.9Hz,1H),7.82(dd,J＝8.8,0.7Hz,1H),7.56(dd,J＝8.7,1.3Hz,1H),4.65(t,J＝5.2Hz,2H),3.88(s,3H),3.85(t,J＝5.2Hz,2H),3.23(s,3H)。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, washed with saturated brine (30 mL×L times), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) 394.0 mg of methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate was obtained as a light oily liquid (yield: 19.7%). LC-MS: RT=1.77 min, [M+H] + =235.16. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.48 (s, 1H), 8.29 (d, J=0.9Hz, 1H), 7.82 (dd, J=8.8, 0.7Hz, 1H), 7.56 (dd, J=8.7, 1.3Hz, 1H), 4.65 (t, J=5.2Hz, 2H), 3.88 (s, 3H), 3.85 (t, J=5.2Hz, 2H), 3.23 (s, 3H).
步骤B：合成(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲醇Step B: Synthesis of (2-(2-methoxyethyl)-2H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000174
Figure PCTCN2021120978-appb-000174
室温下，将2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯(220.0毫克，0.9毫摩尔)溶于四氢呋喃(8毫升)中，冰浴条件下加入四氢铝锂(71.4毫克，1.9毫摩尔)，反应1.0小时。Methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate (220.0 mg, 0.9 mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature, and tetrahydrofuran was added under ice bath conditions. Lithium aluminum hydride (71.4 mg, 1.9 mmol), reacted for 1.0 hour.
反应结束，冰浴条件下缓慢滴加0.1毫升水，0.1毫升15％的氢氧化钠水溶液，0.3毫升水，搅拌5分钟，抽滤，滤液干燥，过滤，旋干得到180.0毫克淡黄色油状物(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲醇(收率：93.0％)。LC-MS:RT＝1.56min,[M+H] +＝207.18。 The reaction was completed, and 0.1 ml of water, 0.1 ml of 15% aqueous sodium hydroxide solution, 0.3 ml of water were slowly added dropwise under ice bath conditions, stirred for 5 minutes, suction filtered, the filtrate was dried, filtered, and spin-dried to obtain 180.0 mg of pale yellow oil ( 2-(2-Methoxyethyl)-2H-indazol-6-yl)methanol (yield: 93.0%). LC-MS: RT=1.56 min, [M+H] + =207.18.
步骤C：合成(S)-2-((4-(6-((2-(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000175
Figure PCTCN2021120978-appb-000175
室温下，将(1-(2-甲氧基乙基)-1H-吲唑-6-基)甲醇(90.0毫克，0.4毫摩尔)、(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(152.0毫克，0.3毫摩尔)和三(二亚苄基丙酮)二钯(34.8毫克，0.04毫摩尔)，2-二环己基磷-2’,4’,6’-三异丙基联苯(35.5毫克，0.07毫摩尔)加入二氧六环(2.0毫升)中，N 2保护下，95摄氏度反应3.0小时。 At room temperature, (1-(2-methoxyethyl)-1H-indazol-6-yl)methanol (90.0 mg, 0.4 mmol), (S)-2-(((4-(6- Chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester ( 152.0 mg, 0.3 mmol) and tris(dibenzylideneacetone)dipalladium (34.8 mg, 0.04 mmol), 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl ( 35.5 mg, 0.07 mmol) was added to dioxane (2.0 mL) and reacted under N2 protection at 95 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(10毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到67.0毫克淡黄色油状物(S)-2-((4-(6-((2-(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：12.5％)。LC-MS:RT＝1.86min,[M+H]+＝667.39。The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (10 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (10 mL×L), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 67.0 mg pale yellow oil (S)-2-((4-(6-((2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield : 12.5%).LC-MS: RT=1.86min, [M+H]+=667.39.
步骤D：合成(S)-2-((4-(6-((2-(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-(2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000176
Figure PCTCN2021120978-appb-000176
室温下，向含有(S)-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(67.0毫克，0.1毫摩尔)的二氯甲烷(0.4毫升)中滴加三氟乙酸(0.4毫升)，室温下反应1.0小时。`At room temperature, the solution containing (S)-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (67.0 mg, 0.1 mmol ) in dichloromethane (0.4 mL) was added dropwise trifluoroacetic acid (0.4 mL), and the reaction was carried out at room temperature for 1.0 hours.`
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(20毫升×升次)萃取，合并有机相，有机相先用氯化铵水溶液(30毫升×升次)洗涤，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由5％乙腈在5.10分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得17.0毫克白色固体(S)-2-((4-(6-((2-(2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：27.8％)。LC-MS:RT＝1.73min,[M+H] +＝611.36。 The reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (20 mL×L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL×L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography. Separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 5% acetonitrile at 5.10 minutes come out; detection wavelength: 254nm. After purification, lyophilization at low temperature gave 17.0 mg of white solid (S)-2-((4-(6-((2-(2-(2-methoxyethyl)-2H-indazol-6-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 27.8%). LC-MS: RT=1.73 min, [M+H] + =611.36.
实施例32Example 32
合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-Methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000177
Figure PCTCN2021120978-appb-000177
具体合成路线如下：The specific synthetic route is as follows:
步骤A:合成6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑Step A: Synthesis of 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000178
Figure PCTCN2021120978-appb-000178
室温下，将2,6二氯吡啶(100毫克，0.68毫摩尔)，(1-甲基-1H-吲唑-6-基)甲醇(100毫克，0.62毫摩尔)和氢氧化钠(74.4毫克，1.86毫摩尔)加入到10毫升干燥的DMF中，升温至130摄氏度反应2小时。At room temperature, 2,6-dichloropyridine (100 mg, 0.68 mmol), (1-methyl-1H-indazol-6-yl)methanol (100 mg, 0.62 mmol) and sodium hydroxide (74.4 mg) were combined , 1.86 mmol) was added to 10 ml of dry DMF, and the temperature was raised to 130 degrees Celsius for 2 hours.
反应结束后，将反应液冷却至室温，倒入20毫升的冰水溶液中，搅拌30分钟后抽滤，水洗滤饼。滤饼干燥后得155毫克白色固体6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑(收率：90.8％)。LC-MS：RT＝2.07min，[M+H] +＝274.14。 After the reaction was completed, the reaction solution was cooled to room temperature, poured into 20 ml of ice-water solution, stirred for 30 minutes, filtered with suction, and the filter cake was washed with water. The filter cake was dried to obtain 155 mg of 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole as a white solid (yield: 90.8%). LC-MS: RT=2.07 min, [M+H] + =274.14.
步骤B:合成4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2021120978-appb-000179
Figure PCTCN2021120978-appb-000179
室温下，将中间体6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑(100毫克，0.37毫摩尔)以及1-叔丁氧羰基哌嗪(82.7毫克，0.44毫摩尔)，三(二亚苄基丙酮)二钯(51毫克，0.06毫摩尔)、1,1'-联萘-2,2'-双二苯膦(46.08毫克，0.074毫摩尔)和碳酸铯(241.1毫克，0.74毫摩尔)加入到10毫升干燥的二氧六环溶液中，N 2保护下100摄氏度反应2小时。 At room temperature, the intermediate 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole (100 mg, 0.37 mmol) and 1-tert-butoxy Carbonylpiperazine (82.7 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (51 mg, 0.06 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (46.08 mg, 0.074 mmol) and cesium carbonate (241.1 mg, 0.74 mmol) were added to 10 mL of dry dioxane solution and reacted under N2 protection at 100 °C for 2 h.
反应结束后，蒸干反应液，20毫升乙酸乙酯萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝5/2)，得91毫克淡黄色固体4-(6-((1-甲基-1H-吲唑-6-基)甲氧 基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(收率：58.7％)。LC-MS：RT＝2.20min，[M+H] +＝424.28。 After the reaction, the reaction solution was evaporated to dryness, extracted with 20 ml of ethyl acetate, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (n-hexane/ethyl acetate=5/2) to obtain 91 mg of pale yellow solid 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridine- 2-yl)piperazine-1-carboxylate tert-butyl ester (yield: 58.7%). LC-MS: RT=2.20 min, [M+H] + =424.28.
步骤C:合成1-甲基-6-(((6-(哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑Step C: Synthesis of 1-methyl-6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000180
Figure PCTCN2021120978-appb-000180
室温下，将4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(90毫克，0.21毫摩尔)溶于10毫升甲醇溶剂中，冰浴下加入3毫升4M/L的盐酸二氧六环溶液，室温反应2小时。At room temperature, tert-butyl 4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (90 mg, 0.21 mmol) was dissolved in 10 ml of methanol solvent, 3 ml of 4M/L hydrochloric acid dioxane solution was added under ice bath, and the reaction was carried out at room temperature for 2 hours.
反应结束后，蒸干反应液得95毫克白色固体1-甲基-6-(((6-(哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑(收率：124.0％)。LC-MS：RT＝1.63min，[M+H] +＝324.27。 After the reaction, the reaction solution was evaporated to dryness to obtain 95 mg of white solid 1-methyl-6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole (Yield: 124.0%). LC-MS: RT=1.63 min, [M+H] + =324.27.
步骤D：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000181
Figure PCTCN2021120978-appb-000181
室温下，将中间体1-甲基-6-(((6-(哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑盐酸盐(77毫克，0.21毫摩尔)以及甲基(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(71.6毫克，0.21毫摩尔)碳酸铯(136.8毫克，0.42毫摩尔)加入至10毫升DMF溶液中，升温至60摄氏度反应2小时。At room temperature, the intermediate 1-methyl-6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole hydrochloride (77 mg, 0.21 mmol) and methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (71.6 mg , 0.21 mmol) cesium carbonate (136.8 mg, 0.42 mmol) was added to 10 mL of DMF solution, and the temperature was raised to 60 degrees Celsius for 2 hours.
反应结束后，将反应液倒入冰水，析出固体，抽滤，水洗滤饼得92毫克白色产品(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯(收率：63.4％)。LC-MS：RT＝1.96min，[M+H] +＝624.41。 After the reaction was completed, the reaction solution was poured into ice water, the solid was precipitated, suction filtered, and the filter cake was washed with water to obtain 92 mg of white product (S)-2-((4-(6-((1-methyl-1H-indazole). -6-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6- tert-Butyl carboxylate (yield: 63.4%). LC-MS: RT=1.96 min, [M+H] + =624.41.
步骤E：合成(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000182
Figure PCTCN2021120978-appb-000182
室温下，将中间体(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯(30毫克，0.048毫摩尔)溶于3.5毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。At room temperature, the intermediate (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1- (30 mg, 0.048 mmol) in 3.5 mL of dichloromethane To the solution, 0.5 ml of trifluoroacetic acid was added dropwise under an ice bath. The reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/)，得20毫克白色固体(S)-2-((4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸(收率：88.7％)。LC-MS：RT＝1.73min，[M+H] +＝568.34。 1H NMR(500MHz,DMSO)δ12.94(s,1H),8.37(s,1H),7.90(d,J＝8.2Hz,1H),7.79(d,J＝8.3Hz,1H),7.71(d,J＝20.7Hz,1H),7.72–7.58(m,2H),7.18(d,J＝8.4Hz,1H),6.91(d,J＝6.8Hz,1H),6.74(d,J＝8.2Hz,1H),6.52(s,1H),5.50(s,2H),5.05(d,J＝5.5Hz,1H),4.81(dd,J＝15.4,6.8Hz,2H),4.70–4.56(m,1H),4.48(d,J＝6.0Hz,1H),4.33(dd,J＝14.7,5.9Hz,1H),3.89(d,J＝4.9Hz,3H),3.76(s,1H),2.93(s,1H),2.69(dd,J＝28.8,20.1Hz,1H),2.33(s,1H),2.25–2.19(m,1H),2.09(m,2H),1.02–0.93(m,2H),0.92–0.78(m,2H). After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/) to obtain 20 mg of white solid (S)-2-((4-(6-((1-methyl-1H-indazol-6-yl)methan) oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid (yield: 88.7%). LC-MS: RT=1.73 min, [M+H] + =568.34. 1 H NMR(500MHz, DMSO)δ12.94(s,1H),8.37(s,1H),7.90(d,J=8.2Hz,1H),7.79(d,J=8.3Hz,1H),7.71( d, J=20.7Hz, 1H), 7.72–7.58 (m, 2H), 7.18 (d, J=8.4Hz, 1H), 6.91 (d, J=6.8Hz, 1H), 6.74 (d, J=8.2 Hz,1H),6.52(s,1H),5.50(s,2H),5.05(d,J=5.5Hz,1H),4.81(dd,J=15.4,6.8Hz,2H),4.70–4.56(m ,1H),4.48(d,J＝6.0Hz,1H),4.33(dd,J＝14.7,5.9Hz,1H),3.89(d,J＝4.9Hz,3H),3.76(s,1H),2.93 (s, 1H), 2.69 (dd, J=28.8, 20.1Hz, 1H), 2.33 (s, 1H), 2.25–2.19 (m, 1H), 2.09 (m, 2H), 1.02–0.93 (m, 2H) ),0.92–0.78(m,2H).
实施例33Example 33
合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1(((S)-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1- yl)methyl)-1(((S)-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000183
Figure PCTCN2021120978-appb-000183
具体合成路线如下：The specific synthetic route is as follows:
步骤A:合成(S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of (S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate tert-butyl acid
Figure PCTCN2021120978-appb-000184
Figure PCTCN2021120978-appb-000184
室温下，将中间体6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑(150毫克，0.55毫摩尔)以及(S)-1-N-Boc-2-甲基哌嗪(131毫克，0.66毫摩尔)，三(二亚苄基丙酮)二钯(75.5毫克，0.08毫摩尔)、1,1'-联萘-2,2'-双二苯膦(68.5毫克，0.11毫摩尔)和碳酸铯(358.4毫克，1.1毫摩尔)加入到10毫升干燥的二氧六环溶液中，N 2保护下100摄氏度反应2小时。 At room temperature, the intermediate 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole (150 mg, 0.55 mmol) and (S)-1 -N-Boc-2-methylpiperazine (131 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium (75.5 mg, 0.08 mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (68.5 mg, 0.11 mmol) and cesium carbonate (358.4 mg, 1.1 mmol) were added to 10 mL of dry dioxane solution and reacted at 100 °C for 2 h under N2 protection.
反应结束后，蒸干反应液，20毫升乙酸乙酯萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝5/2)，得145毫克淡黄色固体(S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(收率：60.4％)。LC-MS：RT＝2.23min，[M+H] +＝438.27。 After the reaction, the reaction solution was evaporated to dryness, extracted with 20 ml of ethyl acetate, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (n-hexane/ethyl acetate=5/2) to obtain 145 mg of pale yellow solid (S)-2-methyl-4-(6-((1-methyl-1H-indazole-6 -yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester (yield: 60.4%). LC-MS: RT=2.23 min, [M+H] + =438.27.
步骤C:合成(S)-1-甲基-6-(((6-(3-甲基哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑Step C: Synthesis of (S)-1-methyl-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000185
Figure PCTCN2021120978-appb-000185
室温下，将(S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧)吡啶-2-基)哌嗪-1-羧酸叔丁酯(145毫克，0.37毫摩尔)溶于10毫升甲醇溶剂中，冰浴下加入5毫升4M/L的盐酸二氧六环溶液，室温反应2小时。(S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid at room temperature Tert-butyl ester (145 mg, 0.37 mmol) was dissolved in 10 mL of methanol solvent, 5 mL of 4M/L hydrochloric acid dioxane solution was added under ice bath, and the reaction was carried out at room temperature for 2 hours.
反应结束后，蒸干反应液得163毫克白色固体(S)-1-甲基-6-(((6-(3-甲基哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑(收率：131.5％)。LC-MS：RT＝1.65min，[M+H] +＝338.27。 After the reaction, the reaction solution was evaporated to dryness to obtain 163 mg of white solid (S)-1-methyl-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy) methyl)-1H-indazole (yield: 131.5%). LC-MS: RT=1.65 min, [M+H] + =338.27.
步骤D：合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1(((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine -1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000186
Figure PCTCN2021120978-appb-000186
室温下，将中间体(S)-1-甲基-6-(((6-(3-甲基哌嗪-1-基)吡啶-2-基)氧基)甲基)-1H-吲唑(124毫克，0.33毫摩尔)以及甲基(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(110.8毫克，0.33毫摩尔)碳酸铯(215.0毫克，0.66毫摩尔)加入至10毫升DMF溶液中，升温至60摄氏度反应2小时。At room temperature, the intermediate (S)-1-methyl-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)-1H-indium azole (124 mg, 0.33 mmol) and methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6- tert-Butyl carboxylate (110.8 mg, 0.33 mmol) and cesium carbonate (215.0 mg, 0.66 mmol) were added to 10 mL of DMF solution, and the temperature was raised to 60 degrees Celsius to react for 2 hours.
反应结束后，将反应液倒入冰水，析出固体，抽滤，水洗滤饼得180毫克白色产品2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1(((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯(收率：86.9％)。LC-MS：RT＝1.97min，[M+H] +＝638.41。 After the reaction, the reaction solution was poured into ice water, the solid was precipitated, suction filtered, and the filter cake was washed with water to obtain 180 mg of white product 2-(((S)-2-methyl-4-(6-((1-methyl) -1H-Indazol-6-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)- Benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 86.9%). LC-MS: RT=1.97 min, [M+H] + =638.41.
步骤E：合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Step E: Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperazine -1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000187
Figure PCTCN2021120978-appb-000187
室温下，将中间体2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸叔丁酯(70毫克，0.11毫摩尔)溶于3.5毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。At room temperature, the intermediate 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperazin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylate tert-butyl ester (70 mg, 0.11 mg mol) was dissolved in 3.5 ml of dichloromethane solution, and 0.5 ml of trifluoroacetic acid was added dropwise under an ice bath. The reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得55毫克白色固体2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸(收率：74.4％)。LC-MS：RT＝1.75min，[M+H] +＝582.35。 1H NMR(500MHz,DMSO)δ8.36(dd,J＝25.3,9.7Hz,1H),8.02(dd,J＝14.3,4.7Hz,1H),7.95–7.85(m,1H),7.82–7.76(m,1H),7.71(dd,J＝8.3,3.6Hz,1H),7.67(s,1H),7.58–7.48(m,1H),7.19(dd,J＝8.3,1.1Hz,1H),6.43(t,J＝10.1Hz,1H),6.26–6.18(m,1H),5.41(d,J＝13.2Hz,2H),5.08–4.99(m,1H),4.98–4.84(m,1H),4.79(dd,J＝15.5,7.1Hz,1H),4.67(dd,J＝15.5,2.5Hz,1H),4.48(dd,J＝13.2,8.3Hz,1H),4.35–4.28(m,1H),4.13(d,J＝14.3Hz,2H),4.00(d,J＝4.2Hz,3H),4.00–3.98(m,1H),3.91(d,J＝20.9Hz,2H),3.47(s,3H),2.75–2.63(m,1H),2.40–2.27(m,1H),1.42–1.30(m,3H)。 After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 55 mg of white solid 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazole) -6-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-benzo[d] Imidazole-6-carboxylic acid (yield: 74.4%). LC-MS: RT=1.75 min, [M+H] + =582.35. 1 H NMR (500MHz, DMSO) δ 8.36 (dd, J=25.3, 9.7Hz, 1H), 8.02 (dd, J=14.3, 4.7Hz, 1H), 7.95-7.85 (m, 1H), 7.82-7.76 (m, 1H), 7.71 (dd, J=8.3, 3.6Hz, 1H), 7.67 (s, 1H), 7.58–7.48 (m, 1H), 7.19 (dd, J=8.3, 1.1Hz, 1H), 6.43(t,J＝10.1Hz,1H),6.26-6.18(m,1H),5.41(d,J＝13.2Hz,2H),5.08-4.99(m,1H),4.98-4.84(m,1H) ,4.79(dd,J＝15.5,7.1Hz,1H),4.67(dd,J＝15.5,2.5Hz,1H),4.48(dd,J＝13.2,8.3Hz,1H),4.35–4.28(m,1H ),4.13(d,J＝14.3Hz,2H),4.00(d,J＝4.2Hz,3H),4.00–3.98(m,1H),3.91(d,J＝20.9Hz,2H),3.47(s , 3H), 2.75–2.63 (m, 1H), 2.40–2.27 (m, 1H), 1.42–1.30 (m, 3H).
实施例34Example 34
合成(S)-2-((4-(6-((1-(2-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000188
Figure PCTCN2021120978-appb-000188
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯和2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-(2-methoxyethyl)-1H-indazole-6-carboxylate and methyl 2-(2-methoxyethyl)-2H-indazole-6-carboxylate ester
Figure PCTCN2021120978-appb-000189
Figure PCTCN2021120978-appb-000189
室温下，将1H-吲唑-6-羧酸甲酯(1.5克，8.5毫摩尔)、1-溴-2-甲氧基乙烷(1.7克，12.7毫摩尔)和碳酸钾(2.3克，17.0毫摩尔)加入N,N-二甲基甲酰胺(15.0毫升)中，25摄氏度反应12小时。At room temperature, methyl 1H-indazole-6-carboxylate (1.5 g, 8.5 mmol), 1-bromo-2-methoxyethane (1.7 g, 12.7 mmol) and potassium carbonate (2.3 g, 17.0 mmol) was added to N,N-dimethylformamide (15.0 mL) and reacted at 25 degrees Celsius for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到667.0毫克淡黄色固体1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯(收率：33.4％)。LC-MS:RT＝1.84min,[M+H] +＝235.15。 1H NMR(500MHz,DMSO-d 6)：δ＝8.33(d,J＝0.8Hz,1H),8.20(d,J＝0.9Hz,1H),7.87(dd,J＝8.4,0.7Hz,1H),7.70(dd,J＝8.5,1.3Hz,1H),4.67(t,J＝5.2Hz,2H),3.91(s,3H),3.76(t,J＝5.2Hz,2H),3.18(s,3H). The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, washed with saturated brine (30 mL×L times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) 667.0 mg of methyl 1-(2-methoxyethyl)-1H-indazole-6-carboxylate were obtained as a pale yellow solid (yield: 33.4%). LC-MS: RT=1.84 min, [M+H] + =235.15. 1 H NMR (500 MHz, DMSO-d 6 ): δ=8.33 (d, J=0.8 Hz, 1H), 8.20 (d, J=0.9 Hz, 1H), 7.87 (dd, J=8.4, 0.7 Hz, 1H) ),7.70(dd,J＝8.5,1.3Hz,1H),4.67(t,J＝5.2Hz,2H),3.91(s,3H),3.76(t,J＝5.2Hz,2H),3.18(s , 3H).
步骤B：合成(1-(2-甲氧基乙基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(2-methoxyethyl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000190
Figure PCTCN2021120978-appb-000190
室温下，将1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯(300.0毫克，1.3毫摩尔)溶于四氢呋喃(8.0毫升)中，冰浴条件下加入四氢铝锂(97.2毫克，2.6毫摩尔)，反应1.0小时。Methyl 1-(2-methoxyethyl)-1H-indazole-6-carboxylate (300.0 mg, 1.3 mmol) was dissolved in tetrahydrofuran (8.0 mL) at room temperature, and tetrahydrofuran was added under ice bath conditions. Lithium aluminum hydride (97.2 mg, 2.6 mmol), reacted for 1.0 hour.
反应结束，冰浴条件下缓慢滴加0.1毫升水，0.1毫升15％的氢氧化钠水溶液，0.3毫升水，搅拌5分钟，抽滤，滤液干燥，过滤，旋干得到220.0毫克淡黄色固体(1-(2-甲氧基乙基)-1H-吲唑-6-基)甲醇(收率：83.4％)。LC-MS:RT＝1.61min,[M+H] +＝207.15 The reaction was completed, and 0.1 ml of water, 0.1 ml of 15% aqueous sodium hydroxide solution, 0.3 ml of water were slowly added dropwise under ice bath conditions, stirred for 5 minutes, suction filtered, the filtrate was dried, filtered, and spin-dried to obtain 220.0 mg of pale yellow solid (1 -(2-Methoxyethyl)-1H-indazol-6-yl)methanol (yield: 83.4%). LC-MS: RT = 1.61 min, [M+H] + = 207.15
步骤C：合成(S)-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000191
Figure PCTCN2021120978-appb-000191
室温下，将(1-(2-甲氧基乙基)-1H-吲唑-6-基)甲醇(120.0毫克，0.5毫摩尔)、(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(203.0毫克，0.4毫摩尔)和三(二亚苄基丙酮)二钯(46.0毫克，0.05毫摩尔)，2-二环己基磷-2,4,6-三异丙基联苯(93.0毫克，0.1毫摩尔)加入二氧六环(4.0毫升)中，N 2保护下，95摄氏度反应3.0小时。 At room temperature, (1-(2-methoxyethyl)-1H-indazol-6-yl)methanol (120.0 mg, 0.5 mmol), (S)-2-((((4-(6- Chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester ( 203.0 mg, 0.4 mmol) and tris(dibenzylideneacetone)dipalladium (46.0 mg, 0.05 mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (93.0 mg, 0.1 mmol) was added to dioxane (4.0 mL), and the reaction was carried out at 95 degrees Celsius for 3.0 hours under the protection of N 2 .
反应结束，加水淬灭，混合液用乙酸乙酯(15毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到76.0毫克淡黄色油状物(S)-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(收率：27.8％)。LC-MS:RT＝1.86min,[M+H]+＝667.42。The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (15 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (20 mL×L), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 76.0 mg pale yellow oil (S)-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 27.8% ).LC-MS: RT=1.86min, [M+H]+=667.42.
步骤D：合成(S)-2-((4-(6-((1-(2-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(2-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000192
Figure PCTCN2021120978-appb-000192
室温下，向含有(S)-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(68.0毫克，0.1毫摩尔)的二氯甲烷(0.4毫升)中滴加三氟乙酸(0.4毫升)，室温下反应1.0小时。`At room temperature, the solution containing (S)-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (68.0 mg, 0.1 mmol ) in dichloromethane (0.4 mL) was added dropwise trifluoroacetic acid (0.4 mL), and the reaction was carried out at room temperature for 1.0 hours.`
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相先用氯化铵水溶液(30毫升×升次)洗涤，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由5％乙腈在5.10分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得20.0毫克白色固体(S)-2-((4-(6-((1-(2-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：32.8％)。LC-MS: RT＝1.72min,[M+H] +＝611.36。 1H NMR(400MHz,DMSO-d 6)δ12.91(s,1H),8.38(s,1H),8.05(s,1H),7.91(dd,J＝8.5,1.5Hz,1H),7.78–7.76(m,4H),7.23(d,J＝8.3Hz,1H),6.94(t,J＝10.6Hz,1H),6.76(d,J＝8.2Hz,1H),5.52(s,2H),5.05(d,J＝5.5Hz,1H),4.82(dd,J＝15.5,6.9Hz,3H),4.68(d,J＝13.6Hz,1H),4.51(dt,J＝13.9,6.3Hz,3H),4.39–4.29(m,1H),3.69(dd,J＝33.6,28.2Hz,6H),3.12(d,J＝6.3Hz,3H),2.95(s,1H),2.71(dd,J＝17.0,8.6Hz,1H),2.38–2.26(m,1H),2.12(s,4H)。 The reaction was completed, quenched by adding water, adjusted to pH 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L), the organic phases were combined, and the organic phase was first used with an aqueous ammonium chloride solution. (30 mL×L times) washed, then dried over anhydrous sodium sulfate, and the crude product was purified by preparative high performance liquid chromatography. Separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 5% acetonitrile at 5.10 minutes come out; detection wavelength: 254nm. After purification, lyophilization at low temperature gave 20.0 mg of white solid (S)-2-((4-(6-((1-(2-(2-methoxyethyl)-1H-indazol-6-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 32.8%). LC-MS: RT=1.72 min, [M+H] + =611.36. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.91 (s, 1H), 8.38 (s, 1H) ), 8.05(s, 1H), 7.91(dd, J=8.5, 1.5Hz, 1H), 7.78–7.76(m, 4H), 7.23(d, J=8.3Hz, 1H), 6.94(t, J= 10.6Hz, 1H), 6.76(d, J＝8.2Hz, 1H), 5.52(s, 2H), 5.05(d, J＝5.5Hz, 1H), 4.82(dd, J＝15.5, 6.9Hz, 3H) ,4.68(d,J＝13.6Hz,1H),4.51(dt,J＝13.9,6.3Hz,3H),4.39–4.29(m,1H),3.69(dd,J＝33.6,28.2Hz,6H), 3.12 (d, J=6.3 Hz, 3H), 2.95 (s, 1H), 2.71 (dd, J=17.0, 8.6 Hz, 1H), 2.38–2.26 (m, 1H), 2.12 (s, 4H).
实施例35Example 35
合成(S)-2-((4-(6-((1-异丙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-isopropyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000193
Figure PCTCN2021120978-appb-000193
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-异丙基-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-isopropyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000194
Figure PCTCN2021120978-appb-000194
室温下，将1H-吲唑-6-羧酸甲酯(1.0克，5.60毫摩尔)和碳酸铯(3.6克，11.2毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入碘代异丙烷(1.0克，6.20毫摩尔)，在室温下搅拌0.5小时。Methyl 1H-indazole-6-carboxylate (1.0 g, 5.60 mmol) and cesium carbonate (3.6 g, 11.2 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature , and then iodoisopropane (1.0 g, 6.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×2次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到600毫克白色固体1-异丙基-1H-吲唑-6-羧酸甲酯和400毫克白色固体2-异丙基-2H-吲唑-6-羧酸甲酯(收率：83％)。LC-MS:RT＝1.98min,[M+H] +＝219.19。 After the reaction, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×2 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/2) to obtain 600 mg of methyl 1-isopropyl-1H-indazole-6-carboxylate as a white solid and 400 mg of methyl 2-isopropyl-2H-indazole-6-carboxylate as a white solid Esters (yield: 83%). LC-MS: RT=1.98 min, [M+H] + =219.19.
步骤B：合成(1-异丙基-1H-吲唑-6基)-甲醇Step B: Synthesis of (1-isopropyl-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000195
Figure PCTCN2021120978-appb-000195
室温下，将1-异丙基-1H-吲唑-6-羧酸甲酯(600毫克，2.75毫摩尔)溶于四氢呋喃(15毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(500毫克，13.76毫摩尔)，在室温下搅拌0.5小时。At room temperature, methyl 1-isopropyl-1H-indazole-6-carboxylate (600 mg, 2.75 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to zero degrees Celsius in an ice bath, and tetrahydrofuran was added. Aluminum lithium (500 mg, 13.76 mmol), stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(50毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到500毫克无色油状液体(1-异丙基-1H-吲唑-6基)-甲醇(收率：95％)。LC-MS:RT＝1.72min,[M+H] +＝191.18。 After the reaction, saturated sodium chloride was added to quench the reaction, then ethyl acetate (50 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 500 mg of colorless oily liquid (1-isopropyl yl)-methanol (yield: 95%). LC-MS: RT=1.72 min, [M+H] + =191.18.
步骤C：(S)-2-((4-(6-((1-异丙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: (S)-2-((4-(6-((1-isopropyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000196
Figure PCTCN2021120978-appb-000196
将(1-异丙基-1H-吲唑-6基)-甲醇(70毫克，0.37毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(182毫克，0.37毫摩尔)，钯催化剂(17毫克)，1,1’-联萘-2,2’-双二苯膦(23毫克)和叔丁醇钠(71毫克，0.74毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌2个小时。(1-Isopropyl-1H-indazol-6yl)-methanol (70 mg, 0.37 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-yl Methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (182 mg, 0.37 mmol), palladium catalyst (17 mg), 1,1'-binaphthyl-2,2'-bis Diphenylphosphine (23 mg) and sodium tert-butoxide (71 mg, 0.74 mmol) were dissolved in dioxane (10 mL) and the temperature was raised to 100°C and stirred for 2 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相纯化得到41.78毫克白色固体(S)-2-((4-(6-((1-异丙基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：19％)。LC-MS:RT＝1.79min,[M+H] +＝595.38。 After the reaction was completed, suction filtration with celite, washed with dichloromethane and concentrated the organic phase, the obtained crude product was purified by high performance liquid phase to obtain 41.78 mg of white solid (S)-2-((4-(6-((1- Isopropyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid (yield: 19%). LC-MS: RT=1.79 min, [M+H] + =595.38.
实施例36Example 36
合成(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000197
Figure PCTCN2021120978-appb-000197
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-5-甲醇Step A: Synthesis of isoquinoline-5-methanol
Figure PCTCN2021120978-appb-000198
Figure PCTCN2021120978-appb-000198
零摄氏度下，异喹啉-5-甲醛(100毫克，0.64毫摩尔)溶于甲醇(2毫升)中，氮气保护下，加入硼氢化钠(49毫克，1.28毫摩尔),搅拌1小时。At zero degrees Celsius, isoquinoline-5-carbaldehyde (100 mg, 0.64 mmol) was dissolved in methanol (2 mL), sodium borohydride (49 mg, 1.28 mmol) was added under nitrogen protection, and the mixture was stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加水(2毫升)，反应液加入乙酸乙酯(30毫升)稀释，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得异喹啉-5-甲醇93毫克(收率：91.4％)。LC-MS：RT＝0.37min,[M+H] +＝160.12。 After the reaction, water (2 mL) was slowly added dropwise under an ice bath, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. After concentration, the obtained white solid was directly used in the next reaction to obtain 93 mg of isoquinoline-5-methanol (yield: 91.4%). LC-MS: RT=0.37 min, [M+H] + =160.12.
步骤B：合成(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000199
Figure PCTCN2021120978-appb-000199
将异喹啉-5-甲醇(30毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。The isoquinoline-5-methanol (30 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindeneacetone)dipalladium (15 mg, 0.016 mmol) were added successively ), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was raised to 100 degrees Celsius at a constant speed, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯75毫克(收率：75.7％)。LC-MS：RT＝1.75min,[M+H] +＝620.37。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, and then saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetert-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 75 mg (yield: 75.7%). LC-MS: RT=1.75 min, [M+H] + =620.37.
步骤C：合成(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000200
Figure PCTCN2021120978-appb-000200
将(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(75毫克，0.12毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (75 mg, 0.12 mmol), dissolved in mixed solvent (2 mL, dichloromethane/trifluoroacetic acid = 6 /1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到29毫克白色固体(S)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：42.8％)。LC-MS：RT＝1.61min,[M+H] +＝564.29。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 29 mg of white solid (S)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 42.8%). LC-MS: RT=1.61 min, [M+H] + =564.29.
实施例37Example 37
合成(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000201
Figure PCTCN2021120978-appb-000201
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-异丙基-2H-吲唑-6-基)羧酸甲酯Step A: Synthesis of Methyl (2-isopropyl-2H-indazol-6-yl)carboxylate
Figure PCTCN2021120978-appb-000202
Figure PCTCN2021120978-appb-000202
将1H-吲唑-6-羧酸甲酯(200毫克，1.14毫摩尔),2-碘丙烷(388毫克，2.28毫摩尔)溶于甲醇(4毫升)中，加入碳酸钾(304毫克，2.28毫摩尔)，加毕，氮气保护下，快速升温至回流,搅拌12小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.14 mmol), 2-iodopropane (388 mg, 2.28 mmol) were dissolved in methanol (4 mL), potassium carbonate (304 mg, 2.28 mmol) was added mmol), the addition was completed, and under nitrogen protection, the temperature was rapidly increased to reflux, and stirred for 12 hours.
反应结束后，冷却至室温，减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体(2-异丙基-2H-吲唑-6-基)羧酸甲酯102毫克(收率：41.0％)。LC-MS：RT＝1.88min,[M+H] +＝219.18。 After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, 30 ml of ethyl acetate was added to the reaction solution, washed with saturated brine (20 ml × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4). 102 mg of methyl (2-isopropyl-2H-indazol-6-yl)carboxylate was obtained as a yellow solid (yield: 41.0%). LC-MS: RT=1.88 min, [M+H] + =219.18.
步骤B：合成(2-异丙基-2H-吲唑-6-基)甲醇Step B: Synthesis of (2-isopropyl-2H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000203
Figure PCTCN2021120978-appb-000203
零摄氏度下，(2-异丙基-2H-吲唑-6-基)羧酸甲酯102毫克，(0.47毫摩尔)溶于四氢呋喃(2毫升)中， 氮气保护下，加入氢化锂铝(38毫克，1.00毫摩尔),搅拌1小时。At zero degrees Celsius, 102 mg of methyl (2-isopropyl-2H-indazol-6-yl)carboxylate, (0.47 mmol) were dissolved in tetrahydrofuran (2 mL), and under nitrogen protection, lithium aluminum hydride ( 38 mg, 1.00 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.1毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×3次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(2-异丙基-2H-吲唑-6-基)甲醇85毫克(收率：95.6％)。LC-MS：RT＝1.70min,[M+H] +＝191.16。 After the reaction, sodium hydroxide solution (5%, 0.1 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × 3 times, dichloromethane/methanol) =10/1) rinsed, combined the organic phases, then washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained white solid was directly used in the next step to obtain (2-isolated) Propyl-2H-indazol-6-yl)methanol 85 mg (yield: 95.6%). LC-MS: RT=1.70 min, [M+H] + =191.16.
步骤C：合成(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000204
Figure PCTCN2021120978-appb-000204
将(2-异丙基-2H-吲唑-6-基)甲醇(34毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，快速升温至100摄氏度,搅拌1小时。(2-Isopropyl-2H-indazol-6-yl)methanol (34 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone) ) Dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was rapidly increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至PH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯77毫克(收率：62.3％)。LC-MS：RT＝1.86min,[M+H] +＝651.43。 After the reaction, cool to room temperature, slowly add saturated ammonium chloride solution to the reaction solution until the pH is neutral, then extract with ethyl acetate (10 ml × 3 times), combine the organic phases, and then add saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A white solid was obtained (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester 77 mg (yield: 62.3%). LC-MS: RT=1.86 min, [M+H] + =651.43.
步骤D：合成(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000205
Figure PCTCN2021120978-appb-000205
将(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(77毫克，0.12毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (77 mg, 0.12 mmol), dissolved in mixed solvent (3 mL, Dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到14毫克白色固体(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：20.0％)。LC-MS：RT＝1.75min,[M+H] +＝595.35。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 14 mg of white solid (S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy) )pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 20.0%). LC-MS: RT=1.75 min, [M+H] + =595.35.
实施例38Example 38
合成(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000206
Figure PCTCN2021120978-appb-000206
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(二氟甲基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-(difluoromethyl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000207
Figure PCTCN2021120978-appb-000207
室温下，将1H-吲唑-6-羧酸甲酯(500.0毫克，2.82毫摩尔)加入乙腈(28.0毫升)中，再依次加入2-溴-2,2-二氟乙酸乙酯(690.2毫克，3.42毫摩尔)、氢氧化钾(314.6毫克，5.63毫摩尔)，N 2保护下，60摄氏度反应16.0小时。 At room temperature, methyl 1H-indazole-6-carboxylate (500.0 mg, 2.82 mmol) was added to acetonitrile (28.0 mL), followed by ethyl 2-bromo-2,2-difluoroacetate (690.2 mg). , 3.42 mmol), potassium hydroxide (314.6 mg, 5.63 mmol), under the protection of N 2 , at 60 degrees Celsius for 16.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝20：1)得到168.0毫克淡黄色固体1-(二氟甲基)-1H-吲唑-6-羧酸甲酯(收率：26.5％)。LC-MS:RT＝1.88min,[M+H] +＝227.13。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 mL×L times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=20:1) 168.0 mg of methyl 1-(difluoromethyl)-1H-indazole-6-carboxylate were obtained as a pale yellow solid (yield: 26.5%). LC-MS: RT=1.88 min, [M+H] + =227.13.
步骤B：合成(1-(二氟甲基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(difluoromethyl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000208
Figure PCTCN2021120978-appb-000208
冰浴下，向含有1-(二氟甲基)-1H-吲唑-6-羧酸甲酯(168.0毫克，0.74毫摩尔)的四氢呋喃(7.0毫升)中滴加四氢铝锂溶液(1摩尔/升，1毫升)，室温下反应0.5小时。A solution of lithium tetrahydroaluminum (1 mol/L, 1 mL), and reacted at room temperature for 0.5 hours.
反应结束，向反应液中缓慢滴加水，待无气泡产生垫硅藻土抽滤。混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相用无水硫酸钠干燥，浓缩得到132毫克淡黄色固体(1-(二氟甲基)-1H-吲唑-6-基)甲醇(收率：89.3％)直接用于下一步反应。LC-MS:RT＝1.63min,[M+H] +＝199.13。 After the reaction was completed, water was slowly added dropwise to the reaction solution, and a pad of diatomaceous earth was suction filtered when no air bubbles were generated. The mixture was extracted with dichloromethane (30 mL×L), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 132 mg of pale yellow solid (1-(difluoromethyl)-1H-indazole- 6-yl)methanol (yield: 89.3%) was directly used in the next reaction. LC-MS: RT=1.63 min, [M+H] + =199.13.
步骤C：合成(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000209
Figure PCTCN2021120978-appb-000209
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、(1-(二氟甲基)-1H-吲唑-6-基)甲醇(60.0毫克，0.32毫摩尔)和叔丁醇钠(58.0毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(37.0毫克，0.06毫摩尔)、三(二亚苄基丙酮)二钯(27.3毫克，0.03毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), (1-(difluoromethyl)-1H-indazol-6-yl)methanol (60.0 mg, 0.32 mmol) and sodium tert-butoxide (58.0 mg, 0.6 mmol) were added to dioxane (10.0 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (37.0 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (27.3 mg, 0.03 mmol), and reacted at 100 degrees Celsius for 3.5 hours under the protection of N 2 .
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到98.0毫克淡黄色油状固体(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：49.3％)。LC-MS:RT＝1.88min,[M+H] +＝659.37。 The reaction was completed, quenched by adding water, and the mixture was extracted with dichloromethane (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 98.0 mg pale yellow oily solid (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 49.3%). LC-MS: RT=1.88 min, [M+H] + =659.37.
步骤D：合成(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000210
Figure PCTCN2021120978-appb-000210
室温下，向含有(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(98.0毫克，0.15毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应12.0小时。At room temperature, the solution containing (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (98.0 mg, 0.15 mmol) in Trifluoroacetic acid (1.0 mL) was added dropwise to chloromethane (8.0 mL), and the mixture was reacted at room temperature for 12.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由9％乙腈在5.30分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得33.2毫克淡黄色固体(S)-2-((4-(6-((1-(二氟甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30.2％)。LC-MS:RT＝1.70min,[M+H] +＝603.27。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L times), the organic phases were combined, and then dried with anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm x 30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 9% acetonitrile at 5.30 minutes come out; detection wavelength: 254nm. After purification, lyophilization at low temperature gave 33.2 mg of pale yellow solid (S)-2-((4-(6-((1-(difluoromethyl)-1H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 30.2% ). LC-MS: RT=1.70 min, [M+H] + =603.27.
实施例39Example 39
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H-indazole-6 -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000211
Figure PCTCN2021120978-appb-000211
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of 1-(oxetan-3-yl)-1H-indazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000212
Figure PCTCN2021120978-appb-000212
室温下，将1H-吲唑-6-羧酸甲酯(500.0毫克，2.82毫摩尔)加入N,N-二甲基甲酰胺(28.0毫升)中，再依次加入3-碘氧杂环丁烷(625.2毫克，3.42毫摩尔)、碳酸钾(779.5毫克，5.64毫摩尔)，N 2保护下，88摄氏度反应14.0小时。 At room temperature, methyl 1H-indazole-6-carboxylate (500.0 mg, 2.82 mmol) was added to N,N-dimethylformamide (28.0 mL) followed by 3-iodooxetane (625.2 mg, 3.42 mmol), potassium carbonate (779.5 mg, 5.64 mmol), under N 2 protection, react at 88 degrees Celsius for 14.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝20：1)得到157.0毫克淡黄色固体1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯(收率：24.2％)。LC-MS:RT＝1.81min,[M+H] +＝233.14。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 mL×L times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=20:1) 157.0 mg of methyl 1-(oxetan-3-yl)-1H-indazole-6-carboxylate were obtained as a pale yellow solid (yield: 24.2%). LC-MS: RT=1.81 min, [M+H] + =233.14.
步骤B：合成(1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(oxetan-3-yl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000213
Figure PCTCN2021120978-appb-000213
冰浴下，向含有1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯(157.0毫克，0.70毫摩尔)的四氢呋喃(7.0毫升)中滴加四氢铝锂溶液(1摩尔/升，1毫升)，室温下反应0.5小时。To methyl 1-(oxetan-3-yl)-1H-indazole-6-carboxylate (157.0 mg, 0.70 mmol) in tetrahydrofuran (7.0 mL) was added dropwise tetrahydroaluminum under ice bath Lithium solution (1 mol/L, 1 mL) was reacted at room temperature for 0.5 hours.
反应结束，向反应液中缓慢滴加水，待无气泡产生垫硅藻土抽滤。混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相用无水硫酸钠干燥，浓缩得到112.3毫克淡黄色固体(1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲醇(收率：78.6％)直接用于下一步反应。LC-MS:RT＝1.57min,[M+H] +＝205.14。 After the reaction was completed, water was slowly added dropwise to the reaction solution, and a pad of diatomaceous earth was suction filtered when no air bubbles were generated. The mixture was extracted with dichloromethane (30 mL×L), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 112.3 mg of pale yellow solid (1-(oxetan-3-yl)-1H -indazol-6-yl)methanol (yield: 78.6%) was directly used in the next reaction. LC-MS: RT=1.57 min, [M+H] + =205.14.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H-indone azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000214
Figure PCTCN2021120978-appb-000214
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、(1-(二氟甲基)-1H-吲唑-6-基)甲醇(60.0毫克，0.29毫摩尔)和叔丁醇钠(58.0毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(37.0毫克，0.06毫摩尔)、三(二亚苄基丙酮)二钯(27.3毫克，0.03毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), (1-(difluoromethyl)-1H-indazol-6-yl)methanol (60.0 mg, 0.29 mmol) and sodium tert-butoxide (58.0 mg, 0.6 mmol) were added to dioxane (10.0 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (37.0 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (27.3 mg, 0.03 mmol), and reacted at 100 degrees Celsius for 3.5 hours under the protection of N 2 .
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到73.0毫克淡黄色油状固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：36.6％)。LC-MS:RT＝1.88min,[M+H] +＝665.41。 The reaction was completed, quenched by adding water, and the mixture was extracted with dichloromethane (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 73.0 mg pale yellow oily solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 36.6 %). LC-MS: RT=1.88 min, [M+H] + =665.41.
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H-indone azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000215
Figure PCTCN2021120978-appb-000215
室温下，向含有(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(73.0毫克，0.11毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应12.0小时。At room temperature, the solution containing (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3-yl)-1H- Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (73.0 mg, 0.11 mg mol) in dichloromethane (8.0 mL) was added dropwise trifluoroacetic acid (1.0 mL), and the reaction was carried out at room temperature for 12.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈；流速：20毫升/分钟；梯度：由8％乙腈在4.80分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得25.1毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：29.2％)。LC-MS:RT＝1.72min,[M+H] +＝609.35。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L times), the organic phases were combined, and then dried with anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm x 30mm 5μM; mobile phase: water (containing 0.1% ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted from 8% acetonitrile at 4.80 minutes ; Detection wavelength: 254nm. After purification, lyophilization at low temperature gave 25.1 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(oxetan-3 -yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield : 29.2%). LC-MS: RT=1.72 min, [M+H] + =609.35.
实施例40Example 40
合成(S)-2-((4-(6-((1,3-二甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1,3-Dimethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000216
Figure PCTCN2021120978-appb-000216
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1,3-二甲基-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1,3-dimethyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000217
Figure PCTCN2021120978-appb-000217
将3-溴-1-甲基-1H-吲唑-6-羧酸甲酯(500毫克,1.86毫摩尔)溶于1,4-二氧六环(20.0毫升)和水(5.0毫升)中，依次将2,4,6-三甲基-1,3,5,2,4,6-三氧三硼硼烷(440毫克,3.49毫摩尔)，碳酸钾(550毫克,3.99毫摩尔)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(150毫克,0.20毫摩尔)加入反应液中，氮气保护后，100摄氏度下搅拌16小时，LC-MS监测至反应完全。Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (500 mg, 1.86 mmol) was dissolved in 1,4-dioxane (20.0 mL) and water (5.0 mL) , followed by 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborolane (440 mg, 3.49 mmol), potassium carbonate (550 mg, 3.99 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.20 mmol) was added to the reaction solution, followed by nitrogen protection, stirred at 100 degrees Celsius for 16 hours, and monitored by LC-MS until the reaction is complete.
向反应液加水(20.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取，合并有机相，有机相用饱和食盐水(25.0毫升×3次)，无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到200毫克白色固体1,3-二甲基-1H-吲唑-6-羧酸甲酯(收率：46.5％)。LC-MS：RT＝1.85min,[M+H] +＝205.16。 Water (20.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. concentrate. The obtained residue was purified by silica gel column chromatography to obtain 200 mg of methyl 1,3-dimethyl-1H-indazole-6-carboxylate as a white solid (yield: 46.5%). LC-MS: RT=1.85 min, [M+H] + =205.16.
步骤B：合成(1,3-二甲基-1H-吲唑-6-基)甲醇Step B: Synthesis of (1,3-Dimethyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000218
Figure PCTCN2021120978-appb-000218
将1,3-二甲基-1H-吲唑-6-羧酸甲酯(200毫克,0.98毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后，将氢化锂铝(38毫克,1.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 1,3-dimethyl-1H-indazole-6-carboxylate (200 mg, 0.98 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at zero degrees Celsius, lithium aluminum hydride ( 38 mg, 1.0 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
向反应液加水(2.0毫升)，析出大量白色固体，向反应液中加无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物经硅胶柱层析纯化得到140毫克白色固体(1,3-二甲基-1H-吲唑-6-基)甲醇(收率：79.0％)。LC-MS：RT＝1.63min,[M+H] +＝177.16。 Water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 140 mg of white solid (1,3 -Dimethyl-1H-indazol-6-yl)methanol (yield: 79.0%). LC-MS: RT=1.63 min, [M+H] + =177.16.
步骤C：合成(S)-2-((4-(6-((1,3-二甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-((1,3-Dimethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000219
Figure PCTCN2021120978-appb-000219
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(95毫克,0.20毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(1,3-二甲基-1H-吲唑-6-基)甲醇(70毫克,0.40毫摩尔),叔丁醇钠(40毫克,0.40毫摩尔),1,1'-联萘-2,2'-双二苯膦(26毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌3小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (95 mg, 0.20 mmol) was dissolved in 1,4-dioxane (10.0 mL) and (1,3-dimethyl-1H- Indazol-6-yl)methanol (70 mg, 0.40 mmol), sodium tert-butoxide (40 mg, 0.40 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26 mg , 0.040 mmol) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.020 mmol) were added to the reaction flask, under nitrogen protection, stirred at 100 degrees Celsius for 3 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余 物经高效液相制备仪分离纯化得到16毫克白色固体(S)-2-((4-(6-((1,3-二甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：13.8％)。LC-MS：RT＝1.75min,[M+H] +＝581.33。 1H NMR(500MHz,DMSO)δ8.22(s,1H),7.80(dd,J＝8.4,1.5Hz,1H),7.62(ddd,J＝19.2,13.8,8.3Hz,4H),7.22–7.14(m,1H),6.86(d,J＝7.3Hz,1H),6.68(d,J＝8.2Hz,1H),5.47(d,J＝4.7Hz,2H),5.17–5.07(m,1H),4.77(dd,J＝15.2,7.2Hz,1H),4.64(dd,J＝15.2,2.8Hz,1H),4.45(dd,J＝13.4,7.7Hz,1H),4.37(dt,J＝9.0,5.9Hz,1H),3.94(d,J＝13.5Hz,1H),3.86(s,3H),3.77(d,J＝13.4Hz,1H),3.02(d,J＝10.9Hz,1H),2.88(d,J＝10.9Hz,1H),2.77–2.56(m,2H),2.46(s,1H),2.43(s,3H),2.21(m,2H),1.88–1.69(m,4H)。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 16 mg of white solid (S)-2-((4-(6-((1,3-dimethyl-1H-indazol-6-yl)methoxy) yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield : 13.8%). LC-MS: RT=1.75 min, [M+H] + =581.33. 1 H NMR (500MHz, DMSO) δ 8.22 (s, 1H), 7.80 (dd, J=8.4, 1.5Hz, 1H), 7.62 (ddd, J=19.2, 13.8, 8.3Hz, 4H), 7.22-7.14 (m, 1H), 6.86 (d, J=7.3Hz, 1H), 6.68 (d, J=8.2Hz, 1H), 5.47 (d, J=4.7Hz, 2H), 5.17–5.07 (m, 1H) ,4.77(dd,J＝15.2,7.2Hz,1H),4.64(dd,J＝15.2,2.8Hz,1H),4.45(dd,J＝13.4,7.7Hz,1H),4.37(dt,J＝9.0 ,5.9Hz,1H),3.94(d,J＝13.5Hz,1H),3.86(s,3H),3.77(d,J＝13.4Hz,1H),3.02(d,J＝10.9Hz,1H), 2.88(d, J＝10.9Hz, 1H), 2.77-2.56(m, 2H), 2.46(s, 1H), 2.43(s, 3H), 2.21(m, 2H), 1.88-1.69(m, 4H) .
实施例41Example 41
合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000220
Figure PCTCN2021120978-appb-000220
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000221
Figure PCTCN2021120978-appb-000221
将(2-甲基苯并[d]噻唑-6基)甲醇(34毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，快速升温至100摄氏度,搅拌1小时。Mix (2-methylbenzo[d]thiazol-6yl)methanol (34 mg, 0.19 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1 ,4-dioxane (1 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone) Dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol) were added, and the temperature was rapidly increased to 100 degrees Celsius under nitrogen protection, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至PH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯69毫克(收率：67.4％)。LC-MS：RT＝1.89min,[M+H] +＝640.33。 After the reaction, cool to room temperature, slowly add saturated ammonium chloride solution to the reaction solution until the pH is neutral, then extract with ethyl acetate (10 ml × 3 times), combine the organic phases, and then add saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A white solid was obtained (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 69 mg (yield: 67.4%). LC-MS: RT=1.89 min, [M+H] + =640.33.
步骤B：合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000222
Figure PCTCN2021120978-appb-000222
将(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲 基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(69毫克，0.11毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (69 mg, 0.11 mmol), dissolved in mixed solvent (3 mL, Dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到19毫克白色固体(S)-2-((4-(6-((2-甲基苯并[d]噻唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30.0％)。LC-MS：RT＝1.75min,[M+H] +＝584.29。 1H NMR(400MHz,DMSO-d 6)δ12.69(s,1H),8.27(s,1H),8.12(s,1H),7.87(d,J＝8.3Hz,1H),7.80(dd,J＝8.4,1.4Hz,1H),7.64(d,J＝8.6Hz,1H),7.60(d,J＝8.0Hz,1H),7.54(dd,J＝8.3,1.6Hz,1H),6.85(d,J＝7.3Hz,1H),6.67(d,J＝8.1Hz,1H),5.74(s,1H),5.49–5.41(m,2H),5.11(d,J＝4.6Hz,1H),4.80(dd,J＝15.1,7.2Hz,1H),4.66(dd,J＝15.2,2.5Hz,1H),4.45(dd,J＝13.4,8.0Hz,1H),4.36(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.8Hz,1H),3.78(d,J＝13.4Hz,1H),3.00(d,J＝10.2Hz,1H),2.86(d,J＝9.0Hz,1H),2.70–2.55(m,2H),2.44(d,J＝8.9Hz,1H),2.30–2.12(m,3H),1.99(d,J＝8.2Hz,1H),1.77(d,J＝17.3Hz,4H)。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 19 mg of white solid (S)-2-((4-(6-((2-methylbenzo[d]thiazol-6-yl)methoxy) )pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 30.0%). LC-MS: RT=1.75 min, [M+H] + =584.29. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.69(s, 1H), 8.27(s, 1H), 8.12(s, 1H), 7.87(d, J=8.3Hz, 1H), 7.80(dd, J=8.4, 1.4Hz, 1H), 7.64(d, J=8.6Hz, 1H), 7.60(d, J=8.0Hz, 1H), 7.54(dd, J=8.3, 1.6Hz, 1H), 6.85( d, J=7.3Hz, 1H), 6.67 (d, J=8.1Hz, 1H), 5.74 (s, 1H), 5.49–5.41 (m, 2H), 5.11 (d, J=4.6Hz, 1H), 4.80(dd,J＝15.1,7.2Hz,1H),4.66(dd,J＝15.2,2.5Hz,1H),4.45(dd,J＝13.4,8.0Hz,1H),4.36(dt,J＝9.0, 5.9Hz, 1H), 3.95 (d, J=13.8Hz, 1H), 3.78 (d, J=13.4Hz, 1H), 3.00 (d, J=10.2Hz, 1H), 2.86 (d, J=9.0Hz) ,1H),2.70–2.55(m,2H),2.44(d,J=8.9Hz,1H),2.30–2.12(m,3H),1.99(d,J=8.2Hz,1H),1.77(d, J=17.3Hz, 4H).
实施例42Example 42
合成(S)-2-((4-(6-((1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000223
Figure PCTCN2021120978-appb-000223
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-((3-methyloxetan-3-yl)methyl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000224
Figure PCTCN2021120978-appb-000224
将1H-吲唑-6-羧酸甲酯(200毫克，1.14毫摩尔),3-(溴甲基)-3-甲基氧杂环丁烷(225毫克，1.36毫摩尔)溶于甲醇(4毫升)中，加入碳酸钾(304毫克，2.28毫摩尔)，加毕，氮气保护下，快速升温至回流,搅拌12小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.14 mmol), 3-(bromomethyl)-3-methyloxetane (225 mg, 1.36 mmol) was dissolved in methanol ( 4 mL), potassium carbonate (304 mg, 2.28 mmol) was added, and after the addition was completed, the temperature was rapidly increased to reflux under nitrogen protection, and stirred for 12 hours.
反应结束后，冷却至室温，减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-羧酸甲酯98毫克(收率：33.1％)。LC-MS：After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, 30 ml of ethyl acetate was added to the reaction solution, washed with saturated brine (20 ml × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4). 98 mg of methyl 1-((3-methyloxetan-3-yl)methyl)-1H-indazole-6-carboxylate was obtained as a yellow solid (yield: 33.1%). LC-MS:
RT＝1.86min,[M+H] +＝261.20。 RT=1.86min, [M+H] + =261.20.
步骤B：合成1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-甲醇Step B: Synthesis of 1-((3-Methyloxetan-3-yl)methyl)-1H-indazole-6-methanol
Figure PCTCN2021120978-appb-000225
Figure PCTCN2021120978-appb-000225
零摄氏度下，1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-羧酸甲酯(98毫克，0.38毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，加入氢化锂铝(43毫克，1.13毫摩尔),搅拌1小时。At zero degrees Celsius, methyl 1-((3-methyloxetan-3-yl)methyl)-1H-indazole-6-carboxylate (98 mg, 0.38 mmol) was dissolved in tetrahydrofuran (2 mL ), under nitrogen protection, was added lithium aluminum hydride (43 mg, 1.13 mmol), and stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.1毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×3次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得1-((3-甲基氧杂环丁-3-基) 甲基)-1H-吲唑-6-甲醇83毫克(收率：93.7％)。LC-MS：RT＝1.65min,[M+H] +＝233.17。 After the reaction, sodium hydroxide solution (5%, 0.1 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × 3 times, dichloromethane/methanol) = 10/1) rinsed, combined the organic phases, then washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained white solid was directly used in the next reaction to obtain 1-(( 3-Methyloxetan-3-yl)methyl)-1H-indazole-6-methanol 83 mg (yield: 93.7%). LC-MS: RT=1.65 min, [M+H] + =233.17.
步骤C：合成(S)-2-((4-(6-((1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methan oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000226
Figure PCTCN2021120978-appb-000226
将1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-甲醇(44毫克，0.19毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。1-((3-Methyloxetan-3-yl)methyl)-1H-indazole-6-methanol (44 mg, 0.19 mmol), (S)-2-((((4- (6-Chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert. Butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenoneacetone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius , stir for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×3次)萃取，合并有机相，然后用饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯83毫克(收率：74.9％)。LC-MS：RT＝1.86min,[M+H] +＝693.46.。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, and then saturated brine (20 mL×3 times), washed with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester 83 mg (yield: 74.9%). LC-MS: RT=1.86 min, [M+H] + =693.46.
步骤D：合成(S)-2-((4-(6-((1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methyl)-1H-indazol-6-yl)methan Oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000227
Figure PCTCN2021120978-appb-000227
将(S)-2-((4-(6-((2-异丙基-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(83毫克，0.12毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((2-isopropyl-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (83 mg, 0.12 mmol), dissolved in mixed solvent (3 mL, Dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到23毫克白色固体(S)-2-((4-(6-((1-((3-甲基氧杂环丁-3-基)甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30.1％)。LC-MS：RT＝1.54min,[M+H] +＝637.38。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 23 mg of white solid (S)-2-((4-(6-((1-((3-methyloxetan-3-yl)methane) yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid (yield: 30.1%). LC-MS: RT=1.54 min, [M+H] + =637.38.
实施例43Example 43
合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000228
Figure PCTCN2021120978-appb-000228
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-氟-5-羟基-4-硝基苯甲酸Step A: Synthesis of 2-fluoro-5-hydroxy-4-nitrobenzoic acid
Figure PCTCN2021120978-appb-000229
Figure PCTCN2021120978-appb-000229
将2,5-二氟-4-硝基苯甲酸(1.2克,6.0毫摩尔)溶于4.0M氢氧化钾溶液(20.0毫升)中，室温搅拌16小时,LC-MS监测至反应完全。2,5-Difluoro-4-nitrobenzoic acid (1.2 g, 6.0 mmol) was dissolved in 4.0 M potassium hydroxide solution (20.0 mL), stirred at room temperature for 16 hours, and monitored by LC-MS until the reaction was complete.
向反应液加4.0M稀盐酸(20.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩,得到1.2克黄色固体2-氟-5-羟基-4-硝基苯甲酸(收率：46.5％)。LC-MS：RT＝1.53min,[M+H] +＝200.11。 4.0M dilute hydrochloric acid (20.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, and the organic phase was washed with saturated brine (25.0 mL×3 times), anhydrous sodium sulfate It was dried and concentrated under reduced pressure to obtain 1.2 g of 2-fluoro-5-hydroxy-4-nitrobenzoic acid as a yellow solid (yield: 46.5%). LC-MS: RT=1.53 min, [M+H] + =200.11.
步骤B：合成2-氟-5-羟基-4-硝基苯甲酸甲酯Step B: Synthesis of methyl 2-fluoro-5-hydroxy-4-nitrobenzoate
Figure PCTCN2021120978-appb-000230
Figure PCTCN2021120978-appb-000230
将2-氟-5-羟基-4-硝基苯甲酸(340毫克,1.7毫摩尔)溶于二氯甲烷(20.0毫升)中,零摄氏度下搅拌15分钟后，将草酰氯(0.4毫升,3.4毫摩尔)和N,N-二甲基甲酰胺(1滴)加入反应液中,零摄氏度下搅拌30分钟后,将反应液滴加到甲醇(20.0毫升)中,室温搅拌1小时。2-Fluoro-5-hydroxy-4-nitrobenzoic acid (340 mg, 1.7 mmol) was dissolved in dichloromethane (20.0 mL), and after stirring for 15 minutes at zero degrees Celsius, oxalyl chloride (0.4 mL, 3.4 mmol) and N,N-dimethylformamide (1 drop) were added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, the reaction was added dropwise to methanol (20.0 mL) and stirred at room temperature for 1 hour.
向反应液加15％碳酸氢钠(20.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩,得到350毫克黄色固体2-氟-5-羟基-4-硝基苯甲酸甲酯(收率：96.4％)。LC-MS：RT＝1.85min,[M+H] +＝214.09。 To the reaction solution was added 15% sodium bicarbonate (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, and the organic phase was washed with saturated brine (25.0 mL×3 times), anhydrous sulfuric acid Dry over sodium and concentrate under reduced pressure to obtain 350 mg of methyl 2-fluoro-5-hydroxy-4-nitrobenzoate as a yellow solid (yield: 96.4%). LC-MS: RT=1.85 min, [M+H] + =214.09.
步骤C：合成4-氨基-2-氟-5-羟基苯甲酸甲酯Step C: Synthesis of methyl 4-amino-2-fluoro-5-hydroxybenzoate
Figure PCTCN2021120978-appb-000231
Figure PCTCN2021120978-appb-000231
将2-氟-5-羟基-4-硝基苯甲酸甲酯(340毫克,1.60毫摩尔)溶于甲醇(10.0毫升)中,将饱和氯化铵溶液(4.0毫升)和还原性铁粉(560毫克,10.0毫摩尔)加入反应液中,室温搅拌16小时,LC-MS监测至反应完全。Methyl 2-fluoro-5-hydroxy-4-nitrobenzoate (340 mg, 1.60 mmol) was dissolved in methanol (10.0 mL), saturated ammonium chloride solution (4.0 mL) and reducing iron powder ( 560 mg, 10.0 mmol) was added to the reaction solution, stirred at room temperature for 16 hours, and monitored by LC-MS until the reaction was complete.
反应液垫硅藻土过滤,滤液减压浓缩。混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到200毫克黄棕色固体4-氨基-2-氟-5-羟基苯甲酸甲酯(收率：67.1％)。LC-MS：RT＝1.60min,[M+H] +＝186.11。 The reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was filtered through a silica gel column. Analytical purification gave 200 mg of methyl 4-amino-2-fluoro-5-hydroxybenzoate as a yellow-brown solid (yield: 67.1%). LC-MS: RT=1.60 min, [M+H] + =186.11.
步骤D：合成5-氟-2-甲基苯并[d]噁唑-6-羧酸甲酯Step D: Synthesis of methyl 5-fluoro-2-methylbenzo[d]oxazole-6-carboxylate
Figure PCTCN2021120978-appb-000232
Figure PCTCN2021120978-appb-000232
将4-氨基-2-氟-5-羟基苯甲酸甲酯(200毫克,1.1毫摩尔)溶于原乙酸三乙酯(3.0毫升)中,100摄氏度下搅拌3小时,LC-MS监测至反应完全。Methyl 4-amino-2-fluoro-5-hydroxybenzoate (200 mg, 1.1 mmol) was dissolved in triethyl orthoacetate (3.0 mL), stirred at 100 degrees Celsius for 3 hours, and the reaction was monitored by LC-MS completely.
向反应液加水(20.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到210毫克黄色固体5-氟-2-甲基苯并[d]噁唑-6-羧酸甲酯(收率：90.9％)。LC-MS：RT＝1.82min,[M+H] +＝210.11。 Water (20.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 210 mg of methyl 5-fluoro-2-methylbenzo[d]oxazole-6-carboxylate as a yellow solid (yield: 90.9%). LC-MS: RT=1.82 min, [M+H] + =210.11.
步骤E：合成(5-氟-2-甲基苯并[d]噁唑-6-基)甲醇Step E: Synthesis of (5-fluoro-2-methylbenzo[d]oxazol-6-yl)methanol
Figure PCTCN2021120978-appb-000233
Figure PCTCN2021120978-appb-000233
将5-氟-2-甲基苯并[d]噁唑-6-羧酸甲酯(210毫克,1.0毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后，将氢化锂铝(76毫克,2.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 5-fluoro-2-methylbenzo[d]oxazole-6-carboxylate (210 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring at 0°C for 15 minutes, the hydrogenated Lithium aluminum (76 mg, 2.0 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
向反应液加水(2.0毫升)，析出大量白色固体，向反应液中加无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物经硅胶柱层析纯化得到130毫克白色固体(5-氟-2-甲基苯并[d]噁唑-6-基)甲醇(收率：71.8％)。LC-MS：RT＝1.59min,[M+H] +＝182.11。 Water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 130 mg of white solid (5-fluoro-2-methylbenzo[d]oxazol-6-yl)methanol (yield: 71.8%). LC-MS: RT=1.59 min, [M+H] + =182.11.
步骤F：合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step F: Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000234
Figure PCTCN2021120978-appb-000234
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(95毫克,0.20毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(5-氟-2-甲基苯并[d]噁唑-6-基)甲醇(86毫克,0.40毫摩尔),叔丁醇钠(40毫克,0.40毫摩尔),1,1'-联萘-2,2'-双二苯膦(26毫克,0.040毫摩尔)和三(二亚苄基丙酮)二钯(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌2小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (95 mg, 0.20 mmol) was dissolved in 1,4-dioxane (10.0 mL), and (5-fluoro-2-methylbenzone) [d]oxazol-6-yl)methanol (86 mg, 0.40 mmol), sodium tert-butoxide (40 mg, 0.40 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26 mg, 0.040 mmol) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.020 mmol) were added to the reaction flask. After nitrogen protection, the mixture was stirred at 100 degrees Celsius for 2 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到80毫克黄色固体(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：33.2％)。LC-MS：RT＝1.86min,[M+H] +＝642.37。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (15.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of yellow solid (S)-2-((4-(6-((5-fluoro-2-methylbenzo[d]oxazol-6-yl]methane oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl Ester (yield: 33.2%). LC-MS: RT=1.86 min, [M+H] + =642.37.
步骤G：合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step G: Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000235
Figure PCTCN2021120978-appb-000235
将(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.12毫摩尔)溶于二氯甲烷(7.0毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌5小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.12 mmol) in dichloro methane (7.0 mL), then trifluoroacetic acid (0.4 mL) was added to the reaction solution, and after stirring at room temperature for 5 hours, LC-MS was monitored until the reaction was complete.
向反应液加二氯甲烷(20.0毫升)和15％碳酸氢钠溶液(10.0毫升),混合液用二氯甲烷/甲醇(9/1,20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到16毫克白色液体(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：22.9％)。LC-MS：RT＝1.73min,[M+H] +＝586.36。 1H NMR(500MHz,DMSO)δ8.23(d,J＝0.9Hz,1H),7.85–7.75(m,2H),7.66–7.54(m,3H),6.87(d,J＝7.0Hz,1H),6.68(dd,J＝8.2,0.6Hz,1H),5.46(s,2H),5.12(ddd,J＝14.5,7.2,3.1Hz,1H),4.79(dd,J＝15.2,7.2Hz,1H),4.66(dd,J＝15.2,2.8Hz,1H),4.47(td,J＝8.3,5.8Hz,1H),4.38(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.00(d,J＝11.0Hz,1H),2.86(d,J＝11.5Hz,1H),2.75–2.66(m,1H),2.66–2.59(m,1H),2.58(s,3H),2.48–2.41(m,1H),2.29–2.13(m,2H),1.86–1.68(m,4H)。 Dichloromethane (20.0 mL) and 15% sodium bicarbonate solution (10.0 mL) were added to the reaction solution, the mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL × 3 times), the organic phases were combined, and the organic phases were combined. Dry with saturated brine (15.0 ml × 3 times), anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 16 mg of white liquid (S)-2-((4-(6-((5-fluoro-2-methylbenzo[d]oxazol-6-yl) ]methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Yield: 22.9%). LC-MS: RT=1.73 min, [M+H] + =586.36. 1 H NMR (500 MHz, DMSO) δ 8.23 (d, J=0.9 Hz, 1 H), 7.85– 7.75(m,2H),7.66–7.54(m,3H),6.87(d,J=7.0Hz,1H),6.68(dd,J=8.2,0.6Hz,1H),5.46(s,2H),5.12 (ddd, J=14.5, 7.2, 3.1Hz, 1H), 4.79 (dd, J=15.2, 7.2Hz, 1H), 4.66 (dd, J=15.2, 2.8Hz, 1H), 4.47 (td, J=8.3 ,5.8Hz,1H),4.38(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.00(d,J = 11.0Hz, 1H), 2.86 (d, J = 11.5Hz, 1H), 2.75–2.66 (m, 1H), 2.66–2.59 (m, 1H), 2.58 (s, 3H), 2.48–2.41 (m, 1H), 2.29–2.13 (m, 2H), 1.86–1.68 (m, 4H).
实施例44Example 44
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹喔啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinoxalin-6-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000236
Figure PCTCN2021120978-appb-000236
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹喔啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step A: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinoxalin-6-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000237
Figure PCTCN2021120978-appb-000237
将喹喔啉-6-基甲醇(100毫克，0.62毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(310毫克，0.62毫摩尔)，钯催化剂(30毫克)，1,1’-联萘-2,2’-双二苯膦(39毫克)和叔丁醇钠(120毫克，0.24毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌2个小时。The quinoxalin-6-ylmethanol (100 mg, 0.62 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] tert-butyl imidazole-6-carboxylate (310 mg, 0.62 mmol), palladium catalyst (30 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (39 mg) and tert. Sodium butoxide (120 mg, 0.24 mmol) was dissolved in dioxane and the temperature was raised to 100°C with stirring for 2 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用高效液相纯化得到21.41毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹喔啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：6％)。LC-MS:RT＝1.68min,[M+H] +＝565.34。 After the reaction was completed, suction filtration with celite, washed with dichloromethane and concentrated the organic phase, the obtained crude product was purified by high performance liquid phase to obtain 21.41 mg of white solid (S)-1-(oxetan-2-ylmethyl) )-2-((4-(6-(quinoxalin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 6%). LC-MS: RT=1.68 min, [M+H] + =565.34.
实施例45Example 45
合成(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000238
Figure PCTCN2021120978-appb-000238
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-羟基-2-甲基丙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000239
Figure PCTCN2021120978-appb-000239
室温下，将1H-吲唑-6-羧酸甲酯(500.0毫克，2.82毫摩尔)加入N,N-二甲基甲酰胺(28.0毫升)中，再依次加入2,2-二甲基环氧乙烷(224.2毫克，3.10毫摩尔)、碳酸钾(428.5毫克，3.10毫摩尔)，N 2保护下，180摄氏度反应1.0小时。 At room temperature, methyl 1H-indazole-6-carboxylate (500.0 mg, 2.82 mmol) was added to N,N-dimethylformamide (28.0 mL) followed by 2,2-dimethyl ring Ethylene oxide (224.2 mg, 3.10 mmol), potassium carbonate (428.5 mg, 3.10 mmol) were reacted under N 2 protection at 180 degrees Celsius for 1.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝20：1)得到223.0毫克白色固体1-(2-羟基-2-甲基丙基)-1H-吲唑-6-羧酸甲酯(收率：32.1％)。LC-MS:RT＝1.81min,[M+H] +＝249.20。 The reaction was completed, quenched by adding water, and the mixture was extracted with ethyl acetate (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 mL×L times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=20:1) 223.0 mg of methyl 1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylate were obtained as a white solid (yield: 32.1%). LC-MS: RT=1.81 min, [M+H] + =249.20.
步骤B：合成1-(6-(羟甲基)-1H-吲唑-1-基)-2-甲基丙烷-2-醇Step B: Synthesis of 1-(6-(hydroxymethyl)-1H-indazol-1-yl)-2-methylpropan-2-ol
Figure PCTCN2021120978-appb-000240
Figure PCTCN2021120978-appb-000240
冰浴下，向含有1-(2-羟基-2-甲基丙基)-1H-吲唑-6-羧酸甲酯(250.0毫克，1.00毫摩尔)的四氢呋喃(9.0毫升)中滴加四氢铝锂溶液(1摩尔/升，1毫升)，室温下反应0.5小时。To methyl 1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylate (250.0 mg, 1.00 mmol) in tetrahydrofuran (9.0 mL) was added dropwise tetrahydrofuran under ice bath. Lithium aluminum hydride solution (1 mol/L, 1 mL) was reacted at room temperature for 0.5 hours.
反应结束，向反应液中缓慢滴加水，待无气泡产生,垫硅藻土抽滤。混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，有机相用无水硫酸钠干燥，浓缩得到200.4毫克淡黄色固体1-(6-(羟甲基)-1H-吲唑-1-基)-2-甲基丙烷-2-醇(收率：87.7％)直接用于下一步反应。LC-MS:RT＝1.59min,[M+H] +＝221.19。 After the reaction was completed, water was slowly added dropwise to the reaction solution, and when no air bubbles were generated, pad celite for suction filtration. The mixture was extracted with dichloromethane (30 mL×L), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 200.4 mg of pale yellow solid 1-(6-(hydroxymethyl)-1H-indazole) -1-yl)-2-methylpropan-2-ol (yield: 87.7%) was directly used in the next reaction. LC-MS: RT=1.59 min, [M+H] + =221.19.
步骤C：合成(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000241
Figure PCTCN2021120978-appb-000241
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、1-(6-(羟甲基)-1H-吲唑-1-基)-2-甲基丙烷-2-醇(65.6毫克，0.30毫摩尔)和叔丁醇钠(58.0毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(37.0毫克，0.06毫摩尔)、三(二亚苄基丙酮)二钯(27.3毫克，0.03毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), 1-(6-(hydroxymethyl)-1H-indazol-1-yl)-2-methyl Propane-2-ol (65.6 mg, 0.30 mmol) and sodium tert-butoxide (58.0 mg, 0.6 mmol) were added to dioxane (10.0 mL) followed by 1,1'-binaphthyl-2 , 2'-bisdiphenylphosphine (37.0 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (27.3 mg, 0.03 mmol), under N 2 protection, reacted at 100 degrees Celsius for 3.5 hours.
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×升次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到87.0毫克淡黄色油状固体(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：42.6％)。LC-MS:RT＝1.84min,[M+H] +＝681.46。 The reaction was completed, quenched by adding water, and the mixture was extracted with dichloromethane (50 mL×L). The organic phases were combined, and the organic phase was washed with saturated brine (30 ml × liter), then dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 87.0 mg pale yellow oily solid (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (Yield: 42.6%).LC-MS: RT=1.84min, [M+H] + =681.46.
步骤D：合成(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000242
Figure PCTCN2021120978-appb-000242
室温下，向含有(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(87.0毫克，0.13毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应12.0小时。At room temperature, to a compound containing (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazol-6-yl)methoxy )pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester ( 87.0 mg, 0.13 mmol) in dichloromethane (8.0 mL) was added dropwise trifluoroacetic acid (1.0 mL), and the reaction was carried out at room temperature for 12.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×升次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈；流速：20毫升/分钟；梯度：由8％乙腈在5.80分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得22.1毫克白色固体合成(S)-2-((4-(6-((1-(2-(2-羟基-2-甲基丙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂 环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：27.2％)。LC-MS:RT＝1.70min,[M+H] +＝625.40。1H NMR(500MHz,DMSO)δ8.29(s,1H),8.04(d,J＝0.9Hz,1H),7.81(dd,J＝8.4,1.5Hz,1H),7.78(s,1H),7.72(dd,J＝8.2,0.6Hz,1H),7.66(d,J＝3.6Hz,1H),7.64(d,J＝0.8Hz,1H),7.22(dd,J＝8.3,1.2Hz,1H),6.88(d,J＝7.2Hz,1H),6.69(d,J＝8.2Hz,1H),5.48(s,2H),5.12(dt,J＝9.4,7.0Hz,1H),4.80(dd,J＝15.1,7.2Hz,2H),4.68(d,J＝3.2Hz,1H),4.64(d,J＝3.8Hz,1H),4.46(dt,J＝8.3,6.3Hz,2H),4.40–4.33(m,2H),4.27(s,2H),3.97(d,J＝13.3Hz,2H),3.79(d,J＝13.9Hz,2H),3.03(dd,J＝11.9,4.1Hz,1H),2.92–2.84(m,1H),2.70(dd,J＝10.1,7.9Hz,1H),2.63(dd,J＝14.0,3.0Hz,1H),2.44(dt,J＝6.8,1.7Hz,1H),1.09(s,6H)。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixed solution was extracted with dichloromethane (30 mL×L times), the organic phases were combined, and then dried with anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% aqueous ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted from 8% acetonitrile at 5.80 minutes ; Detection wavelength: 254nm. After purification, lyophilization at low temperature gave 22.1 mg of white solid. Synthesis of (S)-2-((4-(6-((1-(2-(2-hydroxy-2-methylpropyl)-1H-indazole- 6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 27.2%). LC-MS: RT=1.70 min, [M+H] + =625.40. 1H NMR (500 MHz, DMSO) δ 8.29 (s, 1H), 8.04 (d, J ＝0.9Hz,1H),7.81(dd,J＝8.4,1.5Hz,1H),7.78(s,1H),7.72(dd,J＝8.2,0.6Hz,1H),7.66(d,J＝3.6Hz ,1H),7.64(d,J＝0.8Hz,1H),7.22(dd,J＝8.3,1.2Hz,1H),6.88(d,J＝7.2Hz,1H),6.69(d,J＝8.2Hz ,1H),5.48(s,2H),5.12(dt,J＝9.4,7.0Hz,1H),4.80(dd,J＝15.1,7.2Hz,2H),4.68(d,J＝3.2Hz,1H) ,4.64(d,J=3.8Hz,1H),4.46(dt,J=8.3,6.3Hz,2H),4.40–4.33(m,2H),4.27(s,2H),3.97(d,J=13.3 Hz, 2H), 3.79 (d, J=13.9Hz, 2H), 3.03 (dd, J=11.9, 4.1Hz, 1H), 2.92–2.84 (m, 1H), 2.70 (dd, J=10.1, 7.9Hz) , 1H), 2.63 (dd, J=14.0, 3.0 Hz, 1H), 2.44 (dt, J=6.8, 1.7 Hz, 1H), 1.09 (s, 6H).
实施例46Example 46
合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000243
Figure PCTCN2021120978-appb-000243
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2,2-二氟乙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of 1-(2,2-difluoroethyl)-1H-indazole-6-carboxylic acid methyl ester
Figure PCTCN2021120978-appb-000244
Figure PCTCN2021120978-appb-000244
室温下，将1H-吲唑-6-羧酸甲酯(1.0克，5.60毫摩尔)和碳酸铯(3.7克，11.2毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入1,1-二氟-2-碘乙烷(1.09克，5.60毫摩尔)，在室温下搅拌半个小时。Methyl 1H-indazole-6-carboxylate (1.0 g, 5.60 mmol) and cesium carbonate (3.7 g, 11.2 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature , and then 1,1-difluoro-2-iodoethane (1.09 g, 5.60 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到700毫克白色固体1-(2,2-二氟乙基)-1H-吲唑-6-羧酸甲酯(收率：51％)。LC-MS:RT＝1.68min,[M+H]+＝241.15。After the reaction, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/2) to obtain 700 mg of methyl 1-(2,2-difluoroethyl)-1H-indazole-6-carboxylate as a white solid (yield: 51%). LC-MS: RT=1.68 min, [M+H]+=241.15.
步骤B：合成(1-(2,2-二氟乙基)-1H-吲唑-6基)-甲醇Step B: Synthesis of (1-(2,2-Difluoroethyl)-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000245
Figure PCTCN2021120978-appb-000245
室温下，将1-(2,2-二氟乙基)-1H-吲唑-6-羧酸甲酯(200毫克，0.83毫摩尔)溶于四氢呋喃(10毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(35毫克，0.92毫摩尔)，在室温下搅拌半个小时。Methyl 1-(2,2-difluoroethyl)-1H-indazole-6-carboxylate (200 mg, 0.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature and cooled in an ice bath To zero degrees Celsius, lithium tetrahydroaluminum (35 mg, 0.92 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(50毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到150毫克白色固体(1-(2,2-二氟乙基)-1H-吲唑-6基)-甲醇(收率：85％)。LC-MS:RT＝1.65min,[M+H]+＝213.15。After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (50 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of white solid (1-(2,2 -Difluoroethyl)-1H-indazol-6yl)-methanol (yield: 85%). LC-MS: RT=1.65 min, [M+H]+=213.15.
步骤C：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000246
Figure PCTCN2021120978-appb-000246
将(1-(2,2-二氟乙基)-1H-吲唑-6基)-甲醇(60毫克，0.28毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(140毫克，0.28毫摩尔)，钯催化剂(24毫克)，碳酸铯(182毫克，0.56毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(1-(2,2-Difluoroethyl)-1H-indazol-6yl)-methanol (60 mg, 0.28 mmol), (S)-2-(chloromethyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (140 mg, 0.28 mmol), palladium catalyst (24 mg), cesium carbonate (182 mg, 0.56 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到87毫克白色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：46％)。LC-MS:RT＝1.84min,[M+H]+＝673.41。After completion of the reaction, suction filtration with celite, washing with dichloromethane and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 87 mg of white solid ( S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 46%). LC-MS: RT=1.84 min, [M+H]+=673.41.
步骤D：(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000247
Figure PCTCN2021120978-appb-000247
将(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(87毫克，0.13毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (87 mg, 0.13 mmol) was dissolved in To dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到21.07毫克白色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：26％)。LC-MS:RT＝1.73min,[M+H]+＝617.38。After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 21.07 mg of white solid (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazole- 6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 26%). LC-MS: RT=1.73 min, [M+H]+=617.38.
实施例47Example 47
合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1(((S)-(氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1(((S)-(oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000248
Figure PCTCN2021120978-appb-000248
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑Step A: Synthesis of 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole
Figure PCTCN2021120978-appb-000249
Figure PCTCN2021120978-appb-000249
室温下，将2,6二氯吡啶(100毫克，0.68毫摩尔)，(1-甲基-1H-吲唑-6-基)甲醇(100毫克，0.62毫摩尔)和氢氧化钠(74.4毫克，1.86毫摩尔)加入到10毫升干燥的DMF中，升温至130摄氏度反应2小时。At room temperature, 2,6-dichloropyridine (100 mg, 0.68 mmol), (1-methyl-1H-indazol-6-yl)methanol (100 mg, 0.62 mmol) and sodium hydroxide (74.4 mg) were combined , 1.86 mmol) was added to 10 ml of dry DMF, and the temperature was raised to 130 degrees Celsius for 2 hours.
反应结束后，将反应液冷却至室温，倒入20毫升的冰水溶液中，搅拌30分钟后抽滤，水洗滤饼。滤饼干燥后得155毫克白色固体6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑(收率：90.8％)。LC-MS：RT＝2.07min，[M+H] +＝274.14。 After the reaction was completed, the reaction solution was cooled to room temperature, poured into 20 ml of ice-water solution, stirred for 30 minutes, filtered with suction, and the filter cake was washed with water. The filter cake was dried to obtain 155 mg of 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole as a white solid (yield: 90.8%). LC-MS: RT=2.07 min, [M+H] + =274.14.
步骤B：合成(S)-2'-甲基-6-((1-甲基-1H-吲唑-6-基)甲氧基)-3',6'-二氢-(2,4'-联吡啶)1'(2'H)-羧酸叔丁酯Step B: Synthesis of (S)-2'-methyl-6-((1-methyl-1H-indazol-6-yl)methoxy)-3',6'-dihydro-(2,4 '-bipyridine) 1'(2'H)-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000250
Figure PCTCN2021120978-appb-000250
室温下，将中间体6-(((6-氯吡啶-2-基)氧基)甲基)-1-甲基-1H-吲唑(120毫克，0.44毫摩尔)以及(2S)-2-甲基-N-叔丁氧羰基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(200毫克，0.66毫摩尔)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(48.5毫克，0.066毫摩尔)，碳酸铯(287毫克，0.88毫摩尔)加入至10毫升二氧六环/水(4/1)的混合溶液中，N 2保护下升温至100摄氏度反应2小时。 At room temperature, the intermediate 6-(((6-chloropyridin-2-yl)oxy)methyl)-1-methyl-1H-indazole (120 mg, 0.44 mmol) and (2S)-2 -Methyl-N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (200 mg, 0.66 mmol), [1,1'-bis(diphenyl) Phosphino)ferrocene]palladium dichloride (48.5 mg, 0.066 mmol), cesium carbonate (287 mg, 0.88 mmol) were added to 10 mL of a mixed solution of dioxane/water (4/1), The temperature was raised to 100 degrees Celsius under the protection of N 2 for 2 hours.
反应结束后，蒸干反应液，乙酸乙酯萃取，萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝5/1)，得110毫克(S)-2'-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]1'(2'H)-羧酸叔丁酯(收率：57.6％)。LC-MS：RT＝2.27min，[M-55] -＝435.30。 After the reaction, the reaction solution was evaporated to dryness, extracted with ethyl acetate, extracted, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (n-hexane/ethyl acetate=5/1) to obtain 110 mg of (S)-2'-methyl-4-(6-((1-methyl-1H-indazol-6-yl) )methoxy)-3',6'-dihydro-[2,4'-bipyridine]1'(2'H)-carboxylate tert-butyl ester (yield: 57.6%). LC-MS: RT =2.27min, [M-55] - =435.30.
步骤C:合成(2S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧)吡啶-2-基)哌啶-1-羧酸叔丁酯Step C: Synthesis of (2S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000251
Figure PCTCN2021120978-appb-000251
冰浴下，将(S)-2'-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]1'(2'H)-羧酸叔丁酯(100毫克，0.23毫摩尔)溶于5毫升甲醇溶剂中，冰浴下加入二氧化铂(156.6毫克，0.69毫摩尔)，H 2保护下反应2小时。 Under ice bath, (S)-2'-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)-3',6'-dihydro- [2,4'-bipyridine]1'(2'H)-carboxylate tert-butyl ester (100 mg, 0.23 mmol) was dissolved in 5 mL of methanol solvent, and platinum dioxide (156.6 mg, 0.69 mmol), reacted under the protection of H 2 for 2 h.
反应结束后，蒸干反应液得85毫克白色固体(2S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(收率：85％)。LC-MS：RT＝2.27min，[M+H] +＝437.30 After the reaction, the reaction solution was evaporated to dryness to obtain 85 mg of white solid (2S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidine-1-carboxylate tert-butyl ester (yield: 85%). LC-MS: RT=2.27 min, [M+H] + =437.30
步骤D：合成1-甲基-6-(((6-((2S)-2-甲基哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑Step D: Synthesis of 1-methyl-6-(((6-((2S)-2-methylpiperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000252
Figure PCTCN2021120978-appb-000252
室温下，将(2S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(85毫克，0.19毫摩尔)溶于10毫升甲醇溶剂中，冰浴下加入5毫升4M/L的盐酸二氧六环溶液，室温反应2小时。(2S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate at room temperature Tert-butyl acid (85 mg, 0.19 mmol) was dissolved in 10 mL of methanol solvent, 5 mL of 4M/L hydrochloric acid dioxane solution was added under ice bath, and the reaction was carried out at room temperature for 2 hours.
反应结束后，蒸干反应液得121毫克白色固体1-甲基-6-(((6-((2S)-2-甲基哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑(收率：133.1％)。LC-MS：RT＝1.65min，[M+H] +＝337.25。 After the reaction, the reaction solution was evaporated to dryness to obtain 121 mg of white solid 1-methyl-6-(((6-((2S)-2-methylpiperidin-4-yl)pyridin-2-yl)oxy) methyl)-1H-indazole (yield: 133.1%). LC-MS: RT=1.65 min, [M+H] + =337.25.
步骤E：合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid methyl ester
Figure PCTCN2021120978-appb-000253
Figure PCTCN2021120978-appb-000253
室温下，将中间体1-甲基-6-(((6-((2S)-2-甲基哌啶-4-基)吡啶-2-基)氧基)甲基)-1H-吲唑(50.4毫克，0.19毫摩尔)以及甲基(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(56.1毫克，0.19毫摩尔)碳酸铯(123.8毫克，0.38毫摩尔)加入至10毫升DMF溶液中，升温至60摄氏度反应2小时。At room temperature, the intermediate 1-methyl-6-(((6-((2S)-2-methylpiperidin-4-yl)pyridin-2-yl)oxy)methyl)-1H-indium azole (50.4 mg, 0.19 mmol) and methyl(S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6- Methyl carboxylate (56.1 mg, 0.19 mmol) cesium carbonate (123.8 mg, 0.38 mmol) was added to 10 mL of DMF solution, and the temperature was raised to 60 degrees Celsius to react for 2 hours.
反应结束后，将反应液倒入冰水，析出固体，抽滤，水洗滤饼得75毫克白色产品2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸甲酯(收率：66.4％)。LC-MS：RT＝1.77min，[M+H] +＝595.37。 After the reaction was completed, the reaction solution was poured into ice water, the solid was precipitated, suction filtered, and the filter cake was washed with water to obtain 75 mg of white product 2-(((S)-2-methyl-4-(6-((1-methyl) -1H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)- Methyl benzo[d]imidazole-6-carboxylate (yield: 66.4%). LC-MS: RT=1.77 min, [M+H] + =595.37.
步骤F：合成2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1(((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸Step F: Synthesis of 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000254
Figure PCTCN2021120978-appb-000254
室温下，将中间体2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1(((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸甲酯(70毫克，0.14毫摩尔)溶于3.5毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。At room temperature, the intermediate 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)-benzo[d]imidazole-6-carboxylic acid methyl ester (70 mg, 0.14 mmol ) was dissolved in 3.5 ml of dichloromethane solution, 0.5 ml of trifluoroacetic acid was added dropwise under ice bath, and the reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得45毫克白色固体2-(((S)-2-甲基-4-(6-((1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1(((S)-氧杂环丁-2-基甲基)-苯并[d]咪唑-6-羧酸(收率：55.3％)。LC-MS：RT＝1.73min，[M+H] +＝581.40。 1H NMR(500MHz,DMSO)δ8.01(d,J＝12.1Hz,1H),7.99(s,1H),7.80–7.68(m,3H),7.67–7.55(m,1H),7.37(d,J＝8.3Hz,1H),7.22(d,J＝8.8Hz,1H),6.87(d,J＝7.3Hz,1H),6.67(d,J＝8.2Hz,1H),5.49(q,J＝12.3Hz,2H),5.21–5.09(m,1H),4.70(dd,J＝15.1,7.2Hz,1H),4.56(dd,J＝15.1,3.1Hz,1H),4.46(dd,J＝13.8,7.6Hz,1H),4.41–4.32(m,1H),3.95(t,J＝10.5Hz,1H),3.92(s,3H),3.83(d,J＝13.4Hz,1H),3.19(s,1H),2.91(s,1H),2.72–2.65(m,1H),2.62(d,J＝12.1Hz,1H),2.55–2.51(m,1H),2.44(d,J＝7.5Hz,1H),2.11–1.98(m,1H),1.75–1.64(m,3H),1.14(d,J＝6.6Hz,3H)。 After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 45 mg of white solid 2-(((S)-2-methyl-4-(6-((1-methyl-1H-indazole) -6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1(((S)-oxetan-2-ylmethyl)-benzo[d] Imidazole-6-carboxylic acid (yield: 55.3%). LC-MS: RT=1.73 min, [M+H] + =581.40. 1 H NMR (500 MHz, DMSO) δ 8.01 (d, J=12.1 Hz ,1H),7.99(s,1H),7.80–7.68(m,3H),7.67–7.55(m,1H),7.37(d,J=8.3Hz,1H),7.22(d,J=8.8Hz, 1H), 6.87(d, J＝7.3Hz, 1H), 6.67(d, J＝8.2Hz, 1H), 5.49(q, J＝12.3Hz, 2H), 5.21–5.09(m, 1H), 4.70( dd, J＝15.1, 7.2Hz, 1H), 4.56 (dd, J＝15.1, 3.1Hz, 1H), 4.46 (dd, J＝13.8, 7.6Hz, 1H), 4.41–4.32 (m, 1H), 3.95 (t, J=10.5Hz, 1H), 3.92(s, 3H), 3.83(d, J=13.4Hz, 1H), 3.19(s, 1H), 2.91(s, 1H), 2.72–2.65(m, 1H), 2.62 (d, J=12.1Hz, 1H), 2.55–2.51 (m, 1H), 2.44 (d, J=7.5Hz, 1H), 2.11–1.98 (m, 1H), 1.75–1.64 (m , 3H), 1.14 (d, J=6.6Hz, 3H).
实施例48Example 48
合成(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000255
Figure PCTCN2021120978-appb-000255
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-甲酰基-1-甲基-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 3-formyl-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000256
Figure PCTCN2021120978-appb-000256
零摄氏度下,将1-甲基-1H-吲唑-6-羧酸甲酯(0.2克,1.1毫摩尔)溶于三氯氧磷(3.0毫升)中,加DMF(1.0毫升),100摄氏度下搅拌1.5小时,TLC监测至反应完全。At zero degrees Celsius, dissolve methyl 1-methyl-1H-indazole-6-carboxylate (0.2 g, 1.1 mmol) in phosphorus oxychloride (3.0 ml), add DMF (1.0 ml), 100 degrees Celsius The mixture was stirred for 1.5 hours and monitored by TLC until the reaction was complete.
将反应液滴加到冰水浴(20.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到70毫克白色固体3-甲酰基-1-甲基-1H-吲唑-6-羧酸甲酯(收率：29.2％)。LC-MS：RT＝1.82min,[M+H] +＝219.16。 The reaction was added dropwise to an ice-water bath (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (25.0 mL×L), anhydrous sodium sulfate It was dried and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 70 mg of methyl 3-formyl-1-methyl-1H-indazole-6-carboxylate as a white solid (yield: 29.2%). LC-MS: RT=1.82 min, [M+H] + =219.16.
步骤B：合成3-(二氟甲基)-1-甲基-1H-吲唑-6-羧酸甲酯Step B: Synthesis of methyl 3-(difluoromethyl)-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000257
Figure PCTCN2021120978-appb-000257
将3-甲酰基-1-甲基-1H-吲唑-6-羧酸甲酯(70毫克,0.3毫摩尔)溶于二氯甲烷(8.0毫升)中,零摄氏度下搅拌15分钟后,将二乙胺基三氟化硫(0.5毫升,3.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,室温搅拌5小时。Methyl 3-formyl-1-methyl-1H-indazole-6-carboxylate (70 mg, 0.3 mmol) was dissolved in dichloromethane (8.0 mL) and stirred for 15 minutes at zero degrees Celsius. Diethylaminosulfur trifluoride (0.5 mL, 3.0 mmol) was added to the reaction solution, stirred at zero degrees Celsius for 30 minutes, and then stirred at room temperature for 5 hours.
向反应液加15％碳酸氢钠(20.0毫升),混合液用二氯甲烷(20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(10.0毫升×升次),无水硫酸钠干燥,减压浓缩,得到30毫克黄色固体3-(二氟甲基)-1-甲基-1H-吲唑-6-羧酸甲酯(收率：41.7％)。LC-MS：RT＝1.98min,[M+H] +＝241.13。 To the reaction solution was added 15% sodium bicarbonate (20.0 mL), the mixture was extracted with dichloromethane (20.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (10.0 mL×L), anhydrous sulfuric acid It was dried over sodium and concentrated under reduced pressure to obtain 30 mg of methyl 3-(difluoromethyl)-1-methyl-1H-indazole-6-carboxylate as a yellow solid (yield: 41.7%). LC-MS: RT=1.98 min, [M+H] + =241.13.
步骤C：合成(3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲醇Step C: Synthesis of (3-(difluoromethyl)-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000258
Figure PCTCN2021120978-appb-000258
将3-(二氟甲基)-1-甲基-1H-吲唑-6-羧酸甲酯(55毫克,0.23毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后,将氢化锂铝(19毫克,0.46毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 3-(difluoromethyl)-1-methyl-1H-indazole-6-carboxylate (55 mg, 0.23 mmol) was dissolved in tetrahydrofuran (10.0 mL) and stirred at 0°C for 15 min. , Lithium aluminum hydride (19 mg, 0.46 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, LC-MS was monitored until the reaction was complete.
向反应液加水(2.0毫升),析出大量白色固体,向反应液中加无水硫酸钠干燥,过滤,滤液减压浓缩,得到40毫克黄色固体(3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲醇(收率：61.2％)。LC-MS：RT＝1.73min,[M+H] +＝213.14。 Water (2.0 ml) was added to the reaction solution, a large amount of white solid was precipitated, anhydrous sodium sulfate was added to the reaction solution, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 40 mg of yellow solid (3-(difluoromethyl)-1-methyl) yl-1H-indazol-6-yl)methanol (yield: 61.2%). LC-MS: RT=1.73 min, [M+H] + =213.14.
步骤D：合成(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000259
Figure PCTCN2021120978-appb-000259
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克,0.15毫摩尔)溶于1,4-二氧六环(5.0毫升)中,将(3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲醇(30毫克,0.15毫摩尔),碳酸铯(100毫克,0.30毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌12小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.15 mmol) was dissolved in 1,4-dioxane (5.0 mL), (3-(difluoromethyl)-1 -Methyl-1H-indazol-6-yl)methanol (30 mg, 0.15 mmol), cesium carbonate (100 mg, 0.30 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4 ',6'-Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.020 mmol) It was added to the reaction flask, under nitrogen protection, and stirred at 100 degrees Celsius for 12 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到60毫克黄色固体(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：59.5％)。LC-MS：RT＝1.89min,[M+H] +＝673.39。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated common salt Water (15.0 mL×L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 60 mg of yellow solid (S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazole-6- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl acid (yield: 59.5%). LC-MS: RT=1.89 min, [M+H] + =673.39.
步骤E：合成(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000260
Figure PCTCN2021120978-appb-000260
将(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克,0.09毫摩尔)溶于二氯甲烷(6.0毫升)中,然后将三氟乙酸(0.6毫升)加入反应液中,室温搅拌5小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.09 mmol) in In dichloromethane (6.0 mL), then trifluoroacetic acid (0.6 mL) was added to the reaction solution, and after stirring at room temperature for 5 hours, LC-MS was monitored until the reaction was complete.
向反应液加二氯甲烷(20.0毫升)和15％碳酸氢钠溶液(10.0毫升),混合液用二氯甲烷/甲醇(9/1,20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到10毫克白色液体(S)-2-((4-(6-((3-(二氟甲基)-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：18.2％)。LC-MS：RT＝1.79min,[M+H] +＝617.31。 1H NMR(500MHz,DMSO-d6)δ8.11(s,1H),7.84(s,1H),7.83–7.77(m,2H),7.65–7.61(m,1H),7.47(d,J＝8.2Hz,1H),7.44–7.20(m,2H),6.87(d,J＝7.3Hz,1H),6.70(d,J＝8.2Hz,1H),5.51(d,J＝2.7Hz,2H),5.12(dd,J＝7.2,3.1Hz,1H),4.73(dd,J＝15.3,7.0Hz,1H),4.61(dd,J＝15.2,2.9Hz,1H),4.46(dd,J＝13.3,7.9Hz,1H),4.37(dt,J＝9.1,5.9Hz,1H),4.02(s,3H),3.92(d,J＝13.5Hz,1H),3.76(d,J＝13.4Hz,1H),3.01(d,J＝10.7Hz,1H),2.90(d,J＝11.3Hz,1H),2.73–2.58(m,2H),2.45(t,J＝9.9Hz,1H),2.21(dt,J＝20.5,10.0Hz,2H),1.77(dd,J＝32.2,16.0Hz,4H)。 Dichloromethane (20.0 mL) and 15% sodium bicarbonate solution (10.0 mL) were added to the reaction solution, the mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL×L), the organic phases were combined, and the organic phases were combined. Dry with saturated brine (15.0 mL×L), anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 10 mg of white liquid (S)-2-((4-(6-((3-(difluoromethyl)-1-methyl-1H-indazole- 6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 18.2%). LC-MS: RT=1.79 min, [M+H] + =617.31. 1 H NMR (500MHz, DMSO-d6) δ8.11(s, 1H), 7.84(s, 1H), 7.83-7.77(m, 2H), 7.65-7.61(m, 1H), 7.47(d, J= 8.2Hz, 1H), 7.44–7.20 (m, 2H), 6.87 (d, J=7.3Hz, 1H), 6.70 (d, J=8.2Hz, 1H), 5.51 (d, J=2.7Hz, 2H) ,5.12(dd,J＝7.2,3.1Hz,1H),4.73(dd,J＝15.3,7.0Hz,1H),4.61(dd,J＝15.2,2.9Hz,1H),4.46(dd,J＝13.3 ,7.9Hz,1H),4.37(dt,J=9.1,5.9Hz,1H),4.02(s,3H),3.92(d,J=13.5Hz,1H),3.76(d,J=13.4Hz,1H) ),3.01(d,J＝10.7Hz,1H),2.90(d,J＝11.3Hz,1H),2.73-2.58(m,2H),2.45(t,J＝9.9Hz,1H),2.21(dt , J=20.5, 10.0Hz, 2H), 1.77 (dd, J=32.2, 16.0Hz, 4H).
实施例49Example 49
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H-indazole) -6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000261
Figure PCTCN2021120978-appb-000261
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000262
Figure PCTCN2021120978-appb-000262
室温下，将1H-吲唑-6-羧酸甲酯(500.0毫克，2.82毫摩尔)加入N,N-二甲基甲酰胺(28.0毫升)中，再依次加入1,1,1-三氟-2-碘乙烷(588.2毫克，2.82毫摩尔)、碳酸钾(428.5毫克，3.10毫摩尔)，N 2保护下，88摄氏度反应16.0小时。 At room temperature, methyl 1H-indazole-6-carboxylate (500.0 mg, 2.82 mmol) was added to N,N-dimethylformamide (28.0 mL) followed by 1,1,1-trifluoro -2-iodoethane (588.2 mg, 2.82 mmol), potassium carbonate (428.5 mg, 3.10 mmol), under the protection of N 2 , react at 88 degrees Celsius for 16.0 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝20：1)得到88.0毫克黄色油状固体1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯(收率：12.1％)。LC-MS:RT＝1.88min,[M+H] +＝259.12。 After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried with anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=20:1) 88.0 mg of methyl 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate were obtained as a yellow oily solid (yield: 12.1%). LC-MS: RT=1.88 min, [M+H] + =259.12.
步骤B：合成(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000263
Figure PCTCN2021120978-appb-000263
冰浴下，向含有1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯(88.0毫克，0.34毫摩尔)的四氢呋喃(2.0毫升)中滴加四氢铝锂溶液(1摩尔/升，1毫升)，室温下反应0.5小时。To methyl 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate (88.0 mg, 0.34 mmol) in tetrahydrofuran (2.0 mL) was added dropwise tetrahydrofuran under ice bath. Lithium aluminum hydride solution (1 mol/L, 1 mL) was reacted at room temperature for 0.5 hours.
反应结束，向反应液中缓慢滴加水，待无气泡产生,垫硅藻土抽滤。混合液用二氯甲烷(30毫升×3 次)萃取，合并有机相，有机相用无水硫酸钠干燥，浓缩得到73.4毫克淡黄色固体(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇(收率：93.6％)直接用于下一步反应。LC-MS:RT＝1.68min,[M+H] +＝231.12。 After the reaction was completed, water was slowly added dropwise to the reaction solution, and when no air bubbles were generated, pad celite for suction filtration. The mixture was extracted with dichloromethane (30 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 73.4 mg of pale yellow solid (1-(2,2,2-trifluoroethyl) -1H-Indazol-6-yl)methanol (yield: 93.6%) was directly used in the next reaction. LC-MS: RT=1.68 min, [M+H] + =231.12.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H) -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000264
Figure PCTCN2021120978-appb-000264
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇(69.3毫克，0.30毫摩尔)和叔丁醇钠(58.0毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(37.0毫克，0.06毫摩尔)、三(二亚苄基丙酮)二钯(27.3毫克，0.03毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), (1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl ) methanol (69.3 mg, 0.30 mmol) and sodium tert-butoxide (58.0 mg, 0.6 mmol) were added to dioxane (10.0 mL) followed by 1,1'-binaphthyl-2,2'- Bisdiphenylphosphine (37.0 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (27.3 mg, 0.03 mmol) were reacted under N2 protection at 100 degrees Celsius for 3.5 hours.
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到95.0毫克淡黄色油状固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：46.0％)。LC-MS:RT＝1.88min,[M+H] +＝690.32。 After the reaction was completed, water was added to quench, and the mixture was extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 95.0 mg pale yellow oily solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl) -1H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield : 46.0%). LC-MS: RT=1.88 min, [M+H] + =690.32.
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H) -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000265
Figure PCTCN2021120978-appb-000265
室温下，向含有(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(95.0毫克，0.14毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应12.0小时。At room temperature, to a compound containing (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)- 1H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (95.0 mg, Trifluoroacetic acid (1.0 mL) was added dropwise to dichloromethane (8.0 mL) of 0.14 mmol), and the reaction was carried out at room temperature for 12.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈；流速：20毫升/分钟；梯度：由16％乙腈在6.23分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得26.2毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30.0％)。LC-MS:RT＝1.75min,[M+H] +＝635.37。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixture was extracted with dichloromethane (30 mL×3 times), the organic phases were combined, and then dried over anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% aqueous ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted from 16% acetonitrile at 6.23 minutes ; Detection wavelength: 254nm. After purification, lyophilization at low temperature gave 26.2 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2- Trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 30.0%). LC-MS: RT=1.75 min, [M+H] + =635.37.
实施例50Example 50
合成(S)2-((4-(6-((1-(氰基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S) 2-((4-(6-((1-(cyanomethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000266
Figure PCTCN2021120978-appb-000266
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(1H-吲唑-6-基)甲醇Step A: Synthesis of (1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000267
Figure PCTCN2021120978-appb-000267
室温下，将1H-吲唑-6-羧酸甲酯(350毫克，1.99毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(150毫克，3.98毫摩尔)，在室温下搅拌半个小时。At room temperature, methyl 1H-indazole-6-carboxylate (350 mg, 1.99 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C in an ice bath, and lithium tetrahydroaluminum (150 mg, 1.99 mmol) was added. 3.98 mmol) and stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到280毫克白色固体(1H-吲唑-6-基)甲醇(收率：95％)。LC-MS:RT＝1.80min,[M+H] +＝149.27。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate. After filtration, concentrated to obtain 280 mg of white solid (1H-indazole-6 -base) methanol (yield: 95%). LC-MS: RT=1.80 min, [M+H] + =149.27.
步骤A：合成2-(6-(羟甲基)-1H-吲唑-1-基)乙腈Step A: Synthesis of 2-(6-(hydroxymethyl)-1H-indazol-1-yl)acetonitrile
Figure PCTCN2021120978-appb-000268
Figure PCTCN2021120978-appb-000268
室温下，将(1H-吲唑-6-基)甲醇(280毫克，1.89毫摩尔)和碳酸铯(1.85克，5.67毫摩尔)溶于N,N-二甲基甲酰胺(10毫升)中，再加入溴乙腈(340毫克，2.84毫摩尔)，在室温下搅拌半个小时。(1H-Indazol-6-yl)methanol (280 mg, 1.89 mmol) and cesium carbonate (1.85 g, 5.67 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature , and then bromoacetonitrile (340 mg, 2.84 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到100毫克白色固体2-(6-(羟甲基)-1H-吲唑-1-基)乙腈(收率：28％)。LC-MS:RT＝1.94min,[M+H] +＝188.25。 After the reaction, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/2) to obtain 100 mg of white solid 2-(6-(hydroxymethyl)-1H-indazol-1-yl)acetonitrile (yield: 28%). LC-MS: RT=1.94 min, [M+H] + =188.25.
步骤B:合成(S)2-((4-(6-((1-(氰基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S) 2-((4-(6-((1-(cyanomethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000269
Figure PCTCN2021120978-appb-000269
将2-(6-(羟甲基)-1H-吲唑-1-基)乙腈(100毫克，0.53毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(264毫克，0.53毫摩尔)，钯催化剂(45毫克)，碳酸铯(345毫克，1.06毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌12个小时。2-(6-(Hydroxymethyl)-1H-indazol-1-yl)acetonitrile (100 mg, 0.53 mmol), (S)-2-(chloromethyl)-1-(oxetine) -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (264 mg, 0.53 mmol), palladium catalyst (45 mg), cesium carbonate (345 mg, 1.06 mmol) Dissolve in dioxane (10 mL), raise the temperature to 100°C and stir for 12 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到200毫克白色固体(S)2-((4-(6-((1-(氰基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：58％)。LC-MS:RT＝1.82min,[M+H] +＝648.41。 After the reaction was completed, suction filtration with celite, washed with dichloromethane and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 200 mg of white solid ( S) 2-((4-(6-((1-(cyanomethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 58%). LC-MS: RT=1.82 min, [M+H] + =648.41.
步骤C：合成(S)2-((4-(6-((1-(氰基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S) 2-((4-(6-((1-(cyanomethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000270
Figure PCTCN2021120978-appb-000270
将(S)2-((4-(6-((1-(氰基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(170毫克，0.26毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S) 2-((4-(6-((1-(cyanomethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (170 mg, 0.26 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到42.39毫克白色固体(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：28％)。LC-MS:RT＝1.65min,[M+H] +＝592.36。 1H NMR(500MHz,DMSO)δ8.22(d,J＝0.9Hz,1H),8.15(s,1H),7.90(s,1H),7.84–7.78(m,2H),7.65(dd,J＝8.1,7.4Hz,1H),7.51(d,J＝8.4Hz,1H),7.35 (dd,J＝8.3,1.2Hz,1H),6.89(d,J＝7.2Hz,1H),6.71(d,J＝8.2Hz,1H),5.80(s,2H),5.55–5.49(m,2H),5.12(ddd,J＝14.2,7.0,2.9Hz,1H),4.74(dd,J＝15.3,7.1Hz,1H),4.62(dd,J＝15.2,3.0Hz,1H),4.51–4.43(m,1H),4.37(dt,J＝9.1,5.8Hz,1H),3.93(d,J＝13.4Hz,1H),3.77(d,J＝13.4Hz,1H),3.02(d,J＝10.6Hz,1H),2.89(d,J＝11.1Hz,1H),2.73–2.58(m,2H),2.48–2.39(m,1H),2.21(dt,J＝20.7,9.1Hz,2H),1.90–1.69(m,4H)。 After the reaction was completed, it was concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 42.39 mg of white solid (S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indone) azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylic acid (yield: 28%). LC-MS: RT=1.65 min, [M+H] + =592.36. 1 H NMR (500MHz, DMSO)δ8.22(d,J=0.9Hz,1H),8.15(s,1H),7.90(s,1H),7.84-7.78(m,2H),7.65(dd,J ＝8.1,7.4Hz,1H),7.51(d,J＝8.4Hz,1H),7.35(dd,J＝8.3,1.2Hz,1H),6.89(d,J＝7.2Hz,1H),6.71(d , J=8.2Hz, 1H), 5.80 (s, 2H), 5.55–5.49 (m, 2H), 5.12 (ddd, J=14.2, 7.0, 2.9Hz, 1H), 4.74 (dd, J=15.3, 7.1 Hz, 1H), 4.62 (dd, J=15.2, 3.0Hz, 1H), 4.51–4.43 (m, 1H), 4.37 (dt, J=9.1, 5.8Hz, 1H), 3.93 (d, J=13.4Hz) ,1H),3.77(d,J＝13.4Hz,1H),3.02(d,J＝10.6Hz,1H),2.89(d,J＝11.1Hz,1H),2.73–2.58(m,2H),2.48 -2.39(m,1H),2.21(dt,J=20.7,9.1Hz,2H),1.90-1.69(m,4H).
实施例51Example 51
合成(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000271
Figure PCTCN2021120978-appb-000271
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-乙基苯并[d]噁唑-6-羧酸甲酯Step A: Synthesis of methyl 2-ethylbenzo[d]oxazole-6-carboxylate
Figure PCTCN2021120978-appb-000272
Figure PCTCN2021120978-appb-000272
室温下，将4-氨基-3-羟基苯甲酸甲酯(400.0毫克，2.4毫摩尔)、1,1,1-三甲氧基丙烷(320.0毫克，2.4毫摩尔)溶于甲醇(10.0毫升),回流反应2小时。Methyl 4-amino-3-hydroxybenzoate (400.0 mg, 2.4 mmol), 1,1,1-trimethoxypropane (320.0 mg, 2.4 mmol) were dissolved in methanol (10.0 mL) at room temperature, The reaction was refluxed for 2 hours.
反应结束，旋干得到378.0毫克白色固体2-乙基苯并[d]噁唑-6-羧酸甲酯(收率：76.8％)。LC-MS:RT＝1.91min,[M+H] +＝206.13。 After the reaction was completed, spin-dried to obtain 378.0 mg of methyl 2-ethylbenzo[d]oxazole-6-carboxylate as a white solid (yield: 76.8%). LC-MS: RT=1.91 min, [M+H] + =206.13.
步骤B：合成(2-乙基苯并[d]噁唑-6-基)甲醇Step B: Synthesis of (2-ethylbenzo[d]oxazol-6-yl)methanol
Figure PCTCN2021120978-appb-000273
Figure PCTCN2021120978-appb-000273
室温下，将2-乙基苯并[d]噁唑-6-羧酸甲酯(348.0毫克，1.7毫摩尔)溶于四氢呋喃(6.0毫升)中，冰浴条件下加入四氢铝锂(128.0毫克，3.4毫摩尔)，反应1.0小时。At room temperature, methyl 2-ethylbenzo[d]oxazole-6-carboxylate (348.0 mg, 1.7 mmol) was dissolved in tetrahydrofuran (6.0 mL), and lithium tetrahydroaluminum (128.0 mg, 3.4 mmol), reacted for 1.0 h.
反应结束，冰浴条件下缓慢滴加0.1毫升水，0.1毫升15％的氢氧化钠水溶液，0.3毫升水，搅拌5分钟，抽滤，滤液干燥，过滤，旋干得到123.0毫克淡黄色油状物(2-乙基苯并[d]噁唑-6-基)甲醇(收率：40.8％)。LC-MS:RT＝1.65min,[M+H] +＝178.12 The reaction was completed, and 0.1 ml of water, 0.1 ml of 15% aqueous sodium hydroxide solution, 0.3 ml of water were slowly added dropwise under ice bath conditions, stirred for 5 minutes, suction filtered, the filtrate was dried, filtered, and spin-dried to obtain 123.0 mg of pale yellow oil ( 2-ethylbenzo[d]oxazol-6-yl)methanol (yield: 40.8%). LC-MS: RT=1.65min, [M+H] + =178.12
步骤C：合成(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000274
Figure PCTCN2021120978-appb-000274
室温下，将(2-乙基苯并[d]噁唑-6-基)甲醇(50.0毫克，0.3毫摩尔)、(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(140.0毫克，0.3毫摩尔)和三(二亚苄基丙酮)二钯(25.6毫克，0.03毫摩尔)，2-二环己基磷-2,4,6-三异丙基联苯(26.1毫克，0.05毫摩尔)，碳酸铯(182.5毫克，0.5毫摩尔)加入二氧六环(2.0毫升)中，N 2保护下，95摄氏度反应3.0小时。 At room temperature, (2-ethylbenzo[d]oxazol-6-yl)methanol (50.0 mg, 0.3 mmol), (S)-2-((((4-(6-chloropyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (140.0 mg, 0.3 mg mol) and tris(dibenzylideneacetone)dipalladium (25.6 mg, 0.03 mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (26.1 mg, 0.05 mmol), Cesium carbonate (182.5 mg, 0.5 mmol) was added to dioxane (2.0 mL), and the reaction was carried out at 95 °C for 3.0 h under N2 protection.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到47.0毫克淡黄色固体(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(收率：24.2％)。LC-MS:RT＝1.88min,[M+H]+＝638.39。After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 47.0 mg pale yellow solid (S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 24.2%). LC-MS: RT=1.88 min, [M+H]+=638.39.
步骤D：合成(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000275
Figure PCTCN2021120978-appb-000275
室温下，将(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基]甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-甲酸叔丁酯(47.0毫克，0.07毫摩尔)溶于甲醇(0.5毫升)、水(0.1毫升)，四氢呋喃(0.5毫升)中，接着加入一水合氢氧化锂(14.7毫克)，室温反应4小时。(S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl]methoxy)pyridin-2-yl)piperidine-1- (47.0 mg, 0.07 mmol) in methanol (0.5 mL) ), water (0.1 mL), tetrahydrofuran (0.5 mL), then lithium hydroxide monohydrate (14.7 mg) was added, and the reaction was carried out at room temperature for 4 hours.
反应结束，加入饱和氯化铵水溶液(20毫升)调pH至6，混合液用二氯甲烷(20毫升×4次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化，得到4.74毫克白色固体(S)-2-((4-(6-((2-乙基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：11.6％)。LC-MS:RT＝1.75min,[M+H] +＝582.36。 1H NMR(500MHz,DMSO-d 6)δ8.25(s,1H),7.80–7.79(m,1H),7.74(d,J＝0.8Hz,1H),7.61–7.60(m,3H),7.43–7.41(m,1H),6.86(d,J＝7.2Hz,1H),6.66(d,J＝8.1Hz,1H),5.44(s,2H),5.13–5.08(m,1H),4.79(dd,J＝15.2,7.2Hz,1H),4.66(dd,J＝15.2,2.7Hz,1H),4.45(dd,J＝13.3,8.0Hz,1H),4.38–4.31(m,1H),3.95(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.00(d,J＝11.4Hz,1H),2.94–2.90(m,2H),2.85(d,J＝11.1Hz,1H),2.72–2.66(m,1H),2.64–2.56(m,1H),2.46–2.40(m,1H),2.25–2.14(m,2H),1.83–1.69(m,4H),1.30(t,6Hz,3H)。 After the reaction was completed, a saturated aqueous ammonium chloride solution (20 mL) was added to adjust the pH to 6, the mixture was extracted with dichloromethane (20 mL × 4 times), the organic phases were combined, and then dried over anhydrous sodium sulfate, and the crude product was prepared by using Purification by HPLC gave 4.74 mg of (S)-2-((4-(6-((2-ethylbenzo[d]oxazol-6-yl)methoxy)pyridine-2- as a white solid yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 11.6%). LC-MS: RT=1.75 min, [M+H] + =582.36. 1 H NMR (500MHz, DMSO-d 6 )δ8.25(s, 1H), 7.80-7.79(m, 1H), 7.74(d, J=0.8Hz, 1H), 7.61-7.60(m, 3H), 7.43–7.41 (m, 1H), 6.86 (d, J=7.2Hz, 1H), 6.66 (d, J=8.1Hz, 1H), 5.44 (s, 2H), 5.13–5.08 (m, 1H), 4.79 (dd, J＝15.2, 7.2Hz, 1H), 4.66 (dd, J＝15.2, 2.7Hz, 1H), 4.45 (dd, J＝13.3, 8.0Hz, 1H), 4.38–4.31 (m, 1H), 3.95(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.00(d,J＝11.4Hz,1H),2.94–2.90(m,2H),2.85(d,J = 11.1Hz, 1H), 2.72–2.66 (m, 1H), 2.64–2.56 (m, 1H), 2.46–2.40 (m, 1H), 2.25–2.14 (m, 2H), 1.83–1.69 (m, 4H) ), 1.30(t, 6Hz, 3H).
实施例52Example 52
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-8-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000276
Figure PCTCN2021120978-appb-000276
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-8-甲醇Step A: Synthesis of isoquinoline-8-methanol
Figure PCTCN2021120978-appb-000277
Figure PCTCN2021120978-appb-000277
零摄氏度下，喹啉-8-甲醛(100毫克，0.64毫摩尔)溶于甲醇(2毫升)中，氮气保护下，加入硼氢化钠(49毫克，1.28毫摩尔),搅拌1小时。At zero degrees Celsius, quinoline-8-carbaldehyde (100 mg, 0.64 mmol) was dissolved in methanol (2 mL), and sodium borohydride (49 mg, 1.28 mmol) was added under nitrogen protection, and stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加水(2毫升)，反应液加入乙酸乙酯(30毫升)稀释，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得异喹啉-8-甲醇80毫克(收率：78.6％)。LC-MS：RT＝0.33min,[M+H] +＝160.17。 After the reaction, water (2 mL) was slowly added dropwise under an ice bath, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. After concentration, the obtained white solid was directly used in the next reaction to obtain 80 mg of isoquinoline-8-methanol (yield: 78.6%). LC-MS: RT=0.33 min, [M+H] + =160.17.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-8-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000278
Figure PCTCN2021120978-appb-000278
将异喹啉-8-甲醇(30毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。The isoquinoline-8-methanol (30 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL ), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone)dipalladium (15 mg, 0.016 mmol) , Sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was raised to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯78毫克(收率：78.8％)。LC-MS：RT＝1.82min,[M+H] +＝620.38。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-8-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 78 mg (yield: 78.8%). LC-MS: RT=1.82 min, [M+H] + =620.38.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-8-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000279
Figure PCTCN2021120978-appb-000279
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(78毫克，0.13毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-8-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (78 mg, 0.13 mmol), dissolved in mixed solvent (2 mL, dichloromethane/trifluoroacetic acid=6 /1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到46毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：54.5％)。LC-MS：RT＝1.60min,[M+H] +＝564.29。 1H NMR(500MHz,DMSO-d 6)δ12.69(s,1H),9.54(s,1H),8.54(d,J＝5.6Hz,1H),8.26(s,1H),7.95(d,J＝8.0Hz,1H),7.86(d,J＝5.0Hz,1H),7.81–7.76(m,2H),7.76–7.72(m,1H),7.65–7.60(m,2H),6.88(d,J＝7.2Hz,1H),6.68(d,J＝8.1Hz,1H),5.93(s,2H),5.10(d,J＝7.1Hz,1H),4.78(dd,J＝15.2,7.3Hz,1H),4.65(dd,J＝15.2,2.8Hz,1H),4.43(dd,J＝14.3,6.9Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.94(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),2.99(d,J＝11.0Hz,1H),2.85(d,J＝11.2Hz,1H),2.73–2.58(m,2H),2.45(dd,J＝16.5,7.6Hz,1H),2.21(dt,J＝20.9,10.8Hz,2H),1.80(d,J＝18.6Hz,2H),1.80–1.65(m,2H)。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC preparative apparatus to obtain 46 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinoline- 8-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 54.5%). LC-MS: RT=1.60 min, [M+H] + =564.29. 1 H NMR (500MHz, DMSO-d 6 )δ12.69(s, 1H), 9.54(s, 1H), 8.54(d, J=5.6Hz, 1H), 8.26(s, 1H), 7.95(d, J=8.0Hz,1H),7.86(d,J=5.0Hz,1H),7.81-7.76(m,2H),7.76-7.72(m,1H),7.65-7.60(m,2H),6.88(d , J=7.2Hz, 1H), 6.68 (d, J=8.1Hz, 1H), 5.93 (s, 2H), 5.10 (d, J=7.1Hz, 1H), 4.78 (dd, J=15.2, 7.3Hz) ,1H),4.65(dd,J＝15.2,2.8Hz,1H),4.43(dd,J＝14.3,6.9Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.94(d, J＝13.5Hz, 1H), 3.77(d, J＝13.5Hz, 1H), 2.99(d, J＝11.0Hz, 1H), 2.85(d, J＝11.2Hz, 1H), 2.73–2.58(m, 2H), 2.45(dd, J＝16.5, 7.6Hz, 1H), 2.21(dt, J＝20.9, 10.8Hz, 2H), 1.80(d, J＝18.6Hz, 2H), 1.80–1.65(m, 2H ).
实施例53Example 53
合成(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-Cyclopropylmethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000280
Figure PCTCN2021120978-appb-000280
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(1-环丙基甲基-1H-吲唑-6-基)羧酸甲酯Step A: Synthesis of Methyl (1-cyclopropylmethyl-1H-indazol-6-yl)carboxylate
Figure PCTCN2021120978-appb-000281
Figure PCTCN2021120978-appb-000281
将1H-吲唑-6-羧酸甲酯(200毫克，1.14毫摩尔),溴甲基环丙烷(308毫克，2.28毫摩尔)溶于甲醇(4毫升)中，加入碳酸钾(304毫克，2.28毫摩尔)，加毕，氮气保护下，顺速升温至回流,搅拌12小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.14 mmol), bromomethylcyclopropane (308 mg, 2.28 mmol) were dissolved in methanol (4 mL) and potassium carbonate (304 mg, 2.28 mmol) was added. 2.28 mmol), after the addition was completed, under the protection of nitrogen, the temperature was gradually increased to reflux, and stirred for 12 hours.
反应结束后，冷却至室温，减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体(1-环丙基甲基-1H-吲唑-6-基)羧酸甲酯115毫克(收率：43.9％)。LC-MS：RT＝1.98min,[M+H] +＝231.18。 After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, 30 mL of ethyl acetate was added to the reaction solution, washed with saturated brine (20 mL×L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4). 115 mg of methyl (1-cyclopropylmethyl-1H-indazol-6-yl)carboxylate was obtained as a yellow solid (yield: 43.9%). LC-MS: RT=1.98 min, [M+H] + =231.18.
步骤B：合成(1-环丙基甲基-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-cyclopropylmethyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000282
Figure PCTCN2021120978-appb-000282
零摄氏度下，(1-环丙基甲基-1H-吲唑-6-基)羧酸甲酯115毫克，0.50毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，分批加入氢化锂铝(76毫克，2.0毫摩尔),搅拌1小时。At zero degrees Celsius, methyl (1-cyclopropylmethyl-1H-indazol-6-yl)carboxylate 115 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2 mL) and hydrogenated in portions under nitrogen protection. Lithium aluminum (76 mg, 2.0 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.2毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×升次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(1-环丙基甲基-1H-吲唑-6-基)甲醇89毫克(收率：88.1％)。LC-MS：RT＝1.73min,[M+H] +＝203.37。 After the reaction, sodium hydroxide solution (5%, 0.2 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × liter, dichloromethane/methanol). = 10/1) rinsed, combined the organic phases, then washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained white solid was directly used in the next step to obtain (1-ring) Propylmethyl-1H-indazol-6-yl)methanol 89 mg (yield: 88.1%). LC-MS: RT=1.73 min, [M+H] + =203.37.
步骤C：合成(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-cyclopropylmethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000283
Figure PCTCN2021120978-appb-000283
将(1-环丙基甲基-1H-吲唑-6-基)甲醇(38毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度搅拌1小时。(1-Cyclopropylmethyl-1H-indazol-6-yl)methanol (38 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidine pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in In 1,4-dioxane (1 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indene) were added successively Acetone) dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was gradually increased to 100 degrees Celsius and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯66毫克(收率：62.3％)。LC-MS：RT＝1.91min,[M+H] +＝663.43。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((1-cyclopropylmethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- (yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 66 mg (yield: 62.3%). LC-MS: RT=1.91 min, [M+H] + =663.43.
步骤D：合成(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-Cyclopropylmethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000284
Figure PCTCN2021120978-appb-000284
将(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(66毫克，0.10毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((1-Cyclopropylmethyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (66 mg, 0.10 mmol), dissolved in mixed solvent (3 ml, dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到33毫克白色固体(S)-2-((4-(6-((1-环丙基甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：54.4％)。LC-MS：RT＝1.77min,[M+H] +＝607.38。 1H NMR(500MHz,DMSO-d 6)δ12.71(s,1H),8.26(s,1H),8.01(d,J＝0.7Hz,1H),7.98(d,J＝0.9Hz,1H),7.80(d,J＝8.5Hz,1H),7.72(d,J＝8.3Hz,1H),7.63(dd,J＝16.4,9.0Hz,2H),7.22(dd,J＝8.3,1.1Hz,1H),7.07(d,J＝8.3Hz,1H),6.86(d,J＝7.2Hz,1H),6.68(d,J＝8.1Hz,1H),5.51–5.45(m,2H),5.28(t,J＝5.7Hz,1H),5.10(d,J＝5.3Hz,1H),4.78(dd,J＝15.2,7.3Hz,1H),4.64(t,J＝9.5Hz,2H),4.44(dd,J＝13.9,7.4Hz,1H),4.35(dt,J＝8.9,5.8Hz,1H),4.26–4.21(m,2H),3.95(d,J＝14.0Hz,1H),3.77(d,J＝13.7Hz,1H),3.02(s,1H),2.85(s,1H),2.71–2.58(m,2H),2.43(s,1H),2.21(d,J＝37.5Hz,2H),1.89–1.69(m,4H),1.30–1.16(m,2H)。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 33 mg of white solid (S)-2-((4-(6-((1-cyclopropylmethyl-1H-indazol-6-yl)methane) oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (received rate: 54.4%). LC-MS: RT=1.77 min, [M+H] + =607.38. 1 H NMR (500MHz, DMSO-d 6 ) δ 12.71 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=0.7Hz, 1H), 7.98 (d, J=0.9Hz, 1H) ,7.80(d,J＝8.5Hz,1H),7.72(d,J＝8.3Hz,1H),7.63(dd,J＝16.4,9.0Hz,2H),7.22(dd,J＝8.3,1.1Hz, 1H), 7.07(d, J＝8.3Hz, 1H), 6.86(d, J＝7.2Hz, 1H), 6.68(d, J＝8.1Hz, 1H), 5.51–5.45(m, 2H), 5.28( t,J＝5.7Hz,1H),5.10(d,J＝5.3Hz,1H),4.78(dd,J＝15.2,7.3Hz,1H),4.64(t,J＝9.5Hz,2H),4.44( dd, J=13.9, 7.4Hz, 1H), 4.35 (dt, J=8.9, 5.8Hz, 1H), 4.26–4.21 (m, 2H), 3.95 (d, J=14.0Hz, 1H), 3.77 (d , J＝13.7Hz, 1H), 3.02(s, 1H), 2.85(s, 1H), 2.71–2.58(m, 2H), 2.43(s, 1H), 2.21(d, J＝37.5Hz, 2H) , 1.89–1.69 (m, 4H), 1.30–1.16 (m, 2H).
实施例54Example 54
合成(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-(((4-(6-((3-Chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000285
Figure PCTCN2021120978-appb-000285
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-氯-1-甲基-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 3-chloro-1-methyl-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000286
Figure PCTCN2021120978-appb-000286
零摄氏度下,将1-甲基-1H-吲唑-6-羧酸甲酯(0.5克,3.0毫摩尔)溶于乙腈(10.0毫升)中,加冰醋酸(0.5毫升)和N-氯代丁二酰亚胺(0.6克,3.9毫摩尔),室温搅拌2小时,TLC监测至反应完全。At zero degrees Celsius, methyl 1-methyl-1H-indazole-6-carboxylate (0.5 g, 3.0 mmol) was dissolved in acetonitrile (10.0 mL), glacial acetic acid (0.5 mL) and N-chloroacetate were added. Succinimide (0.6 g, 3.9 mmol) was stirred at room temperature for 2 hours and monitored by TLC until the reaction was complete.
将反应液滴加到水(20.0毫升)中,混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到600毫克白色固体3-氯-1-甲基-1H-吲唑-6-羧酸甲酯(收率：66.0％)。LC-MS：RT＝2.05min,[M+H] +＝225.08。 The reaction was added dropwise to water (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (25.0 mL×L), anhydrous sodium sulfate It was dried and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 600 mg of methyl 3-chloro-1-methyl-1H-indazole-6-carboxylate as a white solid (yield: 66.0%). LC-MS: RT=2.05 min, [M+H] + =225.08.
步骤B：合成(3-氯-1-甲基-1H-吲唑-6-基)甲醇Step B: Synthesis of (3-chloro-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000287
Figure PCTCN2021120978-appb-000287
将3-氯-1-甲基-1H-吲唑-6-羧酸甲酯(424毫克,1.8毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后,将氢化锂铝(137毫克,3.6毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 3-chloro-1-methyl-1H-indazole-6-carboxylate (424 mg, 1.8 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring at (137 mg, 3.6 mmol) was added to the reaction solution, and after stirring at zero degrees Celsius for 30 minutes, the reaction was monitored by LC-MS until the reaction was complete.
向反应液加水(2.0毫升),析出大量白色固体,向反应液中加无水硫酸钠干燥,过滤,滤液减压浓缩,得到300毫克黄色固体(3-氯-1-甲基-1H-吲唑-6-基)甲醇(收率：85.2％)。LC-MS：RT＝1.75min,[M+H] +＝197.10。 Water (2.0 ml) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 300 mg of yellow solid (3-chloro-1-methyl-1H-indium). oxazol-6-yl)methanol (yield: 85.2%). LC-MS: RT=1.75 min, [M+H] + =197.10.
步骤C：合成4-(6(((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step C: Synthesis of tert-butyl 4-(6(((3-chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000288
Figure PCTCN2021120978-appb-000288
将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(150毫克,0.50毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(3-氯-1-甲基-1H-吲唑-6-基)甲醇(150毫克,0.76毫摩尔),碳酸铯(326毫克,1.00毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(44毫克,0.050毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌12小时。4-(6-Chloropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.50 mmol) was dissolved in 1,4-dioxane (10.0 mL), (3- Chloro-1-methyl-1H-indazol-6-yl)methanol (150 mg, 0.76 mmol), cesium carbonate (326 mg, 1.00 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6'-Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (44 mg, 0.050 mmol) was added to the reaction flask, and after nitrogen protection, stirred at 100 degrees Celsius for 12 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(35.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到135毫克黄色固体4-(6(((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：61.2％)。The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (35.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 135 mg of 4-(6(((3-chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine as a yellow solid tert-butyl pyridine-1-carboxylate (yield: 61.2%).
步骤D：合成3-氯-1-甲基-6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)-1H-吲唑Step D: Synthesis of 3-Chloro-1-methyl-6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)-1H-indazole
Figure PCTCN2021120978-appb-000289
Figure PCTCN2021120978-appb-000289
将4-(6(((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(135毫克,0.3毫摩尔)溶于乙酸乙酯(2.0毫升)中,然后将4.0M盐酸1,4-二氧六环溶液(2.0毫升)加入反应液中,室温搅拌2小时。4-(6(((3-Chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.3 mmol) was dissolved in ethyl acetate (2.0 mL), then 4.0 M hydrochloric acid 1,4-dioxane solution (2.0 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
反应液直接减压浓缩得到113毫克白色固体3-氯-1-甲基-6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)-1H-吲唑盐酸盐(收率：94.9％)。The reaction solution was directly concentrated under reduced pressure to obtain 113 mg of white solid 3-chloro-1-methyl-6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)- 1H-Indazole hydrochloride (yield: 94.9%).
步骤E：合成(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-(((4-(6-((3-Chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000290
Figure PCTCN2021120978-appb-000290
将3-氯-1-甲基-6-((((6-(哌啶-4-基)吡啶基-2-基)氧基]甲基)-1H-吲唑盐酸盐(115毫克,0.31毫摩尔)溶于溶于N,N-二甲基甲酰胺(5.0毫升)和三乙胺(0.5毫升,3.9毫摩尔)中,加碳酸钾(166毫克,1.2毫摩尔),(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(120毫克,0.35毫摩尔)加入反应液中,50摄氏度下搅拌2小时后,TLC监测至反应完全。3-Chloro-1-methyl-6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy]methyl)-1H-indazole hydrochloride (115 mg , 0.31 mmol) was dissolved in N,N-dimethylformamide (5.0 mL) and triethylamine (0.5 mL, 3.9 mmol), potassium carbonate (166 mg, 1.2 mmol) was added, (S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (120 mg, 0.35 mmol) was added The reaction solution was stirred at 50°C for 2 hours and monitored by TLC until the reaction was complete.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到160毫克黄色固体(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：83.7％)。LC-MS：RT＝1.91min,[M+H] +＝657.38。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the resulting residue was purified by silica gel column chromatography to give 160 mg of yellow solid (S)-2-(((4-(6-((3-chloro-1-methyl-1H-indazol-6-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert. Butyl ester (yield: 83.7%). LC-MS: RT=1.91 min, [M+H] + =657.38.
步骤F：合成(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-(((4-(6-((3-Chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000291
Figure PCTCN2021120978-appb-000291
将(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(160毫克,0.24毫摩尔)溶于二氯甲烷(8.0毫升)中,然后将三氟乙酸(1.2毫升)加入反应液中,室温搅拌5小时后,LCMS监测至反应完全。(S)-2-(((4-(6-((3-Chloro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- (160 mg, 0.24 mmol) in dichloromethane (8.0 mL), then trifluoroacetic acid (1.2 mL) was added to the reaction solution, stirred at room temperature for 5 hours, and monitored by LCMS until the reaction was complete.
向反应液加二氯甲烷(20.0毫升)和15％碳酸氢钠溶液(10.0毫升),混合液用二氯甲烷/甲醇(9/1,20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残余 物经高效液相制备仪分离纯化得到75毫克白色固体(S)-2-(((4-(6-((3-氯-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：45.8％)。LC-MS：RT＝1.79min,[M+H] +＝601.32。 1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝1.0Hz,1H),7.79(dd,J＝8.4,1.5Hz,1H),7.71(d,J＝8.5Hz,2H),7.68–7.64(m,2H),7.62(dd,J＝8.2,6.2Hz,2H),6.85(d,J＝7.3Hz,1H),6.72(d,J＝8.1Hz,1H),5.48(d,J＝13.9Hz,2H),5.14–5.04(m,1H),4.78(dd,J＝15.2,7.0Hz,1H),4.64(dd,J＝15.2,2.9Hz,1H),4.47(dd,J＝13.7,7.7Hz,1H),4.37(dt,J＝9.2,5.9Hz,1H),3.92(d,J＝13.6Hz,1H),3.75(d,J＝13.6Hz,1H),2.95(d,J＝10.7Hz,1H),2.81(d,J＝10.7Hz,1H),2.74–2.64(m,1H),2.60–2.52(m,1H),2.49(s,6H),2.46–2.37(m,1H),2.27–2.08(m,2H),1.66(ddd,J＝43.9,20.8,10.4Hz,4H)。 Dichloromethane (20.0 mL) and 15% sodium bicarbonate solution (10.0 mL) were added to the reaction solution, the mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL×L), the organic phases were combined, and the organic phases were combined. Dry with saturated brine (15.0 mL×L), anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 75 mg of white solid (S)-2-(((4-(6-((3-chloro-1-methyl-1H-indazol-6-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 45.8%). LC-MS: RT=1.79 min, [M+H] + =601.32. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=1.0 Hz, 1H), 7.79 (dd, J=8.4, 1.5Hz, 1H), 7.71 (d, J=8.5Hz, 2H), 7.68–7.64 (m, 2H), 7.62 (dd, J=8.2, 6.2Hz, 2H), 6.85 ( d, J=7.3Hz, 1H), 6.72 (d, J=8.1Hz, 1H), 5.48 (d, J=13.9Hz, 2H), 5.14–5.04 (m, 1H), 4.78 (dd, J=15.2 ,7.0Hz,1H),4.64(dd,J＝15.2,2.9Hz,1H),4.47(dd,J＝13.7,7.7Hz,1H),4.37(dt,J＝9.2,5.9Hz,1H),3.92 (d, J＝13.6Hz, 1H), 3.75 (d, J＝13.6Hz, 1H), 2.95 (d, J＝10.7Hz, 1H), 2.81 (d, J＝10.7Hz, 1H), 2.74–2.64 (m, 1H), 2.60–2.52 (m, 1H), 2.49 (s, 6H), 2.46–2.37 (m, 1H), 2.27–2.08 (m, 2H), 1.66 (ddd, J=43.9, 20.8, 10.4Hz, 4H).
实施例55Example 55
合成(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000292
Figure PCTCN2021120978-appb-000292
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-甲基-1H-吲哚-4-甲醛Step A: Synthesis of 1-Methyl-1H-indole-4-carbaldehyde
Figure PCTCN2021120978-appb-000293
Figure PCTCN2021120978-appb-000293
室温下，将1H-吲哚-4-甲醛(150.0毫克，1.0毫摩尔)溶于四氢呋喃(4.0毫升)中，冰浴条件下加入钠氢(61.8毫克，1.5毫摩尔)，搅拌10分钟，接着加入碘甲烷(219.0毫克，1.5毫摩尔)，室温反应1小时。At room temperature, 1H-indole-4-carbaldehyde (150.0 mg, 1.0 mmol) was dissolved in tetrahydrofuran (4.0 mL), sodium hydrogen (61.8 mg, 1.5 mmol) was added under ice-bath conditions, stirred for 10 minutes, and then Iodomethane (219.0 mg, 1.5 mmol) was added, and the mixture was reacted at room temperature for 1 hour.
反应结束，加入0.5N盐酸淬灭，混合液用乙酸乙酯(15毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，过滤，旋干得到196.0毫克粗品1-甲基-1H-吲哚-4-甲醛。LC-MS:RT＝1.86min,[M+H] +＝160.12。 After the reaction was completed, 0.5N hydrochloric acid was added for quenching, the mixture was extracted with ethyl acetate (15 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (10 ml × 3 times), and then with anhydrous sulfuric acid. Dry over sodium, filter, and spin dry to give 196.0 mg of crude 1-methyl-1H-indole-4-carbaldehyde. LC-MS: RT=1.86 min, [M+H] + =160.12.
步骤B：合成(1-甲基-1H-吲哚-4-基)甲醇Step B: Synthesis of (1-methyl-1H-indol-4-yl)methanol
Figure PCTCN2021120978-appb-000294
Figure PCTCN2021120978-appb-000294
室温下，将1-甲基-1H-吲哚-4-甲醛(196.0毫克，1.2毫摩尔)溶于甲醇(6.0毫升)中，冰浴条件下加入硼氢化钠(93.0毫克，2.4毫摩尔)，冰浴条件下反应1.0小时。1-Methyl-1H-indole-4-carbaldehyde (196.0 mg, 1.2 mmol) was dissolved in methanol (6.0 mL) at room temperature, and sodium borohydride (93.0 mg, 2.4 mmol) was added under ice bath conditions. , and reacted in ice bath for 1.0 hours.
反应结束，冰浴条件下缓慢滴加0.5摩尔每升的盐酸溶液，调pH至7，混合液用乙酸乙酯(15毫升×4次)萃取，合并有机相，有机相先用饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，旋干得到93.0毫克淡黄色油状物(1-甲基-1H-吲哚-4-基)甲醇(收率：48.1％)。LC-MS:RT＝1.72min,[M+H] +＝162.12 After the reaction was completed, 0.5 mol per liter of hydrochloric acid solution was slowly added dropwise under ice bath conditions to adjust the pH to 7, the mixture was extracted with ethyl acetate (15 ml × 4 times), the organic phases were combined, and the organic phase was washed with saturated brine first. , then dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 93.0 mg of pale yellow oil (1-methyl-1H-indol-4-yl)methanol (yield: 48.1%). LC-MS: RT=1.72min, [M+H] + =162.12
步骤C：合成(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000295
Figure PCTCN2021120978-appb-000295
室温下，将(1-甲基-1H-吲哚-4-基)甲醇(50.0毫克，0.3毫摩尔)、(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(140.0毫克，0.3毫摩尔)和三(二亚苄基丙酮)二钯(28.0毫克，0.03毫摩尔)，2-二环己基磷-2,4,6-三异丙基联苯(28.0毫克，0.06毫摩尔)，碳酸铯(195.6毫克，0.6毫摩尔)加入二氧六环(2.0毫升)中，N 2保护下，95摄氏度反应3.0小时 At room temperature, (1-methyl-1H-indol-4-yl)methanol (50.0 mg, 0.3 mmol), (S)-2-((((4-(6-chloropyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (140.0 mg, 0.3 mmol) and tris(dibenzylideneacetone)dipalladium (28.0 mg, 0.03 mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (28.0 mg, 0.06 mmol), cesium carbonate (195.6 mg, 0.6 mmol) was added to dioxane (2.0 mL) and reacted under N2 protection at 95°C for 3.0 hours
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到43.0毫克淡黄色固体(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：24.2％)。LC-MS:RT＝1.91min,[M+H]+＝622.41。After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 43.0 mg pale yellow solid (S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidin-1- (Yield: 24.2%). LC-MS: RT =1.91min,[M+H]+=622.41.
步骤D：合成(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000296
Figure PCTCN2021120978-appb-000296
室温下，将(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(43.0毫克，0.07毫摩尔)溶于甲醇(0.5毫升)、水(0.1毫升)，四氢呋喃(0.5毫升)中，接着加入一水合氢氧化锂(14.7毫克)，室温反应6小时。(S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (43.0 mg, 0.07 mmol) in methanol (0.5 mL) ), water (0.1 mL), tetrahydrofuran (0.5 mL), then lithium hydroxide monohydrate (14.7 mg) was added, and the mixture was reacted at room temperature for 6 hours.
反应结束，加入饱和氯化铵水溶液调pH至6，混合液用二氯甲烷(25毫升×4次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化，得到13.33毫克白色固体(S)-2-((4-(6-(((1-甲基-1H-吲哚-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：34.0％)。LC-MS:RT＝1.79min,[M+H]+＝566.34。 1H NMR(500MHz,DMSO-d 6)：δ8.26(d,J＝0.9Hz,1H),7.80(dd,J＝8.4,1.5Hz,1H),7.67–7.57(m,2H),7.39(dd,J＝8.4,3.8Hz,1H),7.32(d,J＝3.1Hz,1H),7.16–7.09(m,2H),6.85(d,J＝7.3Hz,1H),6.63(d,J＝8.2Hz,1H),6.50(dd,J＝3.1,0.7Hz,1H),5.65–5.58(m,2H),5.14–5.10(m,1H),4.79(dd,J＝15.2,7.3Hz,1H),4.66(dd,J＝15.1,2.6Hz,1H),4.48–4.33(m,2H),3.96(d,J＝13.5Hz,1H),3.77(d,J＝11.3Hz,4H),3.02(d,J＝11.3Hz,1H),2.86(d,J＝11.2Hz,1H),2.74–2.57(m,2H),2.47–2.39(m,1H),2.26(dd,J＝11.4,8.5Hz,1H),2.18(dd,J＝11.5,9.1Hz,1H),1.89–1.68(m,4H)。 After the reaction, saturated aqueous ammonium chloride solution was added to adjust the pH to 6, the mixed solution was extracted with dichloromethane (25 ml × 4 times), the organic phases were combined, and then dried with anhydrous sodium sulfate, and the crude product was subjected to preparative high performance liquid chromatography. Purification gave 13.33 mg of white solid (S)-2-((4-(6-(((1-methyl-1H-indol-4-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 34.0%). LC-MS: RT= 1.79min, [M+H]+=566.34. 1 H NMR (500MHz, DMSO-d 6 ): δ 8.26 (d, J=0.9Hz, 1H), 7.80 (dd, J=8.4, 1.5Hz, 1H ), 7.67–7.57(m, 2H), 7.39(dd, J=8.4, 3.8Hz, 1H), 7.32(d, J=3.1Hz, 1H), 7.16–7.09(m, 2H), 6.85(d, J=7.3Hz, 1H), 6.63 (d, J=8.2Hz, 1H), 6.50 (dd, J=3.1, 0.7Hz, 1H), 5.65–5.58 (m, 2H), 5.14–5.10 (m, 1H) ),4.79(dd,J＝15.2,7.3Hz,1H),4.66(dd,J＝15.1,2.6Hz,1H),4.48–4.33(m,2H),3.96(d,J＝13.5Hz,1H) ,3.77(d,J＝11.3Hz,4H),3.02(d,J＝11.3Hz,1H),2.86(d,J＝11.2Hz,1H),2.74–2.57(m,2H),2.47–2.39( m, 1H), 2.26 (dd, J=11.4, 8.5 Hz, 1H), 2.18 (dd, J=11.5, 9.1 Hz, 1H), 1.89–1.68 (m, 4H).
实施例56Example 56
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-4-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000297
Figure PCTCN2021120978-appb-000297
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-4-甲醇Step A: Synthesis of isoquinoline-4-methanol
Figure PCTCN2021120978-appb-000298
Figure PCTCN2021120978-appb-000298
零摄氏度下，异喹啉-4-甲醛(100毫克，0.64毫摩尔)溶于甲醇(2毫升)中，氮气保护下，加入硼氢化钠(49毫克，1.28毫摩尔),搅拌1小时。At zero degrees Celsius, isoquinoline-4-carbaldehyde (100 mg, 0.64 mmol) was dissolved in methanol (2 mL), sodium borohydride (49 mg, 1.28 mmol) was added under nitrogen protection, and the mixture was stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加水(2毫升)，反应液加入乙酸乙酯(30毫升)稀释，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得异喹 啉-4-甲醇93毫克(收率：91.3％)。LC-MS：RT＝1.78min,[M+H] +＝160.13。 After the reaction, water (2 mL) was slowly added dropwise under an ice bath, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. After concentration, the obtained white solid was directly used in the next reaction to obtain 93 mg of isoquinoline-4-methanol (yield: 91.3%). LC-MS: RT=1.78 min, [M+H] + =160.13.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-4-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000299
Figure PCTCN2021120978-appb-000299
将异喹啉-4-甲醇(30毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。The isoquinoline-4-methanol (30 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL ), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene indeneacetone)dipalladium (15 mg, 0.016 mmol) , Sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was raised to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯72毫克(收率：72.7％)。LC-MS：RT＝1.81min,[M+H] +＝620.40。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-4-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 72 mg (yield: 72.7%). LC-MS: RT=1.81 min, [M+H] + =620.40.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(isoquinolin-4-ylmethoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000300
Figure PCTCN2021120978-appb-000300
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(72毫克，0.12毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-4-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (72 mg, 0.12 mmol), dissolved in mixed solvent (2 mL, dichloromethane/trifluoroacetic acid=6 /1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到36毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：53.3％)。LC-MS：RT＝1.63min,[M+H] +＝564.34。 1H NMR(500MHz,DMSO-d 6)δ12.71(s,1H),9.30(s,1H),8.65(s,1H),8.26(d,J＝1.0Hz,1H),8.16(t,J＝8.7Hz,2H),7.86–7.78(m,2H),7.71(t,J＝7.1Hz,1H),7.62(dd,J＝17.0,8.0Hz,2H),6.88(d,J＝7.3Hz,1H),6.64(d,J＝8.2Hz,1H),5.81(d,J＝12.8Hz,2H),5.14–5.08(m,1H),4.80(dd,J＝15.2,7.3Hz,1H),4.66(dd,J＝15.2,2.7Hz,1H),4.45–4.40(m,1H),4.35(dt,J＝9.0,5.8Hz,1H),3.96(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),3.01(d,J＝11.1Hz,1H),2.87(d,J＝11.2Hz,1H),2.72–2.60(m,2H),2.43(dd,J＝18.9,7.9Hz,1H),2.22(dt,J＝20.9,10.1Hz,2H),1.87–1.71(m,4H)。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC preparative apparatus to obtain 36 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinoline- 4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 53.3%). LC-MS: RT=1.63 min, [M+H] + =564.34. 1 H NMR (500MHz, DMSO-d 6 )δ12.71(s, 1H), 9.30(s, 1H), 8.65(s, 1H), 8.26(d, J=1.0Hz, 1H), 8.16(t, J=8.7Hz, 2H), 7.86–7.78 (m, 2H), 7.71 (t, J=7.1Hz, 1H), 7.62 (dd, J=17.0, 8.0Hz, 2H), 6.88 (d, J=7.3 Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 5.81 (d, J=12.8Hz, 2H), 5.14–5.08 (m, 1H), 4.80 (dd, J=15.2, 7.3Hz, 1H) ), 4.66 (dd, J=15.2, 2.7Hz, 1H), 4.45–4.40 (m, 1H), 4.35 (dt, J=9.0, 5.8Hz, 1H), 3.96 (d, J=13.6Hz, 1H) ,3.78(d,J＝13.6Hz,1H),3.01(d,J＝11.1Hz,1H),2.87(d,J＝11.2Hz,1H),2.72–2.60(m,2H),2.43(dd, J=18.9, 7.9 Hz, 1H), 2.22 (dt, J=20.9, 10.1 Hz, 2H), 1.87–1.71 (m, 4H).
实施例57Example 57
合成(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000301
Figure PCTCN2021120978-appb-000301
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-(2,2-二氟乙基)-2H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 2-(2,2-difluoroethyl)-2H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000302
Figure PCTCN2021120978-appb-000302
室温下，将1H-吲唑-6-羧酸甲酯(1.0克，5.60毫摩尔)和碳酸铯(3.7克，11.2毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入1,1-二氟-2-碘乙烷(1.09克，5.60毫摩尔)，在室温下搅拌半个小时。Methyl 1H-indazole-6-carboxylate (1.0 g, 5.60 mmol) and cesium carbonate (3.7 g, 11.2 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature , and then 1,1-difluoro-2-iodoethane (1.09 g, 5.60 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到200毫克白色固体2-(2,2-二氟乙基)-2H-吲唑-6-羧酸甲酯(收率：15％)。LC-MS:RT＝1.64min,[M+H] +＝241.12。 After the reaction, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/2) to obtain 200 mg of methyl 2-(2,2-difluoroethyl)-2H-indazole-6-carboxylate as a white solid (yield: 15%). LC-MS: RT=1.64 min, [M+H] + =241.12.
步骤B：合成(2-(2,2-二氟乙基)-2H-吲唑-6基)-甲醇Step B: Synthesis of (2-(2,2-difluoroethyl)-2H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000303
Figure PCTCN2021120978-appb-000303
室温下，将2-(2,2-二氟乙基)-2H-吲唑-6-羧酸甲酯(200毫克，0.83毫摩尔)溶于四氢呋喃(10毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(35毫克，0.92毫摩尔)，在室温下搅拌半个小时。Methyl 2-(2,2-difluoroethyl)-2H-indazole-6-carboxylate (200 mg, 0.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature and cooled in an ice bath To zero degrees Celsius, lithium tetrahydroaluminum (35 mg, 0.92 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(50毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到102毫克白色固体体(2-(2,2-二氟乙基)-2H-吲唑-6基)-甲醇(收率：58％)。LC-MS:RT＝1.63min,[M+H] +＝213.12。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (50 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 102 mg of a white solid (2-(2, 2-Difluoroethyl)-2H-indazol-6yl)-methanol (yield: 58%). LC-MS: RT=1.63 min, [M+H] + =213.12.
步骤C：合成(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000304
Figure PCTCN2021120978-appb-000304
将(2-(2,2-二氟乙基)-2H-吲唑-6基)-甲醇(50毫克，0.24毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(117毫克，0.24毫摩尔)，钯催化剂(24毫克)，碳酸铯(156毫克，0.48毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(2-(2,2-Difluoroethyl)-2H-indazol-6yl)-methanol (50 mg, 0.24 mmol), (S)-2-(chloromethyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (117 mg, 0.24 mmol), palladium catalyst (24 mg), cesium carbonate (156 mg, 0.48 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到40毫克白色固体(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：25％)。LC-MS:RT＝1.86min,[M+H] +＝673.39。 After the reaction was completed, suction filtration with celite, washed with dichloromethane, and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 40 mg of white solid ( S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 25%). LC-MS: RT=1.86 min, [M+H] + =673.39.
步骤D：合成(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000305
Figure PCTCN2021120978-appb-000305
将(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(40毫克，0.06毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (40 mg, 0.06 mmol) was dissolved in To dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到10.64毫克白色固体(S)-2-((4-(6-((2-(2,2-二氟乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：29％)。LC-MS:RT＝1.73min,[M+H] +＝617.38。 1H NMR(400MHz,DMSO-d 6)δ8.40(s,1H),8.04(s,1H),7.76(dd,J＝8.3,1.3Hz,1H),7.71(d,J＝8.7Hz,1H),7.67(s,1H),7.64-7.57(m,1H),7.40(d,J＝8.3Hz,1H),7.14(dd,J＝8.6,1.3Hz,1H),6.85(d,J＝7.2Hz,1H),6.67(d,J＝8.0Hz,1H),6.63(t,J＝3.9Hz,0.3H),6.49(t,J＝3.8Hz,0.4H),6.36(t,J＝3.9Hz,0.3H),5.42(s,2H),5.14–5.04(m,1H),4.93(td,J＝14.9,3.9Hz,2H),4.71(dd,J＝15.1,6.9Hz,1H),4.63–4.52(m,1H),4.45(dd,J＝13.4,7.9Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.89(d,J＝13.4Hz,1H),3.74(d,J＝13.4Hz,1H),2.99(d,J＝11.0Hz,1H),2.87(d,J＝11.2Hz,1H),2.64(td,J＝24.6,13.3,7.3Hz,2H),2.44(dd,J＝19.1,8.1Hz,1H),2.19(dt,J＝23.1,9.7Hz,2H)。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 10.64 mg of white solid (S)-2-((4-(6-((2-(2,2-difluoroethyl)-2H-indazole- 6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 29%). LC-MS: RT=1.73 min, [M+H] + =617.38. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.76 (dd, J=8.3, 1.3 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.67(s, 1H), 7.64-7.57(m, 1H), 7.40(d, J=8.3Hz, 1H), 7.14(dd, J=8.6, 1.3Hz, 1H), 6.85(d, J =7.2Hz,1H),6.67(d,J=8.0Hz,1H),6.63(t,J=3.9Hz,0.3H),6.49(t,J=3.8Hz,0.4H),6.36(t,J ＝3.9Hz, 0.3H), 5.42(s, 2H), 5.14–5.04(m, 1H), 4.93(td, J＝14.9, 3.9Hz, 2H), 4.71(dd, J＝15.1, 6.9Hz, 1H) ), 4.63–4.52 (m, 1H), 4.45 (dd, J=13.4, 7.9Hz, 1H), 4.35 (dt, J=9.0, 5.9Hz, 1H), 3.89 (d, J=13.4Hz, 1H) ,3.74(d,J＝13.4Hz,1H),2.99(d,J＝11.0Hz,1H),2.87(d,J＝11.2Hz,1H),2.64(td,J＝24.6,13.3,7.3Hz, 2H), 2.44 (dd, J=19.1, 8.1 Hz, 1H), 2.19 (dt, J=23.1, 9.7 Hz, 2H).
实施例58Example 58
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrahydro-2H-pyran-4-yl)-1H-indole azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000306
Figure PCTCN2021120978-appb-000306
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000307
Figure PCTCN2021120978-appb-000307
将1-甲基-1H-吲唑-6-羧酸甲酯(530毫克,3.0毫摩尔)溶于溶于N,N-二甲基甲酰胺(10.0毫升)中,加碳酸钾(1.8克,13.0毫摩尔),4-溴四氢-2H-吡喃(0.7毫升,6.0毫摩尔)加入反应液中,室温搅拌18小时后,TLC监测至反应完全。Methyl 1-methyl-1H-indazole-6-carboxylate (530 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (10.0 mL) and potassium carbonate (1.8 g) was added. , 13.0 mmol), 4-bromotetrahydro-2H-pyran (0.7 mL, 6.0 mmol) was added to the reaction solution, stirred at room temperature for 18 hours, and monitored by TLC until the reaction was complete.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到260毫克黄色固体1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-羧酸甲酯(收率：33.3％)。LC-MS：RT＝1.89min,[M+H] +＝261.20。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 260 mg of methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-6-carboxylate as a yellow solid (yield: 33.3%) . LC-MS: RT=1.89 min, [M+H] + =261.20.
步骤B：合成(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000308
Figure PCTCN2021120978-appb-000308
将1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-羧酸甲酯(230毫克,0.89毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后,将氢化锂铝(76毫克,2.0毫摩尔)加入反应液中,零摄氏度下搅拌30分钟后,LC-MS监测至反应完全。Methyl 1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-6-carboxylate (230 mg, 0.89 mmol) was dissolved in tetrahydrofuran (10.0 mL) and stirred at zero degrees C for 15 Minutes later, lithium aluminum hydride (76 mg, 2.0 mmol) was added to the reaction solution, and after stirring for 30 minutes at zero degrees Celsius, LC-MS was monitored until the reaction was complete.
向反应液加水(2.0毫升),析出大量白色固体,向反应液中加无水硫酸钠干燥,过滤,滤液减压浓缩,得到200毫克白色固体(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲醇(收率：96.2％)。LC-MS：RT＝1.66min,[M+H] +＝233.20。 Water (2.0 mL) was added to the reaction solution, a large amount of white solid was precipitated, anhydrous sodium sulfate was added to the reaction solution, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 200 mg of white solid (1-(tetrahydro-2H-pyran-4). -yl)-1H-indazol-6-yl)methanol (yield: 96.2%). LC-MS: RT=1.66 min, [M+H] + =233.20.
步骤C：合成4-(6-((1-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step C: Synthesis of 4-(6-((1-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine tert-Butyl pyridine-1-carboxylate
Figure PCTCN2021120978-appb-000309
Figure PCTCN2021120978-appb-000309
将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(160毫克,0.40毫摩尔)溶于1,4-二氧六环(10.0毫升)中，将(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲醇(160毫克,0.50毫摩尔)，碳酸铯(260毫克,0.80毫摩尔)，甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(35毫克,0.040毫摩尔)加入反应瓶中，氮气保护后,100摄氏度下搅拌12小时。4-(6-Chloropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.40 mmol) was dissolved in 1,4-dioxane (10.0 mL), (1- (Tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)methanol (160 mg, 0.50 mmol), cesium carbonate (260 mg, 0.80 mmol), methanesulfonic acid (2- Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (35 mg, 0.040 mmol) was added to the reaction flask, and after nitrogen protection, stirred at 100 degrees Celsius for 12 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中，混合液用乙酸乙酯(40.0毫升×3次)萃取，合并有机相，有机相用饱和食盐水(35.0毫升×3次),无水硫酸钠干燥，减压浓缩。所得残余物经硅胶柱层析纯化得到180毫克黄色固体4-(6-((1-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：90.9％)。LC-MS：RT＝2.23min,[M+H] +＝493.33。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt Water (35.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 180 mg of 4-(6-((1-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)methane as a yellow solid Oxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 90.9%). LC-MS: RT=2.23 min, [M+H] + =493.33.
步骤D：合成6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吲唑Step D: Synthesis of 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)-1-(tetrahydro-2H-pyran-4-yl)- 1H-Indazole
Figure PCTCN2021120978-appb-000310
Figure PCTCN2021120978-appb-000310
将4-(6-((1-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(180毫克,0.37毫摩尔)溶于乙酸乙酯(2.0毫升)中,然后将4.0M盐酸1,4-二氧六环溶液(2.0毫升)加入反应液中,室温搅拌2小时。4-(6-((1-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 - tert-butyl formate (180 mg, 0.37 mmol) was dissolved in ethyl acetate (2.0 mL), then 4.0 M hydrochloric acid 1,4-dioxane solution (2.0 mL) was added to the reaction solution, stirred at room temperature for 2 Hour.
反应液直接减压浓缩得到150毫克白色固体6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吲唑(收率：94.9％)。LC-MS：RT＝1.65min,[M+H] +＝393.28。 The reaction solution was directly concentrated under reduced pressure to obtain 150 mg of white solid 6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)-1-(tetrahydro-2H-pyridine (Fan-4-yl)-1H-indazole (yield: 94.9%). LC-MS: RT=1.65 min, [M+H] + =393.28.
步骤E：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基哌啶-1-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrahydro-2H-pyran-4-yl)- 1H-Indazol-6-yl)methoxy)pyridin-2-ylpiperidin-1-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000311
Figure PCTCN2021120978-appb-000311
将6-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吲唑盐酸盐(120毫克，0.31毫摩尔)溶于溶于N,N-二甲基甲酰胺(5.0毫升)和三乙胺(0.5毫升,3.9毫摩尔)中，加碳酸钾(166毫克，1.2毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(103毫克，0.31毫摩尔)加入反应液中，50摄氏度下搅拌2小时后，TLC监测至反应完全。6-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indium Azole hydrochloride (120 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (5.0 mL) and triethylamine (0.5 mL, 3.9 mmol) and potassium carbonate (166 mg, 3.9 mmol) was added. 1.2 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (103 mg, 0.31 mmol) was added to the reaction solution, and after stirring at 50 degrees Celsius for 2 hours, TLC was monitored until the reaction was complete.
向反应液加水(30.0毫升)，混合液用乙酸乙酯(40.0毫升×3次)萃取，合并有机相,有机相用饱和食盐水(25.0毫升×3次)，无水硫酸钠干燥，减压浓缩，所得残余物经硅胶柱层析纯化得到190毫克黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基哌啶-1-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：83.7％)。LC-MS：RT＝1.84min,[M+H] +＝693.44。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentrated, and the resulting residue was purified by silica gel column chromatography to give 190 mg of yellow solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrakis) Hydro-2H-pyran-4-yl)-1H-indazol-6-yl)methoxy)pyridin-2-ylpiperidin-1-ylmethyl)-1H-benzo[d]imidazol-6 - tert-butyl carboxylate (yield: 83.7%). LC-MS: RT=1.84 min, [M+H] + =693.44.
步骤F：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrahydro-2H-pyran-4-yl)- 1H-Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000312
Figure PCTCN2021120978-appb-000312
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(180毫克，0.26毫摩尔)溶于二氯甲烷(8.0毫升)中，然后将三氟乙酸(1.2毫升)加入反应液中，室温搅拌5小时后，LC-MS监测至反应完全。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrahydro-2H-pyran-4-yl)-1H-indone azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (180 mg, 0.26 mmol ) was dissolved in dichloromethane (8.0 mL), then trifluoroacetic acid (1.2 mL) was added to the reaction solution, and after stirring at room temperature for 5 hours, the reaction was monitored by LC-MS until the reaction was complete.
向反应液加二氯甲烷(20.0毫升)和15％碳酸氢钠溶液(10.0毫升),混合液用二氯甲烷/甲醇(9/1,20.0毫升×3次)萃取，合并有机相，有机相用饱和食盐水(15.0毫升×3次)，无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到76毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(四氢-2H-吡喃-4-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：45.8％)。LC-MS：RT＝1.72min,[M+H] +＝637.37。 1H NMR(400MHz,DMSO-d6)δ8.06(s,2H),7.85(s,1H),7.79(dd,J＝8.3,1.3Hz,1H),7.73(d,J＝8.2Hz,1H),7.68–7.58(m,1H),7.41(d,J＝8.3Hz,1H),7.24(d,J＝8.2Hz,1H),6.87(d,J＝7.2Hz,1H),6.68(d,J＝8.3Hz,1H),5.48(s,2H),5.11(dd,J＝7.1,3.4Hz,1H),4.94–4.76(m,1H),4.69(dd,J＝15.1,6.9Hz,1H),4.58(dd,J＝15.1,3.4Hz,1H),4.50–4.27(m,2H),3.95(dd,J＝14.4,8.7Hz,3H),3.75(d,J＝13.4Hz,1H),3.51(td,J＝11.8,4.2Hz,2H),3.01(d,J＝11.4Hz,1H),2.90(d,J＝11.0Hz,1H),2.66(ddd,J＝24.1,13.3,9.5Hz,2H),2.48–2.37(m,1H),2.31–2.01(m,4H),1.94–1.62(m,6H)。 Dichloromethane (20.0 mL) and 15% sodium bicarbonate solution (10.0 mL) were added to the reaction solution, the mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL × 3 times), and the organic phases were combined. Dry with saturated brine (15.0 ml × 3 times), anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 76 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-((1-(tetrakis) Hydro-2H-pyran-4-yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole -6-carboxylic acid (yield: 45.8%). LC-MS: RT=1.72 min, [M+H] + =637.37. 1 H NMR(400MHz, DMSO-d6)δ8.06(s,2H),7.85(s,1H),7.79(dd,J=8.3,1.3Hz,1H),7.73(d,J=8.2Hz,1H) ), 7.68–7.58(m, 1H), 7.41(d, J=8.3Hz, 1H), 7.24(d, J=8.2Hz, 1H), 6.87(d, J=7.2Hz, 1H), 6.68(d , J=8.3Hz, 1H), 5.48 (s, 2H), 5.11 (dd, J=7.1, 3.4Hz, 1H), 4.94–4.76 (m, 1H), 4.69 (dd, J=15.1, 6.9Hz, 1H), 4.58 (dd, J=15.1, 3.4Hz, 1H), 4.50–4.27 (m, 2H), 3.95 (dd, J=14.4, 8.7Hz, 3H), 3.75 (d, J=13.4Hz, 1H) ),3.51(td,J＝11.8,4.2Hz,2H),3.01(d,J＝11.4Hz,1H),2.90(d,J＝11.0Hz,1H),2.66(ddd,J＝24.1,13.3, 9.5Hz, 2H), 2.48–2.37 (m, 1H), 2.31–2.01 (m, 4H), 1.94–1.62 (m, 6H).
实施例59Example 59
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-3-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000313
Figure PCTCN2021120978-appb-000313
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成喹啉-3-基甲醇Step A: Synthesis of Quinolin-3-ylmethanol
Figure PCTCN2021120978-appb-000314
Figure PCTCN2021120978-appb-000314
冰浴下，向含有喹啉-3-基甲醛(300.0毫克，1.91毫摩尔)的甲醇(10.0毫升)中加入硼氢化钠(144.4毫升)，室温下反应1.0小时。In an ice bath, sodium borohydride (144.4 mL) was added to methanol (10.0 mL) containing quinolin-3-ylcarbaldehyde (300.0 mg, 1.91 mmol), and the reaction was carried out at room temperature for 1.0 hour.
反应结束，加水淬灭，混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到223.0毫克淡黄色固体喹啉-3-基甲醇(收率：73.8％)。LC-MS:RT＝0.53min,[M+H] +＝160.18。 The reaction was completed, quenched by adding water, the mixture was extracted with dichloromethane (30 ml × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (20 ml × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. 223.0 mg of quinolin-3-ylmethanol was obtained as a pale yellow solid (yield: 73.8%). LC-MS: RT=0.53 min, [M+H] + =160.18.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-3-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000315
Figure PCTCN2021120978-appb-000315
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、喹啉-3-基甲醇(48.3毫克，0.30毫摩尔)和叔丁醇钠(58.0毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再依次加入1,1'-联萘-2,2'-双二苯膦(37.0毫克，0.06毫摩尔)、三(二亚苄基丙酮)二钯(27.3毫克，0.03毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), quinolin-3-ylmethanol (48.3 mg, 0.30 mmol) and sodium tert-butoxide (58.0 mg, 0.6 mmol) was added to dioxane (10.0 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (37.0 mg, 0.06 mmol), tris(dibenzylidene) acetone) dipalladium (27.3 mg, 0.03 mmol), under N 2 protection, reacted at 100 degrees Celsius for 3.5 hours.
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到73.0毫克淡黄色油状固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：39.9％)。LC-MS:RT＝1.79min,[M+H] +＝620.39。 After the reaction was completed, water was added to quench, and the mixture was extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 73.0 mg pale yellow oily solid (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-3-ylmethoxy)pyridine-2- (Yield: 39.9%). LC-MS: RT=1.79 min, [M+H ] + = 620.39.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-3-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000316
Figure PCTCN2021120978-appb-000316
室温下，向含有(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(73.0毫克，0.12毫摩尔)的二氯甲烷(3.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应3.0小时。at room temperature, to a compound containing (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-3-ylmethoxy)pyridin-2-yl) )piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (73.0 mg, 0.12 mmol) in dichloromethane (3.0 mL) was added dropwise trifluoroacetic acid (1.0 mL), and reacted at room temperature for 3.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈；流速：20毫升/分钟；梯度：由25％乙腈在5.55分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得54.2毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-(((4-(6-(喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：72.1％)。LC-MS:RT＝1.63min,[M+H] +＝564.33。 1H NMR(500MHz,DMSO)δ9.02(d,J＝2.2Hz,1H),8.44(s,1H),8.25(s,1H),8.02(d,J＝8.4Hz,1H),7.96–7.92(m,1H),7.81(d,J＝4.9Hz,1H),7.74(t,J＝7.7Hz,1H),7.67–7.60(m,2H),7.57–7.52(m,1H),6.88(d,J＝7.3Hz,1H),6.73(d,J＝8.2Hz,1H),5.58(s,2H),5.18–5.07(m,1H),4.85–4.77(m,1H),4.68(dd,J＝15.2,2.7Hz,1H),4.46(dd,J＝13.6,7.8Hz,1H),4.42–4.33(m,1H),3.96(d,J＝13.5Hz,1H),3.80(d,J＝13.4Hz,1H),3.01(d,J＝4.0Hz,1H),2.87(d,J＝7.6Hz,1H),2.76–2.57(m,3H),2.28–2.14(m,2H),1.87–1.67(m,4H)。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixture was extracted with dichloromethane (30 mL×3 times), the organic phases were combined, and then dried over anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm x 30mm 5μM; mobile phase: water (containing 0.1% aqueous ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted from 25% acetonitrile at 5.55 minutes ; Detection wavelength: 254nm. After purification, lyophilization at low temperature gave 54.2 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-(((4-(6-(quinolin-3-ylmethoxy) )pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 72.1%). LC-MS: RT=1.63 min, [M +H] + = 564.33.1H NMR(500MHz,DMSO)δ9.02(d,J=2.2Hz,1H),8.44(s,1H),8.25(s,1H),8.02(d,J=8.4 Hz, 1H), 7.96–7.92 (m, 1H), 7.81 (d, J=4.9Hz, 1H), 7.74 (t, J=7.7Hz, 1H), 7.67–7.60 (m, 2H), 7.57–7.52 (m,1H),6.88(d,J=7.3Hz,1H),6.73(d,J=8.2Hz,1H),5.58(s,2H),5.18–5.07(m,1H),4.85–4.77( m, 1H), 4.68 (dd, J=15.2, 2.7Hz, 1H), 4.46 (dd, J=13.6, 7.8Hz, 1H), 4.42–4.33 (m, 1H), 3.96 (d, J=13.5Hz) ,1H),3.80(d,J＝13.4Hz,1H),3.01(d,J＝4.0Hz,1H),2.87(d,J＝7.6Hz,1H),2.76–2.57(m,3H),2.28 – 2.14 (m, 2H), 1.87–1.67 (m, 4H).
实施例60Example 60
合成(S)-2-(((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-(((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000317
Figure PCTCN2021120978-appb-000317
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(3-碘-1-甲基-1H-吲唑-6-基)甲醇Step A: Synthesis of (3-iodo-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000318
Figure PCTCN2021120978-appb-000318
零摄氏度下,将1-甲基-1H-吲唑-6-羧酸甲酯(0.5克,3.0毫摩尔)溶于乙腈(10.0毫升)中,加冰醋酸(0.5毫升)和N-碘代丁二酰亚胺(0.6克,3.9毫摩尔),室温搅拌2小时,TLC监测至反应完全。At zero degrees Celsius, methyl 1-methyl-1H-indazole-6-carboxylate (0.5 g, 3.0 mmol) was dissolved in acetonitrile (10.0 mL), and glacial acetic acid (0.5 mL) and N-iodo was added. Succinimide (0.6 g, 3.9 mmol) was stirred at room temperature for 2 hours and monitored by TLC until the reaction was complete.
将反应液滴加到水(20.0毫升)中,混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和 食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到640毫克黄色固体(3-碘-1-甲基-1H-吲唑-6-基)甲醇(收率：66.0％)。The reaction was added dropwise to water (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (25.0 mL×L), anhydrous sodium sulfate It was dried and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 640 mg of yellow solid (3-iodo-1-methyl-1H-indazol-6-yl)methanol (yield: 66.0%).
步骤B：合成3-碘-1-甲基-1H-吲唑-6-甲醛Step B: Synthesis of 3-iodo-1-methyl-1H-indazole-6-carbaldehyde
Figure PCTCN2021120978-appb-000319
Figure PCTCN2021120978-appb-000319
将(3-碘-1-甲基-1H-吲唑-6-基)甲醇(500毫克,2.0毫摩尔)溶于二氯甲烷(20.0毫升)中,零摄氏度下搅拌15分钟后,将戴斯-马丁氧化剂(2.0克,8.0毫摩尔)加入反应液中,室温搅拌60分钟后,LC-MS监测至反应完全。(3-iodo-1-methyl-1H-indazol-6-yl)methanol (500 mg, 2.0 mmol) was dissolved in dichloromethane (20.0 mL), and after stirring at zero degrees Celsius for 15 minutes, the S-Martin oxidant (2.0 g, 8.0 mmol) was added to the reaction solution, and after stirring at room temperature for 60 minutes, LC-MS monitored the reaction until the reaction was complete.
向反应液加碳酸氢钠水溶液(20.0毫升),过滤,滤液减压浓缩,所得残余物经硅胶柱层析纯化得到400毫克黄色固体3-碘-1-甲基-1H-吲唑-6-甲醛(收率：65.2％)。Aqueous sodium bicarbonate solution (20.0 mL) was added to the reaction solution, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 400 mg of yellow solid 3-iodo-1-methyl-1H-indazole-6- Formaldehyde (yield: 65.2%).
步骤C：合成3-氰基-1-甲基-1H-吲唑-6-甲醛Step C: Synthesis of 3-cyano-1-methyl-1H-indazole-6-carbaldehyde
Figure PCTCN2021120978-appb-000320
Figure PCTCN2021120978-appb-000320
将3-碘-1-甲基-1H-吲唑-6-甲醛(300毫克,1.1毫摩尔)溶于溶于N,N-二甲基甲酰胺(5.0毫升)中,加四三苯基膦钯(110毫克,0.1毫摩尔),氰化亚铜(540毫克,6.0毫摩尔)加入反应液中,120摄氏度下微波反应2小时后,TLC监测至反应完全。3-Iodo-1-methyl-1H-indazole-6-carbaldehyde (300 mg, 1.1 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and tetrakistriphenyl was added. Phosphine palladium (110 mg, 0.1 mmol) and cuprous cyanide (540 mg, 6.0 mmol) were added to the reaction solution, and the reaction was microwaved at 120 degrees Celsius for 2 hours. TLC was monitored until the reaction was complete.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到150毫克黄色固体3-氰基-1-甲基-1H-吲唑-6-甲醛(收率：56.3％)。LC-MS：RT＝1.83min,[M+H] +＝186.21。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 150 mg of 3-cyano-1-methyl-1H-indazole-6-carbaldehyde as a yellow solid (yield: 56.3%). LC-MS: RT=1.83 min, [M+H] + =186.21.
步骤D：合成(3-氰基-1-甲基-1H-吲唑-6-基)甲醇Step D: Synthesis of (3-cyano-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000321
Figure PCTCN2021120978-appb-000321
将3-氰基-1-甲基-1H-吲唑-6-甲醛(150毫克,0.8毫摩尔)溶于四氢呋喃(10.0毫升)中,零摄氏度下搅拌15分钟后,将硼氢化钠(100毫克,2.6毫摩尔)加入反应液中,室温搅拌30分钟后,LC-MS监测至反应完全。3-Cyano-1-methyl-1H-indazole-6-carbaldehyde (150 mg, 0.8 mmol) was dissolved in tetrahydrofuran (10.0 mL), and after stirring for 15 minutes at zero degrees Celsius, sodium borohydride (100 mg, 2.6 mmol) was added to the reaction solution, stirred at room temperature for 30 minutes, and monitored by LC-MS until the reaction was complete.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到120毫克黄色固体(3-氰基-1-甲基-1H-吲唑-6-基)甲醇(收率：85.2％)。Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 120 mg of yellow solid (3-cyano-1-methyl-1H-indazol-6-yl)methanol (yield: 85.2%).
步骤E:合成(S)-2-((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000322
Figure PCTCN2021120978-appb-000322
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克,0.20毫摩尔)溶于1,4-二氧六环(5.0毫升)中,将(3-氰基-1-甲基-1H-吲唑-6-基)甲醇(80毫克,0.40毫摩尔),碳酸铯(130毫克,0.40毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌12小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.20 mmol) was dissolved in 1,4-dioxane (5.0 mL), and (3-cyano-1-methyl- 1H-Indazol-6-yl)methanol (80 mg, 0.40 mmol), cesium carbonate (130 mg, 0.40 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6' -Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.020 mmol) was added to the reaction flask , After nitrogen protection, stirred at 100 degrees Celsius for 12 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残 余物经硅胶柱层析纯化得到50毫克黄色固体(S)-2-((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：41.4％)。LC-MS：RT＝1.91min,[M+H] +＝648.43。 The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (20.0 mL×L), the organic phases were combined, and the organic phase was washed with saturated common salt Water (15.0 mL×L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 50 mg of yellow solid (S)-2-((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl)methoxy) yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (Yield: 41.4%). LC-MS: RT=1.91 min, [M+H] + =648.43.
步骤F：合成(S)-2-((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000323
Figure PCTCN2021120978-appb-000323
将(S)-2-((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50毫克,0.08毫摩尔)溶于二氯甲烷(6.0毫升)中,然后将三氟乙酸(0.6毫升)加入反应液中,室温搅拌5小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- (50 mg, 0.08 mmol) in dichloromethane (6.0 mL), then trifluoroacetic acid (0.6 mL) was added to the reaction solution, and after stirring at room temperature for 5 hours, LC-MS was monitored until the reaction was complete.
向反应液加二氯甲烷(20.0毫升)和15％碳酸氢钠溶液(10.0毫升),混合液用二氯甲烷/甲醇(9/1,20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残余物经高效液相制备仪分离纯化得到10毫克白色固体(S)-2-((4-(6-((3-氰基-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：18.2％)。LC-MS：RT＝1.75min,[M+H] +＝592.37。 Dichloromethane (20.0 mL) and 15% sodium bicarbonate solution (10.0 mL) were added to the reaction solution, the mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL×L), the organic phases were combined, and the organic phases were combined. Dry with saturated brine (15.0 mL×L), anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue was separated and purified by HPLC to obtain 10 mg of white solid (S)-2-((4-(6-((3-cyano-1-methyl-1H-indazol-6-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Yield: 18.2%). LC-MS: RT=1.75 min, [M+H] + =592.37.
实施例61Example 61
合成(S)-2-((4-(6-((3-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000324
Figure PCTCN2021120978-appb-000324
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(3-氟-1-甲基-1H-吲唑-6-基)羧酸甲酯Step A: Synthesis of Methyl (3-fluoro-1-methyl-1H-indazol-6-yl)carboxylate
Figure PCTCN2021120978-appb-000325
Figure PCTCN2021120978-appb-000325
将(1-甲基-1H-吲唑-6-基)羧酸甲酯(380毫克，2.0毫摩尔)溶于乙腈(3毫升)中,加入1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(1.4克，4.0毫摩尔)以及乙酸(0.3毫升)，加毕，氮气保护下，在微波反应器中升温至100摄氏度,搅拌反应2小时。Methyl (1-methyl-1H-indazol-6-yl)carboxylate (380 mg, 2.0 mmol) was dissolved in acetonitrile (3 mL), 1-chloromethyl-4-fluoro-1, 4-Diazobicyclo 2.2.2 octane bis(tetrafluoroborate) salt (1.4 g, 4.0 mmol) and acetic acid (0.3 mL) were added, and the temperature was raised to 100 degrees Celsius in a microwave reactor under nitrogen protection , the reaction was stirred for 2 hours.
反应结束后，冷却至室温，反应液减压浓缩，向反应液中加入乙酸乙酯30毫升，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体(3-氟-1-甲基-1H-吲唑-6-基)羧酸甲酯130毫克(收率：31.2％)。LC-MS：RT＝1.95min,[M+H] +＝209.31。 After the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, 30 mL of ethyl acetate was added to the reaction solution, then washed with saturated brine (20 mL × L times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/4). 130 mg of methyl (3-fluoro-1-methyl-1H-indazol-6-yl)carboxylate was obtained as a yellow solid (yield: 31.2%). LC-MS: RT=1.95 min, [M+H] + =209.31.
步骤B：合成(3-氟-1-甲基-1H-吲唑-6-基)甲醇Step B: Synthesis of (3-fluoro-1-methyl-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000326
Figure PCTCN2021120978-appb-000326
零摄氏度下，(3-氟-1-甲基-1H-吲唑-6-基)羧酸甲酯130毫克，0.63毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，分批加入氢化锂铝(76毫克，2.0毫摩尔),搅拌1小时。At zero degrees Celsius, methyl (3-fluoro-1-methyl-1H-indazol-6-yl)carboxylate 130 mg, 0.63 mmol) was dissolved in tetrahydrofuran (2 mL) and added in portions under nitrogen Lithium aluminum hydride (76 mg, 2.0 mmol), stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.2毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×升次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(3-氟-1-甲基-1H-吲唑-6-基)甲醇89毫克(收率：88.1％)。LC-MS：RT＝1.70min,[M+H] +＝181.11。 After the reaction, sodium hydroxide solution (5%, 0.2 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × liter, dichloromethane/methanol). =10/1) rinsed, combined the organic phases, then washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained white solid was directly used in the next reaction to obtain (3-fluoro) -1-Methyl-1H-indazol-6-yl)methanol 89 mg (yield: 88.1%). LC-MS: RT=1.70 min, [M+H] + =181.11.
步骤C：合成(S)-2-((4-(6-((3-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((3-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000327
Figure PCTCN2021120978-appb-000327
将(3-氟-1-甲基-1H-吲唑-6-基)甲醇(34毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。(3-Fluoro-1-methyl-1H-indazol-6-yl)methanol (34 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) Dissolved in 1,4-dioxane (1 mL), followed by 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylidene) Indeneacetone) dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((3-氟-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯72毫克(收率：70.3％)。LC-MS：RT＝1.89min,[M+H] +＝641.40。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((3-fluoro-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl was obtained )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 72 mg (yield: 70.3%). LC-MS: RT=1.89 min, [M+H] + =641.40.
步骤D：合成(S)-2-((4-(6-((3-氟1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((3-Fluoro1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000328
Figure PCTCN2021120978-appb-000328
将(S)-2-((4-(6-((3-氟-1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(72毫克，0.11毫摩尔),溶于混合溶剂(3毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，25摄氏度下搅拌3小时。(S)-2-((4-(6-((3-Fluoro-1-methyl-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (72 mg, 0.11 mmol), dissolved in mixed solvent ( 3 ml, dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到39毫克白色固体(S)-2-((4-(6-((3-氟1-甲基-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：60.7％)。LC-MS：RT＝1.74min,[M+H] +＝585.32。核磁数据： 1H NMR(400MHz,DMSO-d 6)δ12.73(s,1H),8.26(d,J＝1.0Hz,1H),7.80(dd,J＝8.4,1.6Hz,1H),7.71(s,1H),7.64(dt,J＝16.5,8.3Hz,3H),7.26(dd,J＝8.4,1.0Hz,1H),6.86(d,J＝7.2Hz,1H),6.69(d,J＝7.9Hz,1H),5.53–5.43(m,2H),5.11(qd,J＝7.2,2.8Hz,1H),4.78(dd,J＝15.2,7.2Hz,1H),4.65(dd,J＝15.2,2.7Hz,1H),4.45(dt,J＝14.0,7.0Hz,1H),4.36(dt,J＝9.1,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.84(d,J＝1.0Hz,3H),3.77(d,J＝13.5Hz,1H),3.01(d,J＝11.3Hz,1H),2.86(d,J＝11.3Hz,1H),2.70–2.56(m,2H),2.42(dt,J＝11.1,6.0Hz,1H),2.21(ddd,J＝25.5,11.6,8.9Hz,2H),1.85–1.67(m,4H). After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 39 mg of white solid (S)-2-((4-(6-((3-fluoro1-methyl-1H-indazol-6-yl)methane) oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (received rate: 60.7%). LC-MS: RT=1.74 min, [M+H] + =585.32. Nuclear magnetic data: 1 H NMR (400MHz, DMSO-d 6 ) δ 12.73 (s, 1H), 8.26 (d, J=1.0 Hz, 1H), 7.80 (dd, J=8.4, 1.6 Hz, 1H), 7.71 (s,1H),7.64(dt,J=16.5,8.3Hz,3H),7.26(dd,J=8.4,1.0Hz,1H),6.86(d,J=7.2Hz,1H),6.69(d, J=7.9Hz, 1H), 5.53–5.43 (m, 2H), 5.11 (qd, J=7.2, 2.8Hz, 1H), 4.78 (dd, J=15.2, 7.2Hz, 1H), 4.65 (dd, J =15.2,2.7Hz,1H),4.45(dt,J=14.0,7.0Hz,1H),4.36(dt,J=9.1,5.9Hz,1H),3.95(d,J=13.5Hz,1H),3.84 (d, J＝1.0Hz, 3H), 3.77 (d, J＝13.5Hz, 1H), 3.01 (d, J＝11.3Hz, 1H), 2.86 (d, J＝11.3Hz, 1H), 2.70–2.56 (m, 2H), 2.42 (dt, J=11.1, 6.0Hz, 1H), 2.21 (ddd, J=25.5, 11.6, 8.9Hz, 2H), 1.85–1.67 (m, 4H).
实施例62Example 62
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000329
Figure PCTCN2021120978-appb-000329
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成喹啉-8-甲醇Step A: Synthesis of quinoline-8-methanol
Figure PCTCN2021120978-appb-000330
Figure PCTCN2021120978-appb-000330
零摄氏度下，喹啉-8-甲醛(100毫克，0.64毫摩尔)溶于甲醇(2毫升)中，氮气保护下，加入硼氢化钠(49毫克，1.28毫摩尔),搅拌1小时。At zero degrees Celsius, quinoline-8-carbaldehyde (100 mg, 0.64 mmol) was dissolved in methanol (2 mL), and sodium borohydride (49 mg, 1.28 mmol) was added under nitrogen protection, and stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加水(2毫升)，反应液加入乙酸乙酯(30毫升)稀释，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得喹啉-8-甲醇90毫克(收率：88.4％)。LC-MS：RT＝0.62min,[M+H] +＝160.12。 After the reaction, water (2 mL) was slowly added dropwise under an ice bath, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentrated, the obtained white solid was directly used in the next reaction to obtain 90 mg of quinoline-8-methanol (yield: 88.4%). LC-MS: RT=0.62 min, [M+H] + =160.12.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000331
Figure PCTCN2021120978-appb-000331
将喹啉-8-甲醇(30毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。The quinoline-8-methanol (30 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL) , 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenacetone)dipalladium (15 mg, 0.016 mmol) were added in sequence, Sodium tert-butoxide (31 mg, 0.32 mmol) was added, and under nitrogen protection, the temperature was increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯61毫克(收率：61.6％)。LC-MS：RT＝1.91min,[M+H] +＝620.39。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 61 mg (yield: 61.6%). LC-MS: RT=1.91 min, [M+H] + =620.39.
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000332
Figure PCTCN2021120978-appb-000332
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(61毫克，0.10毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕， 25摄氏度下搅拌3小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (61 mg, 0.10 mmol), dissolved in mixed solvent (2 mL, dichloromethane/trifluoroacetic acid=6/ 1), the addition was completed, and the mixture was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到34毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：60.4％)。LC-MS：RT＝1.70min,[M+H] +＝564.31。核磁数据： 1H NMR(500MHz,DMSO-d 6)δ12.72(s,1H),8.95(dd,J＝4.2,1.7Hz,1H),8.40(dd,J＝8.3,1.7Hz,1H),8.25(s,1H),7.94(d,J＝8.1Hz,1H),7.85(d,J＝6.6Hz,1H),7.79(d,J＝8.0Hz,1H),7.68–7.54(m,4H),6.87(d,J＝7.3Hz,1H),6.73(d,J＝8.2Hz,1H),6.00(s,2H),5.75(s,1H),5.07(d,J＝7.2Hz,1H),4.75(dd,J＝15.2,7.2Hz,1H),4.64–4.58(m,1H),4.41(dd,J＝13.7,7.6Hz,1H),4.32(dt,J＝9.1,5.9Hz,1H),3.92(d,J＝13.6Hz,1H),3.74(d,J＝12.8Hz,1H),2.96(s,1H),2.82(s,1H),2.70–2.55(m,2H),2.40(dd,J＝24.1,15.1Hz,1H),2.18(d,J＝37.0Hz,2H),1.72(dd,J＝34.3,16.9Hz,4H). After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 34 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinoline-8) -ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 60.4%). LC-MS: RT=1.70 min, [M+H] + =564.31. Nuclear magnetic data: 1 H NMR (500MHz, DMSO-d 6 ) δ 12.72 (s, 1H), 8.95 (dd, J=4.2, 1.7Hz, 1H), 8.40 (dd, J=8.3, 1.7Hz, 1H) ,8.25(s,1H),7.94(d,J＝8.1Hz,1H),7.85(d,J＝6.6Hz,1H),7.79(d,J＝8.0Hz,1H),7.68–7.54(m, 4H), 6.87(d, J＝7.3Hz, 1H), 6.73(d, J＝8.2Hz, 1H), 6.00(s, 2H), 5.75(s, 1H), 5.07(d, J＝7.2Hz, 1H), 4.75 (dd, J=15.2, 7.2Hz, 1H), 4.64–4.58 (m, 1H), 4.41 (dd, J=13.7, 7.6Hz, 1H), 4.32 (dt, J=9.1, 5.9Hz) ,1H),3.92(d,J＝13.6Hz,1H),3.74(d,J＝12.8Hz,1H),2.96(s,1H),2.82(s,1H),2.70–2.55(m,2H) ,2.40(dd,J＝24.1,15.1Hz,1H),2.18(d,J＝37.0Hz,2H),1.72(dd,J＝34.3,16.9Hz,4H).
实施例63Example 63
合成(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000333
Figure PCTCN2021120978-appb-000333
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 5-fluoro-1-(2-methoxyethyl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000334
Figure PCTCN2021120978-appb-000334
室温下，将5-氟-1H-吲唑-6-羧酸甲酯(200毫克，1.03毫摩尔)和碳酸铯(671毫克，2.06毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，再加入1-溴-2-甲氧基乙烷(284毫克)，在室温下搅拌1个小时。Methyl 5-fluoro-1H-indazole-6-carboxylate (200 mg, 1.03 mmol) and cesium carbonate (671 mg, 2.06 mmol) were dissolved in N,N-dimethylformamide ( 5 mL), 1-bromo-2-methoxyethane (284 mg) was further added, and the mixture was stirred at room temperature for 1 hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到100毫克白色固体5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯(收率：39％)。LC-MS:RT＝1.85min,[M+H] +＝253.19。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/3) to obtain 100 mg of methyl 5-fluoro-1-(2-methoxyethyl)-1H-indazole-6-carboxylate as a white solid (yield: 39%). LC-MS: RT=1.85 min, [M+H] + =253.19.
步骤B：合成(5-氟-1-(2-甲氧基乙基)-1H-吲唑-6基)-甲醇Step B: Synthesis of (5-fluoro-1-(2-methoxyethyl)-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000335
Figure PCTCN2021120978-appb-000335
室温下，将5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-羧酸甲酯(100毫克，0.39毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(17毫克，0.43毫摩尔)，在室温下搅拌半个小时。Methyl 5-fluoro-1-(2-methoxyethyl)-1H-indazole-6-carboxylate (100 mg, 0.39 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature under ice The bath was cooled to 0 degrees Celsius, lithium tetrahydroaluminum (17 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到80毫克白色固体(5-氟-1-(2-甲氧基乙基)-1H-吲唑-6基)-甲醇(收率：91％)。LC-MS:RT＝1.65min,[M] +＝225.14。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (20 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 80 mg of white solid (5-fluoro-1- (2-Methoxyethyl)-1H-indazol-6yl)-methanol (yield: 91%). LC-MS: RT=1.65 min, [M] + =225.14.
步骤C：合成(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000336
Figure PCTCN2021120978-appb-000336
将(5-氟-1-(2-甲氧基乙基)-1H-吲唑-6基)-甲醇(80毫克，0.36毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(177毫克，0.36毫摩尔)，钯催化剂(30毫克)，碳酸铯(174毫克，0.54毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6yl)-methanol (80 mg, 0.36 mmol), (S)-2-(chloromethyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (177 mg, 0.36 mmol), palladium catalyst (30 mg), cesium carbonate (174 mg, 0.54 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到85毫克白色固体(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：35％)。LC-MS:RT＝1.84min,[M+H] +＝685.44。 After the reaction was completed, suction filtration with celite, washed with dichloromethane, and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 85 mg of white solid ( S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 35%). LC-MS: RT=1.84 min, [M+H] + =685.44.
步骤D：合成(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000337
Figure PCTCN2021120978-appb-000337
将(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(85毫克，0.12毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (85 mg, 0.12 mmol ) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到34.92毫克白色固体(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：46％)。LC-MS:RT＝1.70min,[M+H] +＝629.40。 1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝1.0Hz,1H),8.03(d,J＝0.8Hz,1H),7.84(d,J＝5.8Hz,1H),7.79(dd,J＝8.4,1.5Hz,1H),7.62(dd,J＝12.4,5.3Hz,2H),7.55(d,J＝10.2Hz,1H),6.87(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),5.58–5.42(m,2H),5.11(qd,J＝7.3,2.9Hz,1H),4.78(dd,J＝15.3,7.2Hz,1H),4.64(dd,J＝15.2,2.7Hz,1H),4.55–4.42(m,3H),4.37(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),3.67(t,J＝5.3Hz,2H),3.09(s,3H),3.01(d,J＝11.2Hz,1H),2.91–2.83(m,1H),2.74–2.57(m,2H),2.48–2.39(m,1H),2.33–2.11(m,2H)。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 34.92 mg of white solid (S)-2-((4-(6-((5-fluoro-1-(2-methoxyethyl)-1H- Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid (yield: 46%). LC-MS: RT=1.70 min, [M+H] + =629.40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.24 (d, J=1.0 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.84 (d, J=5.8 Hz, 1H), 7.79 (dd,J＝8.4,1.5Hz,1H),7.62(dd,J＝12.4,5.3Hz,2H),7.55(d,J＝10.2Hz,1H),6.87(d,J＝7.2Hz,1H) ,6.69(d,J＝8.0Hz,1H),5.58–5.42(m,2H),5.11(qd,J＝7.3,2.9Hz,1H),4.78(dd,J＝15.3,7.2Hz,1H), 4.64 (dd, J=15.2, 2.7Hz, 1H), 4.55–4.42 (m, 3H), 4.37 (dt, J=9.0, 5.9Hz, 1H), 3.95 (d, J=13.5Hz, 1H), 3.77 (d, J=13.5Hz, 1H), 3.67 (t, J=5.3Hz, 2H), 3.09 (s, 3H), 3.01 (d, J=11.2Hz, 1H), 2.91–2.83 (m, 1H) , 2.74–2.57 (m, 2H), 2.48–2.39 (m, 1H), 2.33–2.11 (m, 2H).
实施例64Example 64
合成(S)-2-((4-(6-((5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000338
Figure PCTCN2021120978-appb-000338
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 5-fluoro-2-(2-methoxyethyl)-2H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000339
Figure PCTCN2021120978-appb-000339
室温下，将5-氟-1H-吲唑-6-羧酸甲酯(200毫克，1.03毫摩尔)和碳酸铯(671毫克，2.06毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，再加入1-溴-2-甲氧基乙烷(284毫克)，在室温下搅拌1个小时。Methyl 5-fluoro-1H-indazole-6-carboxylate (200 mg, 1.03 mmol) and cesium carbonate (671 mg, 2.06 mmol) were dissolved in N,N-dimethylformamide ( 5 mL), 1-bromo-2-methoxyethane (284 mg) was further added, and the mixture was stirred at room temperature for 1 hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到60毫克白色固体5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯(收率：23％)。LC-MS:RT＝1.79min,[M+H] +＝253.18。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/3) to obtain 60 mg of methyl 5-fluoro-2-(2-methoxyethyl)-2H-indazole-6-carboxylate as a white solid (yield: 23%). LC-MS: RT=1.79 min, [M+H] + =253.18.
步骤B：合成(5-氟-2-(2-甲氧基乙基)-2H-吲唑-6基)-甲醇Step B: Synthesis of (5-fluoro-2-(2-methoxyethyl)-2H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000340
Figure PCTCN2021120978-appb-000340
室温下，将5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-羧酸甲酯(60毫克，0.24毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(10毫克，0.26毫摩尔)，在室温下搅拌半个小时。Methyl 5-fluoro-2-(2-methoxyethyl)-2H-indazole-6-carboxylate (60 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature under ice The bath was cooled to 0 degrees Celsius, lithium tetrahydroaluminum (10 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到30毫克白色固体(5-氟-2-(2-甲氧基乙基)-2H-吲唑-6基)-甲醇(收率：56％)。LC-MS:RT＝1.61min,[M] +＝225.15。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (20 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 30 mg of white solid (5-fluoro-2- (2-Methoxyethyl)-2H-indazol-6yl)-methanol (yield: 56%). LC-MS: RT=1.61 min, [M] + =225.15.
步骤C：合成(S)-2-((4-(6-((5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((5-Fluoro-2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000341
Figure PCTCN2021120978-appb-000341
将(5-氟-2-(2-甲氧基乙基)-2H-吲唑-6基)-甲醇(60毫克，0.27毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(133毫克，0.27毫摩尔)，钯催化剂(23毫克)，碳酸铯(131毫克，0.40毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(5-Fluoro-2-(2-methoxyethyl)-2H-indazol-6yl)-methanol (60 mg, 0.27 mmol), (S)-2-(chloromethyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (133 mg, 0.27 mmol), palladium catalyst (23 mg), cesium carbonate (131 mg, 0.40 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到20毫克白色固体(S)-2-((4-(6-((5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：12％)。LC-MS:RT＝1.84min,[M+H] +＝685.49。 After the reaction was completed, suction filtration with celite, washed with dichloromethane and concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 20 mg of white solid ( S)-2-((4-(6-((5-Fluoro-2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 12%). LC-MS: RT=1.84 min, [M+H] + =685.49.
步骤D：合成(S)-2-((4-(6-((5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((5-Fluoro-2-(2-methoxyethyl)-2H-indazol-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000342
Figure PCTCN2021120978-appb-000342
将(S)-2-((4-(6-((5-氟-1-(2-甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(20毫克，0.03毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((5-Fluoro-1-(2-methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (20 mg, 0.03 mmol ) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到2.71毫克白色固体(S)-2-((4-(6-((5-氟-2-(2-甲氧基乙基)-2H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：14％)。LC-MS:RT＝1.72min,[M+H] +＝629.37。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 2.71 mg of white solid (S)-2-((4-(6-((5-fluoro-2-(2-methoxyethyl)-2H- Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid (yield: 14%). LC-MS: RT=1.72 min, [M+H] + =629.37.
实施例65Example 65
合成(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000343
Figure PCTCN2021120978-appb-000343
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 5-fluoro-1-(oxetan-3-yl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000344
Figure PCTCN2021120978-appb-000344
室温下，将5-氟-1H-吲唑-6-羧酸甲酯(200毫克，1.03毫摩尔)和碳酸铯(671毫克，2.06毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，再加入3-碘氧杂环丁烷(189毫克,1.03毫摩尔)，在室温下搅拌1个小时。Methyl 5-fluoro-1H-indazole-6-carboxylate (200 mg, 1.03 mmol) and cesium carbonate (671 mg, 2.06 mmol) were dissolved in N,N-dimethylformamide ( 5 mL), 3-iodooxetane (189 mg, 1.03 mmol) was further added, and the mixture was stirred at room temperature for 1 hour.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到100毫克白色固体5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯(收率：39％)。After the reaction was completed, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (20 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/3) to obtain 100 mg of methyl 5-fluoro-1-(oxetan-3-yl)-1H-indazole-6-carboxylate as a white solid (yield: 39%).
步骤B：合成(5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6基)-甲醇Step B: Synthesis of (5-fluoro-1-(oxetan-3-yl)-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000345
Figure PCTCN2021120978-appb-000345
室温下，将5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-羧酸甲酯(100毫克，0.40毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(30毫克，0.80毫摩尔)，在室温下搅拌半个小时。Methyl 5-fluoro-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (100 mg, 0.40 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature in The mixture was cooled to 0 degrees Celsius in an ice bath, lithium tetrahydroaluminum (30 mg, 0.80 mmol) was added, and the mixture was stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(20毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到67毫克白色固体(5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6基)-甲醇(收率：77％)。After the reaction, saturated sodium chloride was added to quench the reaction, and ethyl acetate (20 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate. (oxetan-3-yl)-1H-indazol-6yl)-methanol (yield: 77%).
步骤C：合成(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000346
Figure PCTCN2021120978-appb-000346
将(5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6基)-甲醇(67毫克，0.30毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2- 基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150毫克，0.30毫摩尔)，钯催化剂(51毫克)，碳酸铯(195毫克，0.60毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6yl)-methanol (67 mg, 0.30 mmol), (S)-2-(chloromethyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (150 mg, 0.30 mmol), palladium catalyst (51 mg), cesium carbonate ( 195 mg, 0.60 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到60毫克白色固体(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：29％)。LC-MS:RT＝1.82min,[M+H] +＝683.29。 After completion of the reaction, suction filtration with celite, washing with dichloromethane, and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 60 mg of white solid ( S)-2-((4-(6-((5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 29%). LC-MS: RT=1.82 min, [M+H] + =683.29.
步骤D：合成(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000347
Figure PCTCN2021120978-appb-000347
将(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.09毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应一个小时。(S)-2-((4-(6-((5-Fluoro-1-(oxetan-3-yl)-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.09 mm mol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for one hour.
反应结束后，浓缩，所得粗品高效液相纯化得到22.72毫克白色固体(S)-2-((4-(6-((5-氟-1-(氧杂环丁-3-基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：40％)。LC-MS:RT＝1.70min,[M+H] +＝627.36。 1H NMR(400MHz,DMSO-d 6)δ8.21(s,1H),8.12(s,1H),7.90(d,J＝5.8Hz,1H),7.77(dd,J＝8.3,1.4Hz,1H),7.68–7.58(m,2H),7.48(d,J＝8.3Hz,1H),6.88(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),6.06–5.93(m,1H),5.52–5.42(m,2H),5.14–5.06(m,1H),5.03–4.93(m,4H),4.73(dd,J＝15.1,7.0Hz,1H),4.60(dd,J＝15.1,2.9Hz,1H),4.46(dt,J＝14.0,7.0Hz,1H),4.36(dt,J＝9.0,5.9Hz,1H),3.92(d,J＝13.4Hz,1H),3.76(d,J＝13.4Hz,1H),3.00(d,J＝10.9Hz,1H),2.88(d,J＝11.2Hz,1H),2.75–2.54(m,3H),2.47–2.37(m,1H),2.29–2.11(m,2H)。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 22.72 mg of white solid (S)-2-((4-(6-((5-fluoro-1-(oxetan-3-yl)-1H -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylic acid (yield: 40%). LC-MS: RT=1.70 min, [M+H] + =627.36. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.90 (d, J=5.8Hz, 1H), 7.77 (dd, J=8.3, 1.4Hz, 1H), 7.68–7.58 (m, 2H), 7.48 (d, J=8.3Hz, 1H), 6.88 (d, J=7.2Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 6.06– 5.93 (m, 1H), 5.52–5.42 (m, 2H), 5.14–5.06 (m, 1H), 5.03–4.93 (m, 4H), 4.73 (dd, J=15.1, 7.0Hz, 1H), 4.60 ( dd, J＝15.1, 2.9Hz, 1H), 4.46 (dt, J＝14.0, 7.0Hz, 1H), 4.36 (dt, J＝9.0, 5.9Hz, 1H), 3.92 (d, J＝13.4Hz, 1H) ), 3.76 (d, J＝13.4Hz, 1H), 3.00 (d, J＝10.9Hz, 1H), 2.88 (d, J＝11.2Hz, 1H), 2.75–2.54 (m, 3H), 2.47–2.37 (m, 1H), 2.29–2.11 (m, 2H).
实施例66Example 66
合成(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000348
Figure PCTCN2021120978-appb-000348
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(氧杂环丁-3-基甲基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of 1-(oxetan-3-ylmethyl)-1H-indazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000349
Figure PCTCN2021120978-appb-000349
室温下，将1H-吲唑-6-羧酸甲酯(200毫克，1.13毫摩尔)和碳酸铯(736毫克，2.26毫摩尔)溶于N,N-二甲基甲酰胺(10毫升)中，再加入3-溴甲基氧杂环丁烷(170毫克，1.13毫摩尔)，在室温下搅拌0.5小时。Methyl 1H-indazole-6-carboxylate (200 mg, 1.13 mmol) and cesium carbonate (736 mg, 2.26 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature , and then 3-bromomethyloxetane (170 mg, 1.13 mmol) was added, and the mixture was stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭反应，用乙酸乙酯(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到150毫克白色固体1-(氧杂环丁-3-基 甲基)-1H-吲唑-6-羧酸甲酯(收率：54％)。After the reaction, saturated sodium chloride was added to quench the reaction, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/ n-hexane=1/2) to obtain 150 mg of methyl 1-(oxetan-3-ylmethyl)-1H-indazole-6-carboxylate as a white solid (yield: 54%).
步骤B：合成(1-(氧杂环丁-3-基甲基)-1H-吲唑-6基)-甲醇Step B: Synthesis of (1-(oxetan-3-ylmethyl)-1H-indazol-6yl)-methanol
Figure PCTCN2021120978-appb-000350
Figure PCTCN2021120978-appb-000350
室温下，将1-(氧杂环丁-3-基甲基)-1H-吲唑-6-羧酸甲酯(150毫克，0.61毫摩尔)溶于四氢呋喃(10毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(46毫克，1.22毫摩尔)，在室温下搅拌0.5小时。Methyl 1-(oxetan-3-ylmethyl)-1H-indazole-6-carboxylate (150 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature in an ice bath The mixture was cooled to 0 degrees Celsius, lithium aluminum tetrahydride (46 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到100毫克白色固体(1-(氧杂环丁-3-基甲基)-1H-吲唑-6基)-甲醇(收率：75％)。After the reaction, saturated sodium chloride was added to quench the reaction, then ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of white solid (1-(oxa But-3-ylmethyl)-1H-indazol-6yl)-methanol (yield: 75%).
步骤C：合成(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000351
Figure PCTCN2021120978-appb-000351
将(1-(氧杂环丁-3-基甲基)-1H-吲唑-6基)-甲醇(50毫克，0.23毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(114毫克，0.23毫摩尔)，钯催化剂(39毫克)，碳酸铯(150毫克，0.46毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌8个小时。(1-(oxetan-3-ylmethyl)-1H-indazol-6yl)-methanol (50 mg, 0.23 mmol), (S)-2-(chloromethyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (114 mg, 0.23 mmol), palladium catalyst (39 mg), cesium carbonate (150 mg) , 0.46 mmol) was dissolved in dioxane (10 mL), the temperature was raised to 100 degrees Celsius and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到70毫克白色固体(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：45％)。After completion of the reaction, suction filtration with celite, washing with dichloromethane, and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 70 mg of white solid ( S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 45%).
步骤D：合成(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indazol-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000352
Figure PCTCN2021120978-appb-000352
将(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(70毫克，0.10毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (70 mg, 0.10 mmol) It was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到1.72毫克白色固体(S)-2-((4-(6-((1-(氧杂环丁-3-基甲基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：3％)。LC-MS:RT＝1.70min,[M+H] +＝623.38。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 1.72 mg of white solid (S)-2-((4-(6-((1-(oxetan-3-ylmethyl)-1H-indone) azol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-Carboxylic acid (yield: 3%). LC-MS: RT=1.70 min, [M+H] + =623.38.
实施例67Example 67
合成(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(isoquinolin-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000353
Figure PCTCN2021120978-appb-000353
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(isoquinolin-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000354
Figure PCTCN2021120978-appb-000354
将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(260.1毫克,0.52毫摩尔)溶于1,4-二氧六环(10.0毫升)中,加入异喹啉-3-基甲醇(100.0毫克,0.63毫摩尔),三(二亚苄基丙酮)二钯(47.9毫克，0.05毫摩尔),1,1'-联萘-2,2'-双二苯膦(32.4毫克,0.05毫摩尔)和碳酸铯(255.6毫克,0.79毫摩尔),氮气保护下,100 6搅拌反应3小时。旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝8/2)得到100.0毫克米黄色固体叔(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：30.8％)。LC-MS：RT＝1.84min,[M+H] +＝620.32。 (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene Iso[d]imidazole-6-carboxylate tert-butyl ester (260.1 mg, 0.52 mmol) was dissolved in 1,4-dioxane (10.0 mL) and added isoquinolin-3-ylmethanol (100.0 mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium (47.9 mg, 0.05 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (32.4 mg, 0.05 mmol) and Cesium carbonate (255.6 mg, 0.79 mmol) was stirred at 100 6 for 3 hours under nitrogen protection. The solvent was spin-dried, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=8/2) to obtain 100.0 mg of beige solid tert(S)-2-((4-(6-( Isoquinolin-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylate tert-butyl ester (yield: 30.8%). LC-MS: RT=1.84 min, [M+H] + =620.32.
步骤B：合成(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-(isoquinolin-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000355
Figure PCTCN2021120978-appb-000355
将(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(90.0毫克,0.15毫摩尔)溶于二氯甲烷(0.6毫升)中,加入三氟乙酸(0.2毫升),室温搅拌4小时。加入饱和碳酸氢钠水溶液中和三氟乙酸，旋干溶剂，送制备液相分离，得30.0毫克白色固体(S)-2-((4-(6-(异喹啉-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：36.7％)。LC-MS：RT＝1.70min,[M+H] +＝564.32。 1H NMR(500MHz,DMSO-d 6)δ9.31(s,1H),8.11(d,J＝7.8Hz,1H),8.03(s,1H),7.90(d,J＝8.2Hz,1H),7.89(s,1H),7.76(dd,J＝8.3,1.3Hz,1H),7.71–7.61(m,3H),7.38(d,J＝8.3Hz,1H),6.87(d,J＝7.2Hz,1H),6.76(d,J＝8.1Hz,1H),5.58(s,2H),5.13–5.06(m,1H),4.68(dd,J＝15.2,7.0Hz,1H),4.57(dd,J＝15.2,3.1Hz,1H),4.50–4.44(m,1H),4.39–4.33(m,1H),3.88(d,J＝13.3Hz,1H),3.72(d,J＝13.3Hz,1H),2.99–2.92(m,1H),2.87–2.80(m,1H),2.72–2.63(m,1H),2.62–2.54(m,1H),2.48–2.41(m,1H),2.23–2.16(m,1H),2.16–2.09(m,1H),1.80–1.61(m,4H)。 (S)-2-((4-(6-(isoquinolin-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (90.0 mg, 0.15 mmol) was dissolved in dichloromethane (0.6 mL), trifluoroacetic acid (0.2 mL) was added ) and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to neutralize trifluoroacetic acid, the solvent was spin-dried, and the preparative liquid phase was separated to obtain 30.0 mg of white solid (S)-2-((4-(6-(isoquinolin-3-ylmethoxy) yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield : 36.7%). LC-MS: RT=1.70 min, [M+H] + =564.32. 1 H NMR (500MHz, DMSO-d 6 ) δ 9.31(s, 1H), 8.11(d, J=7.8Hz, 1H), 8.03(s, 1H), 7.90(d, J=8.2Hz, 1H) ,7.89(s,1H),7.76(dd,J=8.3,1.3Hz,1H),7.71–7.61(m,3H),7.38(d,J=8.3Hz,1H),6.87(d,J=7.2 Hz, 1H), 6.76(d, J=8.1Hz, 1H), 5.58(s, 2H), 5.13–5.06(m, 1H), 4.68(dd, J=15.2, 7.0Hz, 1H), 4.57(dd , J=15.2, 3.1Hz, 1H), 4.50–4.44 (m, 1H), 4.39–4.33 (m, 1H), 3.88 (d, J=13.3Hz, 1H), 3.72 (d, J=13.3Hz, 1H), 2.99–2.92 (m, 1H), 2.87–2.80 (m, 1H), 2.72–2.63 (m, 1H), 2.62–2.54 (m, 1H), 2.48–2.41 (m, 1H), 2.23– 2.16 (m, 1H), 2.16–2.09 (m, 1H), 1.80–1.61 (m, 4H).
实施例68Example 68
合成(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((4-cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000356
Figure PCTCN2021120978-appb-000356
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(溴甲基)-1-萘腈Step A: Synthesis of 4-(bromomethyl)-1-naphthalenecarbonitrile
Figure PCTCN2021120978-appb-000357
Figure PCTCN2021120978-appb-000357
室温下，向含有4-甲基-1-萘腈(500毫克，2.99毫摩尔)的四氯化碳(7.0毫升)中依次加入N-溴代丁二酰亚胺(585毫克，3.29毫摩尔)和偶氮二异丁腈(20毫克，0.12毫摩尔),加热至80摄氏度反应3小时。To 4-methyl-1-naphthalenenitrile (500 mg, 2.99 mmol) in carbon tetrachloride (7.0 mL) was added N-bromosuccinimide (585 mg, 3.29 mmol) sequentially at room temperature ) and azobisisobutyronitrile (20 mg, 0.12 mmol), heated to 80 degrees Celsius and reacted for 3 hours.
反应结束，反应液用二氯甲烷(100毫升)稀释，依次用饱和碳酸氢钠(50毫升)和食盐水(50毫升)洗涤，无水硫酸钠干燥后减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/15)。得到630克白色固体4-(溴甲基)-1-萘腈(收率：85.6％)。After the reaction was completed, the reaction solution was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by analytical method (eluent: ethyl acetate/n-hexane=1/15). 630 g of white solid 4-(bromomethyl)-1-naphthalenecarbonitrile were obtained (yield: 85.6%).
步骤B：合成4-(羟甲基)-1-萘腈Step B: Synthesis of 4-(hydroxymethyl)-1-naphthalenenitrile
Figure PCTCN2021120978-appb-000358
Figure PCTCN2021120978-appb-000358
室温下，向含有4-(溴甲基)-1-萘腈(630毫克，2.56毫摩尔)的1，4-二氧六环/水(6.5毫升/6.5毫升)溶液中加入碳酸钠(542毫克，5.11毫摩尔),加热至100摄氏度反应3小时。To a solution of 4-(bromomethyl)-1-naphthalenecarbonitrile (630 mg, 2.56 mmol) in 1,4-dioxane/water (6.5 mL/6.5 mL) was added sodium carbonate (542 mL) at room temperature mg, 5.11 mmol), heated to 100 degrees Celsius for 3 hours.
反应结束，冷却至室温，用乙酸乙酯(50毫升×升次)萃取，洗涤，有机相用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，得到400毫克白色固体4-(羟甲基)-1-萘腈(收率：85.3％)。[M+H] +＝184.11。 The reaction was completed, cooled to room temperature, extracted with ethyl acetate (50 mL×L), washed, and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 400 mg 4-(hydroxymethyl)-1-naphthalenenitrile as a white solid (yield: 85.3%). [M+H] + =184.11.
步骤C：合成(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((4-cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000359
Figure PCTCN2021120978-appb-000359
室温下，向含有(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(180毫克，0.36毫摩尔)和4-(羟甲基)-1-萘腈(78毫克，0.43毫摩尔)的1,4-二氧六环溶液(2.5毫升)中，依次加入叔丁醇钠(69毫克，0.72毫摩尔)、1,1'-联萘-2,2'-双二苯膦(52毫克，0.083毫摩尔)和三(二亚苄基丙酮)二钯(33毫克，0.036毫摩尔)，置换氮气，110摄氏度反应过夜。at room temperature, to a compound containing (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (180 mg, 0.36 mmol) and 1, 4-(hydroxymethyl)-1-naphthalenenitrile (78 mg, 0.43 mmol) 4-Dioxane solution (2.5 mL) was added successively sodium tert-butoxide (69 mg, 0.72 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (52 mg, 0.083 mmol) and tris(dibenzylideneacetone)dipalladium (33 mg, 0.036 mmol), replaced with nitrogen, and reacted at 110 degrees Celsius overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)。得到150毫克白色固体(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：64.7％)。[M+H] +＝644.40。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (30 mL×L), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×L), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). 150 mg of white solid (S)-2-((4-(6-((4-cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methan was obtained yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 64.7%). [M+H] + =644.40.
步骤D：合成(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((4-cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000360
Figure PCTCN2021120978-appb-000360
室温下，向含有(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(70毫克，0.11毫摩尔)的二氯甲烷溶液(2.0毫升)中，加入三氟乙酸(0.4毫升)，室温反应2小时，反应完毕，减压蒸除溶剂，残余物用制备HPLC纯化，得到15毫克白色固体(S)-2-((4-(6-((4-氰基萘-1-基))甲氧基)吡啶-2-基))哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：23.4％)。LC-MS:RT＝1.80min,[M+H] +＝588.35。 1H NMR(500MHz,DMSO)δ8.29(d,J＝8.1Hz,1H),8.26(d,J＝1.0Hz,1H),8.19–8.14(m,2H),7.85–7.75(m,4H),7.67–7.61(m,2H),6.90(d,J＝7.2Hz,1H),6.73(d,J＝8.0Hz,1H),5.92(d,J＝1.6Hz,2H),5.08(ddd,J＝14.4,7.2,2.8Hz,1H),4.76(dd,J＝15.2,7.2Hz,1H),4.62(dd,J＝15.2,2.7Hz,1H),4.42(dt,J＝14.0,7.0Hz,1H),4.33(dt,J＝9.0,5.9Hz,1H),3.93(d,J＝13.5Hz,1H),3.76(d,J＝13.5Hz,1H),2.97(d,J＝11.2Hz,1H),2.83(d,J＝11.4Hz,1H),2.70–2.56(m,2H),2.44–2.35(m,1H),2.26–2.11(m,2H),1.83–1.61(m,4H)。 At room temperature, the solution containing (S)-2-((4-(6-((4-cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (70 mg, 0.11 mmol) in dichloromethane (2.0 mL) ), trifluoroacetic acid (0.4 mL) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain 15 mg of white solid (S)-2-((4-(6 -((4-Cyanonaphthalen-1-yl))methoxy)pyridin-2-yl))piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-benzo[d]imidazole-6-carboxylic acid (yield: 23.4%). LC-MS: RT=1.80 min, [M+H] + =588.35. 1 H NMR(500MHz,DMSO)δ8.29(d,J=8.1Hz,1H),8.26(d,J=1.0Hz,1H),8.19-8.14(m,2H),7.85-7.75(m,4H) ),7.67–7.61(m,2H),6.90(d,J=7.2Hz,1H),6.73(d,J=8.0Hz,1H),5.92(d,J=1.6Hz,2H),5.08(ddd , J=14.4, 7.2, 2.8Hz, 1H), 4.76 (dd, J=15.2, 7.2Hz, 1H), 4.62 (dd, J=15.2, 2.7Hz, 1H), 4.42 (dt, J=14.0, 7.0 Hz,1H),4.33(dt,J=9.0,5.9Hz,1H),3.93(d,J=13.5Hz,1H),3.76(d,J=13.5Hz,1H),2.97(d,J=11.2 Hz, 1H), 2.83 (d, J=11.4 Hz, 1H), 2.70–2.56 (m, 2H), 2.44–2.35 (m, 1H), 2.26–2.11 (m, 2H), 1.83–1.61 (m, 4H).
实施例69Example 69
合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000361
Figure PCTCN2021120978-appb-000361
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-甲基苯并[d]噻唑-5-基)甲醇Step A: Synthesis of (2-methylbenzo[d]thiazol-5-yl)methanol
Figure PCTCN2021120978-appb-000362
Figure PCTCN2021120978-appb-000362
冰浴下，向含有2-甲基苯并[d]噻唑-5-羧酸(300.0毫克，1.55毫摩尔)的四氢呋喃(2.0毫升)中滴加四氢铝锂溶液(1摩尔/升，1毫升)，60摄氏度下反应12小时。To 2-methylbenzo[d]thiazole-5-carboxylic acid (300.0 mg, 1.55 mmol) in tetrahydrofuran (2.0 mL) was added dropwise a solution of lithium tetrahydroaluminum (1 mol/L, 1 ml), reacted at 60 degrees Celsius for 12 hours.
反应结束，向反应液中缓慢滴加水，待无气泡产生,垫硅藻土抽滤。混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，有机相用无水硫酸钠干燥，浓缩得到98.2毫克淡黄色固体(2-甲基苯并[d]噻唑-5-基)甲醇(收率：35.2％)直接用于下一步反应。LC-MS:RT＝1.65min,[M+H] +＝180.09。 After the reaction was completed, water was slowly added dropwise to the reaction solution, and when no air bubbles were generated, pad celite for suction filtration. The mixture was extracted with dichloromethane (30 mL×3 times), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain 98.2 mg of pale yellow solid (2-methylbenzo[d]thiazol-5-yl ) methanol (yield: 35.2%) was directly used in the next reaction. LC-MS: RT=1.65 min, [M+H] + =180.09.
步骤B：合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000363
Figure PCTCN2021120978-appb-000363
室温下，将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150.0毫克，0.30毫摩尔)、(2-甲基苯并[d]噻唑-5-基)甲醇(54.0毫克，0.30毫摩尔)和碳酸铯(195.6 毫克，0.6毫摩尔)加入二氧六环(10.0毫升)中，再加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(253.8毫克，0.3毫摩尔)，N 2保护下，100摄氏度反应5.0小时。 At room temperature, (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (150.0 mg, 0.30 mmol), (2-methylbenzo[d]thiazol-5-yl)methanol (54.0 mg, 0.30 mmol) ) and cesium carbonate (195.6 mg, 0.6 mmol) were added to dioxane (10.0 mL) followed by methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropane) yl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (253.8 mg, 0.3 mmol), under N2 protection, reacted at 100 °C 5.0 hours.
反应结束，加水淬灭，混合液用二氯甲烷(50毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升×3次)洗涤，然后用无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到56.0毫克淡黄色油状固体(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：29.3％)。LC-MS:RT＝1.89min,[M+H] +＝640.37。 After the reaction was completed, water was added to quench, and the mixture was extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 56.0 mg pale yellow oily solid (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 29.3%). LC-MS: RT=1.89 min, [M+H] + =640.37.
步骤C：合成(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000364
Figure PCTCN2021120978-appb-000364
室温下，向含有(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(56.0毫克，0.09毫摩尔)的二氯甲烷(3.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应3.0小时。At room temperature, the solution containing (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (56.0 mg, 0.09 mmol) in dichloromethane ( 3.0 mL) was added dropwise trifluoroacetic acid (1.0 mL), and the reaction was carried out at room temperature for 3.0 hours.
反应结束，加水淬灭，用碳酸氢钠溶液(0.5摩尔/升)调pH至8，混合液用二氯甲烷(30毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈；流速：20毫升/分钟；梯度：由32.3％乙腈在6.45分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得12.2毫克白色固体(S)-2-((4-(6-((2-甲基苯并[d]噻唑-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：23.3％)。LC-MS:RT＝1.73min,[M+H] +＝584.37。 After the reaction was completed, water was added to quench, the pH was adjusted to 8 with sodium bicarbonate solution (0.5 mol/L), the mixture was extracted with dichloromethane (30 mL×3 times), the organic phases were combined, and then dried over anhydrous sodium sulfate, The crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% ammonia) and acetonitrile; flow rate: 20 ml/min; gradient: eluted from 32.3% acetonitrile at 6.45 minutes ; Detection wavelength: 254nm. After purification, lyophilization at low temperature gave 12.2 mg of white solid (S)-2-((4-(6-((2-methylbenzo[d]thiazol-5-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 23.3%). LC-MS: RT=1.73 min, [M+H] + =584.37.
实施例70Example 70
合成(S)-2-((4-(6-((1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2-fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000365
Figure PCTCN2021120978-appb-000365
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-氟乙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of methyl 1-(2-fluoroethyl)-1H-indazole-6-carboxylate
Figure PCTCN2021120978-appb-000366
Figure PCTCN2021120978-appb-000366
将1H-吲唑-6-羧酸甲酯(350毫克,1.98毫摩尔)和1-氟-2-碘乙烷(348毫克,1.98毫摩尔)溶解于8毫升无水N,N-二甲基甲酰胺中，加入碳酸铯(1.29克,3.96毫摩尔)于室温下反应2小时。反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得296毫克淡黄色固体1-(2-氟乙基)-1H-吲唑-6-羧酸甲酯。LC-MS:RT＝1.86min,[M+H] +＝223.28。 1H-Indazole-6-carboxylate methyl ester (350 mg, 1.98 mmol) and 1-fluoro-2-iodoethane (348 mg, 1.98 mmol) were dissolved in 8 mL of anhydrous N,N-dimethylformaldehyde In the base formamide, cesium carbonate (1.29 g, 3.96 mmol) was added to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), and then dried with anhydrous sodium sulfate. The obtained 296 mg of methyl 1-(2-fluoroethyl)-1H-indazole-6-carboxylate as a pale yellow solid was concentrated under reduced pressure. LC-MS: RT=1.86 min, [M+H] + =223.28.
步骤B：合成(1-(2-氟乙基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(2-Fluoroethyl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000367
Figure PCTCN2021120978-appb-000367
将1-(2-氟乙基)-1H-吲唑-6-羧酸甲酯(296毫克,1.33毫摩尔)溶解于5毫升无水四氢呋喃中，零摄氏度下加入四氢锂铝(50毫克,1.33毫摩尔)于零到室温下反应40分钟，反应结束，零摄氏度下向反应液中滴加0.5毫升水淬灭，加入10克无水硫酸钠，搅拌5分钟过滤，滤液旋干得238毫克淡黄色固体(1-(2-氟乙基)-1H-吲唑-6-基)甲醇。Methyl 1-(2-fluoroethyl)-1H-indazole-6-carboxylate (296 mg, 1.33 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and lithium aluminum tetrahydrogen (50 mg) was added at zero degrees Celsius. , 1.33 mmol) was reacted at zero to room temperature for 40 minutes, the reaction was over, 0.5 ml of water was added dropwise to the reaction solution at zero degrees Celsius to quench, 10 grams of anhydrous sodium sulfate was added, stirred for 5 minutes and filtered, and the filtrate was spin-dried to obtain 238 mg of pale yellow solid (1-(2-fluoroethyl)-1H-indazol-6-yl)methanol.
步骤C：合成(S)-2-((4-(6-((1-(1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(1-(2-fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000368
Figure PCTCN2021120978-appb-000368
将(1-(2-氟乙基)-1H-吲唑-6-基)甲醇(80毫克,0.421毫摩尔)和(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(204毫克,0.421毫摩尔)溶解于8毫升无水二氧六环中，加入碳酸铯(274毫克,0.842毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(36毫克，0.0421毫摩尔)，氮气置换3次，于100摄氏度下反应7小时。反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱(100％乙酸乙酯)分离得112毫克淡黄色固体(S)-2-((4-(6-((1-(1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯。LC-MS:RT＝1.78min,[M-H] -＝655.37。 Combine (1-(2-fluoroethyl)-1H-indazol-6-yl)methanol (80 mg, 0.421 mmol) and (S)-2-(((4-(6-chloropyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (204 mg, 0.421 mg mol) was dissolved in 8 mL of anhydrous dioxane, cesium carbonate (274 mg, 0.842 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-iso) were added Propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.0421 mmol), purged with nitrogen 3 times, at 100 The reaction was carried out for 7 hours at degrees Celsius. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 ml × liters), the organic phases were combined, and the organic phases were washed with saturated brine (20 ml × liters), Dry over sodium sulfate, and finally concentrate the crude product under reduced pressure to obtain 112 mg of pale yellow solid (S)-2-((4-(6-((1-(1-(2- Fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid tert-butyl ester. LC-MS: RT=1.78 min, [MH] − = 655.37.
步骤D：合成(S)-2-((4-(6-((1-(1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(1-(2-fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000369
Figure PCTCN2021120978-appb-000369
将(S)-2-((4-(6-((1-(1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(112毫克,0.171毫摩尔)溶解于4毫升无水二氯甲烷中，加入2毫升三氟乙酸于室温下反应1.5小时。反应结束，反应液减压浓缩所得粗品经碱性反相制备分离得62毫克白色固体(S)-2-((4-(6-((1-(1-(2-氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸。LC-MS:RT＝1.72min,[M+H] +＝599.37。 1H NMR(400MHz,DMSO)δ12.76(s,1H),8.28(d,J＝1.0Hz,1H),8.10(d,J＝0.9Hz,1H),7.71–7.88(m,3H),7.55–7.69(m,2H),7.25(dd,J＝8.3,1.2Hz,1H),6.88(d,J＝7.1Hz,1H),6.70(d,J＝8.2Hz,1H),5.43–5.55(m,2H),5.10–5.16(m,1H),4.58–4.97(m,6H),4.32–4.50(m,2H),3.97(d,J＝13.7Hz,1H),3.79(d,J＝13.4Hz,1H),3.01–3.05(m 1H),2.85–2.95(m,1H),2.74–2.57(m,2H),2.38–2.47(m,1H),2.30–2.15(m,2H),1.72–1.84(m,4H)。 (S)-2-((4-(6-((1-(1-(2-fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (112 mg, 0.171 mmol) was dissolved in In 4 milliliters of anhydrous dichloromethane, 2 milliliters of trifluoroacetic acid were added to react at room temperature for 1.5 hours. The reaction was completed, and the crude product obtained by concentrating the reaction solution under reduced pressure was separated by basic reverse phase preparation to obtain 62 milligrams of white solid (S)-2- ((4-(6-((1-(1-(2-Fluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid. LC-MS: RT=1.72 min, [M+H] + =599.37. 1 H NMR (400MHz, DMSO) δ12.76(s, 1H), 8.28(d, J=1.0Hz, 1H), 8.10(d, J=0.9Hz, 1H), 7.71–7.88(m, 3H), 7.55 –7.69(m,2H),7.25(dd,J=8.3,1.2Hz,1H),6.88(d,J=7.1Hz,1H),6.70(d,J=8.2Hz,1H),5.43–5.55( m, 2H), 5.10–5.16 (m, 1H), 4.58–4.97 (m, 6H), 4.32–4.50 (m, 2H), 3.97 (d, J=13.7Hz, 1H), 3.79 (d, J= 13.4Hz, 1H), 3.01–3.05 (m 1H), 2.85–2.95 (m, 1H), 2.74–2.57 (m, 2H), 2.38–2.47 (m, 1H), 2.30–2.15 (m, 2H), 1.72–1.84 (m, 4H).
实施例71Example 71
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-6-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000370
Figure PCTCN2021120978-appb-000370
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-6-羧酸甲酯Step A: Synthesis of methyl isoquinoline-6-carboxylate
Figure PCTCN2021120978-appb-000371
Figure PCTCN2021120978-appb-000371
将异喹啉-6-羧酸(150毫克，0.87毫摩尔)溶于二氯甲烷(15毫升)中，滴入两滴N,N-二甲基甲酰胺，然后边搅拌边滴加草酰氯(550毫克，8.66毫摩尔)，在室温下反应半个小时。Dissolve isoquinoline-6-carboxylic acid (150 mg, 0.87 mmol) in dichloromethane (15 mL), add dropwise two drops of N,N-dimethylformamide, then add oxalyl chloride dropwise with stirring (550 mg, 8.66 mmol) at room temperature for half an hour.
再将甲醇(5毫升)滴入反应中，搅拌十分钟，再加入氢氧化钠溶液中和至中性，用二氯甲烷(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到95毫克白色固体异喹啉-6-羧酸甲酯(收率：58％)。Methanol (5 mL) was then added dropwise to the reaction, stirred for ten minutes, then neutralized to neutrality by adding sodium hydroxide solution, extracted with dichloromethane (20 mL×L), combined and dried organic phases, and the obtained crude product was concentrated. Purification by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) gave 95 mg of methyl isoquinoline-6-carboxylate as a white solid (yield: 58%).
步骤B：合成异喹啉-6基甲醇Step B: Synthesis of isoquinolin-6ylmethanol
Figure PCTCN2021120978-appb-000372
Figure PCTCN2021120978-appb-000372
室温下，将异喹啉-6-羧酸甲酯(95毫克，0.51毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(20毫克，0.51毫摩尔)，在室温下搅拌半个小时。Methyl isoquinoline-6-carboxylate (95 mg, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, cooled to 0°C in an ice bath, and lithium tetrahydroaluminum (20 mg, 0.51 mmol) was added. mmol) and stirred at room temperature for half an hour.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到80毫克白色固体异喹啉-6基甲醇(收率：97％)。After the reaction, saturated sodium chloride was added to quench the reaction, and ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate. After filtration, concentration was obtained to obtain 80 mg of white solid isoquinolin-6ylmethanol (Yield: 97%).
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-6-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000373
Figure PCTCN2021120978-appb-000373
将异喹啉-6基甲醇(80毫克，0.50毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(250毫克，0.50毫摩尔)，钯催化剂(40毫克)，碳酸铯(326毫克，1.00毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌8个小时。The isoquinolin-6ylmethanol (80 mg, 0.50 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylate tert-butyl ester (250 mg, 0.50 mmol), palladium catalyst (40 mg), cesium carbonate (326 mg, 1.00 mmol) were dissolved in dioxane and the temperature was raised to 100 degrees Celsius Stir for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到60毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：19％)。After completion of the reaction, suction filtration with celite, washing with dichloromethane, and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 60 mg of white solid ( S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-6-ylmethoxy)pyridin-2-yl)piperidine-1- (yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 19%).
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-6-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000374
Figure PCTCN2021120978-appb-000374
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.10毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-6-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid ( 1 ml), react for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到44.88毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：80％)。LC-MS:RT＝1.59min,[M+H] +＝564.33。 1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.39(d,J＝5.7Hz,1H),8.10(d,J＝8.5Hz,1H),8.03(d,J＝16.3Hz,2H),7.82–7.68(m,3H),7.67–7.57(m,1H),7.40(d,J＝8.3Hz,1H),6.86(d,J＝7.2Hz,1H),6.73(d,J＝8.1Hz,1H),5.62-5.49(m,2H),5.10(td,J＝10.1,6.9Hz,1H),4.69(dd,J＝15.1,6.8Hz,1H),4.58(dd,J＝15.1,3.2Hz,1H),4.45(dd,J＝13.6,7.8Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.88(d,J＝13.4Hz,1H),3.73(d,J＝13.3Hz,1H),2.96(d,J＝11.2Hz,1H),2.85(d,J＝11.4Hz,1H),2.73–2.54(m,2H),2.49–2.36(m,2H),2.24–2.07(m,2H)。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 44.88 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinoline- 6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 80%). LC-MS: RT=1.59 min, [M+H] + =564.33. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.39 (d, J=5.7Hz, 1H), 8.10 (d, J=8.5Hz, 1H), 8.03 (d, J= 16.3Hz, 2H), 7.82–7.68 (m, 3H), 7.67–7.57 (m, 1H), 7.40 (d, J=8.3Hz, 1H), 6.86 (d, J=7.2Hz, 1H), 6.73 ( d, J＝8.1Hz, 1H), 5.62-5.49(m, 2H), 5.10(td, J＝10.1, 6.9Hz, 1H), 4.69(dd, J＝15.1, 6.8Hz, 1H), 4.58(dd , J＝15.1, 3.2Hz, 1H), 4.45 (dd, J＝13.6, 7.8Hz, 1H), 4.35 (dt, J＝9.0, 5.9Hz, 1H), 3.88 (d, J＝13.4Hz, 1H) ,3.73(d,J＝13.3Hz,1H),2.96(d,J＝11.2Hz,1H),2.85(d,J＝11.4Hz,1H),2.73–2.54(m,2H),2.49–2.36( m, 2H), 2.24–2.07 (m, 2H).
实施例72Example 72
合成(S)-2-((4-(6-((1-(2-,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Synthesis of (S)-2-((4-(6-((1-(2-,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine pyridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000375
Figure PCTCN2021120978-appb-000375
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-氯-5-硝基亚油酸Step A: Synthesis of 6-chloro-5-nitrolinoleic acid
Figure PCTCN2021120978-appb-000376
Figure PCTCN2021120978-appb-000376
将2-氯-6-甲基-3-硝基吡啶(15克,87.0毫摩尔)溶于浓硫酸(100.0毫升)中,零摄氏度下搅拌15分钟后,零摄氏度下将三氧化铬(26克,261毫摩尔)分成10批次缓慢加入到反应液中,保持反应液温度不超过50摄氏度,3小时内加料完毕后,室温搅拌16小时,LC-MS监测至反应完全。2-Chloro-6-methyl-3-nitropyridine (15 g, 87.0 mmol) was dissolved in concentrated sulfuric acid (100.0 mL), and after stirring for 15 minutes at zero degrees Celsius, chromium trioxide (26 g, 261 mmol) was slowly added to the reaction solution in 10 batches, keeping the temperature of the reaction solution not higher than 50 degrees Celsius, after the addition was completed within 3 hours, stirred at room temperature for 16 hours, and monitored by LC-MS until the reaction was complete.
将反应液缓慢滴加到冰水中,混合液用乙酸乙酯(200.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(100.0毫升×升次),无水硫酸钠干燥,减压浓缩,得到16.8克绿色固体6-氯-5-硝基亚油酸(收率：100％)。LC-MS：RT＝1.50min,[M+H] +＝201.05。 The reaction solution was slowly added dropwise to ice water, the mixture was extracted with ethyl acetate (200.0 mL×L), the organic phases were combined, the organic phase was washed with saturated brine (100.0 mL×L), dried over anhydrous sodium sulfate, and then reduced to 50%. It was concentrated under pressure to obtain 16.8 g of green solid 6-chloro-5-nitrolinoleic acid (yield: 100%). LC-MS: RT=1.50 min, [M+H] + =201.05.
步骤B：合成6-氯-5-硝基亚油酸异丙酯Step B: Synthesis of isopropyl 6-chloro-5-nitrolinoleate
Figure PCTCN2021120978-appb-000377
Figure PCTCN2021120978-appb-000377
将6-氯-5-硝基亚油酸(2.9克,14.5毫摩尔)溶于二氯甲烷(100.0毫升)中,零摄氏度下搅拌15分钟后,将草酰氯(2.5毫升,29毫摩尔)和N,N-二甲基甲酰胺(0.5毫升)加入该混悬液中,零摄氏度下搅拌30分钟后,将反应液滴加到异丙醇(20.0毫升)中,室温搅拌1小时。6-Chloro-5-nitrolinoleic acid (2.9 g, 14.5 mmol) was dissolved in dichloromethane (100.0 mL), and after stirring for 15 min at zero degrees Celsius, oxalyl chloride (2.5 mL, 29 mmol) was added. and N,N-dimethylformamide (0.5 mL) were added to the suspension, and after stirring at zero degrees Celsius for 30 minutes, the reaction was added dropwise to isopropanol (20.0 mL) and stirred at room temperature for 1 hour.
反应液减压浓缩后,用正己烷打浆得到2.6克白色固体6-氯-5-硝基亚油酸异丙酯(收率：74.3％)。LC-MS：RT＝1.97min,[M+H] +＝245.11。 After the reaction solution was concentrated under reduced pressure, it was slurried with n-hexane to obtain 2.6 g of white solid isopropyl 6-chloro-5-nitrolinoleate (yield: 74.3%). LC-MS: RT=1.97 min, [M+H] + =245.11.
步骤C：合成(S)-5-硝基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯Step C: Synthesis of (S)-isopropyl 5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate
Figure PCTCN2021120978-appb-000378
Figure PCTCN2021120978-appb-000378
将6-氯-5-硝基亚油酸(2.6克,11.0毫摩尔)溶于四氢呋喃(40.0毫升)和三乙胺(4.0毫升,33.0毫摩尔)中, 加(S)-氧杂环丁-2-基甲胺(1.2毫升,16.5毫摩尔),室温搅拌1小时。6-Chloro-5-nitrolinoleic acid (2.6 g, 11.0 mmol) was dissolved in tetrahydrofuran (40.0 mL) and triethylamine (4.0 mL, 33.0 mmol) and (S)-oxetine was added -2-ylmethylamine (1.2 mL, 16.5 mmol) and stirred at room temperature for 1 hour.
向反应液加水(40.0毫升),混合液用乙酸乙酯(60.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(40.0毫升×升次),无水硫酸钠干燥,减压浓缩,得到2.0克黄色固体(S)-5-硝基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯(收率：74.3％)。LC-MS：RT＝1.98min,[M+H] +＝296.19。 Water (40.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (60.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (40.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentration gave 2.0 g of (S)-isopropyl 5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate as a yellow solid (yield: 74.3%). LC-MS: RT=1.98 min, [M+H] + =296.19.
步骤D：合成(S)-5-氨基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯Step D: Synthesis of (S)-isopropyl 5-amino-6-((oxetan-2-ylmethyl)amino)picolinate
Figure PCTCN2021120978-appb-000379
Figure PCTCN2021120978-appb-000379
将(S)-5-硝基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯(2.0克,6.76毫摩尔)溶于甲醇(40.0毫升)中,氮气保护后,将湿钯碳(200毫克,10％)加入反应液中,氢气置换3次后,室温搅拌3小时,LC-MS监测至反应完全。(S)-Isopropyl 5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate (2.0 g, 6.76 mmol) was dissolved in methanol (40.0 mL) under nitrogen After protection, wet palladium carbon (200 mg, 10%) was added to the reaction solution, and after hydrogen replacement for 3 times, the mixture was stirred at room temperature for 3 hours, and the reaction was monitored by LC-MS until the reaction was complete.
反应液垫硅藻土过滤,滤液减压浓缩得到1.1克白色固体(S)-5-氨基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯(收率：67.1％)。LC-MS：RT＝1.54min,[M+H] +＝266.64。 The reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain 1.1 g of white solid (S)-5-amino-6-((oxetan-2-ylmethyl)amino)isopropylpicolinate (yield : 67.1%). LC-MS: RT=1.54 min, [M+H] + =266.64.
步骤E：合成(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯Step E: Synthesis of (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid isopropyl ester
Figure PCTCN2021120978-appb-000380
Figure PCTCN2021120978-appb-000380
将(S)-5-氨基-6-((氧杂环丁-2-基甲基)氨基)吡啶甲酸异丙酯(1.1克,4.1毫摩尔)溶于四氢呋喃(30.0毫升)中,,加氯乙酸酐(1.4克,8.2毫摩尔),60摄氏度下搅拌3小时,LCMS监测至反应完全。(S)-Isopropyl 5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (1.1 g, 4.1 mmol) was dissolved in tetrahydrofuran (30.0 mL), and added Chloroacetic anhydride (1.4 g, 8.2 mmol) was stirred at 60 degrees Celsius for 3 hours, and monitored by LCMS until the reaction was complete.
向反应液加水(20.0毫升),混合液用乙酸乙酯(40.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×升次),无水硫酸钠干燥,减压浓缩,所得残余物经硅胶柱层析纯化得到700毫克黄色固体(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(收率：53.8％)。LC-MS：RT＝1.86min,[M+H] +＝324.17。 Water (20.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×L), the organic phases were combined, and the organic phases were washed with saturated brine (25.0 mL×L), dried over anhydrous sodium sulfate, and dried under reduced pressure. It was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 700 mg of yellow solid (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4, 5-b] Pyridine-5-carboxylate isopropyl ester (yield: 53.8%). LC-MS: RT=1.86 min, [M+H] + =324.17.
步骤F：合成S)-2-((4-(6-((1-(2-,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯Step F: Synthesis of S)-2-((4-(6-((1-(2-,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester
Figure PCTCN2021120978-appb-000381
Figure PCTCN2021120978-appb-000381
将1-(2,2-二氟乙基)-6-((((6-(哌啶-4-基)吡啶-2-基氧基)甲基)-1H-吲唑盐酸盐(300毫克,0.73毫摩尔)溶于溶于乙腈(30.0毫升)和三乙胺(5毫升,3.9毫摩尔)中,加碳酸钾(166毫克,1.2毫摩尔),(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(237毫克,0.73毫摩尔)加入反应液中,50摄氏度下搅拌2小时后,TLC监测至反应完全。1-(2,2-Difluoroethyl)-6-(((((6-(piperidin-4-yl)pyridin-2-yloxy)methyl)-1H-indazole hydrochloride ( 300 mg, 0.73 mmol) was dissolved in acetonitrile (30.0 mL) and triethylamine (5 mL, 3.9 mmol), potassium carbonate (166 mg, 1.2 mmol), (S)-2-(chloro) was added Methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (237 mg, 0.73 mmol) was added to the reaction solution After stirring at 50°C for 2 hours, TLC was monitored until the reaction was complete.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(25.0毫升×3次),无水硫酸钠干燥,减压浓缩,得到450毫克黄色固体(S)-2-((4-(6-((1-(2-,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(收率：83.7％)。LC-MS：RT＝1.81min,[M+H] +＝660.36。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL×3 times), the organic phases were combined, the organic phases were washed with saturated brine (25.0 mL×3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentration gave 450 mg of yellow solid (S)-2-((4-(6-((1-(2-,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl Ester (yield: 83.7%). LC-MS: RT=1.81 min, [M+H] + =660.36.
步骤G：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Step G: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000382
Figure PCTCN2021120978-appb-000382
将(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(450毫克,0.73毫摩尔)溶于四氢呋喃(30.0毫升)和甲醇(10.0毫升)中,然后将氢氧化锂(84毫克,2.0毫摩尔)的水溶液(10.0毫升)加入反应液中,室温搅拌5小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (450 mg, 0.73 mm mol) was dissolved in tetrahydrofuran (30.0 mL) and methanol (10.0 mL), then an aqueous solution (10.0 mL) of lithium hydroxide (84 mg, 2.0 mmol) was added to the reaction solution, and after stirring at room temperature for 5 hours, LC-MS Monitor until the reaction is complete.
混合液用二氯甲烷/甲醇(9/1,20.0毫升×升次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×升次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到287毫克白色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(收率：63.8％)。LC-MS：RT＝1.70min,[M+H] +＝618.36。 1H NMR(500MHz,DMSO-d6)δ8.14(d,J＝0.9Hz,1H),8.04(d,J＝8.2Hz,1H),7.96(d,J＝8.2Hz,1H),7.82(s,1H),7.79–7.73(m,1H),7.63(dd,J＝8.2,7.4Hz,1H),7.27(dd,J＝8.3,1.2Hz,1H),6.87(d,J＝7.1Hz,1H),6.69(d,J＝8.2Hz,1H),6.58–6.19(m,1H),5.47(s,2H),5.11–4.78(m,4H),4.68(dd,J＝14.7,2.8Hz,1H),4.33(ddt,J＝15.1,8.9,6.0Hz,2H),4.06(d,J＝13.6Hz,1H),3.79(d,J＝13.5Hz,1H),3.01(d,J＝10.8Hz,1H),2.86(d,J＝11.4Hz,1H),2.61(t,J＝11.9Hz,1H),2.43(s,1H),2.35–2.11(m,3H),1.96–1.52(m,4H)。 The mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL×L), the organic phases were combined, the organic phases were washed with saturated brine (15.0 mL×L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 287 mg of white solid (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-indazol-6-yl) )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine- 5-carboxylic acid (yield: 63.8%). LC-MS: RT=1.70 min, [M+H] + =618.36. 1 H NMR(500MHz, DMSO-d6)δ8.14(d,J=0.9Hz,1H),8.04(d,J=8.2Hz,1H),7.96(d,J=8.2Hz,1H),7.82( s, 1H), 7.79–7.73 (m, 1H), 7.63 (dd, J=8.2, 7.4Hz, 1H), 7.27 (dd, J=8.3, 1.2Hz, 1H), 6.87 (d, J=7.1Hz) ,1H),6.69(d,J=8.2Hz,1H),6.58–6.19(m,1H),5.47(s,2H),5.11–4.78(m,4H),4.68(dd,J=14.7,2.8 Hz,1H),4.33(ddt,J=15.1,8.9,6.0Hz,2H),4.06(d,J=13.6Hz,1H),3.79(d,J=13.5Hz,1H),3.01(d,J =10.8Hz,1H),2.86(d,J=11.4Hz,1H),2.61(t,J=11.9Hz,1H),2.43(s,1H),2.35–2.11(m,3H),1.96–1.52 (m, 4H).
实施例73Example 73
合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000383
Figure PCTCN2021120978-appb-000383
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000384
Figure PCTCN2021120978-appb-000384
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(153毫克,0.31毫摩尔)，(2-甲基苯并[d]噁唑-5-基)甲醇(50毫克,0.31毫摩尔)，碳酸铯(150毫克,0.46毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(26毫克,0.03毫摩尔)加入反应瓶中,加入1,4-二氧六环(2毫升)，鼓入氮气1min后,在氮气保护下反应液在100摄氏度下搅拌16小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (153 mg, 0.31 mmol), (2-methylbenzo[d]oxazol-5-yl)methanol (50 mg, 0.31 mmol), Cesium carbonate (150 mg, 0.46 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2' -Amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.03 mmol) was added to the reaction flask, 1,4-dioxane (2 mL) was added, and nitrogen was bubbled for 1 min After that, the reaction solution was stirred at 100 °C for 16 h under nitrogen protection.
TLC检测反应完全后，将反应液直接拉干后用硅胶柱层析纯化(洗脱剂：二氯/甲醇＝10/1)得到90毫克浅黄色的焦状粗品产物(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：47.1％)。LC-MS：RT＝1.82，[M+H] +＝624.33。 After the completion of the reaction was detected by TLC, the reaction solution was directly dried and purified by silica gel column chromatography (eluent: dichloro/methanol=10/1) to obtain 90 mg of pale yellow coke-like crude product (S)-2-( (4-(6-((2-Methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxa Cyclobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 47.1%). LC-MS: RT=1.82, [M+H] + =624.33 .
步骤B：合成(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((2-methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000385
Figure PCTCN2021120978-appb-000385
将(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克,0.13毫摩尔)溶于二氯甲烷(2毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌3小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((2-methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL ), then trifluoroacetic acid (0.4 mL) was added to the reaction solution, and after stirring at room temperature for 3 hours, LC-MS was monitored until the reaction was complete.
将反应液用饱和碳酸氢钠溶液调至pH 8-9，直接拉干后用碱性反相制备分离纯化。得到34.81毫克白色固体(S)-2-((4-(6-((2-甲基苯并[d]噁唑-5-基)甲氧基]吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：46.4％)。LC-MS：RT＝1.72min，[M+H] +＝568.35。 1H NMR(500MHz,DMSO)δ8.04(d,J＝0.6Hz,1H),7.77(dd,J＝8.3,1.3Hz,1H),7.74(d,J＝1.1Hz,1H),7.62(dd,J＝12.1,5.2Hz,2H),7.44(dd,J＝8.4,1.6Hz,1H),7.41–7.38(m,1H),6.86(d,J＝7.2Hz,1H),6.66(d,J＝7.9Hz,1H),5.44(s,2H),5.11(qd,J＝7.0,3.3Hz,1H),4.71(dd,J＝15.2,6.9Hz,1H),4.60(dd,J＝15.2,3.2Hz,1H),4.45(td,J＝8.2,5.8Hz,1H),4.36(dt,J＝9.0,5.9Hz,1H),3.90(d,J＝13.4Hz,1H),3.75(d,J＝13.3Hz,1H),2.99(d,J＝11.1Hz,1H),2.88(d,J＝11.5Hz,1H),2.69(ddd,J＝8.7,8.1,5.5Hz,1H),2.66–2.60(m,1H),2.59(s,3H),2.48–2.41(m,1H),2.26–2.11(m,2H),1.85–1.66(m,4H)。 The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate solution, directly pulled to dryness, and separated and purified by basic reverse-phase preparation. 34.81 mg of white solid (S)-2-((4-(6-((2-methylbenzo[d]oxazol-5-yl)methoxy]pyridin-2-yl)piperidin-1 was obtained -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 46.4%). LC-MS: RT=1.72 min, [M+H] + =568.35. 1 H NMR (500MHz, DMSO) δ 8.04(d, J=0.6Hz, 1H), 7.77(dd, J=8.3, 1.3Hz, 1H), 7.74(d , J＝1.1Hz, 1H), 7.62(dd, J＝12.1, 5.2Hz, 2H), 7.44(dd, J＝8.4, 1.6Hz, 1H), 7.41–7.38(m, 1H), 6.86(d, J=7.2Hz, 1H), 6.66 (d, J=7.9Hz, 1H), 5.44 (s, 2H), 5.11 (qd, J=7.0, 3.3Hz, 1H), 4.71 (dd, J=15.2, 6.9 Hz, 1H), 4.60(dd, J＝15.2, 3.2Hz, 1H), 4.45(td, J＝8.2, 5.8Hz, 1H), 4.36(dt, J＝9.0, 5.9Hz, 1H), 3.90(d ,J=13.4Hz,1H),3.75(d,J=13.3Hz,1H),2.99(d,J=11.1Hz,1H),2.88(d,J=11.5Hz,1H),2.69(ddd,J = 8.7, 8.1, 5.5Hz, 1H), 2.66–2.60 (m, 1H), 2.59 (s, 3H), 2.48–2.41 (m, 1H), 2.26–2.11 (m, 2H), 1.85–1.66 (m , 4H).
实施例74Example 74
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000386
Figure PCTCN2021120978-appb-000386
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成吡唑并[1,5-a]吡啶-4-羧酸甲酯Step A: Synthesis of methyl pyrazolo[1,5-a]pyridine-4-carboxylate
Figure PCTCN2021120978-appb-000387
Figure PCTCN2021120978-appb-000387
将吡唑并[1,5-a]吡啶-4-羧酸(120毫克，740微摩尔)溶于二氯甲烷(10毫升)的溶液中。随后，在0摄氏度条件下向上述溶液中加入草酰氯(140毫克.1.1毫摩尔)，N,N-二甲基甲酰胺(0.05毫升)，在室温条件下搅拌1小时。然后，向反应液加入甲醇(5毫升)并搅拌1小时。Pyrazolo[1,5-a]pyridine-4-carboxylic acid (120 mg, 740 μmol) was dissolved in a solution of dichloromethane (10 mL). Subsequently, oxalyl chloride (140 mg. 1.1 mmol) and N,N-dimethylformamide (0.05 mL) were added to the above solution at 0 degrees Celsius, and the mixture was stirred at room temperature for 1 hour. Then, methanol (5 mL) was added to the reaction solution, followed by stirring for 1 hour.
将反应液减压浓缩得到130毫克灰色油状物吡唑并[1,5-a]吡啶-4-羧酸甲酯(收率：100％)。The reaction solution was concentrated under reduced pressure to obtain 130 mg of methyl pyrazolo[1,5-a]pyridine-4-carboxylate as a gray oil (yield: 100%).
步骤B：合成吡唑并[1,5-a]吡啶-4-基甲醇Step B: Synthesis of Pyrazolo[1,5-a]pyridin-4-ylmethanol
Figure PCTCN2021120978-appb-000388
Figure PCTCN2021120978-appb-000388
将吡唑并[1,5-a]吡啶-4-羧酸甲酯(130毫克，740微摩尔)溶于四氢呋喃(10毫升)的溶液中。随后，在零摄氏度条件下向上述溶液中加入四氢铝锂(65毫克，1.7毫摩尔)，在室温条件下搅拌1小时。Methyl pyrazolo[1,5-a]pyridine-4-carboxylate (130 mg, 740 μmol) was dissolved in a solution of tetrahydrofuran (10 mL). Subsequently, lithium tetrahydroaluminum (65 mg, 1.7 mmol) was added to the above solution at zero degrees Celsius, followed by stirring at room temperature for 1 hour.
将反应液中加入1毫升乙酸乙酯，搅拌10分钟后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到60毫克白色固体吡唑并[1,5-a]吡啶-4-基甲醇(收率：54.7％)。1 ml of ethyl acetate was added to the reaction solution, and the mixture was stirred for 10 minutes and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 60 mg of white solid pyrazolo[1,5-a]pyridin-4-ylmethanol (yield: 54.7%).
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000389
Figure PCTCN2021120978-appb-000389
将吡唑并[1,5-a]吡啶-4-基甲醇(60毫克，405微摩尔)溶于1,4-二氧六环(10毫升)的溶液中，随后向上述溶液中加入(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(301毫克，608微摩尔)，甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(67毫克，40微摩尔)，碳酸铯(264毫克，810微摩尔)，在100摄氏度条件下搅拌8小时。To the above solution was added ( S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Imidazole-6-carboxylate tert-butyl ester (301 mg, 608 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (67 mg, 40 micromoles), cesium carbonate (264 mg, 810 micromoles), in Stir at 100 degrees Celsius for 8 hours.
将反应液缓慢滴加到饱和氯化钠溶液(30毫升)中。混合液用乙酸乙酯(20毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×升次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到100毫克白色油状(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：41.1％)。LC-MS：RT＝1.77min，[M+H] +＝609.30。 The reaction solution was slowly added dropwise to saturated sodium chloride solution (30 mL). The mixture was extracted with ethyl acetate (20 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 mL×liter), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 100 mg of (S)-1-(oxetan-2-ylmethyl)-2 as a white oil -((4-(6-(Pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[ d] tert-butyl imidazole-6-carboxylate (yield: 41.1%). LC-MS: RT=1.77 min, [M+H] + =609.30.
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000390
Figure PCTCN2021120978-appb-000390
将S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克，164微摩尔)溶于二氯甲烷(4毫升)的溶液中。随后，向上述溶液中加入三氟乙酸(0.6毫升)，在室温下搅拌2个小时。S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 164 μmol) in dichloromethane (4 mL) middle. Subsequently, trifluoroacetic acid (0.6 ml) was added to the above solution, followed by stirring at room temperature for 2 hours.
将反应液pH值用碳酸氢钠溶液调至7并减压浓缩。所得残余物用制备HPLC纯化得到40毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：44.0％)。LC-MS：RT＝1.70min，[M+H] +＝553.30。 1H NMR(400MHz,DMSO)δ8.63(d,J＝7.0Hz,1H),8.06–7.97(m,2H),7.76(dd,J＝8.3,1.3Hz,1H),7.67–7.58(m,1H),7.39(d,J＝8.3Hz,1H),7.27(d,J＝6.9Hz,1H),6.86(t,J＝7.1Hz,2H),6.71–6.63(m,2H),5.58(d,J＝13.2Hz,2H),5.09(dt,J＝10.3,7.0Hz,1H),4.68(dd,J＝15.1,6.8Hz,1H),4.57(dd,J＝15.1,3.3Hz,1H),4.44(dd,J＝13.6,7.8Hz,1H),4.35(dt,J＝8.9,5.9Hz,1H),3.88(d,J＝13.3Hz,1H),3.73(d,J＝13.3Hz,1H),2.96(d,J＝11.3Hz,1H),2.85(d,J＝11.2Hz,1H),2.74–2.54(m,2H),2.42(dd,J＝19.1,8.0Hz,1H),2.26–2.01(m,3H),1.88–1.60(m,4H)。 The pH of the reaction solution was adjusted to 7 with sodium bicarbonate solution and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 40 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a) ]pyridin-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 44.0%). LC-MS: RT=1.70 min, [M+H] + =553.30. 1 H NMR (400MHz, DMSO) δ 8.63 (d, J=7.0Hz, 1H), 8.06-7.97 (m, 2H), 7.76 (dd, J=8.3, 1.3Hz, 1H), 7.67-7.58 (m ,1H),7.39(d,J＝8.3Hz,1H),7.27(d,J＝6.9Hz,1H),6.86(t,J＝7.1Hz,2H),6.71–6.63(m,2H),5.58 (d, J=13.2Hz, 2H), 5.09 (dt, J=10.3, 7.0Hz, 1H), 4.68 (dd, J=15.1, 6.8Hz, 1H), 4.57 (dd, J=15.1, 3.3Hz, 1H),4.44(dd,J=13.6,7.8Hz,1H),4.35(dt,J=8.9,5.9Hz,1H),3.88(d,J=13.3Hz,1H),3.73(d,J=13.3 Hz, 1H), 2.96 (d, J=11.3Hz, 1H), 2.85 (d, J=11.2Hz, 1H), 2.74–2.54 (m, 2H), 2.42 (dd, J=19.1, 8.0Hz, 1H) ), 2.26–2.01 (m, 3H), 1.88–1.60 (m, 4H).
实施例75Example 75
合成(S)-2-((4-(6-((2-环丙基-5-氟噁唑并[5,4-b]吡啶基-6-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-Cyclopropyl-5-fluorooxazolo[5,4-b]pyridinyl-6-yl)methoxy)pyridinyl-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000391
Figure PCTCN2021120978-appb-000391
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(环丙烷甲酰胺基)-2-氟-5-羟基苯甲酸甲酯Step A: Synthesis of methyl 4-(cyclopropanecarboxamido)-2-fluoro-5-hydroxybenzoate
Figure PCTCN2021120978-appb-000392
Figure PCTCN2021120978-appb-000392
将4-氨基-2-氟-5-羟基苯甲酸甲酯(500毫克，2.71毫摩尔)，环丙烷酰氯(280毫克，2.71毫摩尔)，三乙胺(0.57毫升)溶于二氯甲烷(5毫升)中，室温搅拌0.5个小时。Methyl 4-amino-2-fluoro-5-hydroxybenzoate (500 mg, 2.71 mmol), cyclopropane chloride (280 mg, 2.71 mmol), triethylamine (0.57 mL) were dissolved in dichloromethane ( 5 mL) and stirred at room temperature for 0.5 hours.
反应结束后，用水淬灭反应，乙酸乙酯(30毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到500毫克黄色固体4-(环丙烷甲酰胺基)-2-氟-5-羟基苯甲酸甲酯(收率：73％)。LC-MS:RT＝1.94min,[M+H] +＝254.33。 After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/ 3) 500 mg of methyl 4-(cyclopropanecarboxamido)-2-fluoro-5-hydroxybenzoate was obtained as a yellow solid (yield: 73%). LC-MS: RT=1.94 min, [M+H] + =254.33.
步骤B：合成2-环丙基-5-氟苯并[d]噁唑-6-羧酸甲酯Step B: Synthesis of methyl 2-cyclopropyl-5-fluorobenzo[d]oxazole-6-carboxylate
Figure PCTCN2021120978-appb-000393
Figure PCTCN2021120978-appb-000393
将4-(环丙烷甲酰胺基)-2-氟-5-羟基苯甲酸甲酯(200毫克，0.80毫摩尔)，4-甲基苯磺酸(27毫克，0.16毫摩尔)溶于甲苯(2毫升)中，温度升高到80摄氏度搅拌4个小时。Methyl 4-(cyclopropanecarboxamido)-2-fluoro-5-hydroxybenzoate (200 mg, 0.80 mmol), 4-methylbenzenesulfonic acid (27 mg, 0.16 mmol) were dissolved in toluene ( 2 ml), the temperature was raised to 80 degrees Celsius and stirred for 4 hours.
反应结束后，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到80毫克黄色固体(2-环丙基-5-氟苯并[d]噁唑-6-基)甲酸甲酯(收率：43％)。LC-MS:RT＝2.12min,[M+H] +＝236.29。 After the reaction was completed, the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 80 mg of yellow solid (2-cyclopropyl-5-fluorobenzo[d]oxane). oxazol-6-yl)carboxylate (yield: 43%). LC-MS: RT=2.12 min, [M+H] + =236.29.
步骤C：合成(2-环丙基-5-氟苯并[d]噁唑-6-基)甲醇Step C: Synthesis of (2-cyclopropyl-5-fluorobenzo[d]oxazol-6-yl)methanol
Figure PCTCN2021120978-appb-000394
Figure PCTCN2021120978-appb-000394
室温下，将(2-环丙基-5-氟苯并[d]噁唑-6-基)甲酸甲酯(80毫克，0.34毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(20毫克，0.51毫摩尔)，在室温下搅拌0.5小时。Methyl (2-cyclopropyl-5-fluorobenzo[d]oxazol-6-yl)carboxylate (80 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature in an ice bath After cooling to zero degrees Celsius, lithium tetrahydroaluminum (20 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到60毫克白色固体(2-环丙基-5-氟苯并[d]噁唑-6-基)甲醇(收率：75％)。After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 60 mg of white solid (2-cyclopropyl- 5-Fluorobenzo[d]oxazol-6-yl)methanol (yield: 75%).
步骤D：合成(S)-2-((4-(6-((2-环丙基-5-氟噁唑并[5,4-b]吡啶基-6-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((2-cyclopropyl-5-fluorooxazolo[5,4-b]pyridinyl-6-yl)methoxy)pyridine yl-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000395
Figure PCTCN2021120978-appb-000395
将(2-环丙基-5-氟苯并[d]噁唑-6-基)甲醇(60毫克，0.28毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(208毫克，0.42毫摩尔)，钯催化剂(39毫克)，碳酸铯(182毫克，0.56毫摩尔)溶于二氧六环(10毫升)中，温度升高到100摄氏度搅拌过夜。(2-Cyclopropyl-5-fluorobenzo[d]oxazol-6-yl)methanol (60 mg, 0.28 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (208 mg, 0.42 mmol), palladium catalyst (39 mg), cesium carbonate (182 mg, 0.56 mmol) were dissolved in dioxane (10 mL), the temperature was raised to 100°C and stirred overnight.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到150毫克黄色固体(S)-2-((4-(6-((2-环丙基-6-氟噁唑并[5,4-b]吡啶基-5-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：83％)。LC-MS:RT＝1.87min,[M+H] +＝668.27。 After the reaction was completed, suction filtration with celite, washed with dichloromethane, and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 150 mg of yellow solid ( S)-2-((4-(6-((2-Cyclopropyl-6-fluorooxazolo[5,4-b]pyridinyl-5-yl)methoxy)pyridinyl-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 83%) . LC-MS: RT=1.87 min, [M+H] + =668.27.
步骤H：合成(S)-2-((4-(6-((2-环丙基-5-氟噁唑并[5,4-b]吡啶基-6-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step H: Synthesis of (S)-2-((4-(6-((2-cyclopropyl-5-fluorooxazolo[5,4-b]pyridinyl-6-yl)methoxy)pyridine yl-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000396
Figure PCTCN2021120978-appb-000396
将(S)-2-((4-(6-((2-环丙基-5-氟噁唑并[5,4-b]吡啶基-6-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150毫克，0.22毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应一个小时。(S)-2-((4-(6-((2-Cyclopropyl-5-fluorooxazolo[5,4-b]pyridinyl-6-yl)methoxy)pyridinyl-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (150 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for one hour.
反应结束后，浓缩，所得粗品高效液相纯化得到52.8毫克白色固体(S)-2-((4-(6-((2-环丙基-5-氟噁唑并[5,4-b]吡啶基-6-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：39％)。LC-MS:RT＝1.77min,[M+H] +＝612.35。 1H NMR(500MHz,DMSO)δ8.06(d,J＝0.6Hz,1H),7.83–7.76(m,2H),7.63(dd,J＝8.1,7.4Hz,1H),7.52(d,J＝9.8Hz,1H),7.44–7.37(m,1H),6.88(d,J＝7.2Hz,1H),6.68(d,J＝7.7Hz,1H),5.45(s,2H),5.16–5.07(m,1H),4.73(dd,J＝15.2,6.9Hz,1H),4.62(dd,J＝15.1,3.2Hz,1H),4.51–4.45(m,1H),4.38(dt,J＝9.1,5.9Hz,1H),3.91(d,J＝13.3Hz,1H),3.76(d,J＝13.3Hz,1H),3.00(d,J＝11.4Hz,1H),2.89(d,J＝11.4Hz,1H),2.75–2.67(m,1H),2.65–2.58(m,1H),2.46(dt,J＝11.2,6.0Hz,1H),2.23(tt,J＝8.2,4.9Hz,2H),2.16(dd,J＝11.7,8.8Hz,1H),1.76(dd,J＝15.7,5.4Hz,4H),1.22–1.16(m,2H),1.12(qd,J＝4.9,2.8Hz,2H)。 After the reaction was completed, it was concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 52.8 mg of white solid (S)-2-((4-(6-((2-cyclopropyl-5-fluorooxazolo[5,4-b) ]pyridinyl-6-yl)methoxy)pyridinyl-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Imidazole-6-carboxylic acid (yield: 39%). LC-MS: RT=1.77 min, [M+H] + =612.35. 1 H NMR (500MHz, DMSO)δ8.06(d,J=0.6Hz,1H),7.83-7.76(m,2H),7.63(dd,J=8.1,7.4Hz,1H),7.52(d,J = 9.8Hz, 1H), 7.44–7.37 (m, 1H), 6.88 (d, J=7.2Hz, 1H), 6.68 (d, J=7.7Hz, 1H), 5.45 (s, 2H), 5.16–5.07 (m, 1H), 4.73 (dd, J=15.2, 6.9Hz, 1H), 4.62 (dd, J=15.1, 3.2Hz, 1H), 4.51–4.45 (m, 1H), 4.38 (dt, J=9.1 ,5.9Hz,1H),3.91(d,J＝13.3Hz,1H),3.76(d,J＝13.3Hz,1H),3.00(d,J＝11.4Hz,1H),2.89(d,J＝11.4 Hz, 1H), 2.75–2.67 (m, 1H), 2.65–2.58 (m, 1H), 2.46 (dt, J=11.2, 6.0Hz, 1H), 2.23 (tt, J=8.2, 4.9Hz, 2H) ,2.16(dd,J＝11.7,8.8Hz,1H),1.76(dd,J＝15.7,5.4Hz,4H),1.22–1.16(m,2H),1.12(qd,J＝4.9,2.8Hz,2H) ).
实施例76Example 76
合成(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000397
Figure PCTCN2021120978-appb-000397
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成7-氟喹啉-6-羧酸乙酯Step A: Synthesis of ethyl 7-fluoroquinoline-6-carboxylate
Figure PCTCN2021120978-appb-000398
Figure PCTCN2021120978-appb-000398
室温下，将4-氨基-2-氟-苯甲酸(1.0克，6.38毫摩尔)、丙三醇(2.1毫升，28.7毫摩尔)、间硝基苯磺酸钠(2.93克，12.8毫摩尔)加入到15毫升75％的硫酸溶液中，100摄氏度反应2小时。随后降温至60摄氏度，加入5毫升乙醇，60摄氏度反应48小时。At room temperature, combine 4-amino-2-fluoro-benzoic acid (1.0 g, 6.38 mmol), glycerol (2.1 mL, 28.7 mmol), sodium m-nitrobenzenesulfonate (2.93 g, 12.8 mmol) It was added to 15 ml of 75% sulfuric acid solution and reacted at 100 degrees Celsius for 2 hours. Subsequently, the temperature was lowered to 60 degrees Celsius, 5 ml of ethanol was added, and the reaction was carried out at 60 degrees Celsius for 48 hours.
反应结束后，反应液倒入冰水中，加入饱和的羟胺水溶液调节pH至中性。加入50毫升乙酸乙酯，萃取3次，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(正己烷/乙酸乙酯＝2/1)，得240毫克白色固体7-氟喹啉-6-羧酸乙酯(收率：17.2％)。LC-MS：RT＝1.86min，[M+H] +＝220.18. After the reaction, the reaction solution was poured into ice water, and a saturated aqueous hydroxylamine solution was added to adjust the pH to neutrality. 50 ml of ethyl acetate was added, extracted three times, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purification by column chromatography (n-hexane/ethyl acetate=2/1) gave 240 mg of ethyl 7-fluoroquinoline-6-carboxylate as a white solid (yield: 17.2%). LC-MS: RT=1.86min, [M+H] + =220.18.
步骤B：合成(7-氟喹啉-6基)甲醇Step B: Synthesis of (7-fluoroquinolin-6yl)methanol
Figure PCTCN2021120978-appb-000399
Figure PCTCN2021120978-appb-000399
冰浴下，将7-氟喹啉-6-羧酸乙酯(200毫克，0.91毫摩尔)溶于无水四氢呋喃溶液中，分批加入四氢锂铝(173.5毫克，4.57毫摩尔)，零摄氏度反应2小时。Under ice bath, ethyl 7-fluoroquinoline-6-carboxylate (200 mg, 0.91 mmol) was dissolved in anhydrous tetrahydrofuran solution, and lithium aluminum tetrahydrohydride (173.5 mg, 4.57 mmol) was added in portions, zero Celsius for 2 hours.
反应结束后，反应液加入5％的氢氧化钠溶液淬灭反应，随后硅藻土抽滤。滤液加入30毫升乙酸乙 酯，萃取3次，分出乙酸乙酯层，无水硫酸钠干燥，蒸干有机层得145毫克淡黄色固体(7-氟喹啉-6基)甲醇(收率：90.0％)。LC-MS：RT＝1.36min，[M+H] +＝178.14。 After the reaction, 5% sodium hydroxide solution was added to the reaction solution to quench the reaction, and then celite was suction filtered. The filtrate was added with 30 ml of ethyl acetate, extracted three times, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and the organic layer was evaporated to dryness to obtain 145 mg of pale yellow solid (7-fluoroquinolin-6yl)methanol (yield: 90.0%). LC-MS: RT=1.36 min, [M+H] + =178.14.
步骤C：合成(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000400
Figure PCTCN2021120978-appb-000400
室温下，将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克，0.20毫摩尔)、(7-氟喹啉-6基)甲醇(47毫克，0.26毫摩尔)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(50.7毫克，0.06毫摩尔)和碳酸铯(130.4毫克，0.4毫摩尔)加入到10毫升干燥的二氧六环溶液中，N 2保护下100摄氏度反应2小时。 At room temperature, (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.20 mmol), (7-fluoroquinolin-6yl)methanol (47 mg, 0.26 mmol), methanesulfonic acid (2 -Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (50.7 mg, 0.06 mmol) and cesium carbonate (130.4 mg, 0.4 mmol) were added to 10 mL of dry dioxane solution and reacted at 100 °C for 2 h under N2 protection.
反应结束后，加入20毫升乙酸乙酯，萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得73毫克白色固体(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：53.7％)。LC-MS：RT＝1.82min，[M+H] +＝638.42。 After the reaction, 20 ml of ethyl acetate was added, extracted, and the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to give 73 mg of white solid (S)-2-((4-(6-((7-fluoroquinolin-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (received rate: 53.7%). LC-MS: RT=1.82 min, [M+H] + =638.42.
步骤D:合成(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000401
Figure PCTCN2021120978-appb-000401
室温下，(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.094毫摩尔)溶于6毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。(S)-2-((4-(6-((7-Fluoroquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 at room temperature -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.094 mmol) was dissolved in 6 mL dichloromethane solution, ice bath 0.5 ml of trifluoroacetic acid was added dropwise. The reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得30毫克白色固体(S)-2-((4-(6-((7-氟喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：54.9％)。LC-MS：RT＝1.70min，[M+H] +＝582.30。 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.2Hz,1H),8.35(d,J＝7.6Hz,1H),8.25(s,1H),8.18(d,J＝8.2Hz,1H),7.86–7.73(m,2H),7.64(t,J＝7.9Hz,2H),7.45(dd,J＝8.3,4.3Hz,1H),6.87(d,J＝7.2Hz,1H),6.72(d,J＝8.2Hz,1H),5.58(s,2H),5.10(d,J＝7.0Hz,1H),4.82–4.73(m,1H),4.66(d,J＝13.1Hz,1H),4.50–4.40(m,1H),4.38–4.29(m,1H),3.94(d,J＝13.5Hz,2H),3.77(d,J＝13.4Hz,2H),2.99(d,J＝11.5Hz,1H),2.83(s,1H),2.72–2.59(m,2H),2.22(d,J＝16.8Hz,2H),1.76(d,J＝18.1Hz,3H)。 After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 30 mg of white solid (S)-2-((4-(6-((7-fluoroquinolin-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 54.9 %). LC-MS: RT=1.70 min, [M+H] + =582.30. 1 H NMR(400MHz, DMSO)δ8.88(d,J=4.2Hz,1H),8.35(d,J=7.6Hz,1H),8.25(s,1H),8.18(d,J=8.2Hz, 1H), 7.86–7.73 (m, 2H), 7.64 (t, J=7.9Hz, 2H), 7.45 (dd, J=8.3, 4.3Hz, 1H), 6.87 (d, J=7.2Hz, 1H), 6.72(d,J＝8.2Hz,1H),5.58(s,2H),5.10(d,J＝7.0Hz,1H),4.82–4.73(m,1H),4.66(d,J＝13.1Hz,1H) ), 4.50–4.40 (m, 1H), 4.38–4.29 (m, 1H), 3.94 (d, J=13.5Hz, 2H), 3.77 (d, J=13.4Hz, 2H), 2.99 (d, J= 11.5Hz, 1H), 2.83 (s, 1H), 2.72–2.59 (m, 2H), 2.22 (d, J=16.8Hz, 2H), 1.76 (d, J=18.1Hz, 3H).
实施例77Example 77
合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000402
Figure PCTCN2021120978-appb-000402
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成咪唑并[1,5-a]吡啶-7-基甲醇Step A: Synthesis of Imidazo[1,5-a]pyridin-7-ylmethanol
Figure PCTCN2021120978-appb-000403
Figure PCTCN2021120978-appb-000403
零摄氏度下，向含有咪唑并[1,5-a]吡啶-7-羧酸(300毫克，1.85毫摩尔)的四氢呋喃(5毫升)中，滴加硼烷四氢呋喃溶液(3.7毫升，1.0摩尔每升)，N 2保护下，于50摄氏度下搅拌反应1小时。 To a solution of imidazo[1,5-a]pyridine-7-carboxylic acid (300 mg, 1.85 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of borane in tetrahydrofuran (3.7 mL, 1.0 mol per 1), the reaction was stirred at 50 °C for 1 h under N2 protection.
反应结束，向反应液中缓慢滴入0.5毫升冰水搅拌至无气泡产生，旋干柱层析(二氯甲烷:甲醇＝0-15％)纯化得到75毫克白色固体咪唑并[1,5-a]吡啶-7-基甲醇。LC-MS:RT＝0.52min,[M+H] +＝149.17。 After the reaction was completed, 0.5 ml of ice water was slowly added dropwise to the reaction solution and stirred until no bubbles were generated, and then purified by spin column chromatography (dichloromethane:methanol=0-15%) to obtain 75 mg of white solid imidazo[1,5- a] Pyridin-7-ylmethanol. LC-MS: RT=0.52 min, [M+H] + =149.17.
步骤B：合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000404
Figure PCTCN2021120978-appb-000404
将咪唑并[1,5-a]吡啶-7-基甲醇(75毫克,0.506毫摩尔)和(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(251毫克,0.506毫摩尔)溶解于8毫升无水二氧六环中，加入碳酸铯(364毫克,1.12毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(43毫克，0.0506毫摩尔)，氮气置换3次，于100摄氏度下反应7小时。反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱(二氯甲烷:甲醇＝0-10％)分离得102毫克淡黄色固体(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯。LC-MS:RT＝1.71min,[M+H] +＝609.37。 Imidazo[1,5-a]pyridin-7-ylmethanol (75 mg, 0.506 mmol) and (S)-2-(((4-(6-chloropyridin-2-yl)piperidine-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (251 mg, 0.506 mmol) was dissolved in 8 mL In anhydrous dioxane, add cesium carbonate (364 mg, 1.12 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43 mg, 0.0506 mmol), replaced with nitrogen three times, and reacted at 100 degrees Celsius for 7 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), and then dried with anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was separated by column (dichloromethane:methanol=0-10%) to obtain 102 mg of pale yellow solid (S)-2-((4-(6-(imidazo[1,5-a]pyridine) -7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 - tert-butyl carboxylate. LC-MS: RT=1.71 min, [M+H] + =609.37.
步骤C：合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000405
Figure PCTCN2021120978-appb-000405
将(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(102毫克,0.167毫摩尔)溶解于4毫升无水二氯甲烷中，加入2毫升三氟乙酸于室温下反应1.5小时。反应结束，反应液减压浓缩所得粗品经柱层析(二氯甲烷:甲醇＝0-15％)分离得80毫克白色固体((S)-2-((4-(6-(咪唑并[1,5-a]吡啶-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸。LC-MS:RT＝1.52min,[M-H] -＝553.31。 1H NMR(400MHz,DMSO)δ12.90(s,1H),8.80(s,1H),8.36(s,1H),8.05(s,1H),7.89(d,J＝8.5Hz,1H),7.77(d,J＝9.0Hz,1H),7.65–7.70(m,3H),7.49(d,J＝9.8Hz,1H),6.93(d,J＝7.2Hz,1H),6.74(d,J＝8.2Hz,1H),5.41(s,2H),5.04–5.11(m,2H),4.77–4.87(m,2H),4.66–4.71(m,2H),4.47–4.51(m,2H),4.30–4.40(m,2H),2.66–2.75(m,2H),2.32–2.42(m,2H),1.96–2.07(m,4H)。 (S)-2-((4-(6-(imidazo[1,5-a]pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (102 mg, 0.167 mmol) was dissolved in 4 mL of dry dichloromethane, 2 ml of trifluoroacetic acid was added to react at room temperature for 1.5 hours. After the reaction was completed, the crude product obtained by concentrating the reaction solution under reduced pressure was separated by column chromatography (dichloromethane: methanol=0-15%) to obtain 80 mg of white solid ((S)-2-((4-(6-(imidazo[ 1,5-a]Pyridin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene and [d]imidazole-6-carboxylic acid. LC-MS: RT=1.52 min, [MH] − =553.31. 1 H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 8.80 (s, 1H) ,8.36(s,1H),8.05(s,1H),7.89(d,J＝8.5Hz,1H),7.77(d,J＝9.0Hz,1H),7.65–7.70(m,3H),7.49( d,J＝9.8Hz,1H),6.93(d,J＝7.2Hz,1H),6.74(d,J＝8.2Hz,1H),5.41(s,2H),5.04–5.11(m,2H), 4.77–4.87 (m, 2H), 4.66–4.71 (m, 2H), 4.47–4.51 (m, 2H), 4.30–4.40 (m, 2H), 2.66–2.75 (m, 2H), 2.32–2.42 (m , 2H), 1.96–2.07 (m, 4H).
实施例78Example 78
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000406
Figure PCTCN2021120978-appb-000406
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-7-羧酸甲酯Step A: Synthesis of methyl isoquinoline-7-carboxylate
Figure PCTCN2021120978-appb-000407
Figure PCTCN2021120978-appb-000407
将异喹啉-7-羧酸(150毫克，0.87毫摩尔)溶于二氯甲烷(15毫升)中，滴入两滴N,N-二甲基甲酰胺，然后边搅拌边滴加草酰氯(550毫克，8.66毫摩尔)，在室温下反应0.5小时。Dissolve isoquinoline-7-carboxylic acid (150 mg, 0.87 mmol) in dichloromethane (15 mL), add dropwise two drops of N,N-dimethylformamide, then add oxalyl chloride dropwise with stirring (550 mg, 8.66 mmol) at room temperature for 0.5 h.
再将甲醇(5毫升)滴入反应中，搅拌十分钟，再加入氢氧化钠溶液中和至中性，用二氯甲烷(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到102毫克白色固体异喹啉-7-羧酸甲酯(收率：63％)。Methanol (5 mL) was then added dropwise to the reaction, stirred for ten minutes, then neutralized to neutrality by adding sodium hydroxide solution, extracted with dichloromethane (20 mL×L), combined and dried organic phases, and the obtained crude product was concentrated. Purification by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) gave 102 mg of methyl isoquinoline-7-carboxylate as a white solid (yield: 63%).
步骤B：合成异喹啉-7基甲醇Step B: Synthesis of isoquinolin-7ylmethanol
Figure PCTCN2021120978-appb-000408
Figure PCTCN2021120978-appb-000408
室温下，将异喹啉-7-羧酸甲酯(102毫克，0.55毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(22毫克，0.55毫摩尔)，在室温下搅拌0.5小时。Methyl isoquinoline-7-carboxylate (102 mg, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, cooled to 0°C in an ice bath, and lithium tetrahydroaluminum (22 mg, 0.55 mmol) and stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到62毫克白色固体异喹啉-7基甲醇(收率：71％)。After the reaction, saturated sodium chloride was added to quench the reaction, and ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried with anhydrous sodium sulfate, filtered and concentrated to obtain 62 mg of white solid isoquinolin-7ylmethanol (Yield: 71%).
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000409
Figure PCTCN2021120978-appb-000409
将异喹啉-7基甲醇(62毫克，0.39毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(193毫克，0.39毫摩尔)，钯催化剂(50毫克)，碳酸铯(254毫克，0.78毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌8个小时。The isoquinolin-7ylmethanol (62 mg, 0.39 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylate tert-butyl ester (193 mg, 0.39 mmol), palladium catalyst (50 mg), cesium carbonate (254 mg, 0.78 mmol) were dissolved in dioxane and the temperature was raised to 100°C Stir for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到60毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：25％)。After the reaction was completed, suction filtration with celite, washed with dichloromethane, and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 60 mg of white solid ( S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl)piperidine-1- (yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 25%).
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000410
Figure PCTCN2021120978-appb-000410
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.10毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1 小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-7-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid ( 1 mL), and reacted for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到49.94毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：88％)。LC-MS:RT＝1.61min,[M+H] +＝564.33。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 49.94 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinoline- 7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 88%). LC-MS: RT=1.61 min, [M+H] + =564.33.
实施例79Example 79
合成(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000411
Figure PCTCN2021120978-appb-000411
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-氯喹啉-8-羧酸甲酯Step A: Synthesis of methyl 6-chloroquinoline-8-carboxylate
Figure PCTCN2021120978-appb-000412
Figure PCTCN2021120978-appb-000412
将6-氯喹啉-8-羧酸(200.0毫克,0.96毫摩尔)溶于甲醇(10.0毫升)中,加入N,N-二甲基甲酰胺(30.0毫克，0.41毫摩尔)，将体系降温至0体，加入氯化亚砜(573.0毫克,4.82毫摩尔)，升温至65摄氏度，搅拌反应5小时。旋干溶剂，加入乙酸乙酯(50毫升)稀释，饱和碳酸氢钠水溶液洗涤，旋干溶剂，柱层析分离(乙酸乙酯：正己烷＝4：6)，得80.0毫克米黄色固6-氯喹啉-8-羧酸甲酯(收率：37.5％)。LC-MS：RT＝1.79min,[M+H] +＝222.11。 6-Chloroquinoline-8-carboxylic acid (200.0 mg, 0.96 mmol) was dissolved in methanol (10.0 mL), N,N-dimethylformamide (30.0 mg, 0.41 mmol) was added, and the system was cooled to 0 body, thionyl chloride (573.0 mg, 4.82 mmol) was added, the temperature was raised to 65 degrees Celsius, and the reaction was stirred for 5 hours. The solvent was spin-dried, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution, the solvent was spin-dried, and separated by column chromatography (ethyl acetate:n-hexane=4:6) to obtain 80.0 mg of beige solid 6- Methyl chloroquinoline-8-carboxylate (yield: 37.5%). LC-MS: RT=1.79 min, [M+H] + =222.11.
步骤B：合成(6-氯喹啉-8-基)甲醇Step B: Synthesis of (6-chloroquinolin-8-yl)methanol
Figure PCTCN2021120978-appb-000413
Figure PCTCN2021120978-appb-000413
将6-氯喹啉-8-羧酸甲酯(70.0毫克,0.32毫摩尔)溶于四氢呋喃(3.0毫升)中,将体系降温至0系，加入氢化铝锂(18.0毫克，0.47毫摩尔)，升温至室温搅拌反应1小时，加入十水硫酸钠淬灭反应，过滤，旋干滤液,柱层析分离(乙酸乙酯：正己烷＝4：1)得48.0毫克米黄色固体(6-氯喹啉-8-基)甲醇(收率：78.5％)。LC-MS：RT＝1.73min,[M+H] +＝194.10。 Methyl 6-chloroquinoline-8-carboxylate (70.0 mg, 0.32 mmol) was dissolved in tetrahydrofuran (3.0 mL), the system was cooled to 0 series, lithium aluminum hydride (18.0 mg, 0.47 mmol) was added, and the temperature was increased. The reaction was stirred at room temperature for 1 hour, sodium sulfate decahydrate was added to quench the reaction, filtered, the filtrate was spin-dried, and separated by column chromatography (ethyl acetate:n-hexane=4:1) to obtain 48.0 mg of beige solid (6-chloroquinoline- 8-yl)methanol (yield: 78.5%). LC-MS: RT=1.73 min, [M+H] + =194.10.
步骤C：合成(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000414
Figure PCTCN2021120978-appb-000414
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(123.2毫克,0.25毫摩尔)溶于1,4-二氧六环(5.0毫升)中,加入(6-氯喹啉-8-基)甲醇(48.0毫克,0.25毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(21.2毫克,0.03毫摩尔)，旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝4/1)得到30.0毫克米黄色固体(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：18.5％)。LC-MS：RT＝1.95min,[M+H] +＝654.33。 (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (123.2 mg, 0.25 mmol) was dissolved in 1,4-dioxane (5.0 mL) and (6-chloroquinolin-8-yl)methanol was added (48.0 mg, 0.25 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (21.2 mg, 0.03 mmol), the solvent was spin-dried, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane =4/1) to give 30.0 mg of beige solid (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidine-1- (Yield: 18.5%). LC-MS: RT =1.95min, [M+H] + =654.33.
步骤D：合成(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000415
Figure PCTCN2021120978-appb-000415
将(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(30.0毫克,0.05毫摩尔)溶于二氯甲烷(2.4毫升)中,加入三氟乙酸(0.8毫升)，室温条件下，搅拌反应4小时。旋干溶剂，送制备液相分离，得16.0毫克白色固体(S)-2-((4-(6-((6-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：58.3％)。LC-MS：RT＝1.82min,[M+H] +＝598.28。 1H NMR(400MHz,DMSO-d 6)δ8.98(dd,J＝4.2,1.7Hz,1H),8.39(dd,J＝8.4,1.7Hz,1H),8.24(s,1H),8.10(d,J＝2.4Hz,1H),7.82(d,J＝2.3Hz,1H),7.79(dd,J＝8.4,1.5Hz,1H),7.69-7.59(m,3H),6.89(d,J＝7.2Hz,1H),6.79(d,J＝8.1Hz,1H),6.00(s,2H),5.11-5.05(m,1H),4.79–4.72(m,1H),4.65–4.59(m,1H),4.46–4.39(m,1H),4.46–4.39(m,1H),3.92(d,J＝13.5Hz,1H),3.75(d,J＝13.4Hz,1H),2.99–2.94(m,1H),2.84–2.79(m,1H),2.70–2.65(m,1H),2.64–2.57(m,1H),2.43–2.38(m,1H),2.26–2.19(m,1H),2.16–2.10(m,1H),1.78–1.64(m,4H)。 (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (30.0 mg, 0.05 mmol) was dissolved in dichloromethane (2.4 mL) and trifluoroacetic acid was added (0.8 mL), and the reaction was stirred at room temperature for 4 hours. The solvent was spin-dried and sent to preparative liquid phase separation to obtain 16.0 mg of white solid (S)-2-((4-(6-((6-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 58.3%). LC-MS: RT=1.82 min, [M+H] + =598.28. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (dd, J=4.2, 1.7 Hz, 1H), 8.39 (dd, J=8.4, 1.7 Hz, 1H), 8.24 (s, 1H), 8.10 ( d,J＝2.4Hz,1H),7.82(d,J＝2.3Hz,1H),7.79(dd,J＝8.4,1.5Hz,1H),7.69-7.59(m,3H),6.89(d,J =7.2Hz,1H),6.79(d,J=8.1Hz,1H),6.00(s,2H),5.11-5.05(m,1H),4.79-4.72(m,1H),4.65-4.59(m, 1H), 4.46–4.39 (m, 1H), 4.46–4.39 (m, 1H), 3.92 (d, J=13.5Hz, 1H), 3.75 (d, J=13.4Hz, 1H), 2.99–2.94 (m ,1H),2.84–2.79(m,1H),2.70–2.65(m,1H),2.64–2.57(m,1H),2.43–2.38(m,1H),2.26–2.19(m,1H),2.16 –2.10(m,1H),1.78–1.64(m,4H).
实施例80Example 80
合成(S)-2-((4-(6-((7-氟-3-甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-Fluoro-3-methylquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000416
Figure PCTCN2021120978-appb-000416
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-氨基-2-氟-5-硝基苯甲酸Step A: Synthesis of 4-amino-2-fluoro-5-nitrobenzoic acid
Figure PCTCN2021120978-appb-000417
Figure PCTCN2021120978-appb-000417
25摄氏度下，2,4-二氟-5-硝基苯甲酸(500毫克，2.47毫摩尔)溶于1,4-二氧六环(10毫升)中，再加入氢氧化铵(10毫升)，搅拌8小时。2,4-Difluoro-5-nitrobenzoic acid (500 mg, 2.47 mmol) was dissolved in 1,4-dioxane (10 mL) at 25°C, followed by ammonium hydroxide (10 mL) , and stirred for 8 hours.
反应结束后，反应液过滤，收集滤饼，40摄氏度真空干燥,所得黄色固体直接用于下一步反应，得4-氨基-2-氟-5-硝基苯甲酸380毫克(收率：77.7％)。LC-MS：RT＝1.64min,[M+H] +＝199.05。 After the reaction, the reaction solution was filtered, the filter cake was collected, and the resulting yellow solid was vacuum-dried at 40 degrees Celsius. The obtained yellow solid was directly used in the next step to obtain 380 mg of 4-amino-2-fluoro-5-nitrobenzoic acid (yield: 77.7%). ). LC-MS: RT=1.64 min, [M+H] + =199.05.
步骤B：合成4，5-二氨基-2-氟苯甲酸Step B: Synthesis of 4,5-diamino-2-fluorobenzoic acid
Figure PCTCN2021120978-appb-000418
Figure PCTCN2021120978-appb-000418
将4-氨基-2-氟-5-硝基苯甲酸(380毫克，1.91毫摩尔)溶于甲醇(10毫升)中，加入钯碳催化剂(366毫克，0.1当量，10％的钯负载于炭，55％的水润湿)，50摄氏度下于氢气氛围中搅拌反应6小时。4-Amino-2-fluoro-5-nitrobenzoic acid (380 mg, 1.91 mmol) was dissolved in methanol (10 mL) and a palladium-carbon catalyst (366 mg, 0.1 equiv, 10% palladium on carbon was added) , 55% water wet), and the reaction was stirred at 50 degrees Celsius in a hydrogen atmosphere for 6 hours.
反应结束后，反应液过滤，收集滤液，浓缩,所得黄色固体直接用于下一步反应，得4，5-二氨基-2-氟苯甲酸320毫克(收率：98.5％)。LC-MS：RT＝0.31min,[M+H] +＝171.25。 After the reaction, the reaction solution was filtered, the filtrate was collected and concentrated, and the obtained yellow solid was directly used in the next reaction to obtain 320 mg of 4,5-diamino-2-fluorobenzoic acid (yield: 98.5%). LC-MS: RT=0.31 min, [M+H] + =171.25.
步骤C：合成7-氟-3-甲基喹喔啉-6-羧酸Step C: Synthesis of 7-fluoro-3-methylquinoxaline-6-carboxylic acid
Figure PCTCN2021120978-appb-000419
Figure PCTCN2021120978-appb-000419
将4，5-二氨基-2-氟苯甲酸(320毫克，1.88毫摩尔)，2-羰基丙醛(338毫克，1.88毫摩尔,40％的水溶液)溶于乙醇(10毫升)中，加入乙酸(2毫升)，氮气保护下回流2小时。4,5-Diamino-2-fluorobenzoic acid (320 mg, 1.88 mmol), 2-carbonylpropanal (338 mg, 1.88 mmol, 40% in water) were dissolved in ethanol (10 mL) and added Acetic acid (2 mL) was refluxed under nitrogen for 2 hours.
反应结束后，降至室温，反应液减压浓缩,浓缩液用乙酸乙酯(30毫升)稀释，并用饱和食盐水(30毫升×升次)洗涤，分液，有机相用无水硫酸钠干燥，随后减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝15/1)。得淡黄色固体7-氟-3-甲基喹喔啉-6-羧酸250毫克(收率：62.2％)。LC-MS：RT＝1.75min,[M+H] +＝207.12。 After the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, the concentrated solution was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL×L), separated, and the organic phase was dried over anhydrous sodium sulfate. , followed by concentration under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: dichloromethane/methanol=15/1). 250 mg of 7-fluoro-3-methylquinoxaline-6-carboxylic acid was obtained as a pale yellow solid (yield: 62.2%). LC-MS: RT=1.75 min, [M+H] + =207.12.
步骤D：合成7-氟-3-甲基喹喔啉-6-羧酸甲酯Step D: Synthesis of methyl 7-fluoro-3-methylquinoxaline-6-carboxylate
Figure PCTCN2021120978-appb-000420
Figure PCTCN2021120978-appb-000420
将7-氟-3-甲基喹喔啉-6-羧酸(250毫克，1.21毫摩尔)溶于甲醇(5毫升)中，0℃下加入缓慢滴入二氯亚砜(431毫克，3.62毫摩尔)，保温搅拌10分钟，随后升温至60摄氏度搅拌反应两小时。7-Fluoro-3-methylquinoxaline-6-carboxylic acid (250 mg, 1.21 mmol) was dissolved in methanol (5 mL), and thionyl chloride (431 mg, 3.62 m mmol), kept stirring for 10 minutes, and then heated to 60 degrees Celsius and stirred for two hours.
反应结束后，降至室温，减压浓缩,所得黄色固体直接用于下一步反应，得淡7-氟-3-甲基喹喔啉-6-羧酸甲酯266毫克(收率：100％)。LC-MS：RT＝1.79min,[M+H] +＝221.12。 After the reaction was completed, it was lowered to room temperature and concentrated under reduced pressure. The obtained yellow solid was directly used in the next step to obtain 266 mg of light 7-fluoro-3-methylquinoxaline-6-carboxylate methyl ester (yield: 100%). ). LC-MS: RT=1.79 min, [M+H] + =221.12.
步骤E：合成7-氟-3-甲基喹喔啉-6-甲醇Step E: Synthesis of 7-fluoro-3-methylquinoxaline-6-methanol
Figure PCTCN2021120978-appb-000421
Figure PCTCN2021120978-appb-000421
零摄氏度下，将7-氟-3-甲基喹喔啉-6-羧酸甲酯(110毫克，0.50毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，分批加入氢化锂铝(76毫克，2.0毫摩尔)，搅拌1小时。Methyl 7-fluoro-3-methylquinoxaline-6-carboxylate (110 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2 mL) at zero degrees Celsius, and lithium aluminum hydride was added in portions under nitrogen (76 mg, 2.0 mmol) and stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.2毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×升次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得淡黄色固体直接用于下一步反应，得7-氟-3-甲基喹喔啉-6-甲醇78毫克(收率：81.3％)。LC-MS：RT＝1.59min,[M+H] +＝193.13。 After the reaction was completed, sodium hydroxide solution (5%, 0.2 mL) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 mL×L, dichloromethane/methanol). = 10/1) rinsed, combined the organic phases, then washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained pale yellow solid was directly used in the next reaction to obtain 7-fluoro -3-Methylquinoxaline-6-methanol 78 mg (yield: 81.3%). LC-MS: RT=1.59 min, [M+H] + =193.13.
步骤F：合成(S)-2-((4-(6-((7-氟-3-甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step F: Synthesis of (S)-2-((4-(6-((7-Fluoro-3-methylquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000422
Figure PCTCN2021120978-appb-000422
将7-氟-3-甲基喹喔啉-6-甲醇(36毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。7-Fluoro-3-methylquinoxaline-6-methanol (36 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1,4 - dioxane (1 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-2-((4-(6-((7-氟-3- 甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯68毫克(收率：65.2％)。LC-MS：RT＝1.89min,[M+H] +＝653.39。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid (S)-2-((4-(6-((7-fluoro-3-methylquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidine-1- (yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester 68 mg (yield: 65.2%). LC-MS: RT=1.89 min, [M+H] + =653.39.
步骤G：合成(S)-2-((4-(6-((7-氟-3-甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step G: Synthesis of (S)-2-((4-(6-((7-Fluoro-3-methylquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000423
Figure PCTCN2021120978-appb-000423
将(S)-2-((4-(6-((7-氟-3-甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(68毫克，0.10毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，于25摄氏度下搅拌反应3小时。(S)-2-((4-(6-((7-Fluoro-3-methylquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (68 mg, 0.10 mmol), dissolved in mixed solvent (2 mL , dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the reaction was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到31毫克白色固体(S)-2-((4-(6-((7-氟-3-甲基喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：52.0％)。LC-MS：RT＝1.74min,[M+H] +＝594.30。核磁数据： 1H NMR(500MHz,DMSO-d 6)δ12.71(s,1H),9.30(s,1H),8.65(s,1H),8.26(d,J＝1.0Hz,1H),8.16(t,J＝8.7Hz,2H),7.86–7.78(m,2H),7.71(t,J＝7.1Hz,1H),7.62(dd,J＝17.0,8.0Hz,2H),6.88(d,J＝7.3Hz,1H),6.64(d,J＝8.2Hz,1H),5.81(d,J＝12.8Hz,2H),5.14–5.08(m,1H),4.80(dd,J＝15.2,7.3Hz,1H),4.66(dd,J＝15.2,2.7Hz,1H),4.45–4.40(m,1H),4.35(dt,J＝9.0,5.8Hz,1H),3.96(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),3.01(d,J＝11.1Hz,1H),2.87(d,J＝11.2Hz,1H),2.72–2.60(m,2H),2.43(dd,J＝18.9,7.9Hz,1H),2.22(dt,J＝20.9,10.1Hz,2H),1.87–1.71(m,4H)。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 31 mg of white solid (S)-2-((4-(6-((7-fluoro-3-methylquinoxalin-6-yl)methoxy) yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield : 52.0%). LC-MS: RT=1.74 min, [M+H] + =594.30. Nuclear magnetic data: 1 H NMR (500MHz, DMSO-d 6 )δ12.71(s, 1H), 9.30(s, 1H), 8.65(s, 1H), 8.26(d, J=1.0Hz, 1H), 8.16 (t, J=8.7Hz, 2H), 7.86–7.78 (m, 2H), 7.71 (t, J=7.1Hz, 1H), 7.62 (dd, J=17.0, 8.0Hz, 2H), 6.88 (d, J=7.3Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 5.81 (d, J=12.8Hz, 2H), 5.14–5.08 (m, 1H), 4.80 (dd, J=15.2, 7.3 Hz, 1H), 4.66 (dd, J=15.2, 2.7Hz, 1H), 4.45–4.40 (m, 1H), 4.35 (dt, J=9.0, 5.8Hz, 1H), 3.96 (d, J=13.6Hz) ,1H),3.78(d,J＝13.6Hz,1H),3.01(d,J＝11.1Hz,1H),2.87(d,J＝11.2Hz,1H),2.72–2.60(m,2H),2.43 (dd, J=18.9, 7.9 Hz, 1H), 2.22 (dt, J=20.9, 10.1 Hz, 2H), 1.87–1.71 (m, 4H).
实施例81Example 81
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-2-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000424
Figure PCTCN2021120978-appb-000424
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-2-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000425
Figure PCTCN2021120978-appb-000425
将喹啉-2-基甲醇(60毫克，0.38毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(279毫克，0.57毫摩尔)，钯催化剂(32毫克)，碳酸铯(248毫克，0.76毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌12个小时。The quinolin-2-ylmethanol (60 mg, 0.38 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (279 mg, 0.57 mmol), palladium catalyst (32 mg), cesium carbonate (248 mg, 0.76 mmol) was dissolved in dioxane, the temperature was raised to 100 degrees Celsius and stirred for 12 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到150毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：64％)。LC-MS:RT＝1.91min,[M+H] +＝620.37。 After completion of the reaction, suction filtration with celite, washing with dichloromethane, and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 150 mg of white solid ( S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-2-ylmethoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 64%). LC-MS: RT=1.91 min, [M+H] + =620.37.
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-2-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000426
Figure PCTCN2021120978-appb-000426
将合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150毫克，0.24毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-2-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (150 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid ( 1 ml), react for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到71.54毫克白色固体合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：80％)。LC-MS:RT＝1.70min,[M+H] +＝564.33。 1H NMR(500MHz,DMSO)δ8.35(d,J＝8.3Hz,1H),8.06(dd,J＝1.3,0.6Hz,1H),7.99–7.92(m,2H),7.79(dd,J＝8.3,1.4Hz,1H),7.71(dd,J＝8.4,1.5Hz,1H),7.68–7.64(m,1H),7.57(dd,J＝8.1,1.8Hz,2H),7.40(dd,J＝8.3,0.6Hz,1H),6.88(d,J＝7.1Hz,1H),6.80(dd,J＝8.2,0.6Hz,1H),5.60(s,2H),5.08(dd,J＝14.4,3.4Hz,1H),4.65(dd,J＝15.2,7.0Hz,1H),4.53(dd,J＝15.2,3.2Hz,1H),4.49–4.43(m,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.85(d,J＝13.3Hz,1H),3.70(d,J＝13.3Hz,1H),2.89(d,J＝11.3Hz,1H),2.77(d,J＝11.1Hz,1H),2.72–2.62(m,1H),2.59–2.53(m,1H),2.47–2.38(m,1H),2.15(dd,J＝11.6,9.0Hz,1H),2.08(dd,J＝11.6,8.8Hz,1H),1.74–1.55(m,4H)。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 71.54 mg of white solid. Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinoline- 2-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 80%). LC-MS: RT=1.70 min, [M+H] + =564.33. 1 H NMR (500MHz, DMSO) δ 8.35 (d, J=8.3 Hz, 1H), 8.06 (dd, J=1.3, 0.6 Hz, 1H), 7.99-7.92 (m, 2H), 7.79 (dd, J =8.3,1.4Hz,1H),7.71(dd,J=8.4,1.5Hz,1H),7.68–7.64(m,1H),7.57(dd,J=8.1,1.8Hz,2H),7.40(dd, J＝8.3,0.6Hz,1H),6.88(d,J＝7.1Hz,1H),6.80(dd,J＝8.2,0.6Hz,1H),5.60(s,2H),5.08(dd,J＝14.4 ,3.4Hz,1H),4.65(dd,J＝15.2,7.0Hz,1H),4.53(dd,J＝15.2,3.2Hz,1H),4.49–4.43(m,1H),4.35(dt,J＝ 9.0, 5.9Hz, 1H), 3.85 (d, J=13.3Hz, 1H), 3.70 (d, J=13.3Hz, 1H), 2.89 (d, J=11.3Hz, 1H), 2.77 (d, J= 11.1Hz, 1H), 2.72–2.62 (m, 1H), 2.59–2.53 (m, 1H), 2.47–2.38 (m, 1H), 2.15 (dd, J=11.6, 9.0Hz, 1H), 2.08 (dd , J = 11.6, 8.8 Hz, 1H), 1.74–1.55 (m, 4H).
实施例82Example 82
合成(S)-7-氟-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-7-fluoro-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000427
Figure PCTCN2021120978-appb-000427
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2,3-二氟-4-硝基苯甲酸Step A: Synthesis of 2,3-difluoro-4-nitrobenzoic acid
Figure PCTCN2021120978-appb-000428
Figure PCTCN2021120978-appb-000428
将2,3-二氟-1-甲基-4-硝基苯(2克，11.5毫摩尔)溶于乙酸(30毫升)的溶液中。随后，在冰浴条件下向上述溶液中加入高锰酸钾(4.4克，14.9毫摩尔)，浓硫酸(7毫升)。在95摄氏度条件下搅拌2小时。2,3-Difluoro-1-methyl-4-nitrobenzene (2 g, 11.5 mmol) was dissolved in a solution of acetic acid (30 mL). Subsequently, potassium permanganate (4.4 g, 14.9 mmol) and concentrated sulfuric acid (7 mL) were added to the above solution under ice bath conditions. Stir at 95°C for 2 hours.
将反应液缓慢滴加到冰水(100毫升)中。混合液用乙酸乙酯(50毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×3次)，然后用无水硫酸钠干燥，最后减压浓缩1.4克绿色2,3-二氟-4-硝基苯甲酸(收率：60.0％)。The reaction solution was slowly added dropwise to ice water (100 mL). The mixture was extracted with ethyl acetate (50 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 ml × 3 times), then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure with 1.4 g of green 2,3-difluoro-4-nitrobenzoic acid (yield: 60.0%) .
步骤B：合成2,3-二氟-4-硝基苯甲酸甲酯Step B: Synthesis of methyl 2,3-difluoro-4-nitrobenzoate
Figure PCTCN2021120978-appb-000429
Figure PCTCN2021120978-appb-000429
将2,3-二氟-4-硝基苯甲酸(1.4克，6.89毫摩尔)溶于二氯甲烷(14毫升)的溶液中。随后，在0摄氏度条件下向上述溶液中加入草酰氯(2.6克.20.6毫摩尔)，N,N-二甲基甲酰胺(0.1毫升)。在室温条件下搅拌1小时。然后，向反应液加入甲醇(5毫升)并搅拌1小时。2,3-Difluoro-4-nitrobenzoic acid (1.4 g, 6.89 mmol) was dissolved in a solution of dichloromethane (14 mL). Subsequently, oxalyl chloride (2.6 g. 20.6 mmol), N,N-dimethylformamide (0.1 mL) was added to the above solution at 0 degrees Celsius. Stir at room temperature for 1 hour. Then, methanol (5 mL) was added to the reaction solution, followed by stirring for 1 hour.
将反应液减压浓缩得到1.5克灰色油状物2,3-二氟-4-硝基苯甲酸甲酯(收率：100％)。The reaction solution was concentrated under reduced pressure to obtain 1.5 g of methyl 2,3-difluoro-4-nitrobenzoate as a gray oil (yield: 100%).
步骤C：合成(S)-2-氟-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯Step C: Synthesis of (S)-methyl 2-fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate
Figure PCTCN2021120978-appb-000430
Figure PCTCN2021120978-appb-000430
将2,3-二氟-4-硝基苯甲酸甲酯(700毫克，3.22毫摩尔)溶于四氢呋喃(15毫升)的溶液中。随后，向上述溶液中加入(S)-氧杂环丁-2-基甲胺(308毫克,3.54毫摩尔)，N,N-二异丙基乙胺(627毫克，4.83毫摩尔)。在冰浴条件下搅拌2个小时。Methyl 2,3-difluoro-4-nitrobenzoate (700 mg, 3.22 mmol) was dissolved in a solution of tetrahydrofuran (15 mL). Subsequently, (S)-oxetan-2-ylmethanamine (308 mg, 3.54 mmol), N,N-diisopropylethylamine (627 mg, 4.83 mmol) was added to the above solution. Stir in ice bath for 2 hours.
将反应液缓慢滴加到饱和氯化钠溶液(50毫升)中。混合液用乙酸乙酯(20毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×升次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到530毫克黄色油状(S)-2-氟-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(收率：59.0％)。LCMS：RT＝1.78min，[M+H] +＝285.18。 The reaction solution was slowly added dropwise to saturated sodium chloride solution (50 mL). The mixture was extracted with ethyl acetate (20 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 mL×liter), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 530 mg of (S)-2-fluoro-4-nitro-3-((oxoheterocycle as a yellow oil. But-2-ylmethyl)amino)benzoic acid methyl ester (yield: 59.0%). LCMS: RT=1.78 min, [M+H] + =285.18.
步骤D：合成(S)-4-氨基-2-氟-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯Step D: Synthesis of (S)-methyl 4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate
Figure PCTCN2021120978-appb-000431
Figure PCTCN2021120978-appb-000431
将(S)-2-氟-4-硝基-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(530毫克，1.86毫摩尔)溶于甲醇(15毫升)的溶液中。随后，向上述溶液中加入铁粉(1.1克,19毫摩尔)，饱和氯化铵水溶液(1毫升)。在室温条件下搅拌2个小时。(S)-Methyl 2-fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (530 mg, 1.86 mmol) was dissolved in methanol (15 mL) in the solution. Subsequently, iron powder (1.1 g, 19 mmol) and saturated aqueous ammonium chloride solution (1 mL) were added to the above solution. Stir at room temperature for 2 hours.
将反应液过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到450毫克棕色油状物(S)-4-氨基-2-氟-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(收率：96.2％)。LC-MS：RT＝1.72min，[M+H] +＝255.18。 The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 450 mg of (S)-4-amino-2-fluoro-3-((oxoheterocycle) as a brown oily substance But-2-ylmethyl)amino)benzoic acid methyl ester (yield: 96.2%). LC-MS: RT=1.72 min, [M+H] + =255.18.
步骤E：合成(S)-2-(氯甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of (S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000432
Figure PCTCN2021120978-appb-000432
将(S)-4-氨基-2-氟-3-((氧杂环丁-2-基甲基)氨基)苯甲酸甲酯(450毫克，1.77毫摩尔)溶于四氢呋喃(7毫升)的溶液中。随后，向上述溶液中加入2-氯-1,1,1-三甲氧基乙烷(595毫克,3.5毫摩尔)。在80摄氏度条件下搅拌2个小时。(S)-Methyl 4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate (450 mg, 1.77 mmol) was dissolved in tetrahydrofuran (7 mL) in solution. Subsequently, 2-chloro-1,1,1-trimethoxyethane (595 mg, 3.5 mmol) was added to the above solution. Stir at 80°C for 2 hours.
将反应液缓慢滴加到饱和氯化钠溶液(50毫升)中。混合液用乙酸乙酯(20毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×升次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到250毫克无色油状物(S)-2-(氯甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：45.2％)。LC-MS：RT＝1.85min，[M+H] + ＝313.15。 The reaction solution was slowly added dropwise to saturated sodium chloride solution (50 mL). The mixture was extracted with ethyl acetate (20 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 mL×liter), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 250 mg of (S)-2-(chloromethyl)-7-fluoro-1- as a colorless oily substance (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 45.2%). LC-MS: RT=1.85 min, [M+H] + =313.15.
步骤F：合成(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step F: Synthesis of (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-fluoro-1-(oxetan-2- methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000433
Figure PCTCN2021120978-appb-000433
将(S)-2-(氯甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(172毫克，0.55毫摩尔)溶于N,N-二甲基甲酰胺(7毫升)的溶液中。随后，向上述溶液中加入2-氯-6-(哌啶-4-基)吡啶(90毫克,0.46毫摩尔)，碳酸钾(63毫克，0.92毫摩尔)。在50摄氏度条件下搅拌2个小时。(S)-Methyl 2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (172 mg , 0.55 mmol) in N,N-dimethylformamide (7 mL). Subsequently, 2-chloro-6-(piperidin-4-yl)pyridine (90 mg, 0.46 mmol), potassium carbonate (63 mg, 0.92 mmol) were added to the above solution. Stir at 50°C for 2 hours.
将反应液缓慢滴加到饱和氯化钠溶液(50毫升)中。混合液用乙酸乙酯(20毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×升次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯)得到140毫克无色油状物(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：54.0％)。LC-MS：RT＝1.68min，[M+H] +＝473.22。 The reaction solution was slowly added dropwise to saturated sodium chloride solution (50 mL). The mixture was extracted with ethyl acetate (20 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 mL×liter), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 140 mg of (S)-2-(((4-(6-chloropyridin-2-yl)piperidine-1) as a colorless oily substance -yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 54.0%).LC -MS: RT=1.68 min, [M+H] + =473.22.
步骤G：合成(S)-7-氟-2-((4-(6-((1-(2-(甲氧乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯Step G: Synthesis of (S)-7-fluoro-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000434
Figure PCTCN2021120978-appb-000434
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-7-氟-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(140毫克，297微摩尔)溶于1,4-二氧六环(10毫升)的溶液中，随后向上述溶液中加入(1-(2-甲氧基乙基)-1H-吲唑-6-基)甲醇(67毫克，326微摩尔)，甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(25毫克，29微摩尔)，碳酸铯(193毫克，594微摩尔)，在100摄氏度条件下搅拌18小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylate methyl ester (140 mg, 297 μmol) in 1,4-dioxane (10 mL), to which was then added ( 1-(2-Methoxyethyl)-1H-indazol-6-yl)methanol (67 mg, 326 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6 '-Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 29 μmol), cesium carbonate (193 mg, 594 μmol) and stirred at 100 degrees Celsius for 18 hours.
将反应液缓慢滴加到饱和氯化钠溶液(30毫升)中。混合液用乙酸乙酯(20毫升×升次)萃取。合并有机相。有机相先用饱和食盐水(15毫升×升次)，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯)得到130毫克白色油状(S)-7-氟-2-((4-(6-((1-(2-(甲氧乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(收率：68.1％)。LC-MS：RT＝1.67min，[M+H] +＝643.33。 The reaction solution was slowly added dropwise to saturated sodium chloride solution (30 mL). The mixture was extracted with ethyl acetate (20 mL×L). Combine the organic phases. The organic phase was first washed with saturated brine (15 mL×liter), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 130 mg of (S)-7-fluoro-2-((4-(6-((1-(2-(methoxy) as a white oil) Ethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H -Methyl benzo[d]imidazole-6-carboxylate (yield: 68.1%). LC-MS: RT=1.67 min, [M+H] + =643.33.
步骤H：合成(S)-7-氟-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step H: Synthesis of (S)-7-fluoro-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000435
Figure PCTCN2021120978-appb-000435
将(S)-7-氟-2-((4-(6-((1-(2-(甲氧乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁 -2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(130毫克，202微摩尔)溶于四氢呋喃/水/甲醇(2/1/1，4毫升)的溶液中。随后，向上述溶液中加入一水合氢氧化锂(16毫克,404毫摩尔)，在室温下搅拌3个小时。(S)-7-Fluoro-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (130 mg, 202 μmol) Dissolved in a solution of tetrahydrofuran/water/methanol (2/1/1, 4 mL). Subsequently, lithium hydroxide monohydrate (16 mg, 404 mmol) was added to the above solution, and the mixture was stirred at room temperature for 3 hours.
将反应液减压浓缩。所得残余物用制备HPLC纯化得到70毫克白色固体(S)-7-氟-2-((4-(6-((1-(2-(甲氧基乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：55.1％)。LC-MS：RT＝1.66min，[M+H] +＝629.20。 1H NMR(400MHz,DMSO)δ8.03(d,J＝0.7Hz,1H),7.76–7.69(m,2H),7.65–7.58(m,1H),7.40(dd,J＝8.2,6.7Hz,1H),7.20(t,J＝7.5Hz,2H),6.86(d,J＝7.2Hz,1H),6.67(d,J＝8.1Hz,1H),5.46(s,2H),5.08(s,1H),4.80(dd,J＝15.2,6.9Hz,1H),4.64(dd,J＝15.2,3.4Hz,1H),4.52–4.42(m,3H),4.35(dt,J＝9.0,6.0Hz,1H),3.88(d,J＝13.4Hz,1H),3.76(d,J＝13.4Hz,1H),3.69(t,J＝5.3Hz,2H),3.12(s,3H),2.99(d,J＝11.3Hz,1H),2.90(d,J＝11.0Hz,1H),2.67(ddd,J＝33.9,18.5,9.3Hz,3H),2.48–2.37(m,2H),2.20(dt,J＝21.4,10.2Hz,2H),1.78(dd,J＝28.3,10.3Hz,4H)。 The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 70 mg of (S)-7-fluoro-2-((4-(6-((1-(2-(methoxyethyl)-1H-indazole-6) as a white solid -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6- Carboxylic acid (yield: 55.1%). LC-MS: RT=1.66 min, [M+H] + =629.20. 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J=0.7 Hz, 1H), 7.76–7.69 (m, 2H), 7.65–7.58 (m, 1H), 7.40 (dd, J=8.2, 6.7Hz, 1H), 7.20 (t, J=7.5Hz, 2H), 6.86 (d, J= 7.2Hz, 1H), 6.67(d, J=8.1Hz, 1H), 5.46(s, 2H), 5.08(s, 1H), 4.80(dd, J=15.2, 6.9Hz, 1H), 4.64(dd, J=15.2, 3.4Hz, 1H), 4.52–4.42 (m, 3H), 4.35 (dt, J=9.0, 6.0Hz, 1H), 3.88 (d, J=13.4Hz, 1H), 3.76 (d, J ＝13.4Hz, 1H), 3.69(t, J＝5.3Hz, 2H), 3.12(s, 3H), 2.99(d, J＝11.3Hz, 1H), 2.90(d, J＝11.0Hz, 1H), 2.67(ddd,J=33.9,18.5,9.3Hz,3H),2.48–2.37(m,2H),2.20(dt,J=21.4,10.2Hz,2H),1.78(dd,J=28.3,10.3Hz, 4H).
实施例83Example 83
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000436
Figure PCTCN2021120978-appb-000436
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成喹啉-7基甲醇Step A: Synthesis of Quinolin-7ylmethanol
Figure PCTCN2021120978-appb-000437
Figure PCTCN2021120978-appb-000437
将喹啉7-羧酸甲酯(200毫克,1.07毫摩尔)溶于四氢呋喃(4.0毫升)中,冷却至零度后，将四氢铝锂(81毫克，2.14毫摩尔)缓慢的加入，加入完全后在室温下搅拌1小时。Methyl quinoline 7-carboxylate (200 mg, 1.07 mmol) was dissolved in tetrahydrofuran (4.0 mL), and after cooling to zero, lithium tetrahydroaluminum (81 mg, 2.14 mmol) was added slowly, and the addition was complete. It was then stirred at room temperature for 1 hour.
TLC显示原料反应完全，有新点生成。将反应液将至零度后依次逐滴加入水(0.1毫升)、85％氢氧化钠溶液(0.1毫升)和水(0.3毫升)，室温搅拌10min后拉干，得到的粗品用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝0/1)得到124毫克黄色的油状喹啉-7基甲醇(收率：72.9％)。TLC showed that the starting material was completely reacted and new spots were formed. After the reaction solution was brought to zero, water (0.1 mL), 85% sodium hydroxide solution (0.1 mL) and water (0.3 mL) were added dropwise in sequence, stirred at room temperature for 10 min, and then pulled to dryness. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=0/1) to obtain 124 mg of yellow oily quinolin-7ylmethanol (yield: 72.9%).
步骤B：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000438
Figure PCTCN2021120978-appb-000438
将喹啉-7基甲醇(50毫克,0.31毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(172毫克,0.31毫摩尔)，碳酸铯(154毫克,0.47毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(27毫克,0.03毫摩尔)加入反应瓶中,加入1,4-二氧六环(2毫升)，鼓入氮气1分钟后,在氮气保护下反应液在100摄氏度下搅拌16小时。The quinolin-7ylmethanol (50 mg, 0.31 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (172 mg, 0.31 mmol), cesium carbonate (154 mg, 0.47 mmol) and methane Sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2 - base) palladium (II) (27 mg, 0.03 mmol) was added to the reaction flask, 1,4-dioxane (2 ml) was added, nitrogen was bubbled for 1 minute, and the reaction solution was heated at 100 degrees Celsius under nitrogen protection under stirring for 16 hours.
TLC检测反应完全后，将反应液直接拉干后用硅胶柱层析纯化(洗脱剂：二氯/甲醇＝10/1)得到108毫克浅黄色的焦状粗品产物(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：55.5％)。After the completion of the reaction was detected by TLC, the reaction solution was directly dried and purified by silica gel column chromatography (eluent: dichloro/methanol=10/1) to obtain 108 mg of pale yellow coke-like crude product (S)-1-( Oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H - tert-butyl benzo[d]imidazole-6-carboxylate (yield: 55.5%).
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H- 苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000439
Figure PCTCN2021120978-appb-000439
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克,0.16毫摩尔)溶于二氯甲烷(2毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌3小时后,LC-MS监测至反应完全。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), followed by trifluoroacetic acid (0.4 mL) ) was added to the reaction solution, stirred at room temperature for 3 hours, and monitored by LC-MS until the reaction was complete.
将反应液用饱和碳酸氢钠溶液调至pH 8-9，直接拉干后用碱性反相制备分离纯化。得到38.22毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(喹啉-7-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：40.8％)。LC-MS：RT＝1.66min，[M+H] +＝564.34。 The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate solution, directly pulled to dryness, and separated and purified by basic reverse-phase preparation. Obtained 38.22 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(quinolin-7-ylmethoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 40.8%). LC-MS: RT=1.66 min, [M+H] + =564.34.
实施例84Example 84
合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-5-ylmethoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000440
Figure PCTCN2021120978-appb-000440
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成吡唑并[1,5-a]吡啶-5-羧酸甲酯Step A: Synthesis of methyl pyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000441
Figure PCTCN2021120978-appb-000441
将吡唑并[1,5-a]吡啶-5-羧酸(150毫克，0.93毫摩尔)溶于二氯甲烷(15毫升)中，滴入两滴N,N-二甲基甲酰胺，然后边搅拌边滴加草酰氯(472毫克，3.72毫摩尔)，在室温下反应0.5小时。Pyrazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 0.93 mmol) was dissolved in dichloromethane (15 mL), two drops of N,N-dimethylformamide were added dropwise, Then, oxalyl chloride (472 mg, 3.72 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 0.5 hour.
再将甲醇(5毫升)滴入反应中，搅拌十分钟，再加入氢氧化钠溶液中和至中性，用二氯甲烷(20毫升×升次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到150毫克白色固体吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：92％)。Methanol (5 mL) was then added dropwise to the reaction, stirred for ten minutes, then neutralized to neutrality by adding sodium hydroxide solution, extracted with dichloromethane (20 mL×L), combined and dried the organic phases, and the crude product obtained was concentrated. Purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 150 mg of methyl pyrazolo[1,5-a]pyridine-5-carboxylate as a white solid (yield: 92 %).
步骤B：合成吡唑并[1,5-a]吡啶-5-基甲醇Step B: Synthesis of Pyrazolo[1,5-a]pyridin-5-ylmethanol
Figure PCTCN2021120978-appb-000442
Figure PCTCN2021120978-appb-000442
室温下，将吡唑并[1,5-a]吡啶-5-羧酸甲酯(150毫克，0.85毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(70毫克，1.82毫摩尔)，在室温下搅拌0.5小时。Methyl pyrazolo[1,5-a]pyridine-5-carboxylate (150 mg, 0.85 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, and tetrahydrofuran was added. Lithium aluminum hydride (70 mg, 1.82 mmol) was stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭反应，再加入乙酸乙酯(30毫升)用水洗两次有机相并用无水硫酸钠干燥，过滤后浓缩得到130毫克白色固体吡唑并[1,5-a]吡啶-5-基甲醇(收率：90％)。After the reaction was completed, saturated sodium chloride was added to quench the reaction, and ethyl acetate (30 mL) was added to wash the organic phase twice with water and dried over anhydrous sodium sulfate, filtered and concentrated to obtain 130 mg of white solid pyrazolo[1,5 -a]pyridin-5-ylmethanol (yield: 90%).
步骤C：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-5-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000443
Figure PCTCN2021120978-appb-000443
将吡唑并[1,5-a]吡啶-5-基甲醇(50毫克，0.34毫摩尔)，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(253毫克，0.51毫摩尔)，钯催化剂(30毫克)，碳酸铯(222毫克，0.68毫摩尔)溶于二氧六环中，温度升高到100摄氏度搅拌12个小时。Pyrazolo[1,5-a]pyridin-5-ylmethanol (50 mg, 0.34 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl) (253 mg, 0.51 mmol), palladium catalyst (30 mg), cesium carbonate (222 mg, 0.68 mmol) in dioxane In the ring, the temperature was raised to 100 degrees Celsius and stirred for 12 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到160毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-3-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：77％)。LC-MS:RT＝1.90min,[M+H] +＝609.30。 After completion of the reaction, suction filtration with celite, washing with dichloromethane, and then concentrating the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 160 mg of white solid ( S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-3-ylmethoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 77%). LC-MS: RT=1.90 min, [M+H] + =609.30.
步骤D：合成(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-5-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000444
Figure PCTCN2021120978-appb-000444
将(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(异喹啉-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(160毫克，0.26毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(isoquinolin-5-ylmethoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (160 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid ( 1 ml), react for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到43.19毫克白色固体(S)-1-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-5-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：30％)。LC-MS:RT＝1.70min,[M+H] +＝553.30。 1H NMR(500MHz,DMSO)δ8.65(d,J＝7.2Hz,1H),8.06(s,1H),7.96(d,J＝2.2Hz,1H),7.79(dd,J＝8.3,1.3Hz,1H),7.73(s,1H),7.68–7.62(m,1H),7.41(d,J＝8.3Hz,1H),6.93(dd,J＝7.2,1.8Hz,1H),6.89(d,J＝7.3Hz,1H),6.73(d,J＝8.2Hz,1H),6.57(d,J＝2.2Hz,1H),5.40(s,2H),5.15–5.07(m,1H),4.70(dd,J＝15.3,6.9Hz,1H),4.59(dd,J＝15.1,3.3Hz,1H),4.47(dd,J＝13.5,7.9Hz,1H),4.37(dt,J＝8.9,5.8Hz,1H),2.99(d,J＝10.8Hz,1H),2.88(d,J＝11.5Hz,1H),2.69(dt,J＝14.5,8.1Hz,1H),2.61(t,J＝11.7Hz,1H),2.45(dd,J＝19.1,8.0Hz,1H),2.19(dt,J＝20.6,9.1Hz,2H),1.85–1.66(m,4H)。 After the reaction was completed, it was concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 43.19 mg of white solid (S)-1-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[ 1,5-a]Pyridin-5-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 30 %). LC-MS: RT=1.70 min, [M+H] + =553.30. 1 H NMR (500MHz, DMSO) δ 8.65 (d, J=7.2Hz, 1H), 8.06 (s, 1H), 7.96 (d, J=2.2Hz, 1H), 7.79 (dd, J=8.3, 1.3 Hz, 1H), 7.73(s, 1H), 7.68–7.62(m, 1H), 7.41(d, J=8.3Hz, 1H), 6.93(dd, J=7.2, 1.8Hz, 1H), 6.89(d , J＝7.3Hz, 1H), 6.73(d, J＝8.2Hz, 1H), 6.57(d, J＝2.2Hz, 1H), 5.40(s, 2H), 5.15–5.07(m, 1H), 4.70 (dd, J=15.3, 6.9Hz, 1H), 4.59 (dd, J=15.1, 3.3Hz, 1H), 4.47 (dd, J=13.5, 7.9Hz, 1H), 4.37 (dt, J=8.9, 5.8 Hz,1H),2.99(d,J＝10.8Hz,1H),2.88(d,J＝11.5Hz,1H),2.69(dt,J＝14.5,8.1Hz,1H),2.61(t,J＝11.7 Hz, 1H), 2.45 (dd, J=19.1, 8.0 Hz, 1H), 2.19 (dt, J=20.6, 9.1 Hz, 2H), 1.85–1.66 (m, 4H).
实施例85Example 85
合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000445
Figure PCTCN2021120978-appb-000445
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成咪唑并[1,5-a]吡啶-6-基甲醇Step A: Synthesis of Imidazo[1,5-a]pyridin-6-ylmethanol
Figure PCTCN2021120978-appb-000446
Figure PCTCN2021120978-appb-000446
将咪唑并[1,5-a]吡啶-6-羧酸甲酯(200毫克,1.14毫摩尔)溶于四氢呋喃(5.0毫升)中,冷却至零度后，将四氢铝锂(86毫克，2.72毫摩尔)缓慢的加入，加入完全后在室温下搅拌2h。Methyl imidazo[1,5-a]pyridine-6-carboxylate (200 mg, 1.14 mmol) was dissolved in tetrahydrofuran (5.0 mL), cooled to zero, and tetrahydroaluminum lithium (86 mg, 2.72 mmol) was dissolved in tetrahydrofuran (5.0 mL). mmol) was added slowly, and the mixture was stirred at room temperature for 2 h after the addition was complete.
TLC显示原料反应完全，有新点生成。将反应液将至零度后依次逐滴加入水(0.1毫升)、85％氢氧化钠溶液(0.1毫升)和水(0.3毫升)，室温搅拌5分钟后加入过量乙酸乙酯，搅拌0.5小时后过滤，用甲醇洗涤3遍滤饼后过滤，滤液旋干后得到粗品产物。得到的粗品用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到50毫克黄色固体咪唑并[1,5-a]吡啶-6-基甲醇(收率：29.7％)。TLC showed that the starting material was completely reacted and new spots were formed. After the reaction solution was brought to zero, water (0.1 mL), 85% sodium hydroxide solution (0.1 mL) and water (0.3 mL) were added dropwise in sequence, and the mixture was stirred at room temperature for 5 minutes and then added with excess ethyl acetate. After stirring for 0.5 hours, the mixture was filtered. , the filter cake was washed 3 times with methanol and then filtered, and the filtrate was spin-dried to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 50 mg of yellow solid imidazo[1,5-a]pyridin-6-ylmethanol (yield: 29.7%) ).
步骤B：合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000447
Figure PCTCN2021120978-appb-000447
将咪唑并[1,5-a]吡啶-6-基甲醇(45毫克,0.30毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(151毫克,0.30毫摩尔)，碳酸铯(149毫克,0.46毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(26毫克,0.03毫摩尔)加入反应瓶中,加入1,4-二氧六环(2毫升)，鼓入氮气1分钟后,在氮气保护下反应液在100摄氏度下搅拌16小时。The imidazo[1,5-a]pyridin-6-ylmethanol (45 mg, 0.30 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (151 mg, 0.30 mmol), cesium carbonate ( 149 mg, 0.46 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.03 mmol) was added to the reaction flask, 1,4-dioxane (2 mL) was added, and nitrogen was bubbled for 1 min. The reaction solution was stirred at 100°C for 16 hours under nitrogen protection.
TLC检测反应完全后，将反应液直接拉干后用硅胶柱层析纯化(洗脱剂：二氯/甲醇＝10/1)得到120毫克浅黄色的焦状粗品产物(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：64.9％)。After the completion of the reaction was detected by TLC, the reaction solution was directly dried and purified by silica gel column chromatography (eluent: dichloro/methanol=10/1) to obtain 120 mg of pale yellow coke-like crude product (S)-2-( (4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 64.9%).
步骤C：合成(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000448
Figure PCTCN2021120978-appb-000448
将(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(120毫克,0.20毫摩尔)溶于二氯甲烷(2毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌3小时后,LC-MS监测至反应完全。(S)-2-((4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (120 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), Then trifluoroacetic acid (0.4 mL) was added to the reaction solution, and after stirring at room temperature for 3 hours, LC-MS was monitored until the reaction was complete.
将反应液用饱和碳酸氢钠溶液调至pH 8-9，直接拉干后用碱性反相制备分离纯化。得到5.01毫克浅黄色固体(S)-2-((4-(6-(咪唑并[1,5-a]吡啶-6-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：4.5％)。LC-MS：RT＝1.57min，[M+H] +＝553.32。 The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate solution, directly pulled to dryness, and separated and purified by basic reverse-phase preparation. 5.01 mg of pale yellow solid (S)-2-((4-(6-(imidazo[1,5-a]pyridin-6-ylmethoxy)pyridin-2-yl)piperidin-1-yl was obtained )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 4.5%). LC-MS: RT=1.57 min, [M+H] + =553.32.
实施例86Example 86
合成(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000449
Figure PCTCN2021120978-appb-000449
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step A: Synthesis of (S)-2-((4-(6-(isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000450
Figure PCTCN2021120978-appb-000450
将异喹啉-1-基甲醇(50毫克,0.31毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(172毫克,0.35毫摩尔)，碳酸铯(154毫克,0.47毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(27毫克,0.03毫摩尔)加入反应 瓶中，加入1,4-二氧六环(2毫升)，鼓入氮气1分钟后,在氮气保护下反应液在100摄氏度下搅拌16小时。The isoquinolin-1-ylmethanol (50 mg, 0.31 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (172 mg, 0.35 mmol), cesium carbonate (154 mg, 0.47 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl) -2-yl)palladium(II) (27 mg, 0.03 mmol) was added to the reaction flask, 1,4-dioxane (2 mL) was added, and nitrogen was bubbled for 1 minute. Under nitrogen protection, the reaction solution was Stir at 100°C for 16 hours.
TLC检测反应完全后，将反应液拉干后用硅胶柱层析纯化(洗脱剂：二氯/甲醇＝10/1)得到15毫克浅黄色的焦状产物(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：7.7％)。LC-MS：RT＝1.70min，[M+H] +＝620.36。 After the completion of the reaction was detected by TLC, the reaction solution was dried and purified by silica gel column chromatography (eluent: dichloro/methanol=10/1) to obtain 15 mg of light yellow coke-like product (S)-2-((4 -(6-(Isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 7.7%). LC-MS: RT=1.70 min, [M+H] + =620.36.
步骤B：合成(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-(isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000451
Figure PCTCN2021120978-appb-000451
将(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(15毫克,0.02毫摩尔)溶于二氯甲烷(1毫升)中,然后将三氟乙酸(0.2毫升)加入反应液中,室温搅拌3小时后,LC-MS监测至反应完全。(S)-2-((4-(6-(isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetine -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (15 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) was added to the reaction solution, stirred at room temperature for 3 hours, and monitored by LC-MS until the reaction was complete.
将反应液直接拉干后用碱性反相制备分离纯化。得到1.98毫克白色固体(S)-2-((4-(6-(异喹啉-1-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：14.1％)。LC-MS：RT＝1.63min，[M+H] +＝564.34。 The reaction solution was directly pulled to dryness and then separated and purified by alkaline reverse-phase preparation. Obtained 1.98 mg of white solid (S)-2-((4-(6-(isoquinolin-1-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 14.1%). LC-MS: RT=1.63 min, [M+H] + =564.34.
实施例87Example 87
合成(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((6-chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000452
Figure PCTCN2021120978-appb-000452
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(6-氯喹啉-3-基)甲醇Step A: Synthesis of (6-chloroquinolin-3-yl)methanol
Figure PCTCN2021120978-appb-000453
Figure PCTCN2021120978-appb-000453
将6-氯喹啉-3-羧酸(150毫克,0.73毫摩尔)溶于四氢呋喃(2毫升)中,冷却至零度后，将硼烷溶液(1.45毫升，1.45毫摩尔，1M硼烷在四氢呋喃溶液)缓慢的加入，加入完全后在室温下搅拌2小时。6-Chloroquinoline-3-carboxylic acid (150 mg, 0.73 mmol) was dissolved in tetrahydrofuran (2 mL), and after cooling to zero, a solution of borane (1.45 mL, 1.45 mmol, 1M borane in tetrahydrofuran was added) ) was added slowly, and after the addition was complete, the mixture was stirred at room temperature for 2 hours.
TLC显示原料反应完全，有新点生成。向反应液中加入水(2毫升)并在室温下搅拌0.5小时。将反应液拉干后用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到60毫克浅黄色固体(6-氯喹啉-3-基)甲醇(收率：42.9％)。LC-MS：RT＝1.66min，[M+H] +＝194.13。 TLC showed that the starting material was completely reacted and new spots were formed. Water (2 mL) was added to the reaction solution, followed by stirring at room temperature for 0.5 hour. The reaction solution was dried and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 60 mg of pale yellow solid (6-chloroquinolin-3-yl)methanol (yield: 42.9 %). LC-MS: RT=1.66 min, [M+H] + =194.13.
步骤B：合成(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step B: Synthesis of (S)-2-((4-(6-((6-chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000454
Figure PCTCN2021120978-appb-000454
将(6-氯喹啉-3-基)甲醇(55毫克,0.28毫摩尔),(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(155毫克,0.31毫摩尔)，碳酸铯(139毫克,0.43毫摩尔)和甲烷磺 酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(24毫克,0.03毫摩尔)加入反应瓶中,加入1,4-二氧六环(2毫升)，鼓入氮气1分钟后,在氮气保护下反应液在100摄氏度下搅拌16小时。(6-Chloroquinolin-3-yl)methanol (55 mg, 0.28 mmol), (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methan yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (155 mg, 0.31 mmol), cesium carbonate (139 mg, 0.43 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1' - Biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol) was added to the reaction flask, 1,4-dioxane (2 mL) was added, and nitrogen was bubbled for 1 min, under nitrogen protection The reaction solution was stirred at 100 degrees Celsius for 16 hours.
TLC检测反应完全后，将反应液直接拉干后用硅胶柱层析纯化(洗脱剂：二氯/甲醇＝10/1)得到110毫克浅黄色的焦状产物(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：59.2％)。LC-MS：RT＝1.90min，[M+H] +＝654.41。 After the completion of the reaction detected by TLC, the reaction solution was directly dried and purified by silica gel column chromatography (eluent: dichloro/methanol=10/1) to obtain 110 mg of light yellow coke-like product (S)-2-(( 4-(6-((6-Chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 59.2%). LC-MS: RT=1.90 min, [M+H] + =654.41.
步骤C：合成(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-((6-chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000455
Figure PCTCN2021120978-appb-000455
将(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克,0.15毫摩尔)溶于二氯甲烷(2毫升)中,然后将三氟乙酸(0.4毫升)加入反应液中,室温搅拌3小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((6-chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), then trifluoro Acetic acid (0.4 mL) was added to the reaction solution, stirred at room temperature for 3 hours, and monitored by LC-MS until the reaction was complete.
将反应液直接拉干后用碱性反相制备分离纯化。得到15.28毫克白色固体(S)-2-((4-(6-((6-氯喹啉-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：16.3％)。LC-MS：RT＝1.75min，[M+H] +＝598.27。 1H NMR(400MHz,DMSO)δ9.04(d,J＝2.1Hz,1H),8.40(s,1H),8.12(d,J＝2.4Hz,1H),8.06–8.00(m,2H),7.80–7.72(m,2H),7.67–7.61(m,1H),7.39(d,J＝8.2Hz,1H),6.88(d,J＝7.3Hz,1H),6.72(d,J＝8.1Hz,1H),5.57(s,2H),5.15–5.05(m,1H),4.71(dd,J＝15.2,6.9Hz,1H),4.59(dd,J＝15.0,3.1Hz,1H),4.47(dd,J＝13.7,7.5Hz,1H),4.36(dt,J＝9.3,6.0Hz,1H),3.89(d,J＝13.4Hz,1H),3.75(d,J＝13.2Hz,1H),2.98(d,J＝10.0Hz,1H),2.87(d,J＝11.1Hz,1H),2.72–2.55(m,2H),2.46–2.40(m,1H),2.25–2.11(m,2H),1.74(dd,J＝29.6,12.5Hz,4H)。 The reaction solution was directly pulled to dryness and then separated and purified by alkaline reverse-phase preparation. 15.28 mg of white solid (S)-2-((4-(6-((6-chloroquinolin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 16.3%). LC-MS: RT=1.75 min, [M+H] + =598.27. 1 H NMR(400MHz,DMSO)δ9.04(d,J=2.1Hz,1H),8.40(s,1H),8.12(d,J=2.4Hz,1H),8.06-8.00(m,2H), 7.80-7.72(m,2H),7.67-7.61(m,1H),7.39(d,J=8.2Hz,1H),6.88(d,J=7.3Hz,1H),6.72(d,J=8.1Hz ,1H),5.57(s,2H),5.15–5.05(m,1H),4.71(dd,J=15.2,6.9Hz,1H),4.59(dd,J=15.0,3.1Hz,1H),4.47( dd,J＝13.7,7.5Hz,1H),4.36(dt,J＝9.3,6.0Hz,1H),3.89(d,J＝13.4Hz,1H),3.75(d,J＝13.2Hz,1H), 2.98(d,J=10.0Hz,1H), 2.87(d,J=11.1Hz,1H), 2.72-2.55(m,2H), 2.46-2.40(m,1H), 2.25-2.11(m,2H) , 1.74 (dd, J=29.6, 12.5 Hz, 4H).
实施例88Example 88
合成(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-Fluoroquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000456
Figure PCTCN2021120978-appb-000456
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-氨基-2-氟-5-硝基苯甲酸Step A: Synthesis of 4-amino-2-fluoro-5-nitrobenzoic acid
Figure PCTCN2021120978-appb-000457
Figure PCTCN2021120978-appb-000457
25摄氏度下，2,4-二氟-5-硝基苯甲酸(500毫克，2.47毫摩尔)溶于1,4-二氧六环(10毫升)中，再加入氢氧化铵(10毫升)，搅拌8小时。2,4-Difluoro-5-nitrobenzoic acid (500 mg, 2.47 mmol) was dissolved in 1,4-dioxane (10 mL) at 25°C, followed by ammonium hydroxide (10 mL) , and stirred for 8 hours.
反应结束后，反应液过滤，收集滤饼，40摄氏度真空干燥,所得黄色固体直接用于下一步反应，得4-氨基-2-氟-5-硝基苯甲酸380毫克(收率：77.7％)。LC-MS：RT＝1.64min,[M+H] +＝199.05。 After the reaction, the reaction solution was filtered, the filter cake was collected, and the resulting yellow solid was vacuum-dried at 40 degrees Celsius. The obtained yellow solid was directly used in the next step to obtain 380 mg of 4-amino-2-fluoro-5-nitrobenzoic acid (yield: 77.7%). ). LC-MS: RT=1.64 min, [M+H] + =199.05.
步骤B：合成4，5-二氨基-2-氟苯甲酸Step B: Synthesis of 4,5-diamino-2-fluorobenzoic acid
Figure PCTCN2021120978-appb-000458
Figure PCTCN2021120978-appb-000458
将4-氨基-2-氟-5-硝基苯甲酸(380毫克，1.91毫摩尔)溶于甲醇(10毫升)中，加入钯碳催化剂(366毫克，0.1当量，10％的钯负载于炭，55％的水润湿)，50摄氏度下于氢气氛围中搅拌反应6小时。4-Amino-2-fluoro-5-nitrobenzoic acid (380 mg, 1.91 mmol) was dissolved in methanol (10 mL) and a palladium-carbon catalyst (366 mg, 0.1 equiv, 10% palladium on carbon was added) , 55% water wet), and the reaction was stirred at 50 degrees Celsius in a hydrogen atmosphere for 6 hours.
反应结束后，反应液过滤，收集滤液，浓缩,所得黄色固体直接用于下一步反应，得4，5-二氨基-2-氟苯甲酸320毫克(收率：98.5％)。LC-MS：RT＝0.31min,[M+H] +＝171.25。 After the reaction, the reaction solution was filtered, the filtrate was collected, concentrated, and the obtained yellow solid was directly used in the next reaction to obtain 320 mg of 4,5-diamino-2-fluorobenzoic acid (yield: 98.5%). LC-MS: RT=0.31 min, [M+H] + =171.25.
步骤C：合成7-氟喹喔啉-6-羧酸Step C: Synthesis of 7-fluoroquinoxaline-6-carboxylic acid
Figure PCTCN2021120978-appb-000459
Figure PCTCN2021120978-appb-000459
将4，5-二氨基-2-氟苯甲酸(320毫克，1.88毫摩尔)，乙二醛(272毫克，1.88毫摩尔,40％的水溶液)溶于乙醇(10毫升)中，加入乙酸(2毫升)，氮气保护下回流2小时。4,5-Diamino-2-fluorobenzoic acid (320 mg, 1.88 mmol), glyoxal (272 mg, 1.88 mmol, 40% in water) were dissolved in ethanol (10 mL) and acetic acid ( 2 mL), refluxed for 2 hours under nitrogen protection.
反应结束后，降至室温，反应液减压浓缩,浓缩液用乙酸乙酯(30毫升)稀释，并用饱和食盐水(30毫升×升次)洗涤，分液，有机相用无水硫酸钠干燥，随后减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝15/1)。得淡黄色固体7-氟喹喔啉-6-羧酸236毫克(收率：65.4％)。LC-MS：RT＝1.48min,[M+H] +＝191.09。 After the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, the concentrated solution was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL×L), separated, and the organic phase was dried over anhydrous sodium sulfate. , followed by concentration under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: dichloromethane/methanol=15/1). 236 mg of 7-fluoroquinoxaline-6-carboxylic acid was obtained as a pale yellow solid (yield: 65.4%). LC-MS: RT=1.48 min, [M+H] + =191.09.
步骤D：合成7-氟喹喔啉-6-羧酸甲酯Step D: Synthesis of methyl 7-fluoroquinoxaline-6-carboxylate
Figure PCTCN2021120978-appb-000460
Figure PCTCN2021120978-appb-000460
将7-氟喹喔啉-6-羧酸(235毫克，1.23毫摩尔)溶于甲醇(5毫升)中，0℃下加入缓慢滴入二氯亚砜(438毫克，3.69毫摩尔)，保温搅拌10分钟，随后升温至60摄氏度搅拌反应2小时。7-Fluoroquinoxaline-6-carboxylic acid (235 mg, 1.23 mmol) was dissolved in methanol (5 mL), and thionyl chloride (438 mg, 3.69 mmol) was slowly added dropwise at 0 °C, and the mixture was incubated. Stir for 10 minutes, then warm to 60 degrees Celsius and stir the reaction for 2 hours.
反应结束后，降至室温，减压浓缩,所得黄色固体直接用于下一步反应，得淡7-氟喹喔啉-6-羧酸甲酯251毫克(收率：100％)。LC-MS：RT＝1.74min,[M+H] +＝207.13。 After the reaction, it was lowered to room temperature and concentrated under reduced pressure. The obtained yellow solid was directly used in the next reaction to obtain 251 mg of light 7-fluoroquinoxaline-6-carboxylate methyl ester (yield: 100%). LC-MS: RT=1.74 min, [M+H] + =207.13.
步骤E：合成7-氟喹喔啉-6-甲醇Step E: Synthesis of 7-Fluoroquinoxaline-6-methanol
Figure PCTCN2021120978-appb-000461
Figure PCTCN2021120978-appb-000461
零摄氏度下，将7-氟喹喔啉-6-羧酸甲酯(102毫克，0.50毫摩尔)溶于四氢呋喃(2毫升)中，氮气保护下，分批加入氢化锂铝(76毫克，2.0毫摩尔),搅拌1小时。At zero degrees Celsius, methyl 7-fluoroquinoxaline-6-carboxylate (102 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (76 mg, 2.0 mmol), and stirred for 1 hour.
反应结束后，冰浴下缓慢加入滴加氢氧化钠溶液(5％,0.2毫升)，反应液用硅藻土过滤，然后硅藻土用混合溶剂(10毫升×升次,二氯甲烷/甲醇＝10/1)冲洗，合并有机相，然后用饱和食盐水(10毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝15/1)，得7-氟喹喔啉-6-甲醇49毫克(收率：55.1％)。LC-MS：RT＝1.52min,[M+H] +＝179.12。 After the reaction, sodium hydroxide solution (5%, 0.2 ml) was slowly added dropwise under ice bath, the reaction solution was filtered with celite, and then the celite was mixed with solvent (10 ml × liter, dichloromethane/methanol). =10/1), the organic phases were combined, then washed with saturated brine (10 mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: two Methyl chloride/methanol=15/1) to obtain 49 mg of 7-fluoroquinoxaline-6-methanol (yield: 55.1%). LC-MS: RT=1.52 min, [M+H] + =179.12.
步骤F：合成(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step F: Synthesis of (S)-2-((4-(6-((7-Fluoroquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000462
Figure PCTCN2021120978-appb-000462
将7-氟-2-甲基喹喔啉-6-甲醇(34毫克，0.19毫摩尔),(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依 次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度,搅拌1小时。7-Fluoro-2-methylquinoxaline-6-methanol (34 mg, 0.19 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidine-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1,4 - dioxane (1 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束后，冷却至室温，向反应液中缓慢加入饱和氯化铵溶液至pH为中性，然后用乙酸乙酯(10毫升×升次)萃取，合并有机相，然后用饱和食盐水(20毫升×升次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得淡黄色固体(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯58毫克(收率：65.2％)。LC-MS：RT＝1.85min,[M+H] +＝639.41。 After the reaction was completed, it was cooled to room temperature, and saturated ammonium chloride solution was slowly added to the reaction solution until the pH was neutral, then extracted with ethyl acetate (10 mL×L), the organic phases were combined, and then saturated brine (20 mL) was used for extraction. mL×L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A pale yellow solid was obtained (S)-2-((4-(6-((7-fluoroquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 58 mg (yield: 65.2%). LC-MS: RT=1.85 min, [M+H] + =639.41.
步骤G：合成(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step G: Synthesis of (S)-2-((4-(6-((7-Fluoroquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000463
Figure PCTCN2021120978-appb-000463
将(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(68毫克，0.10毫摩尔),溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，于25摄氏度下搅拌反应3小时。(S)-2-((4-(6-((7-Fluoroquinoxalin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (68 mg, 0.10 mmol), dissolved in mixed solvent (2 mL, dichloromethane/ Trifluoroacetic acid = 6/1), the addition was completed, and the reaction was stirred at 25 degrees Celsius for 3 hours.
反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到31毫克白色固体(S)-2-((4-(6-((7-氟喹喔啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：52.0％)。LC-MS：RT＝1.72min,[M+H] +＝583.38。 After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain 31 mg of white solid (S)-2-((4-(6-((7-fluoroquinoxalin-6-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 52.0%). LC-MS: RT=1.72 min, [M+H] + =583.38.
实施例89Example 89
合成(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000464
Figure PCTCN2021120978-appb-000464
具体合成路线如下：The specific synthetic route is as follows:
步骤A:合成3-氟-4-甲基喹啉Step A: Synthesis of 3-fluoro-4-methylquinoline
Figure PCTCN2021120978-appb-000465
Figure PCTCN2021120978-appb-000465
冰浴下，向3-氨基-4-甲基喹啉(100毫克，0.64毫摩尔)中缓慢加入40的％四氟硼酸溶液(279.6毫克，1.27毫摩尔)，冰浴下反应0.5小时。随后加入50％亚硝酸钠的水溶液(44.2毫克，0.64毫摩尔)，加毕，室温反应0.5小时。Under ice bath, 40% tetrafluoroboric acid solution (279.6 mg, 1.27 mmol) was slowly added to 3-amino-4-methylquinoline (100 mg, 0.64 mmol), and reacted under ice bath for 0.5 hours. Subsequently, a 50% aqueous solution of sodium nitrite (44.2 mg, 0.64 mmol) was added, and the addition was completed, and the reaction was carried out at room temperature for 0.5 hours.
反应结束后，将析出的固体抽滤，水洗滤饼3次，干燥得中间体备用。随后将固体加入至邻二氯苯中，升温至130摄氏度反应2小时。反应结束后，将所得固体残余物用乙酸乙酯溶解，柱层析纯化(正己烷/乙酸乙酯＝10/1)，得58毫克白色固体3-氟-4-甲基喹啉(收率：56.8％)。LC-MS：RT＝2.0min，[M+H] +＝162.12. After the reaction, the precipitated solid was suction filtered, the filter cake was washed with water 3 times, and dried to obtain an intermediate for subsequent use. Then the solid was added to o-dichlorobenzene, and the temperature was raised to 130 degrees Celsius to react for 2 hours. After the reaction, the obtained solid residue was dissolved in ethyl acetate and purified by column chromatography (n-hexane/ethyl acetate=10/1) to obtain 58 mg of white solid 3-fluoro-4-methylquinoline (yield : 56.8%). LC-MS: RT=2.0 min, [M+H] + =162.12.
步骤B:合成3-氟喹啉-4-羧酸Step B: Synthesis of 3-fluoroquinoline-4-carboxylic acid
Figure PCTCN2021120978-appb-000466
Figure PCTCN2021120978-appb-000466
室温下，将3-氟-4-甲基喹啉(82毫克，0.51毫摩尔)溶于4毫升乙酸溶液中，再加入重铬酸钾(225毫克，0.76毫摩尔),加毕，室温搅拌10分钟，随后加入2毫升浓硫酸。升温至120摄氏度反应2小时。At room temperature, 3-fluoro-4-methylquinoline (82 mg, 0.51 mmol) was dissolved in 4 mL of acetic acid solution, then potassium dichromate (225 mg, 0.76 mmol) was added, and the addition was completed, stirring at room temperature 10 minutes, followed by the addition of 2 ml of concentrated sulfuric acid. The temperature was raised to 120 degrees Celsius for 2 hours.
反应结束后，将反应液降至室温，随后倒入冰水中，加入30毫升乙酸乙酯，萃取3次，分出乙酸乙酯层，无水硫酸钠干燥，蒸干有机层得40毫克淡黄色固体3-氟喹啉-4-羧酸(收率：41.2％)。LC-MS：RT＝0.76min，[M+H] +＝192.09. After the reaction was completed, the reaction solution was cooled to room temperature, then poured into ice water, 30 ml of ethyl acetate was added, extracted three times, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and the organic layer was evaporated to dryness to obtain 40 mg of light yellow Solid 3-fluoroquinoline-4-carboxylic acid (yield: 41.2%). LC-MS: RT=0.76min, [M+H] + =192.09.
步骤C:合成(3-氟喹啉-4-基)甲醇Step C: Synthesis of (3-fluoroquinolin-4-yl)methanol
Figure PCTCN2021120978-appb-000467
Figure PCTCN2021120978-appb-000467
冰浴下，将7-氟喹啉-6-羧酸乙酯(40毫克，0.21毫摩尔)溶于3毫升无水四氢呋喃溶液中，加入1mol/L的硼烷四氢呋喃溶液0.5毫升，零摄氏度反应2小时。Under ice bath, ethyl 7-fluoroquinoline-6-carboxylate (40 mg, 0.21 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran solution, 0.5 mL of 1 mol/L borane tetrahydrofuran solution was added, and the reaction was carried out at zero degrees Celsius. 2 hours.
反应结束后，反应液加入0.5毫升甲醇溶液淬灭反应，反应液倒入水中。加入30毫升乙酸乙酯，萃取3次，分出乙酸乙酯层，无水硫酸钠干燥，蒸干有机层得30毫克淡黄色固体(3-氟喹啉-4-基)甲醇(收率：81.1％)。LC-MS：RT＝1.59min，[M+H] +＝178.16. After the reaction, 0.5 ml of methanol solution was added to the reaction solution to quench the reaction, and the reaction solution was poured into water. 30 ml of ethyl acetate was added, extracted three times, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and the organic layer was evaporated to dryness to obtain 30 mg of pale yellow solid (3-fluoroquinolin-4-yl)methanol (yield: 81.1%). LC-MS: RT=1.59 min, [M+H] + =178.16.
步骤D:合成(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000468
Figure PCTCN2021120978-appb-000468
室温下，将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(70毫克，0.14毫摩尔)、(3-氟喹啉-4-基)甲醇(30毫克，0.17毫摩尔)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(23.7毫克，0.03毫摩尔)和碳酸铯(91.3毫克，0.28毫摩尔)加入到10毫升干燥的二氧六环溶液中，N 2保护下100摄氏度反应2小时。 At room temperature, (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (70 mg, 0.14 mmol), (3-fluoroquinolin-4-yl)methanol (30 mg, 0.17 mmol), methanesulfonic acid ( 2-Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (23.7 mg, 0.03 mmol) and cesium carbonate (91.3 mg, 0.28 mmol) were added to 10 mL of dry dioxane solution and reacted at 100 °C for 2 h under N2 protection.
反应结束后，加入20毫升乙酸乙酯，萃取，分出乙酸乙酯层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得45毫克白色固体(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：50.0％)。LC-MS：RT＝1.89min，[M+H] +＝638.41. After the reaction, 20 ml of ethyl acetate was added, extracted, and the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 45 mg of white solid (S)-2-((4-(6-((3-fluoroquinolin-4-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (received rate: 50.0%). LC-MS: RT=1.89 min, [M+H] + =638.41.
步骤E:合成(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000469
Figure PCTCN2021120978-appb-000469
室温下，(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(45毫克，0.071毫摩尔)溶于6毫升二氯甲烷溶液中，冰浴下滴加0.5毫升三氟乙酸。室温反应4小时。(S)-2-((4-(6-((3-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 at room temperature -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (45 mg, 0.071 mmol) was dissolved in 6 mL dichloromethane solution, ice bath 0.5 ml of trifluoroacetic acid was added dropwise. The reaction was carried out at room temperature for 4 hours.
反应结束后，向反应液中加入20毫升二氯甲烷稀释反应液，随后加水洗涤二氯甲烷层三次，分出有机层，无水硫酸钠干燥，蒸干得淡黄色固体。柱层析纯化(二氯甲烷/甲醇＝10/1)，得20毫克白色固体(S)-2-((4-(6-((3-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：48.7％)。After the reaction, 20 ml of dichloromethane was added to the reaction solution to dilute the reaction solution, followed by adding water to wash the dichloromethane layer three times, separating the organic layer, drying over anhydrous sodium sulfate, and evaporating to dryness to obtain a pale yellow solid. Purified by column chromatography (dichloromethane/methanol=10/1) to obtain 20 mg of white solid (S)-2-((4-(6-((3-fluoroquinolin-4-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 48.7 %).
实施例90Example 90
合成(S)-2-((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxygen Hetidine-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000470
Figure PCTCN2021120978-appb-000470
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-氯-8-甲基喹啉Step A: Synthesis of 4-chloro-8-methylquinoline
Figure PCTCN2021120978-appb-000471
Figure PCTCN2021120978-appb-000471
冰水浴下，将8-甲基喹啉-4(1H)-酮(300毫克，1.88毫摩尔)溶于三氯氧磷(2毫升)中，温度升高到100摄氏度搅拌0.5个小时。Under ice-water bath, 8-methylquinolin-4(1H)-one (300 mg, 1.88 mmol) was dissolved in phosphorus oxychloride (2 mL), the temperature was raised to 100°C and stirred for 0.5 h.
反应结束后，滴加到40摄氏度左右水中淬灭反应，混合液用乙酸乙酯萃取(10毫升×升次)，合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，浓缩得到300毫克白色固体4-氯-8-甲基喹啉(收率：90％)。LC-MS:RT＝2.07min,[M+H] +＝178.07。 After the reaction was completed, the reaction was quenched by adding dropwise to water at about 40 degrees Celsius, the mixed solution was extracted with ethyl acetate (10 ml × liter times), the organic phases were combined and dried with anhydrous sodium sulfate, the organic phase was concentrated after filtration, and concentrated to obtain 300 mg 4-Chloro-8-methylquinoline as a white solid (yield: 90%). LC-MS: RT=2.07 min, [M+H] + =178.07.
步骤B：合成8-(溴甲基)-4-氯喹啉Step B: Synthesis of 8-(bromomethyl)-4-chloroquinoline
Figure PCTCN2021120978-appb-000472
Figure PCTCN2021120978-appb-000472
冰水浴下，将4-氯-8-甲基喹啉(300毫克，1.67毫摩尔),N-溴代丁二酰亚胺(356毫克，2.0毫摩尔)溶于四氯化碳(5毫升)中，温度升高到80摄氏度搅拌4个小时。Under ice-water bath, dissolve 4-chloro-8-methylquinoline (300 mg, 1.67 mmol), N-bromosuccinimide (356 mg, 2.0 mmol) in carbon tetrachloride (5 mL ), the temperature was raised to 80°C and stirred for 4 hours.
反应结束后，冷却至室温，过滤后浓缩，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到300毫克白色固体8-(溴甲基)-4-氯喹啉(收率：70％)。LC-MS:RT＝2.17min,[M+H] +＝256.09。 After the reaction was completed, it was cooled to room temperature, filtered and concentrated, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 300 mg of white solid 8-(bromomethyl)- 4-Chloroquinoline (yield: 70%). LC-MS: RT=2.17 min, [M+H] + =256.09.
步骤C：合成(4-氯喹啉-8-基)乙酸甲酯Step C: Synthesis of methyl (4-chloroquinolin-8-yl)acetate
Figure PCTCN2021120978-appb-000473
Figure PCTCN2021120978-appb-000473
室温下，将8-(溴甲基)-4-氯喹啉(300毫克，1.17毫摩尔),N-溴代丁二酰亚胺(356毫克，2.0毫摩尔)溶于四氯化碳(5毫升)中，温度升高到80摄氏度搅拌4个小时。8-(Bromomethyl)-4-chloroquinoline (300 mg, 1.17 mmol), N-bromosuccinimide (356 mg, 2.0 mmol) were dissolved in carbon tetrachloride (5 ml), the temperature was raised to 80°C and stirred for 4 hours.
反应结束后，冷却至室温，过滤后浓缩，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到250毫克白色固体(4-氯喹啉-8-基)乙酸甲酯(收率：90％)。LC-MS:RT＝2.04min,[M+H] +＝236.10。 After the reaction was completed, it was cooled to room temperature, filtered and concentrated, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 250 mg of white solid (4-chloroquinoline-8- yl) methyl acetate (yield: 90%). LC-MS: RT=2.04 min, [M+H] + =236.10.
步骤D：合成(4-氯喹啉-8-基)甲醇Step D: Synthesis of (4-chloroquinolin-8-yl)methanol
Figure PCTCN2021120978-appb-000474
Figure PCTCN2021120978-appb-000474
室温下，将(4-氯喹啉-8-基)乙酸甲酯(250毫克，1.06毫摩尔),氢氧化钠(85毫克，2.12毫摩尔)溶于甲醇(4毫升)和水(1毫升)中，室温下搅拌1个小时。Methyl (4-chloroquinolin-8-yl)acetate (250 mg, 1.06 mmol), sodium hydroxide (85 mg, 2.12 mmol) were dissolved in methanol (4 mL) and water (1 mL) at room temperature , and stirred at room temperature for 1 hour.
反应结束后，加入水稀释，用乙酸乙酯(10毫升×升次)萃取，合并并干燥有机相，浓缩得到200毫克黄色固体(4-氯喹啉-8-基)甲醇(收率：97％)。LC-MS:RT＝1.71min,[M+H] +＝194.07。 After the reaction, add water to dilute, extract with ethyl acetate (10 mL×L), combine and dry the organic phases, and concentrate to obtain 200 mg of yellow solid (4-chloroquinolin-8-yl) methanol (yield: 97%) ). LC-MS: RT=1.71 min, [M+H] + =194.07.
步骤E：合成4-(6-(((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step E: Synthesis of tert-butyl 4-(6-(((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000475
Figure PCTCN2021120978-appb-000475
室温下，将(4-氯喹啉-8-基)甲醇(200毫克，1.0毫摩尔)溶于四氢呋喃(5毫升)中，冰水浴下加入氢化钠(80毫克，2.0毫摩尔)，室温下搅拌0.5个小时，加入4-(6-氟吡啶-2-基)哌啶-1-甲酸叔丁酯(336毫克，1.2毫摩尔)。At room temperature, (4-chloroquinolin-8-yl)methanol (200 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (80 mg, 2.0 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature. Over 0.5 hours, tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (336 mg, 1.2 mmol) was added.
反应结束后，到入水中淬灭反应，用乙酸乙酯萃取(30毫升×升次)，合并有机相并用无水硫酸钠干燥，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到80毫克无色油状物4-(6-(((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：18％)。LC-MS:RT＝2.34min,[M+H] +＝454.27。 After the reaction was completed, the reaction was quenched into water, extracted with ethyl acetate (30 mL×L), the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate). ester/n-hexane = 1/10) to give 80 mg of tertiary 4-(6-(((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid as a colorless oil Butyl ester (yield: 18%). LC-MS: RT=2.34 min, [M+H] + =454.27.
步骤F：合成4-氯-8-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉Step F: Synthesis of 4-chloro-8-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
Figure PCTCN2021120978-appb-000476
Figure PCTCN2021120978-appb-000476
室温下，将4-(6-(((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(80毫克，0.18毫摩尔)溶于二氧六环(2毫升)中，冰水浴下加入氯化氢二氧六环溶液(2毫升)，室温下搅拌0.5个小时。At room temperature, tert-butyl 4-(6-(((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (80 mg, 0.18 mmol) was dissolved in In dioxane (2 mL), hydrogen chloride dioxane solution (2 mL) was added under ice-water bath, and the mixture was stirred at room temperature for 0.5 hour.
反应结束后，浓缩得到70毫克白色固体4-氯-8-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(收率：97％)。LC-MS:RT＝1.65min,[M+H] +＝354.25。 After the reaction, concentrated to obtain 70 mg of white solid 4-chloro-8-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (yield: 97 %).LC-MS: RT=1.65 min, [M+H] + =354.25.
步骤G：合成(S)-2-(((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step G: Synthesis of (S)-2-(((4-(6-((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000477
Figure PCTCN2021120978-appb-000477
室温下，将4-氯-8-((((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(70毫克0.18毫摩尔)溶于N,N-二甲基甲酰胺(2毫升)中，加入(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(64毫克，0.22毫摩尔)，搅拌加入碳酸铯(326毫克，0.54毫摩尔)，室温下搅拌3个小时。4-Chloro-8-((((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (70 mg 0.18 mmol) was dissolved in N at room temperature, N-dimethylformamide (2 mL) was added (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole- Methyl 6-carboxylate (64 mg, 0.22 mmol), cesium carbonate (326 mg, 0.54 mmol) was added with stirring, and the mixture was stirred at room temperature for 3 hours.
反应结束后，加入饱和氯化钠淬灭反应，混合液用乙酸乙酯萃取(10毫升×2次)，合并有机相并用无水硫酸钠干燥，过滤后浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到50毫克无色油状液体(S)-2-(((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：42％)。LC-MS:RT＝1.97min,[M+H] +＝654.36。 After the reaction was completed, saturated sodium chloride was added to quench the reaction, the mixture was extracted with ethyl acetate (10 ml × 2 times), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the obtained crude product was subjected to a silica gel column layer. analytical purification (eluent: ethyl acetate/n-hexane=1/1) to give 50 mg of colorless oily liquid (S)-2-(((4-(6-((4-chloroquinolin-8-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert. Butyl ester (yield: 42%). LC-MS: RT=1.97 min, [M+H] + =654.36.
步骤H：合成(S)-2-(((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step H: Synthesis of (S)-2-(((4-(6-((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000478
Figure PCTCN2021120978-appb-000478
将(S)-2-(((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50毫克，0.07毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-(((4-(6-((4-chloroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL) and added at room temperature Trifluoroacetic acid (1 mL) was reacted for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到37.94毫克白色固体(S)-2-(((4-(6-((4-氯喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：83％)。LC-MS:RT＝1.82min,[M+H] +＝598.27。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 37.94 mg of white solid (S)-2-(((4-(6-((4-chloroquinolin-8-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 83%).LC -MS: RT=1.82 min, [M+H] + =598.27.
实施例91Example 91
合成(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000479
Figure PCTCN2021120978-appb-000479
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-氟吡唑并[1,5-a]吡啶-4-羧酸甲酯Step A: Synthesis of methyl 3-fluoropyrazolo[1,5-a]pyridine-4-carboxylate
Figure PCTCN2021120978-appb-000480
Figure PCTCN2021120978-appb-000480
室温下，将吡唑并[1,5-a]吡啶-4-羧酸甲酯(200.0毫克，1.14毫摩尔)和选择性氟试剂(403.9毫克，1.14毫摩尔)加入N,N-二甲基甲酰胺(3.0毫升)中，滴加三氟甲磺酸(1.0毫升)，微波反应20分钟。Methyl pyrazolo[1,5-a]pyridine-4-carboxylate (200.0 mg, 1.14 mmol) and selective fluorine reagent (403.9 mg, 1.14 mmol) were added to N,N-dimethyl at room temperature Trifluoromethanesulfonic acid (1.0 mL) was added dropwise to dimethylformamide (3.0 mL), and the reaction was microwaved for 20 minutes.
反应结束，冷却至室温，乙酸乙酯稀释，加水淬灭，混合液用乙酸乙酯(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到140.0毫克无色透明液体3-氟吡唑并[1,5-a]吡啶-4-羧酸甲酯(收率：63.0％)。LC-MS:RT＝1.75min,[M+H] +＝195.10。 The reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×L), the organic phases were combined, and the organic phase was washed with saturated brine (20 mL×L). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). 140.0 mg of methyl 3-fluoropyrazolo[1,5-a]pyridine-4-carboxylate was obtained as a colorless transparent liquid (yield: 63.0%). LC-MS: RT=1.75 min, [M+H] + =195.10.
步骤B：合成(3-氟吡唑并[1,5-a]吡啶-4-基)甲醇Step B: Synthesis of (3-fluoropyrazolo[1,5-a]pyridin-4-yl)methanol
Figure PCTCN2021120978-appb-000481
Figure PCTCN2021120978-appb-000481
零摄氏度下，向含有3-氟吡唑并[1,5-a]吡啶-4-羧酸甲酯(140.0毫克，0.72毫摩尔)的四氢呋喃中，加入氢化铝锂(41.8毫克，1.1毫摩尔)，室温反应1小时。To methyl 3-fluoropyrazolo[1,5-a]pyridine-4-carboxylate (140.0 mg, 0.72 mmol) in tetrahydrofuran at zero degrees Celsius was added lithium aluminum hydride (41.8 mg, 1.1 mmol) ) for 1 hour at room temperature.
反应结束，加水淬灭，加入氢氧化钠溶液至反应液澄清，混合液用乙酸乙酯(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/5)。得到50.0毫克无色透明液体3-氟吡唑并[1,5-a]吡啶-4-基)甲醇(收率：41.6％)。LC-MS:RT＝1.51min,[M+H] +＝167.11。 The reaction was completed, quenched by adding water, sodium hydroxide solution was added until the reaction solution was clear, the mixture was extracted with ethyl acetate (20 mL×L), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL×L) Washed, then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/5). 50.0 mg of 3-fluoropyrazolo[1,5-a]pyridin-4-yl)methanol was obtained as a colorless transparent liquid (yield: 41.6%). LC-MS: RT=1.51 min, [M+H] + =167.11.
步骤C：合成(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((3-Fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000482
Figure PCTCN2021120978-appb-000482
零摄氏度下，向含有3-氟吡唑并[1,5-a]吡啶-4-基)甲醇(50.0毫克，0.30毫摩尔)的1,4-二氧六环中，加入(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(148.8毫克，0.30毫摩尔)、碳酸铯(195.0毫克，0.60毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(50.8毫克，0.06毫摩尔)，100摄氏度反应2小时。To 1,4-dioxane containing 3-fluoropyrazolo[1,5-a]pyridin-4-yl)methanol (50.0 mg, 0.30 mmol) at zero degrees Celsius, (S)- 2-(((4-(6-Chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] tert-Butyl imidazole-6-carboxylate (148.8 mg, 0.30 mmol), cesium carbonate (195.0 mg, 0.60 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'- Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (50.8 mg, 0.06 mmol), reacted at 100 degrees Celsius for 2 hours .
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到90.0毫克黄色油状物(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧 基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：47.9％)。LC-MS:RT＝1.84min,[M+H] +＝627.37。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×L), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×L), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 90.0 mg of (S)-2-((4-(6-((3-fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl) was obtained as a yellow oil Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 47.9%). LC-MS: RT=1.84 min, [M+H] + =627.37.
步骤D：合成(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((3-Fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000483
Figure PCTCN2021120978-appb-000483
室温下，将(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(90.0毫克，0.14毫摩尔)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(1.0毫升)，室温反应2小时。(S)-2-((4-(6-((3-Fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (90.0 mg, 0.14 mmol) was added to two Trifluoroacetic acid (1.0 mL) was added dropwise to methyl chloride (2.0 mL), and the mixture was reacted at room temperature for 2 hours.
反应结束，蒸干二氯甲烷并用油泵抽干三氟乙酸，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到45.0毫克白色固体(S)-2-((4-(6-((3-氟吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：56.4％)。LC-MS:RT＝1.70min,[M+H] +＝571.31。 After the reaction was completed, dichloromethane was evaporated to dryness and trifluoroacetic acid was evaporated to dryness with an oil pump, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 45.0 mg of white solid (S)-2-((4-(6-((3-fluoropyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine was obtained Perid-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 56.4%). LC-MS: RT=1.70 min, [M+H] + =571.31.
实施例92Example 92
合成(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000484
Figure PCTCN2021120978-appb-000484
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成7-氟-4-甲基喹啉Step A: Synthesis of 7-fluoro-4-methylquinoline
Figure PCTCN2021120978-appb-000485
Figure PCTCN2021120978-appb-000485
将4-溴-7-氟喹啉(300.0毫克,1.33毫摩尔)溶于1,4-二氧六环(3.0毫升)中,加入三甲基环三硼氧烷(0.4毫升,1.33毫摩尔，3.5摩尔/升),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(108.6毫克，1.33毫摩尔),碳酸钾水溶液(1.0毫升,2.0摩尔/升)。置换氮气后，氮气保护下,100摄氏度搅拌反应4小时。过滤，旋干滤液，柱层析分离(洗脱剂：乙酸乙酯/正己烷＝1/5)，得到200.0毫克米黄色固体7-氟-4-甲基喹啉(收率：93.5％)。LC-MS：RT＝0.84min,[M+H] +＝162.14。 4-Bromo-7-fluoroquinoline (300.0 mg, 1.33 mmol) was dissolved in 1,4-dioxane (3.0 mL) and trimethylcyclotriboroxane (0.4 mL, 1.33 mmol) was added , 3.5 mol/L), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (108.6 mg, 1.33 mmol), aqueous potassium carbonate (1.0 mL, 2.0 moles/liter). After replacing nitrogen, the reaction was stirred at 100 degrees Celsius for 4 hours under nitrogen protection. Filter, spin dry the filtrate, and separate by column chromatography (eluent: ethyl acetate/n-hexane=1/5) to obtain 200.0 mg of beige solid 7-fluoro-4-methylquinoline (yield: 93.5%) . LC-MS: RT=0.84 min, [M+H] + =162.14.
步骤B：合成4-(溴甲基)-7-氟喹啉Step B: Synthesis of 4-(bromomethyl)-7-fluoroquinoline
Figure PCTCN2021120978-appb-000486
Figure PCTCN2021120978-appb-000486
将7-氟-4-甲基喹啉(200.0毫克,1.24毫摩尔)溶于四氯化碳(5.0毫升)中,加入N-溴代丁二酰亚胺(265.2毫克,1.49毫摩尔),偶氮二异丁腈(19.7毫克，0.12毫摩尔)。升温至77摄氏度搅拌反应2小时。过滤，旋干滤液，得到210.0毫克米黄色固体4-(溴甲基)-7-氟喹啉(收率：70.5％)。LC-MS：RT＝1.88min,[M+H] +＝240.08。 7-Fluoro-4-methylquinoline (200.0 mg, 1.24 mmol) was dissolved in carbon tetrachloride (5.0 mL), N-bromosuccinimide (265.2 mg, 1.49 mmol) was added, Azobisisobutyronitrile (19.7 mg, 0.12 mmol). The temperature was raised to 77°C and the reaction was stirred for 2 hours. After filtration, the filtrate was spin-dried to obtain 210.0 mg of 4-(bromomethyl)-7-fluoroquinoline as a beige solid (yield: 70.5%). LC-MS: RT=1.88 min, [M+H] + =240.08.
步骤C：合成(7-氟喹啉-4-基)乙酸甲酯Step C: Synthesis of Methyl (7-fluoroquinolin-4-yl)acetate
Figure PCTCN2021120978-appb-000487
Figure PCTCN2021120978-appb-000487
将4-(溴甲基)-7-氟喹啉(180.0毫克,0.75毫摩尔)溶于N,N-二甲基甲酰胺(3.0毫升)中,加入乙酸钾(147.2毫克,1.50毫摩尔)。升温至50摄氏度搅拌反应1小时。加入40毫升乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离(洗脱剂：乙酸乙酯/正己烷＝1/2)，得到150.0毫克米黄色固体(7-氟喹啉-4-基)乙酸甲酯(收率：91.3％)。LC-MS：RT＝1.73min,[M+H] +＝220.15。 4-(Bromomethyl)-7-fluoroquinoline (180.0 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (3.0 mL) and potassium acetate (147.2 mg, 1.50 mmol) was added . The temperature was raised to 50 degrees Celsius and the reaction was stirred for 1 hour. 40 mL of ethyl acetate was added to dilute, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 150.0 mg of beige solid (7-fluoro Methyl quinolin-4-yl)acetate (yield: 91.3%). LC-MS: RT=1.73 min, [M+H] + =220.15.
步骤D：合成(7-氟喹啉-4-基)甲醇Step D: Synthesis of (7-fluoroquinolin-4-yl)methanol
Figure PCTCN2021120978-appb-000488
Figure PCTCN2021120978-appb-000488
将(7-氟喹啉-4-基)乙酸甲酯(150.0毫克,0.68毫摩尔)溶于甲醇(2.0毫升)中,加入氢氧化钠水溶液(0.7毫升,1.37毫摩尔,2.0摩尔/升)。室温条件下搅拌反应1小时。旋干溶剂，加入40毫升乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离(洗脱剂：乙酸乙酯/正己烷＝2/1)，得到64.0毫克米黄色固体(7-氟喹啉-4-基)甲醇(收率：52.8％)。LC-MS：RT＝0.60min,[M+H] +＝178.13。 Methyl (7-fluoroquinolin-4-yl)acetate (150.0 mg, 0.68 mmol) was dissolved in methanol (2.0 mL), and aqueous sodium hydroxide solution (0.7 mL, 1.37 mmol, 2.0 mol/L) was added . The reaction was stirred at room temperature for 1 hour. The solvent was spin-dried, diluted with 40 ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 64.0 mg of a beige solid (7-Fluoroquinolin-4-yl)methanol (yield: 52.8%). LC-MS: RT=0.60 min, [M+H] + =178.13.
步骤E：合成(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000489
Figure PCTCN2021120978-appb-000489
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(168.9毫克,0.36毫摩尔)溶于1,4-二氧六环(3.0毫升)中,加入(7-氟喹啉-4-基)甲醇(64.0毫克,0.36毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(30.6毫克,0.04毫摩尔)，旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝4/1)得到135.0毫克黄色油状物(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：62.3％)。LC-MS：RT＝1.86min,[M+H] +＝638.38。 (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylate tert-butyl ester (168.9 mg, 0.36 mmol) was dissolved in 1,4-dioxane (3.0 mL) and (7-fluoroquinolin-4-yl) was added Methanol (64.0 mg, 0.36 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'- Amino-1,1'-biphenyl-2-yl)palladium(II) (30.6 mg, 0.04 mmol), the solvent was spun dry, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane alkane=4/1) to give 135.0 mg of yellow oil (S)-2-((4-(6-((7-fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-(oxetan-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 62.3%). LC-MS: RT=1.86 min, [M+H] + =638.38.
步骤F：合成(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((7-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000490
Figure PCTCN2021120978-appb-000490
将(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(125.0毫克,0.20毫摩尔)溶于二氯甲烷(1.5毫升)中,加入三氟乙酸(0.5毫升),室温搅拌2小时。旋干溶剂，送制备液相分离，得51.2毫克白色固体(S)-2-((4-(6-((7-氟喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：44.9％)。LC-MS：RT＝1.69min,[M+H] +＝582.31。 (S)-2-((4-(6-((7-Fluoroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( Oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (125.0 mg, 0.20 mmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid was added (0.5 mL), and stirred at room temperature for 2 hours. The solvent was spin-dried and sent to preparative liquid phase separation to obtain 51.2 mg of white solid (S)-2-((4-(6-((7-fluoroquinolin-4-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 44.9%). LC-MS: RT=1.69 min, [M+H] + =582.31.
实施例93Example 93
合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H-indazole) -6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000491
Figure PCTCN2021120978-appb-000491
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯Step A: Synthesis of 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000492
Figure PCTCN2021120978-appb-000492
将1H-吲唑-6-羧酸甲酯(3.0克,17.04毫摩尔)和1,1,1-三氟-2-碘乙烷(3.56克,17.04毫摩尔)溶解于8毫升无水乙腈和8毫升N,N-二甲基甲酰胺中，加入碳酸铯(11.1克,34.08毫摩尔)于60摄氏度下反应2小时。反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱分离纯化得804毫克白色固体1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯。LC-MS:RT＝1.87min,[M+H] +＝259.28。 Methyl 1H-indazole-6-carboxylate (3.0 g, 17.04 mmol) and 1,1,1-trifluoro-2-iodoethane (3.56 g, 17.04 mmol) were dissolved in 8 mL of dry acetonitrile and 8 ml of N,N-dimethylformamide, add cesium carbonate (11.1 g, 34.08 mmol) and react at 60 degrees Celsius for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 mL×L), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×L), and then dried with anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was purified by column separation to obtain 804 mg of methyl 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate as a white solid. LC-MS: RT=1.87 min, [M+H] + =259.28.
步骤B：合成(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇Step B: Synthesis of (1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methanol
Figure PCTCN2021120978-appb-000493
Figure PCTCN2021120978-appb-000493
将1-(2,2,2-三氟乙基)-1H-吲唑-6-羧酸甲酯(804毫克,3.10毫摩尔)溶解于5毫升无水四氢呋喃中，零摄氏度下加入四氢锂铝(117毫克,3.10毫摩尔)于零到室温下反应40分钟，反应结束，零摄氏度下向反应液中滴加0.5毫升水淬灭，加入10克无水硫酸钠，搅拌5分钟过滤，滤液旋干得690毫克白色固体(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇。Methyl 1-(2,2,2-trifluoroethyl)-1H-indazole-6-carboxylate (804 mg, 3.10 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and tetrahydrofuran was added at zero degrees Celsius Lithium aluminum (117 mg, 3.10 mmol) was reacted at room temperature for 40 minutes, the reaction was over, 0.5 ml of water was added dropwise to the reaction solution at zero degrees Celsius to quench, 10 grams of anhydrous sodium sulfate was added, stirred for 5 minutes and filtered, The filtrate was spin-dried to give 690 mg of white solid (1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methanol.
步骤C：合成4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step C: Synthesis of 4-(6-((1-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine - tert-Butyl 1-carboxylate
Figure PCTCN2021120978-appb-000494
Figure PCTCN2021120978-appb-000494
将(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲醇(220毫克,0.956毫摩尔)和4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(238毫克,0.956毫摩尔)溶解于8毫升无水二氧六环中，加入碳酸铯(623毫克,1.912毫摩尔)和(2二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(85毫克,0.0956毫摩尔)，氮气置换3次于100摄氏度下反应7小时。反应结束，反应液加水稀释，用乙酸乙酯(50毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱(乙酸乙酯＝100％)分离得386毫克淡黄色固体4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯。LC-MS:RT＝1.81min,[M+H] +＝491.23。 Combine (1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methanol (220 mg, 0.956 mmol) and 4-(6-chloropyridin-2-yl)piperidine tert-Butyl-1-carboxylate (238 mg, 0.956 mmol) was dissolved in 8 mL of anhydrous dioxane, cesium carbonate (623 mg, 1.912 mmol) and (2-dicyclohexylphosphino-2', 4',6'-Triisopropyl-1,1'-biphenyl[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (85 mg, 0.0956 mmol) under nitrogen Replaced 3 times and reacted for 7 hours at 100 degrees Celsius. The reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (50 ml × liter), the organic phases were combined, and the organic phase was first saturated brine (20 ml × liter) Washed, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure, the crude product obtained was separated by column (ethyl acetate=100%) to obtain 386 mg of pale yellow solid 4-(6-((1-(1-(2,2, 2-Trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: RT=1.81 min, [M+H ] + = 491.23.
步骤D：合成4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶Step D: Synthesis of 4-(6-((1-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine
Figure PCTCN2021120978-appb-000495
Figure PCTCN2021120978-appb-000495
将4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(386毫克,0.786毫摩尔)溶解于5毫升甲醇中，零摄氏度下加入4M盐酸二氧六环溶液(3毫升)于零到室温下反应40分钟，反应结束，反应液直接旋干得336毫克白色固体4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶盐酸盐直接用于下一步。4-(6-((1-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine-1- Tert-butyl formate (386 mg, 0.786 mmol) was dissolved in 5 ml of methanol, 4M hydrochloric acid dioxane solution (3 ml) was added at zero degrees Celsius, and the reaction was carried out at room temperature for 40 minutes. Dry to give 336 mg of white solid 4-(6-((1-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl) Piperidine hydrochloride was used directly in the next step.
步骤E：合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯Step E: Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester
Figure PCTCN2021120978-appb-000496
Figure PCTCN2021120978-appb-000496
将4-(6-((1-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶盐酸盐(220毫克,0.417毫摩尔)和(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(135毫克,0.417毫摩尔)溶解于5毫升无水乙腈中，加入碳酸铯(272毫克,0.834毫摩尔)于50摄氏度下反应1.5小时。反应结束，反应液加水稀释，用乙酸乙酯(30毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×升次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱分离纯化得221毫克淡黄色固体(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯。LC-MS:RT＝1.86min,[M+H] +＝678.39。 4-(6-((1-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidine hydrochloride (220 mg, 0.417 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5 - isopropyl carboxylate (135 mg, 0.417 mmol) was dissolved in 5 ml of anhydrous acetonitrile, and cesium carbonate (272 mg, 0.834 mmol) was added to react at 50 degrees Celsius for 1.5 hours. The reaction was completed, and the reaction solution was diluted with water, Extract with ethyl acetate (30 mL×L), combine the organic phases, wash the organic phase with saturated brine (20 mL×L), then dry with anhydrous sodium sulfate, and finally concentrate the obtained crude product under reduced pressure. Purified to give 221 mg of pale yellow solid (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl) )-1H-indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Propyl ester. LC-MS: RT=1.86 min, [M+H] + =678.39.
步骤F：合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Step F: Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H) -Indazol-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000497
Figure PCTCN2021120978-appb-000497
将(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(160毫克,0.236毫摩尔)溶解于5毫升四氢呋喃和1毫升水中，加入氢氧化锂(17毫克,0.708毫摩尔)和1毫升乙醇于室温下反应50分钟。反应结束，反应液加水稀释，用二氯甲烷(30毫升×升次)萃取，合并有机相，无水硫酸钠干燥，最后减压浓缩所得粗品经过柱分离纯化得126毫克白色固体(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-((1-(2,2,2-三氟乙基)-1H-吲唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸。LC-MS:RT＝1.73min,[M+H] +＝636.31。 (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H-indazole -6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (160 mg, 0.236 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 mL of water, lithium hydroxide (17 mg, 0.708 mmol) and 1 mL of ethanol were added to react at room temperature for 50 minutes. The reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane (30 ml × liter), the organic phases were combined, dried over anhydrous sodium sulfate, and finally the crude product obtained by concentrating under reduced pressure was purified by column separation to obtain 126 mg of white solid (S)- 3-(oxetan-2-ylmethyl)-2-((4-(6-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid. LC-MS: RT=1.73 min, [M+H] + =636.31.
实施例94Example 94
合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridine -2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000498
Figure PCTCN2021120978-appb-000498
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000499
Figure PCTCN2021120978-appb-000499
将吡唑并[1,5-a]吡啶-4-基甲醇(100毫克，0.68毫摩尔)和4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(201毫克，0.68毫摩尔)溶解于4毫升无水二氧六环中，加入碳酸铯(443毫克，1.36毫摩尔)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(58毫克，0.068毫摩尔)，氮气置换3次于100摄氏度下反应7小时。Combine pyrazolo[1,5-a]pyridin-4-ylmethanol (100 mg, 0.68 mmol) and tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (201 mg , 0.68 mmol) was dissolved in 4 mL of anhydrous dioxane, cesium carbonate (443 mg, 1.36 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl) were added Palladium-1,1'-biphenyl[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (58 mg, 0.068 mmol), nitrogen purged 3 times at 100 degrees Celsius for reaction 7 Hour.
反应结束，反应液加水稀释，用乙酸乙酯(50毫升×2次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱(正己烷/乙酸乙酯＝4/1)分离得150毫克淡黄色固体4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：54.4％)。LC-MS:RT＝2.20min,[M+H] +＝409.26。 After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL×2 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2 times), then dried with anhydrous sodium sulfate, and finally The crude product obtained by concentration under reduced pressure was separated by column (n-hexane/ethyl acetate=4/1) to obtain 150 mg of pale yellow solid 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy) ) pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 54.4%). LC-MS: RT=2.20 min, [M+H] + =409.26.
步骤B：合成4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶Step B: Synthesis of 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidine
Figure PCTCN2021120978-appb-000500
Figure PCTCN2021120978-appb-000500
将4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(150毫克，0.37毫摩尔)溶解于3毫升甲醇中，零摄氏度下加入4M盐酸二氧六环溶液(3毫升)，升至室温下反应40分钟。Dissolve tert-butyl 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate (150 mg, 0.37 mmol) In 3 mL of methanol, 4M hydrochloric acid dioxane solution (3 mL) was added at zero degrees Celsius, and the reaction was carried out at room temperature for 40 minutes.
反应结束，反应液直接旋干得128毫克白色固体4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶，直接用于下一步反应。LC-MS:RT＝1.59min,[M+H] +＝309.25。 After the reaction was completed, the reaction solution was directly spin-dried to obtain 128 mg of white solid 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidine, which was directly used for next reaction. LC-MS: RT=1.59 min, [M+H] + =309.25.
步骤C：合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯Step C: Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester
Figure PCTCN2021120978-appb-000501
Figure PCTCN2021120978-appb-000501
将4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶(128毫克，0.37毫摩尔)和(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(109毫克，0.37毫摩尔)溶解于5毫升无水乙腈中，加入碳酸铯(241毫克，0.74毫摩尔)于50摄氏度下反应1.5小时。Combine 4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidine (128 mg, 0.37 mmol) and (S)-2-( Methyl chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (109 mg, 0.37 mmol) was dissolved in 5 In mL of anhydrous acetonitrile, cesium carbonate (241 mg, 0.74 mmol) was added to react at 50 degrees Celsius for 1.5 hours.
反应结束，反应液加水稀释，用乙酸乙酯(30毫升×2次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经过柱分离纯化得181毫克淡黄色固体(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(收率：86.5％)。LC-MS:RT＝1.70min,[M+H] +＝568.31。 After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (30 mL×2 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2 times), then dried with anhydrous sodium sulfate, and finally The crude product obtained by concentration under reduced pressure was purified by column separation to obtain 181 mg of pale yellow solid (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1, 5-a]Pyridin-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester ( Yield: 86.5%). LC-MS: RT=1.70 min, [M+H] + =568.31.
步骤D：合成(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Step D: Synthesis of (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000502
Figure PCTCN2021120978-appb-000502
将(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(181毫克，0.32毫摩尔)溶解于5毫升四氢呋喃和1毫升水中，加入氢氧化 锂(15毫克，0.64毫摩尔)和1毫升乙醇于室温下反应50分钟。(S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[1,5-a]pyridin-4-ylmethoxy)pyridine -2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester (181 mg, 0.32 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 In mL of water, lithium hydroxide (15 mg, 0.64 mmol) and 1 mL of ethanol were added to react at room temperature for 50 minutes.
反应结束，反应液加水稀释，用二氯甲烷(30毫升×2次)萃取，合并有机相，无水硫酸钠干燥，反应结束后，反应液减压浓缩。所得残余物经高效液相制备仪器制备纯化后得到126毫克白色固体(S)-3-(氧杂环丁-2-基甲基)-2-((4-(6-(吡唑并[1,5-a]吡啶-4-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(收率：71.2％)。LC-MS:RT＝1.71min,[M+H] +＝554.33。 After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane (30 mL×2 times), the organic phases were combined and dried over anhydrous sodium sulfate. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by HPLC preparative apparatus to obtain 126 mg of white solid (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-(pyrazolo[ 1,5-a]pyridin-4-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ( Yield: 71.2%). LC-MS: RT=1.71 min, [M+H] + =554.33.
实施例95Example 95
合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000503
Figure PCTCN2021120978-appb-000503
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(6((5-fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000504
Figure PCTCN2021120978-appb-000504
将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(300毫克,1.00毫摩尔)溶于1,4-二氧六环(10.0毫升)中,将(5-氟-2-甲基苯并[d]噁唑-6-基)甲醇(250毫克,1.4毫摩尔),碳酸铯(660毫克,2.00毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(84毫克,0.10毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌12小时。4-(6-Chloropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10.0 mL), (5- Fluoro-2-methylbenzo[d]oxazol-6-yl)methanol (250 mg, 1.4 mmol), cesium carbonate (660 mg, 2.00 mmol), methanesulfonic acid (2-dicyclohexylphosphino) -2',4',6'-Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (84 mg , 0.10 mmol) was added to the reaction flask, and after nitrogen protection, stirred at 100 degrees Celsius for 12 hours.
将反应液垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,混合液用乙酸乙酯(40.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(35.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到400毫克黄色固体4-(6((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：90.7％)。The reaction solution was filtered through a pad of celite, the filtrate was slowly added dropwise to a saturated aqueous ammonium chloride solution (20.0 mL), the mixture was extracted with ethyl acetate (40.0 mL × 3 times), the organic phases were combined, and the organic phase was washed with saturated common salt water (35.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 400 mg of yellow solid 4-(6((5-fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl) tert-Butyl piperidine-1-carboxylate (yield: 90.7%).
步骤B：合成5-氟-2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并[d]噁唑Step B: Synthesis of 5-fluoro-2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzo[d]oxazole
Figure PCTCN2021120978-appb-000505
Figure PCTCN2021120978-appb-000505
将4-(6((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(400毫克,0.90毫摩尔)溶于乙酸乙酯(2.0毫升)中,然后将4.0M盐酸1,4-二氧六环溶液(2.0毫升)加入反应液中,室温搅拌2小时。4-(6((5-Fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.90 mmol) was dissolved in ethyl acetate (2.0 mL), then 4.0 M hydrochloric acid 1,4-dioxane solution (2.0 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
反应液直接减压浓缩得到300毫克白色固体5-氟-2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并[d]噁唑盐酸盐(收率：94.9％)。The reaction solution was directly concentrated under reduced pressure to obtain 300 mg of white solid 5-fluoro-2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzoyl [d] Oxazole hydrochloride (yield: 94.9%).
步骤C：合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯Step C: Synthesis of (S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine Isopropyl pyridine-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000506
Figure PCTCN2021120978-appb-000506
将5-氟-2-甲基-6-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并[d]噁唑盐酸盐(250毫克,0.66毫摩尔)溶 于溶于乙腈(30.0毫升)和三乙胺(5毫升,3.9毫摩尔)中，加碳酸钾(166毫克,1.2毫摩尔),(S)-2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(237毫克,0.73毫摩尔)加入反应液中，50摄氏度下搅拌2小时后,TLC监测至反应完全。5-Fluoro-2-methyl-6-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzo[d]oxazole hydrochloride (250 mg, 0.66 mmol) was dissolved in acetonitrile (30.0 mL) and triethylamine (5 mL, 3.9 mmol), potassium carbonate (166 mg, 1.2 mmol), (S)-2-(chloromethane) was added yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (237 mg, 0.73 mmol) was added to the reaction solution , after stirring for 2 hours at 50 degrees Celsius, TLC monitoring to complete the reaction.
向反应液加水(30.0毫升),混合液用乙酸乙酯(40.0毫升×3次)萃取，合并有机相,有机相用饱和食盐水(25.0毫升×3次)，无水硫酸钠干燥，减压浓缩，得到150毫克黄色固体(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(收率：53.7％)。LC-MS：RT＝1.77min,[M+H] +＝629.34。 Water (30.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (40.0 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25.0 mL × 3 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentration gave 150 mg of yellow solid (S)-2-((4-(6-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (received rate: 53.7%). LC-MS: RT=1.77 min, [M+H] + =629.34.
步骤D：合成(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸Step D: Synthesis of (S)-2-((4-(6-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine pyridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000507
Figure PCTCN2021120978-appb-000507
将(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸异丙酯(100毫克,0.73毫摩尔)溶于四氢呋喃(30.0毫升)和甲醇(10.0毫升)中,然后将氢氧化锂(84毫克,2.0毫摩尔)的水溶液(10.0毫升)加入反应液中,室温搅拌5小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((5-Fluoro-2-methylbenzo[d]oxazol-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate isopropyl ester (100 mg, 0.73 mmol) It was dissolved in tetrahydrofuran (30.0 mL) and methanol (10.0 mL), and then an aqueous solution (10.0 mL) of lithium hydroxide (84 mg, 2.0 mmol) was added to the reaction solution. After stirring at room temperature for 5 hours, LC-MS was monitored to The reaction is complete.
混合液用二氯甲烷/甲醇(9/1,20.0毫升×3次)萃取,合并有机相,有机相用饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到40毫克白色固体(S)-2-((4-(6-((5-氟-2-甲基苯并[d]噁唑-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(收率：63.8％)。LC-MS：RT＝1.72min,[M+H] +＝587.36。 The mixture was extracted with dichloromethane/methanol (9/1, 20.0 mL×3 times), the organic phases were combined, the organic phases were washed with saturated brine (15.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 40 mg of white solid (S)-2-((4-(6-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)methan) oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5- Carboxylic acid (yield: 63.8%). LC-MS: RT=1.72 min, [M+H] + =587.36.
实施例96Example 96
合成(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-( oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000508
Figure PCTCN2021120978-appb-000508
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-氟-8-甲基喹啉Step A: Synthesis of 3-fluoro-8-methylquinoline
Figure PCTCN2021120978-appb-000509
Figure PCTCN2021120978-appb-000509
室温下，向含有8-溴-3-氟喹啉(200毫克，0.89毫摩尔)的1,4-二氧六环/水溶液(3.4/1.0毫升)中，依次加入三甲基环三硼氧烷(0.25毫升，0.89毫摩尔)、1,1'-双二苯基膦二茂铁二氯化钯(32毫克，0.044毫摩尔)和碳酸钾(244毫克，1.77毫摩尔)，置换氮气，100摄氏度反应3小时。反应结束，反应液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到128毫克白色固体3-氟-8-甲基喹啉(收率：89.8％)。[M+H] +＝2.01min,[M+H] +＝162.14。 To a solution of 8-bromo-3-fluoroquinoline (200 mg, 0.89 mmol) in 1,4-dioxane/water solution (3.4/1.0 mL) at room temperature was added trimethylcyclotriboroxy alkane (0.25 mL, 0.89 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (32 mg, 0.044 mmol) and potassium carbonate (244 mg, 1.77 mmol), replacing nitrogen, 100 degrees Celsius for 3 hours. The reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, the organic phase was first washed with saturated brine (30 mL×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure . The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 128 mg of white solid 3-fluoro-8-methylquinoline were obtained (yield: 89.8%). [M+H] + =2.01 min, [M+H] + =162.14.
步骤B：合成8-(溴甲基)-3-氟喹啉Step B: Synthesis of 8-(bromomethyl)-3-fluoroquinoline
Figure PCTCN2021120978-appb-000510
Figure PCTCN2021120978-appb-000510
室温下，向含有3-氟-8-甲基喹啉(128毫克，0.80毫摩尔)的四氯化碳(4.0毫升)中依次加入N-溴代丁二酰亚胺(156毫克，0.88毫摩尔)和偶氮二异丁腈(5毫克，0.032毫摩尔),加热至80摄氏度反应1小时。反应结束，反应液用二氯甲烷(100毫升)稀释，依次用饱和碳酸氢钠(50毫升)和食盐水(50毫升)洗涤，无水硫酸钠干燥后减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/15)。得到90毫克白色固体8-(溴甲基)-3-氟喹啉(收率：46.9％)。LC-MS:RT＝2.05min,[M+H] +＝242.05。 To 3-fluoro-8-methylquinoline (128 mg, 0.80 mmol) in carbon tetrachloride (4.0 mL) was added N-bromosuccinimide (156 mg, 0.88 mmol) sequentially at room temperature mol) and azobisisobutyronitrile (5 mg, 0.032 mmol), heated to 80 degrees Celsius and reacted for 1 hour. After the reaction was completed, the reaction solution was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by analytical method (eluent: ethyl acetate/n-hexane=1/15). 90 mg of white solid 8-(bromomethyl)-3-fluoroquinoline were obtained (yield: 46.9%). LC-MS: RT=2.05 min, [M+H] + =242.05.
步骤C：合成(3-氟喹啉-8-基)甲醇Step C: Synthesis of (3-fluoroquinolin-8-yl)methanol
Figure PCTCN2021120978-appb-000511
Figure PCTCN2021120978-appb-000511
室温下，向含有8-(溴甲基)-3-氟喹啉(90毫克，0.38毫摩尔)的1，4-二氧六环/水(1.5毫升/1.5毫升)溶液中加入碳酸钠(119毫克，1.13毫摩尔),加热至100摄氏度反应3小时。To a solution of 8-(bromomethyl)-3-fluoroquinoline (90 mg, 0.38 mmol) in 1,4-dioxane/water (1.5 mL/1.5 mL) was added sodium carbonate ( 119 mg, 1.13 mmol), heated to 100 degrees Celsius for 3 hours.
反应结束，冷却至室温，用乙酸乙酯(50毫升×2次)萃取，洗涤，有机相用饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/8)。得到40毫克白色固体(3-氟喹啉-8-基)甲醇(收率：59.5％)。LC-MS:RT＝1.72min,[M+H] +＝178.15。 The reaction was completed, cooled to room temperature, extracted with ethyl acetate (50 mL×2 times), washed, and the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain the residue. Purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8). 40 mg of white solid (3-fluoroquinolin-8-yl)methanol was obtained (yield: 59.5%). LC-MS: RT=1.72 min, [M+H] + =178.15.
步骤D：合成(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000512
Figure PCTCN2021120978-appb-000512
室温下，向含有(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(100毫克，0.20毫摩尔)和(3-氟喹啉-8-基)甲醇(40毫克，0.23毫摩尔)的1,4-二氧六环溶液(2.0毫升)中，依次加入叔丁醇钠(38毫克，0.40毫摩尔)、1,1'-联萘-2,2'-双二苯膦(25毫克，0.04毫摩尔)和三(二亚苄基丙酮)二钯(18毫克，0.02毫摩尔)，置换氮气，110摄氏度反应2小时。at room temperature, to a compound containing (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl) )-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.20 mmol) and (3-fluoroquinolin-8-yl)methanol (40 mg, 0.23 mmol) in 1, 4-dioxane solution (2.0 mL) was added successively sodium tert-butoxide (38 mg, 0.40 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (25 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), replace nitrogen, and react at 110 degrees Celsius for 2 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到116毫克淡黄色油状物(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：90.9％)。LC-MS:RT＝1.95min,[M+H] +＝638.39。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 116 mg of (S)-2-((4-(6-((3-fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan was obtained as a pale yellow oil yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 90.9%). LC-MS: RT=1.95 min, [M+H] + =638.39.
步骤E：合成(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((3-Fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000513
Figure PCTCN2021120978-appb-000513
室温下，向含有(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(116毫克，0.18毫摩尔)的二氯甲烷溶液(2.0毫升)中，加入三氟乙酸(1.0毫升)，室温反应2小时，反应完毕，减压蒸除溶剂，残余物用制备HPLC纯化，得到65毫 克白色固体(S)-2-((4-(6-((3-氟喹啉-8-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(收率：61.4％)。LC-MS:RT＝1.80min,[M+H] +＝582.31。 at room temperature, to a compound containing (S)-2-((4-(6-((3-fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (116 mg, 0.18 mmol) in dichloromethane (2.0 mL) , added trifluoroacetic acid (1.0 mL), and reacted at room temperature for 2 hours, the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain 65 mg of white solid (S)-2-((4-(6-( (3-Fluoroquinolin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene and [d]imidazole-6-carboxylic acid (yield: 61.4%). LC-MS: RT=1.80 min, [M+H] + =582.31.
实施例97Example 97
合成(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸Synthesis of (S)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane -2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000514
Figure PCTCN2021120978-appb-000514
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成喹啉-8-甲醇Step A: Synthesis of quinoline-8-methanol
Figure PCTCN2021120978-appb-000515
Figure PCTCN2021120978-appb-000515
将异喹啉-8-甲醛(500毫克,3.18毫摩尔)溶于10毫升无水甲醇中，零摄氏度下加入硼氢化钠(145毫克,3.82毫摩尔)于室温度下反应30分钟。反应结束，反应液倒入50毫升碳酸氢钠溶液中，用乙酸乙酯(30毫升×2次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得350毫克喹啉-8-甲醇(收率：68.9％)。LCMS:RT＝1.78min,[M+H] +＝160.17。 Isoquinoline-8-carbaldehyde (500 mg, 3.18 mmol) was dissolved in 10 mL of anhydrous methanol, and sodium borohydride (145 mg, 3.82 mmol) was added at zero degrees Celsius to react at room temperature for 30 minutes. The reaction was completed, the reaction solution was poured into 50 ml of sodium bicarbonate solution, extracted with ethyl acetate (30 ml × 2 times), the organic phases were combined, the organic phase was washed with saturated brine (20 ml × 2 times), and then Dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure to obtain 350 mg of quinoline-8-methanol (yield: 68.9%). LCMS: RT=1.78 min, [M+H] + =160.17.
步骤B：合成4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000516
Figure PCTCN2021120978-appb-000516
室温下，向含有4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(277毫克，0.943毫摩尔)，喹啉-8-甲醇(150毫克，0.943毫摩尔)的1,4-二氧六环(5毫升)中，加入碳酸铯(614毫克，1.88毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(80.0毫克，0.0943毫摩尔)，100摄氏度反应3小时。To the mixture containing tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (277 mg, 0.943 mmol), quinoline-8-methanol (150 mg, 0.943 mmol) at room temperature of 1,4-dioxane (5 mL), add cesium carbonate (614 mg, 1.88 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triiso Propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (80.0 mg, 0.0943 mmol), reacted at 100 degrees Celsius for 3 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)。得到280毫克淡黄色固体4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(收率：70.7％)。LCMS:RT＝2.23min,[M+H] +＝420.27。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). 280 mg of tert-butyl 4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate was obtained as a pale yellow solid (yield: 70.7%). LCMS: RT=2.23 min, [M+H] + =420.27.
步骤C：合成8-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)喹啉Step C: Synthesis of 8-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)quinoline
Figure PCTCN2021120978-appb-000517
Figure PCTCN2021120978-appb-000517
将4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(280毫克,0.666毫摩尔)溶于5毫升甲醇中，加入4摩尔的盐酸二氧六环溶液2毫升于室温下反应30分钟。反应结束，反应液减压浓缩得230毫克8-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)喹啉盐酸盐(收率：96.6％)。LCMS:RT＝1.97min,[M+H] +＝320.27。 Dissolve tert-butyl 4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate (280 mg, 0.666 mmol) in 5 mL of methanol, add 4 2 ml of molar hydrochloric acid dioxane solution was reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 230 mg of 8-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)quinoline hydrochloride (yield: 96.6%) . LCMS: RT=1.97 min, [M+H] + =320.27.
步骤D：合成(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯Step D: Synthesis of (S)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxa Cyclobutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester
Figure PCTCN2021120978-appb-000518
Figure PCTCN2021120978-appb-000518
室温下，向含有6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)异喹啉盐酸盐(100毫克,0.280毫摩尔)的乙腈(5.0毫升)中，加入(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(86.8毫克,0.280毫摩尔)和碳酸钾(96.6毫克,0.700毫摩尔)，室温下反应3小时。反应结束，向反应液中加水淬灭，用乙酸乙酯(30毫升×2次)萃取，洗涤，有机相用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1。得到120毫克淡黄色固体(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯(收率：74.1％)。LCMS:RT＝2.12min,[M+H] +＝579.27。 Add 6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)isoquinoline hydrochloride (100 mg, 0.280 mmol) in acetonitrile (5.0 mmol) at room temperature mL), add (S)-2-(chloromethyl)-3-(oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Methyl acid (86.8 mg, 0.280 mmol) and potassium carbonate (96.6 mg, 0.700 mmol) were reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched by adding water, extracted with ethyl acetate (30 mL×2 times), washed, and the organic phase was washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure , the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1. 120 mg of pale yellow solid (S)-2-((4-(6-(quinoline-8) were obtained. -ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine -5-Carboxylic acid methyl ester (yield: 74.1%). LCMS: RT=2.12 min, [M+H] + =579.27.
步骤E：合成(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸Step E: Synthesis of (S)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxa Cyclobutan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000519
Figure PCTCN2021120978-appb-000519
将(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯(120毫克,0.207毫摩尔)溶解于4毫升四氢呋喃中，加入单水氢氧化锂(31.9毫克,0.759毫摩尔)，1毫升水和1毫升乙醇于室温下反应50分钟。反应结束，反应液加入20毫升饱和氯化铵中和，用乙酸乙酯(30毫升×2次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩所得粗品经柱层析分离制备得80.6毫克淡黄色固体(S)-2-((4-(6-(喹啉-8-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸(收率：68.8％)。 1H NMR(400MHz,DMSO)δ8.95(dd,J＝4.1,1.7Hz,1H),8.38(dd,J＝8.3,1.6Hz,1H),8.06(d,J＝8.2Hz,1H),7.94(dd,J＝11.1,8.5Hz,2H),7.84(d,J＝6.7Hz,1H),7.66–7.52(m,3H),6.86(d,J＝7.3Hz,1H),6.72(d,J＝8.2Hz,1H),5.99(s,2H),5.13–5.03(m,1H),4.85–4.79(m,1H),4.67(dd,J＝14.8,2.8Hz,1H),4.40(dd,J＝13.9,7.6Hz,1H),4.33–4.28(m,1H),3.98(d,J＝13.5Hz,1H),3.81(d,J＝13.6Hz,1H),2.98–2.91(m,1H),2.87–2.79(m,1H),2.62–2.52(m,2H),2.42–2.35(m,1H),2.27–2.13(m,2H),1.81–1.62(m,4H).LCMS:RT＝1.72min,[M+H] +＝565.29。 (S)-2-((4-(6-(quinolin-8-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane Methyl -2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (120 mg, 0.207 mmol) was dissolved in 4 mL of tetrahydrofuran and added with lithium hydroxide monohydrate (31.9 mg , 0.759 mmol), 1 mL of water and 1 mL of ethanol were reacted at room temperature for 50 minutes. After the reaction was completed, the reaction solution was neutralized by adding 20 mL of saturated ammonium chloride, extracted with ethyl acetate (30 mL×2 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2 times), and then washed with Dry over anhydrous sodium sulfate, and finally concentrate the crude product under reduced pressure to prepare 80.6 mg of pale yellow solid (S)-2-((4-(6-(quinolin-8-ylmethoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (yield : 68.8%). 1 H NMR (400MHz, DMSO) δ 8.95 (dd, J=4.1, 1.7Hz, 1H), 8.38 (dd, J=8.3, 1.6Hz, 1H), 8.06 (d, J=8.2Hz, 1H), 7.94(dd,J=11.1,8.5Hz,2H),7.84(d,J=6.7Hz,1H),7.66–7.52(m,3H),6.86(d,J=7.3Hz,1H),6.72(d , J=8.2Hz, 1H), 5.99(s, 2H), 5.13-5.03(m, 1H), 4.85-4.79(m, 1H), 4.67(dd, J=14.8, 2.8Hz, 1H), 4.40( dd, J=13.9, 7.6Hz, 1H), 4.33–4.28 (m, 1H), 3.98 (d, J=13.5Hz, 1H), 3.81 (d, J=13.6Hz, 1H), 2.98–2.91 (m LCMS : RT=1.72 min, [M+H] + =565.29.
实施例98Example 98
合成(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸Synthesis of (S)-2-((4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-((oxygen Hetetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000520
Figure PCTCN2021120978-appb-000520
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成异喹啉-6-甲醇Step A: Synthesis of isoquinoline-6-methanol
Figure PCTCN2021120978-appb-000521
Figure PCTCN2021120978-appb-000521
将异喹啉-6-羧酸(300毫克,1.73毫摩尔)溶于10毫升无水四氢呋喃中，零下20摄氏度下加入2毫升1摩尔硼烷四氢呋喃溶液，于该温度下反应40分钟。反应结束，反应液倒入50毫升碳酸氢钠溶液中，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩得246毫克喹啉-6-甲醇(收率：88.8％)。LC-MS:RT＝1.76min,[M+H] +＝160.17。 Dissolve isoquinoline-6-carboxylic acid (300 mg, 1.73 mmol) in 10 mL of anhydrous tetrahydrofuran, add 2 mL of 1 mol borane tetrahydrofuran solution at minus 20 degrees Celsius, and react at this temperature for 40 minutes. The reaction was completed, the reaction solution was poured into 50 ml of sodium bicarbonate solution, extracted with ethyl acetate (30 ml × 2 times), the organic phases were combined, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, reduced It was concentrated under pressure to obtain 246 mg of quinoline-6-methanol (yield: 88.8%). LC-MS: RT=1.76 min, [M+H] + =160.17.
步骤B：合成4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000522
Figure PCTCN2021120978-appb-000522
室温下，向含有4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(185毫克，0.625毫摩尔)，异喹啉-6-甲醇(100毫克，0.625毫摩尔)的1,4-二氧六环(5毫升)中，加入碳酸铯(407毫克，1.25毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(53.0毫克，0.0625毫摩尔)，100摄氏度反应3小时。To the mixture containing tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (185 mg, 0.625 mmol), isoquinoline-6-methanol (100 mg, 0.625 mmol) at room temperature ) in 1,4-dioxane (5 mL), cesium carbonate (407 mg, 1.25 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (53.0 mg, 0.0625 mmol), reacted at 100 degrees Celsius for 3 hours.
反应结束，加水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)。得到108毫克淡黄色固体4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(收率：41.2％)。LC-MS:RT＝1.93min,[M+H] +＝420.27。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). 108 mg of tert-butyl 4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate were obtained as a pale yellow solid (yield: 41.2%). LC-MS: RT=1.93 min, [M+H] + =420.27.
步骤C：合成6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)异喹啉Step C: Synthesis of 6-((((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)isoquinoline
Figure PCTCN2021120978-appb-000523
Figure PCTCN2021120978-appb-000523
将4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(108毫克,0.257毫摩尔)溶于4毫升甲醇中，加入4摩尔的盐酸二氧六环溶液2毫升于室温下反应30分钟。Dissolve tert-butyl 4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (108 mg, 0.257 mmol) in 4 mL methanol , 2 ml of 4 mol hydrochloric acid dioxane solution was added and the reaction was carried out at room temperature for 30 minutes.
反应结束，反应液倒入50毫升碳酸氢钠溶液中乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩得91毫克6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)异喹啉(收率：99.5％)。LC-MS:RT＝1.88min,[M+H] +＝320.23。 After the reaction was completed, the reaction solution was poured into 50 ml of sodium bicarbonate solution and extracted with ethyl acetate (30 ml × 2 times), the organic phases were combined, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, and reduced under reduced pressure. Concentration gave 91 mg of 6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)isoquinoline (yield: 99.5%). LC-MS: RT=1.88 min, [M+H] + =320.23.
步骤D：合成(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯Step D: Synthesis of (S)-2-((4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3- ((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester
Figure PCTCN2021120978-appb-000524
Figure PCTCN2021120978-appb-000524
室温下，向含有6-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)异喹啉(91毫克,0.255毫摩尔)的乙腈(8.0毫升)中，加入(S)-2-(氯甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(78.8毫克,0.255毫摩尔)和碳酸钾(70.4毫克,0.51毫摩尔)，室温下反应3小时。To acetonitrile (8.0 mL) containing 6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)isoquinoline (91 mg, 0.255 mmol) at room temperature , adding (S)-2-(chloromethyl)-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The ester (78.8 mg, 0.255 mmol) and potassium carbonate (70.4 mg, 0.51 mmol) were reacted at room temperature for 3 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1。得到110毫克淡黄色固体(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯(收率：74.5％)。LC-MS:RT＝1.97min,[M+H] +＝579.27。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×2 times), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography Purification (eluent: ethyl acetate/n-hexane=5/1. Obtained 110 mg of pale yellow solid (S)-2-((4-(6-((isoquinolin-6-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Acid methyl ester (yield: 74.5%). LC-MS: RT=1.97 min, [M+H] + =579.27.
步骤E：合成(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸Step E: Synthesis of (S)-2-((4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3- ((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
Figure PCTCN2021120978-appb-000525
Figure PCTCN2021120978-appb-000525
将(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸甲酯(110毫克,0.189毫摩尔)溶解于4毫升四氢呋喃中，加入氢氧化锂一水合物(31.9毫克,0.759毫摩尔)，1毫升水和1毫升乙醇于室温下反应50分钟。(S)-2-((4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-((oxygen Hetetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester (110 mg, 0.189 mmol) was dissolved in 4 mL of tetrahydrofuran and lithium hydroxide was added Monohydrate (31.9 mg, 0.759 mmol), 1 mL of water and 1 mL of ethanol were reacted at room temperature for 50 minutes.
反应结束，加入饱和氯化铵(20ml)中和，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得粗品经柱层析分离制备得34毫克淡黄色固体(S)-2-((4-(6-((异喹啉-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-((氧杂环丁烷-2-基)甲基)-3H-咪唑[4,5-b]吡啶-5-羧酸(收率：31.7％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),9.27(s,1H),8.41(d,J＝5.7Hz,1H),8.10(dd,J＝8.3,5.0Hz,2H),8.02–7.97(m,2H),7.78–7.71(m,2H),7.64(dd,J＝8.1,7.4Hz,1H),6.86(d,J＝7.2Hz,1H),6.73(d,J＝8.0Hz,1H),5.56(s,2H),5.17–5.12(m,1H),4.85(dd,J＝14.6,6.7Hz,1H),4.72(dd,J＝14.7,3.8Hz,1H),4.47–4.43(m,1H),4.37–4.33(m,1H),4.00(d,J＝13.7Hz,1H),3.88(d,J＝13.6Hz,1H),2.97–2.87(m,2H),2.67–2.56(m,2H),2.46–2.41(m,1H),2.26–2.19(m,2H),1.77–1.69(m,4H)。LC-MS:RT＝1.56min,[M+H] +＝565.33。 After the reaction was completed, saturated ammonium chloride (20 ml) was added for neutralization, extracted with ethyl acetate (30 ml × 2 times), the organic phases were combined, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product obtained by concentration was separated by column chromatography to prepare 34 mg of pale yellow solid (S)-2-((4-(6-((isoquinolin-6-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (yield: 31.7%) . 1 H NMR(500MHz, DMSO)δ12.71(s,1H),9.27(s,1H),8.41(d,J=5.7Hz,1H),8.10(dd,J=8.3,5.0Hz,2H), 8.02–7.97 (m, 2H), 7.78–7.71 (m, 2H), 7.64 (dd, J=8.1, 7.4Hz, 1H), 6.86 (d, J=7.2Hz, 1H), 6.73 (d, J= 8.0Hz, 1H), 5.56 (s, 2H), 5.17–5.12 (m, 1H), 4.85 (dd, J=14.6, 6.7Hz, 1H), 4.72 (dd, J=14.7, 3.8Hz, 1H), 4.47–4.43 (m, 1H), 4.37–4.33 (m, 1H), 4.00 (d, J=13.7Hz, 1H), 3.88 (d, J=13.6Hz, 1H), 2.97–2.87 (m, 2H) , 2.67–2.56 (m, 2H), 2.46–2.41 (m, 1H), 2.26–2.19 (m, 2H), 1.77–1.69 (m, 4H). LC-MS: RT=1.56 min, [M+H] + =565.33.
实施例99Example 99
合成(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000526
Figure PCTCN2021120978-appb-000526
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-胺Step A: Synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-amine
Figure PCTCN2021120978-appb-000527
Figure PCTCN2021120978-appb-000527
室温下，向含有2-氨基-3-羟甲基吡啶(2.0克，16.11毫摩尔)的N,N-二甲基甲酰胺(15.0毫升)中，加入咪唑(5.5克，80.55摩尔)和叔丁基二苯基氯硅烷(5.76克，20.94摩尔)，室温反应2小时。To 2-amino-3-hydroxymethylpyridine (2.0 g, 16.11 mmol) in N,N-dimethylformamide (15.0 mL) at room temperature was added imidazole (5.5 g, 80.55 mol) and tert. Butyldiphenylchlorosilane (5.76 g, 20.94 mol) was reacted at room temperature for 2 hours.
反应结束，冷却至室温，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，用无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/0)。得到5.53克黄色固体3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-胺(收率：94.4％)。LC-MS:RT＝1.91min,[M+H] +＝363.3。 The reaction was completed, cooled to room temperature, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/0). 5.53 g of yellow solid 3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-amine was obtained (yield: 94.4%). LC-MS: RT=1.91 min, [M+H] + =363.3.
步骤B：合成(E)-N-(3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-基)-N'-羟基甲酰亚胺Step B: Synthesis of (E)-N-(3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-yl)-N'-hydroxycarboximide
Figure PCTCN2021120978-appb-000528
Figure PCTCN2021120978-appb-000528
零摄氏度下，向含有3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-胺(5.53克，15.19毫摩尔)的异丙醇(20.0毫升)中，加入N,N-二甲基甲酰胺二甲基缩醛(3.03毫升)，于90摄氏度反应1.5小时后 降至室温，向体系中加入盐酸羟胺(1.37克，19.75毫摩尔)，50摄氏度反应0.5小时。To 3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-amine (5.53 g, 15.19 mmol) in isopropanol (20.0 mL) at zero degrees Celsius, Add N,N-dimethylformamide dimethyl acetal (3.03 ml), react at 90 degrees Celsius for 1.5 hours and then reduce to room temperature, add hydroxylamine hydrochloride (1.37 g, 19.75 mmol) to the system, and react at 50 degrees Celsius for 0.5 Hour.
反应结束，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到5.75克白色固体(E)-N-(3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-基)-N'-羟基甲酰亚胺(收率：93.3％)。LC-MS:RT＝2.23min,[M+H] +＝406.29。 After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 5.75 g of white solid (E)-N-(3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-yl)-N'-hydroxycarboximide (received rate: 93.3%). LC-MS: RT=2.23 min, [M+H] + =406.29.
步骤C：合成8-(((叔丁基二苯基甲硅烷基)氧基)甲基)-[1,2,4]三唑并[1,5-a]吡啶Step C: Synthesis of 8-(((tert-butyldiphenylsilyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine
Figure PCTCN2021120978-appb-000529
Figure PCTCN2021120978-appb-000529
零摄氏度下，向含有(E)-N-(3-(((叔丁基二苯基甲硅烷基)氧基)甲基)吡啶-2-基)-N'-羟基甲酰亚胺(5.75克，14.18毫摩尔)的四氢呋喃(30.0毫升)中，缓慢滴加三氟乙酸酐(7.9毫升)，室温反应过夜。at zero degrees Celsius, to a compound containing (E)-N-(3-(((tert-butyldiphenylsilyl)oxy)methyl)pyridin-2-yl)-N'-hydroxycarboximide ( 5.75 g, 14.18 mmol) in tetrahydrofuran (30.0 mL) was slowly added dropwise trifluoroacetic anhydride (7.9 mL), and the reaction was carried out at room temperature overnight.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)。得到2.97克黄色固体8-(((叔丁基二苯基甲硅烷基)氧基)甲基)-[1,2,4]三唑并[1,5-a]吡啶(收率：53.9％)。LC-MS:RT＝2.34min,[M+H] +＝388.26。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). 2.97 g of yellow solid 8-(((tert-butyldiphenylsilyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine (yield: 53.9 %). LC-MS: RT=2.34 min, [M+H] + =388.26.
步骤D：合成[1,2,4]三唑并[1,5-a]吡啶-8-基甲醇Step D: Synthesis of [1,2,4]triazolo[1,5-a]pyridin-8-ylmethanol
Figure PCTCN2021120978-appb-000530
Figure PCTCN2021120978-appb-000530
零摄氏度下，向含有8-(((叔丁基二苯基甲硅烷基)氧基)甲基)-[1,2,4]三唑并[1,5-a]吡啶(2.97克，7.63毫摩尔)的四氢呋喃(15.0毫升)中，加入四丁基氟化铵(15.3毫升)，室温反应1.5小时。Add 8-(((tert-butyldiphenylsilyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine (2.97 g, 7.63 mmol) of tetrahydrofuran (15.0 ml), tetrabutylammonium fluoride (15.3 ml) was added, and the reaction was carried out at room temperature for 1.5 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯)。得到780毫克白色固体[1,2,4]三唑并[1,5-a]吡啶-8-基甲醇(收率：68.2％)。LC-MS:RT＝0.63min,[M+H] +＝150.17。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate). 780 mg of white solid [1,2,4]triazolo[1,5-a]pyridin-8-ylmethanol was obtained (yield: 68.2%). LC-MS: RT=0.63 min, [M+H] + =150.17.
步骤E：合成(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000531
Figure PCTCN2021120978-appb-000531
室温下，向含有[1,2,4]三唑并[1,5-a]吡啶-8-基甲醇(50.0毫克，0.33毫摩尔)的1,4-二氧六环(2.0毫升)中，加入(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(138.0毫克，0.33毫摩尔)、碳酸铯(181.0毫克，0.66毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(23.5毫克，0.03毫摩尔)，100摄氏度反应2小时。To [1,2,4]triazolo[1,5-a]pyridin-8-ylmethanol (50.0 mg, 0.33 mmol) in 1,4-dioxane (2.0 mL) at room temperature , adding (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (138.0 mg, 0.33 mmol), cesium carbonate (181.0 mg, 0.66 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (23.5 mg, 0.03 mM mol), and reacted at 100 degrees Celsius for 2 hours.
反应结束，加水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到90.0毫克黄色油状物(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：44.7％)。LC-MS:RT＝1.79min,[M+H] +＝610.41。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 90.0 mg of yellow oil (S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester ( Yield: 44.7%). LC-MS: RT=1.79 min, [M+H] + =610.41.
步骤F：合成(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000532
Figure PCTCN2021120978-appb-000532
室温下，将(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯(90.0毫克，0.15毫摩尔)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(1.0毫升)，室温反应2小时。(S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridine-2- yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (90.0 mg , 0.15 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 2 hours.
反应结束，蒸干二氯甲烷并用油泵抽干三氟乙酸，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到50.0毫克白色固体(S)-2-((4-(6-(([1,2,4]三唑并[1,5-a]吡啶-8-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-苯并[d]咪唑-6-羧酸(收率：60.1％)。LC-MS:RT＝1.65min,[M+H] +＝554.41。 1H NMR(500MHz,DMSO)δ8.94(d,J＝6.8Hz,1H),8.53(s,1H),8.37(s,1H),7.90(d,J＝9.8Hz,1H),7.80(d,J＝8.5Hz,1H),7.76–7.69(m,2H),7.23(t,J＝7.8Hz,1H),6.96(d,J＝9.2Hz,1H),6.81(d,J＝7.6Hz,1H),5.73(s,2H),5.10–4.95(m,1H),4.91–4.74(m,3H),4.67(dd,J＝15.5,2.0Hz,1H),4.49(dd,J＝13.2,7.1Hz,1H),4.33(dt,J＝8.8,6.1Hz,1H),4.12–3.97(m,1H),3.83–3.66(m,2H),3.01–2.86(m,1H),2.77–2.67(m,1H),2.37–2.23(m,1H),2.23–2.14(m,1H),2.14–1.99(m,4H)。 After the reaction was completed, dichloromethane was evaporated to dryness and trifluoroacetic acid was evaporated to dryness with an oil pump, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 50.0 mg of white solid (S)-2-((4-(6-(([1,2,4]triazolo[1,5-a]pyridin-8-yl)methoxy)pyridine-2 was obtained -yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 60.1 %). LC-MS: RT=1.65 min, [M+H] + =554.41. 1 H NMR(500MHz, DMSO)δ8.94(d,J=6.8Hz,1H),8.53(s,1H),8.37(s,1H),7.90(d,J=9.8Hz,1H),7.80( d, J=8.5Hz, 1H), 7.76–7.69 (m, 2H), 7.23 (t, J=7.8Hz, 1H), 6.96 (d, J=9.2Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.73 (s, 2H), 5.10–4.95 (m, 1H), 4.91–4.74 (m, 3H), 4.67 (dd, J=15.5, 2.0Hz, 1H), 4.49 (dd, J= 13.2, 7.1Hz, 1H), 4.33 (dt, J=8.8, 6.1Hz, 1H), 4.12–3.97 (m, 1H), 3.83–3.66 (m, 2H), 3.01–2.86 (m, 1H), 2.77 – 2.67 (m, 1H), 2.37 – 2.23 (m, 1H), 2.23 – 2.14 (m, 1H), 2.14 – 1.99 (m, 4H).
实施例100Example 100
合成(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000533
Figure PCTCN2021120978-appb-000533
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成咪唑并[1,2-a]吡啶-8-基甲醇Step A: Synthesis of Imidazo[1,2-a]pyridin-8-ylmethanol
Figure PCTCN2021120978-appb-000534
Figure PCTCN2021120978-appb-000534
冰浴下，向含有咪唑并[1,2-a]吡啶-8-羧酸(400.0毫克，2.47毫摩尔)的四氢呋喃(5.0毫升)中加入硼烷的四氢呋喃溶液(4.0毫升)，60摄氏度反应4.0小时。In an ice bath, a solution of borane in tetrahydrofuran (4.0 mL) was added to tetrahydrofuran (5.0 mL) containing imidazo[1,2-a]pyridine-8-carboxylic acid (400.0 mg, 2.47 mmol), and the reaction was carried out at 60 degrees Celsius. 4.0 hours.
反应结束，加水淬灭，二氯甲烷(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。得到163.0毫克淡黄色油状物咪唑并[1,2-a]吡啶-8-基甲醇(收率：44.3％)。LC-MS:RT＝1.47min,[M+H] +＝149.15。 The reaction was completed, quenched by adding water, extracted with dichloromethane (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 163.0 mg of imidazo[1,2-a]pyridin-8-ylmethanol was obtained as a pale yellow oil (yield: 44.3%). LC-MS: RT=1.47 min, [M+H] + =149.15.
步骤B：合成4-(6-((咪唑并[1,2-a]吡啶-8-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000535
Figure PCTCN2021120978-appb-000535
室温下，将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(150.0毫克，0.50毫摩尔)、咪唑并[1,2-a]吡啶-8-基甲醇(74.0毫克，0.50毫摩尔)和碳酸铯(326.0毫克，1.00毫摩尔)加入二氧六环(5.0毫升)中，再依次加入2-二环己基磷-2,4,6-三异丙基联苯(47.0毫克，0.1毫摩尔)、三(二亚苄基丙酮)二钯(46.0毫克，0.05毫摩尔)，N2保护下，95摄氏度反应3.0小时。At room temperature, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (150.0 mg, 0.50 mmol), imidazo[1,2-a]pyridin-8-ylmethanol ( 74.0 mg, 0.50 mmol) and cesium carbonate (326.0 mg, 1.00 mmol) were added to dioxane (5.0 mL), followed by 2-dicyclohexylphosphorus-2,4,6-triisopropylbicarbonate Benzene (47.0 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium (46.0 mg, 0.05 mmol) were reacted under N2 protection at 95 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1)，得到77.3毫克淡黄色固体4-(6-((咪唑并[1,2-a]吡啶-8-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：37.8％)。LC-MS:RT＝2.02min,[M+H-Boc] +＝353.27。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1) to obtain 77.3 mg of pale yellow solid 4-(6-((imidazo[1,2-a]pyridine- 8-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 37.8%). LC-MS: RT=2.02 min, [M+H-Boc] + =353.27.
步骤C：合成8-((((6-(哌啶-4-基)吡啶)-2-基)氧基)甲基)咪唑并[1,2-a]吡啶Step C: Synthesis of 8-((((6-(piperidin-4-yl)pyridin)-2-yl)oxy)methyl)imidazo[1,2-a]pyridine
Figure PCTCN2021120978-appb-000536
Figure PCTCN2021120978-appb-000536
室温下，将4-(6-(咪唑并[1,2-a]吡啶-8-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(77.3毫克，0.19毫摩尔)加入二氧六环的盐酸溶液(1.00毫摩尔/毫升，5毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(6-(imidazo[1,2-a]pyridin-8-ylmethoxy)pyridin-2-yl)piperidine-1-carboxylate (77.3 mg, 0.19 mmol ) was added to a hydrochloric acid solution of dioxane (1.00 mmol/mL, 5 mL), and the reaction was carried out under the protection of N 2 for 1 hour at room temperature.
反应结束，减压浓缩。得到55.0毫克乳白色固体8-((((6-(哌啶-4-基)吡啶)-2-基)氧基)甲基)咪唑并[1,2-a]吡啶(收率：94.3％)直接用于下步反应。LC-MS:RT＝1.73min,[M+H] +＝309.15。 After the reaction was completed, it was concentrated under reduced pressure. 55.0 mg of milky white solid 8-((((6-(piperidin-4-yl)pyridin)-2-yl)oxy)methyl)imidazo[1,2-a]pyridine (yield: 94.3%) was obtained ) was directly used in the next reaction. LC-MS: RT=1.73 min, [M+H] + =309.15.
步骤D：合成(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000537
Figure PCTCN2021120978-appb-000537
室温下，将8-((((6-(哌啶-4-基)吡啶)-2-基)氧基)甲基)咪唑并[1,2-a]吡啶(55.0毫克，0.18毫摩尔)、(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(60.5毫克，0.18毫摩尔)和碳酸铯(117.4毫克，0.36毫摩尔)加入N,N-二甲基甲酰胺(10.0毫升)中，最后加入N,N-二异丙基乙胺，N 2保护下，50摄氏度反应4.0小时。 8-((((6-(piperidin-4-yl)pyridin)-2-yl)oxy)methyl)imidazo[1,2-a]pyridine (55.0 mg, 0.18 mmol) at room temperature ), (S)-2-(chloromethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (60.5 mg, 0.18 mmol) and cesium carbonate (117.4 mg, 0.36 mmol) were added to N,N-dimethylformamide (10.0 mL) and finally N,N-diisopropylethylamine, under N2 protection , 50 degrees Celsius for 4.0 hours.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到47.0毫克淡黄色固体(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：42.9％)。LC-MS:RT＝1.86min,[M+H] +＝609.14。 The reaction was completed, quenched by adding water, and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 47.0 mg of pale yellow solid ( S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 42.9%). LC-MS: RT=1.86 min, [M+H] + =609.14.
步骤E：合成(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000538
Figure PCTCN2021120978-appb-000538
室温下，向含有(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯(47.0毫克，0.08毫摩尔)的二氯甲烷(4.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应1.0小时。At room temperature, the solution containing (S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl)piperidin-1- Dimethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (47.0 mg, 0.08 mmol) Trifluoroacetic acid (1.0 mL) was added dropwise to chloromethane (4.0 mL), and the mixture was reacted at room temperature for 1.0 hour.
反应结束，加水淬灭，用碳酸氢钠水溶液(0.5摩尔/升)调pH至6，二氯甲烷(30毫升×3次)萃取，合并有机相，碳酸氢钠溶液(30毫升×2次)洗涤，无水硫酸钠干燥，粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由8％乙腈在5.10分钟洗脱出来；检测波长：254nm。纯化后，低温冻干得到14.2毫克白色固体(S)-2-((4-(6-((咪唑并[1,2-a]吡啶-8-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：33.0％)。LC-MS:RT＝1.75min,[M+H] +＝553.17。 1H NMR(400MHz,DMSO)δ8.51(dd,J＝6.7,0.8Hz,1H),8.05(s,1H),7.99(d,J＝1.2Hz,1H),7.78(dd,J＝8.3,1.3Hz,1H),7.65(dd,J＝8.1,7.5Hz,1H),7.57(d,J＝1.1Hz,1H),7.40(d, J＝8.4Hz,1H),7.27(dd,J＝6.9,1.0Hz,1H),6.88(d,J＝6.7Hz,2H),6.72(d,J＝8.1Hz,1H),5.67(s,2H),5.14–5.04(m,1H),4.73–4.63(m,1H),4.56(dd,J＝14.9,3.3Hz,1H),4.45(dd,J＝11.2,8.6Hz,1H),4.40–4.31(m,1H),3.89(d,J＝13.3Hz,1H),3.72(d,J＝13.2Hz,1H),2.97(d,J＝13.8Hz,1H),2.85(d,J＝12.6Hz,1H),2.62(dd,J＝24.1,10.4Hz,2H),2.17(dt,J＝27.3,8.2Hz,2H),1.85–1.63(m,5H)。 The reaction was completed, quenched by adding water, adjusted to pH 6 with aqueous sodium bicarbonate solution (0.5 mol/L), extracted with dichloromethane (30 mL × 3 times), combined with organic phases, sodium bicarbonate solution (30 mL × 2 times) After washing, drying over anhydrous sodium sulfate, the crude product was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 8% acetonitrile at 5.10 minutes come out; detection wavelength: 254nm. After purification, lyophilization gave 14.2 mg of white solid (S)-2-((4-(6-((imidazo[1,2-a]pyridin-8-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 33.0%). LC-MS: RT=1.75 min, [M+H] + =553.17. 1 H NMR (400MHz, DMSO) δ 8.51 (dd, J=6.7, 0.8Hz, 1H), 8.05 (s, 1H), 7.99 (d, J=1.2Hz, 1H), 7.78 (dd, J=8.3 ,1.3Hz,1H),7.65(dd,J＝8.1,7.5Hz,1H),7.57(d,J＝1.1Hz,1H),7.40(d,J＝8.4Hz,1H),7.27(dd,J =6.9,1.0Hz,1H),6.88(d,J=6.7Hz,2H),6.72(d,J=8.1Hz,1H),5.67(s,2H),5.14–5.04(m,1H),4.73 –4.63(m,1H),4.56(dd,J=14.9,3.3Hz,1H),4.45(dd,J=11.2,8.6Hz,1H),4.40–4.31(m,1H),3.89(d,J =13.3Hz,1H),3.72(d,J=13.2Hz,1H),2.97(d,J=13.8Hz,1H),2.85(d,J=12.6Hz,1H),2.62(dd,J=24.1 , 10.4Hz, 2H), 2.17 (dt, J=27.3, 8.2Hz, 2H), 1.85–1.63 (m, 5H).
实施例101Example 101
合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((pyrazolo[1,5-a]pyridin-7-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000539
Figure PCTCN2021120978-appb-000539
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成吡唑并[1,5-a]吡啶-7-羧酸甲酯Step A: Synthesis of methyl pyrazolo[1,5-a]pyridine-7-carboxylate
Figure PCTCN2021120978-appb-000540
Figure PCTCN2021120978-appb-000540
将吡唑并[1,5-a]吡啶-7-羧酸(500毫克，3.1毫摩尔)溶于二氯甲烷(15毫升)中，滴入两滴N,N-二甲基甲酰胺，然后边搅拌边滴加草酰氯(1.5克，12.3毫摩尔)，在室温下反应0.5小时。Pyrazolo[1,5-a]pyridine-7-carboxylic acid (500 mg, 3.1 mmol) was dissolved in dichloromethane (15 mL), two drops of N,N-dimethylformamide were added dropwise, Then, oxalyl chloride (1.5 g, 12.3 mmol) was added dropwise with stirring, and the reaction was carried out at room temperature for 0.5 hour.
将甲醇(5毫升)滴入反应中，搅拌十分钟，加入氢氧化钠溶液中和至中性，二氯甲烷(20毫升×2次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到250毫克黄色油状液体吡唑并[1,5-a]吡啶-7-羧酸甲酯(收率：46％)。LC-MS:RT＝1.88min,[M+H] +＝177.15。 Methanol (5 mL) was added dropwise to the reaction, stirred for ten minutes, neutralized to neutrality by adding sodium hydroxide solution, extracted with dichloromethane (20 mL × 2 times), combined and dried the organic phases, and the obtained crude product was concentrated using a silica gel column. Purification by chromatography (eluent: ethyl acetate/n-hexane=1/3) gave 250 mg of methyl pyrazolo[1,5-a]pyridine-7-carboxylate as a yellow oily liquid (yield: 46%) . LC-MS: RT=1.88 min, [M+H] + =177.15.
步骤B：合成吡唑并[1,5-a]吡啶-7-基甲醇Step B: Synthesis of Pyrazolo[1,5-a]pyridin-7-ylmethanol
Figure PCTCN2021120978-appb-000541
Figure PCTCN2021120978-appb-000541
室温下，将吡唑并[1,5-a]吡啶-7-羧酸甲酯(80毫克，0.45毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(24毫克，0.9毫摩尔)，在室温下搅拌0.5小时。Methyl pyrazolo[1,5-a]pyridine-7-carboxylate (80 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, cooled to zero degrees Celsius in an ice bath, and tetrahydrofuran was added. Lithium aluminum hydride (24 mg, 0.9 mmol) was stirred at room temperature for 0.5 h.
反应结束后，加入饱和氯化钠淬灭，乙酸乙酯(30毫升)萃取，用水洗两次，无水硫酸钠干燥，过滤后浓缩得到50毫克黄色油状液体吡唑并[1,5-a]吡啶-7-基甲醇(收率：75％)。LC-MS:RT＝1.80min,[M+H] +＝149.23。 After the reaction, saturated sodium chloride was added to quench, extracted with ethyl acetate (30 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 50 mg of yellow oily liquid pyrazolo[1,5-a ]pyridin-7-ylmethanol (yield: 75%). LC-MS: RT=1.80 min, [M+H] + =149.23.
步骤C：合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((pyrazolo[1,5-a]pyridine-7 -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000542
Figure PCTCN2021120978-appb-000542
将吡唑并[1,5-a]吡啶-7-基甲醇(50毫克，0.34毫摩尔)，(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(200毫克，0.4毫摩尔)，钯催化剂(25毫克)，碳酸铯(328毫克，1.0毫摩尔)溶于二氧六环中，升温至100摄氏度搅拌8小时。Pyrazolo[1,5-a]pyridin-7-ylmethanol (50 mg, 0.34 mmol), (S)-2-(chloromethyl)-1-((oxetane-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (200 mg, 0.4 mmol), palladium catalyst (25 mg), cesium carbonate (328 mg, 1.0 mmol) dissolved in In dioxane, the temperature was raised to 100 degrees Celsius and stirred for 8 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到50毫克白色固体(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡 啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：24％)。LC-MS:RT＝1.82min,[M+H] +＝609.23。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 50 mg of white solid (S) -1-((oxetan-2-yl)methyl)-2-((4-(6-((pyrazolo[1,5-a]pyridin-7-yl)methoxy) Pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 24%). LC-MS: RT=1.82 min, [M+H] + =609.23.
步骤D：合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((pyrazolo[1,5-a]pyridine-7 -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000543
Figure PCTCN2021120978-appb-000543
将(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50毫克，0.08毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((pyrazolo[1,5-a]pyridin-7-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50 mg, 0.08 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束后，浓缩，所得粗品高效液相纯化得到49.94毫克白色固体(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((吡唑并[1,5-a]吡啶-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：88％)。LC-MS:RT＝1.62min,[M+H] +＝553.35。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 49.94 mg of white solid (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-(( Pyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Yield: 88%). LC-MS: RT=1.62 min, [M+H] + =553.35.
实施例102Example 102
合成(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000544
Figure PCTCN2021120978-appb-000544
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-氟-1-甲基异喹啉Step A: Synthesis of 6-fluoro-1-methylisoquinoline
Figure PCTCN2021120978-appb-000545
Figure PCTCN2021120978-appb-000545
室温下，向含有1-氯-6-氟-异喹啉(976.0毫克，5.37毫摩尔)的1,4-二氧六环(12.0毫升)中，加入三甲基环三硼氧烷(1.5毫升)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(395.1毫克，0.54毫摩尔)和碳酸铯(2.63克，8.06毫摩尔)，100摄氏度反应2小时。To 1-chloro-6-fluoro-isoquinoline (976.0 mg, 5.37 mmol) in 1,4-dioxane (12.0 mL) was added trimethylcyclotriboroxane (1.5 mL) at room temperature mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (395.1 mg, 0.54 mmol) and cesium carbonate (2.63 g, 8.06 mmol), reacted at 100 degrees Celsius for 2 hours .
反应结束，冷却至室温，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/4)。得到620.0毫克无色液体6-氟-1-甲基异喹啉(收率：73.6％)。LC-MS:RT＝0.76min,[M+H] +＝162.13。 The reaction was completed, cooled to room temperature, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). 620.0 mg of colorless liquid 6-fluoro-1-methylisoquinoline was obtained (yield: 73.6%). LC-MS: RT=0.76 min, [M+H] + =162.13.
步骤B：合成1-(溴甲基)-6-氟异喹啉Step B: Synthesis of 1-(bromomethyl)-6-fluoroisoquinoline
Figure PCTCN2021120978-appb-000546
Figure PCTCN2021120978-appb-000546
室温下，向含有6-氟-1-甲基异喹啉(620.0毫克，3.85毫摩尔)的四氯化碳(15.0毫升)中，加入N-溴代丁二酰亚胺(754.7毫克，4.24毫摩尔)和偶氮二异丁腈(64.0毫克，0.39毫摩尔)，77摄氏度反应4小时。To 6-fluoro-1-methylisoquinoline (620.0 mg, 3.85 mmol) in carbon tetrachloride (15.0 mL) was added N-bromosuccinimide (754.7 mg, 4.24 mL) at room temperature mmol) and azobisisobutyronitrile (64.0 mg, 0.39 mmol) at 77 degrees Celsius for 4 hours.
反应结束，过滤，滤液减压浓缩得到924毫克浅黄色液体1-(溴甲基)-6-氟异喹啉，直接用于下一 步。LC-MS:RT＝1.91min,[M+H] +＝240.03。 The reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to obtain 924 mg of light yellow liquid 1-(bromomethyl)-6-fluoroisoquinoline, which was directly used in the next step. LC-MS: RT=1.91 min, [M+H] + =240.03.
步骤C：合成(6-氟异喹啉-1-基)乙酸甲酯Step C: Synthesis of Methyl (6-fluoroisoquinolin-1-yl)acetate
Figure PCTCN2021120978-appb-000547
Figure PCTCN2021120978-appb-000547
室温下，向含有1-(溴甲基)-6-氟异喹啉(924.0毫克，3.85毫摩尔)的N,N-二甲基甲酰胺(10.0毫升)中，加入醋酸钾(755.7毫克，7.70毫摩尔)，50摄氏度反应2小时。To 1-(bromomethyl)-6-fluoroisoquinoline (924.0 mg, 3.85 mmol) in N,N-dimethylformamide (10.0 mL) at room temperature was added potassium acetate (755.7 mg, 7.70 mmol), reacted at 50 degrees Celsius for 2 hours.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)。得到190.0毫克无色液体(6-氟异喹啉-1-基)乙酸甲酯(收率：22.5％)。LC-MS:RT＝1.70min,[M+H] +＝220.14。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 190.0 mg of methyl (6-fluoroisoquinolin-1-yl)acetate was obtained as a colorless liquid (yield: 22.5%). LC-MS: RT=1.70 min, [M+H] + =220.14.
步骤D：合成(6-氟异喹啉-1-基)甲醇Step D: Synthesis of (6-fluoroisoquinolin-1-yl)methanol
Figure PCTCN2021120978-appb-000548
Figure PCTCN2021120978-appb-000548
室温下，向含有(6-氟异喹啉-1-基)乙酸甲酯(190.0毫克，0.867毫摩尔)的甲醇(3.0毫升)中，加入氢氧化钠水溶液(1.0毫升,2.0摩尔每毫升)，室温反应1.0小时。To methyl (6-fluoroisoquinolin-1-yl)acetate (190.0 mg, 0.867 mmol) in methanol (3.0 mL) was added aqueous sodium hydroxide (1.0 mL, 2.0 mol per mL) at room temperature , and reacted at room temperature for 1.0 hours.
反应结束，蒸除甲醇，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)。得到120.0毫克白色固体(6-氟异喹啉-1-基)甲醇(收率：78.1％)。LC-MS:RT＝1.60min,[M+H] +＝178.13。 After the reaction was completed, methanol was evaporated, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). 120.0 mg of white solid (6-fluoroisoquinolin-1-yl)methanol was obtained (yield: 78.1%). LC-MS: RT=1.60 min, [M+H] + =178.13.
步骤E：合成(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000549
Figure PCTCN2021120978-appb-000549
室温下，向含有[1,2,4]三唑并[1,5-a]吡啶-8-基甲醇(120.0毫克，0.68毫摩尔)的1,4-二氧六环(15.0毫升)中，加入(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(336.5毫克，0.68毫摩尔)、碳酸铯(330.9毫克，1.02毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(23.5毫克，0.03毫摩尔)，100摄氏度反应2小时。To [1,2,4]triazolo[1,5-a]pyridin-8-ylmethanol (120.0 mg, 0.68 mmol) in 1,4-dioxane (15.0 mL) at room temperature , adding (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl) -1H-Benzo[d]imidazole-6-carboxylate tert-butyl ester (336.5 mg, 0.68 mmol), cesium carbonate (330.9 mg, 1.02 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (23.5 mg, 0.03 mM mol), and reacted at 100 degrees Celsius for 2 hours.
反应结束，加水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到161.0毫克黄色固体(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：37.2％)。LC-MS:RT＝1.89min,[M+H] +＝638.33。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 161.0 mg of yellow solid (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl was obtained )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 37.2%). LC-MS: RT=1.89 min, [M+H] + =638.33.
步骤F：合成(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000550
Figure PCTCN2021120978-appb-000550
室温下，将(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸叔丁酯(161.0毫克，0.25毫摩尔)加入二氯甲烷(6.0毫升)中，滴加三氟乙酸(2.0毫升)，室温反应3小时。At room temperature, (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) - tert-butyl 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (161.0 mg, 0.25 mmol) was added to dichloromethane (6.0 mL) ), trifluoroacetic acid (2.0 mL) was added dropwise, and the mixture was reacted at room temperature for 3 hours.
反应结束，蒸干二氯甲烷并用油泵抽干三氟乙酸，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到64.0毫克白色固体(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸(收率：43.6％)。LC-MS:RT＝1.72min,[M+H] +＝582.27。 After the reaction was completed, dichloromethane was evaporated to dryness and trifluoroacetic acid was evaporated to dryness with an oil pump, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 64.0 mg of white solid (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl was obtained )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 43.6%). LC-MS: RT=1.72 min, [M+H] + =582.27.
实施例103Example 103
合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolone[4,3-c]pyridin-6-yl)methoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000551
Figure PCTCN2021120978-appb-000551
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-羧酸甲酯Step A: Synthesis of 1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000552
Figure PCTCN2021120978-appb-000552
室温下，向含有1H-吡唑并[4,3-c]吡啶-6-羧酸甲酯(245毫克,1.38毫摩尔)的N,N-二甲基甲酰胺(8.0毫升)中，加入1,1-二氟-2-碘乙烷(317毫克,1.66毫摩尔)和碳酸钾(381毫克,2.76毫摩尔)，于60摄氏度下反应1小时。反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到126毫克白色固体1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-羧酸甲酯(收率：37.7％)。LC-MS:RT＝1.79min,[M+H] +＝242.27。 To methyl 1H-pyrazolo[4,3-c]pyridine-6-carboxylate (245 mg, 1.38 mmol) in N,N-dimethylformamide (8.0 mL) at room temperature was added 1,1-Difluoro-2-iodoethane (317 mg, 1.66 mmol) and potassium carbonate (381 mg, 2.76 mmol) were reacted at 60 degrees Celsius for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×2 times), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography Purification (eluent: ethyl acetate/n-hexane=1/2) gave 126 mg of white solid 1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6 -Methyl carboxylate (yield: 37.7%). LC-MS: RT=1.79 min, [M+H] + =242.27.
步骤B：合成(1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)甲醇Step B: Synthesis of (1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol
Figure PCTCN2021120978-appb-000553
Figure PCTCN2021120978-appb-000553
将1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-羧酸甲酯(126毫克,0.52毫摩尔)溶于5毫升无水四氢呋喃中，零下10摄氏度下加入氢化铝锂(39.5毫克,1.04毫摩尔)于该温度下反应30分钟。Methyl 1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (126 mg, 0.52 mmol) was dissolved in 5 mL of dry tetrahydrofuran , Lithium aluminum hydride (39.5 mg, 1.04 mmol) was added at minus 10 degrees Celsius to react at this temperature for 30 minutes.
反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到35毫克白色固体(1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)甲醇(收率：31.5％)。LC-MS:RT＝1.83min,[M+H] +＝214.17。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 ml × 2 times), combined with the organic phases, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue using a silica gel column. Purification by chromatography (eluent: ethyl acetate/n-hexane=1/1) gave 35 mg of white solid (1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-c] Pyridin-6-yl)methanol (yield: 31.5%). LC-MS: RT=1.83 min, [M+H] + =214.17.
步骤C：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolone[4,3-c]pyridin-6-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 - tert-butyl carboxylate
Figure PCTCN2021120978-appb-000554
Figure PCTCN2021120978-appb-000554
室温下，向含有(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80.8毫克，0.163毫摩尔)，(1-(2,2-二氟乙基)-1H-吡唑并[4,3-c]吡啶-6-基)甲醇(35毫克，0.163毫摩尔)的1,4-二氧六环(5毫升)中，加入碳酸铯(106毫克，0.326毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(13.8毫克，0.0163毫摩尔)，100摄氏度反应4小时。at room temperature, to a compound containing (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80.8 mg, 0.163 mmol), (1-(2,2-difluoroethyl)-1H-pyrazolo[4 ,3-c]pyridin-6-yl)methanol (35 mg, 0.163 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (106 mg, 0.326 mmol) and methanesulfonic acid (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (13.8 mg, 0.0163 mmol) was reacted at 100 degrees Celsius for 4 hours.
反应结束，加水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1)。得到62毫克淡黄色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：56.3％)。LC-MS:RT＝1.87min,[M+H] +＝673.37。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 ml × 3 times), combined with the organic phases, washed with saturated brine (30 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue using a silica gel column. Purification by chromatography (eluent: ethyl acetate/n-hexane=5/1). 62 mg of pale yellow solid (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolone[4,3-c]pyridine-6) was obtained -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole - tert-butyl 6-carboxylate (yield: 56.3%). LC-MS: RT=1.87 min, [M+H] + =673.37.
步骤D：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolone[4,3-c]pyridin-6-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid
Figure PCTCN2021120978-appb-000555
Figure PCTCN2021120978-appb-000555
将(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯(62毫克,0.092毫摩尔)溶于4毫升无水二氯甲烷中，加入2毫升三氟乙酸，于室温下反应40分钟。(S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolone[4,3-c]pyridin-6-yl)methoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The tert-butyl ester (62 mg, 0.092 mmol) was dissolved in 4 mL of anhydrous dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes.
反应结束，反应液倒入20毫升碳酸氢钠溶液中，二氯甲烷(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝10/1)得到22毫克淡黄色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑啉酮[4,3-c]吡啶-6-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-苯并[d]咪唑-6-羧酸(收率：38.7％)。 1H NMR(400MHz,DMSO)δ12.75(s,1H),9.08(s,1H),8.37(d,J＝0.8Hz,1H),8.26(s,1H),7.86–7.75(m,2H),7.68–7.62(m,2H),6.88(d,J＝7.3Hz,1H),6.77(d,J＝8.1Hz,1H),6.40(tt,J＝54.6,3.4Hz,1H),5.54(s,2H),5.15–5.03(m,1H),4.99–4.91(m,2H),4.77(dd,J＝15.2,7.2Hz,1H),4.63(dd,J＝15.2,2.6Hz,1H),4.47(dd,J＝13.6,7.8Hz,1H),4.37–4.33(m,1H),3.95–3.72(m,2H),3.00–2.79(m,2H),2.71–2.56(m,2H),2.48–2.38(m,1H),2.25–2.12(m,2H),1.83–1.63(m,4H)。LC-MS:RT＝1.64min,[M+H] +＝618.32。 The reaction was completed, the reaction solution was poured into 20 mL of sodium bicarbonate solution, extracted with dichloromethane (30 mL × 2 times), the organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, reduced The resulting residue was concentrated under pressure and purified by silica gel column chromatography (eluent: methanol/dichloromethane=10/1) to obtain 22 mg of a pale yellow solid (S)-2-((4-(6-((1-( 2,2-Difluoroethyl)-1H-pyrazolone[4,3-c]pyridin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 38.7%). 1 H NMR(400MHz, DMSO)δ12.75(s,1H),9.08(s,1H),8.37(d,J=0.8Hz,1H),8.26(s,1H),7.86-7.75(m,2H) ),7.68–7.62(m,2H),6.88(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),6.40(tt,J=54.6,3.4Hz,1H),5.54 (s, 2H), 5.15–5.03 (m, 1H), 4.99–4.91 (m, 2H), 4.77 (dd, J=15.2, 7.2Hz, 1H), 4.63 (dd, J=15.2, 2.6Hz, 1H) ), 4.47 (dd, J=13.6, 7.8Hz, 1H), 4.37–4.33 (m, 1H), 3.95–3.72 (m, 2H), 3.00–2.79 (m, 2H), 2.71–2.56 (m, 2H) ), 2.48–2.38 (m, 1H), 2.25–2.12 (m, 2H), 1.83–1.63 (m, 4H). LC-MS: RT=1.64 min, [M+H] + =618.32.
实施例104Example 104
合成(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000556
Figure PCTCN2021120978-appb-000556
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-羧酸甲酯Step A: Synthesis of methyl 1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate
Figure PCTCN2021120978-appb-000557
Figure PCTCN2021120978-appb-000557
将1H-吡唑并[4,3-b]吡啶-6-羧酸甲酯(236毫克，1.33毫摩尔)，1-氟-2-碘乙烷(254毫克，1.33毫摩尔)溶于N,N-二甲基甲酰胺(4毫升)中，加入碳酸钾(368毫克，2.66毫摩尔)，加毕，氮气保护下，快速升温至60摄氏度，搅拌6小时。Methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate (236 mg, 1.33 mmol), 1-fluoro-2-iodoethane (254 mg, 1.33 mmol) was dissolved in N , N-dimethylformamide (4 mL), potassium carbonate (368 mg, 2.66 mmol) was added, and after the addition was completed, the temperature was rapidly raised to 60 degrees Celsius under nitrogen protection, and stirred for 6 hours.
反应结束后，冷却至室温，减压浓缩，向浓缩液中加入乙酸乙酯萃取(30毫升)，饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-羧酸甲酯105毫克(收率：35.4％)。LC-MS：RT＝1.91min,[M+H] +＝224.16。 After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate (30 mL), washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/4). 105 mg of methyl 1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate was obtained as a yellow solid (yield: 35.4%). LC-MS: RT=1.91 min, [M+H] + =224.16.
步骤B：合成(1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-基)甲醇Step B: Synthesis of (1-(2-Fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol
Figure PCTCN2021120978-appb-000558
Figure PCTCN2021120978-appb-000558
零摄氏度下，将1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-羧酸甲酯(105毫克，0.47毫摩尔)溶于四氢呋喃(5毫升)中，氮气保护下，分批加入氢化锂铝(79毫克，1.88毫摩尔)，搅拌1小时。Methyl 1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (105 mg, 0.47 mmol) was dissolved in tetrahydrofuran (5 mL) at zero degrees Celsius Under nitrogen protection, lithium aluminum hydride (79 mg, 1.88 mmol) was added in portions and stirred for 1 hour.
反应结束，冰浴下缓慢加入滴加氢氧化钠溶液(5％，0.2毫升)，用硅藻土过滤，混合溶剂(10毫升×3次，二氯甲烷/甲醇＝10/1)淋洗滤饼，萃取，合并有机相，饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得白色固体直接用于下一步反应，得(1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-基)甲醇86毫克(收率：75.9％)。LC-MS：RT＝1.71min,[M+H] +＝242.12。 After the reaction was completed, sodium hydroxide solution (5%, 0.2 mL) was slowly added dropwise under ice bath, filtered with celite, and the mixed solvent (10 mL×3 times, dichloromethane/methanol=10/1) was rinsed and filtered The cake was extracted, and the organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained white solid was directly used in the next reaction to obtain (1-(2-fluoroethyl) )-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol 86 mg (yield: 75.9%). LC-MS: RT=1.71 min, [M+H] + =242.12.
步骤C：合成(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy )pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert. Butyl ester
Figure PCTCN2021120978-appb-000559
Figure PCTCN2021120978-appb-000559
将(1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-基)甲醇，(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，顺速升温至100摄氏度，搅拌1小时。(1-(2-Fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methanol, (S)-2-((4-(6-chloropyridine-2- yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris( Dibenzylidene indeneacetone) dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, under nitrogen protection, the temperature was gradually increased to 100 degrees Celsius, and stirred for 1 hour.
反应结束，冷却至室温，缓慢加入饱和氯化铵溶液至pH为中性，乙酸乙酯(10毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯43毫克(收率：39.9％)。LC-MS：RT＝1.82min,[M+H] +＝674.36。 The reaction was completed, cooled to room temperature, slowly added saturated ammonium chloride solution until the pH became neutral, extracted with ethyl acetate (10 mL×3 times), combined organic phases, washed with saturated brine (20 mL×3 times), and anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). White solid (S)-2-((4-(6-((1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy) was obtained Pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl Ester 43 mg (yield: 39.9%). LC-MS: RT=1.82 min, [M+H] + =674.36.
步骤D：合成(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy )pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000560
Figure PCTCN2021120978-appb-000560
将(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯(43毫克，0.06毫摩尔)，溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，室温下搅拌3小时。(S)-2-((4-(6-((1-(2-fluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester ( 43 mg, 0.06 mmol), dissolved in a mixed solvent (2 mL, dichloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at room temperature for 3 hours.
反应结束，减压浓缩，所得残余物经高效液相制备仪器制备纯化后得到26毫克白色固体(S)-2-((4-(6-((1-(2-氟乙基)-1H-吡唑并[4,3-b]吡啶-6-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-苯并[d]咪唑-6-羧酸(收率：66.0％)。LC-MS：RT＝1.68min,[M+H] +＝618.31。 1H NMR(400MHz,DMSO-d 6)δ8.26(d,J＝1.0Hz,1H),7.83–7.73(m,4H),7.64(dd,J＝7.9,6.8Hz,2H),6.88(d,J＝7.2Hz,1H),6.71(d,J＝8.0Hz,1H),5.49(s,2H),5.10(d,J＝7.3Hz,1H),4.80(dd,J＝15.2,7.2Hz,1H),4.69–4.63(m,1H),4.48(dd,J＝13.6,7.6Hz,1H),4.38(dt,J＝9.0,5.8Hz,1H),3.94(d,J＝13.5Hz,1H),3.77(d,J＝13.6Hz,1H),2.97(d,J＝10.4Hz,1H),2.84(d,J＝11.0Hz,1H),2.75–2.65(m,2H),2.59(s,2H),2.41(d,J＝6.9Hz,1H),2.27–2.12(m,3H),1.81–1.60(m,5H)。 The reaction was completed, concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation equipment to obtain 26 mg of white solid (S)-2-((4-(6-((1-(2-fluoroethyl)-1H) -Pyrazolo[4,3-b]pyridin-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetane-2- yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 66.0%). LC-MS: RT=1.68 min, [M+H] + =618.31. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (d, J=1.0 Hz, 1H), 7.83-7.73 (m, 4H), 7.64 (dd, J=7.9, 6.8 Hz, 2H), 6.88 ( d,J＝7.2Hz,1H),6.71(d,J＝8.0Hz,1H),5.49(s,2H),5.10(d,J＝7.3Hz,1H),4.80(dd,J＝15.2,7.2 Hz, 1H), 4.69–4.63 (m, 1H), 4.48 (dd, J=13.6, 7.6Hz, 1H), 4.38 (dt, J=9.0, 5.8Hz, 1H), 3.94 (d, J=13.5Hz) ,1H),3.77(d,J＝13.6Hz,1H),2.97(d,J＝10.4Hz,1H),2.84(d,J＝11.0Hz,1H),2.75–2.65(m,2H),2.59 (s, 2H), 2.41 (d, J=6.9Hz, 1H), 2.27–2.12 (m, 3H), 1.81–1.60 (m, 5H).
实施例105Example 105
合成(S)-2-((4-(6-((7-氰基喹啉-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-cyanoquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000561
Figure PCTCN2021120978-appb-000561
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成7-氰基喹啉-4-羧酸甲酯Step A: Synthesis of methyl 7-cyanoquinoline-4-carboxylate
Figure PCTCN2021120978-appb-000562
Figure PCTCN2021120978-appb-000562
将7-溴喹啉-4-羧酸甲酯(120毫克，0.45毫摩尔)，氰化锌(64毫克，0.54毫摩尔)溶于N,N-二甲基甲酰胺(2毫升)中，加入四三苯基膦钯(104毫克，0.09毫摩尔)，加毕，氮气保护下，迅速升温至130摄氏度，搅拌8小时。Methyl 7-bromoquinoline-4-carboxylate (120 mg, 0.45 mmol), zinc cyanide (64 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (2 mL), Tetratriphenylphosphine palladium (104 mg, 0.09 mmol) was added, and after the addition was completed, the temperature was rapidly raised to 130 degrees Celsius under nitrogen protection, and stirred for 8 hours.
反应结束，冷却至室温，加入乙酸乙酯30毫升，萃取，饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/石油醚＝1/4)。得黄色固体7-氰基喹啉-4-羧酸甲酯75毫克(收率：78.6％)。LC-MS：RT＝1.89min,[M+H] +＝213.36。 The reaction was completed, cooled to room temperature, 30 mL of ethyl acetate was added, extracted, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting Agent: ethyl acetate/petroleum ether=1/4). 75 mg of methyl 7-cyanoquinoline-4-carboxylate was obtained as a yellow solid (yield: 78.6%). LC-MS: RT=1.89 min, [M+H] + =213.36.
步骤B：合成4-(羟甲基)喹啉-7-甲腈Step B: Synthesis of 4-(hydroxymethyl)quinoline-7-carbonitrile
Figure PCTCN2021120978-appb-000563
Figure PCTCN2021120978-appb-000563
零摄氏度下，将7-氰基喹啉-4-羧酸甲酯(75毫克，0.35毫摩尔)溶于甲醇(5毫升)中，氮气保护下，分批加入硼氢化钠(37毫克，1.08毫摩尔)，搅拌2小时。At zero degrees Celsius, methyl 7-cyanoquinoline-4-carboxylate (75 mg, 0.35 mmol) was dissolved in methanol (5 mL), and sodium borohydride (37 mg, 1.08 mg) was added in portions under nitrogen mmol) and stirred for 2 hours.
反应结束，过滤，滤液减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)，得淡黄色油状物4-(羟甲基)喹啉-7-甲腈46毫克(收率：71.4％)。LC-MS：RT＝1.73min,[M+H] +＝185.06。 The reaction was completed, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 4-(hydroxymethyl)quinoline as a pale yellow oil -7-carbonitrile 46 mg (yield: 71.4%). LC-MS: RT=1.73 min, [M+H] + =185.06.
步骤C：合成(S)-2-((4-(6-((7-氰基喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((7-cyanoquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000564
Figure PCTCN2021120978-appb-000564
将4-(羟甲基)喹啉-7-甲腈，(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(80毫克，0.16毫摩尔)溶于1,4-二氧六环(1毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，迅速升温至100摄氏度，搅拌1小时。4-(Hydroxymethyl)quinoline-7-carbonitrile, (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-( (oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindeneacetone)dipalladium (15 mg, 0.016 mmol) were added successively ), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, the temperature was rapidly increased to 100 degrees Celsius under nitrogen protection, and stirred for 1 hour.
反应结束，冷却至室温，缓慢加入饱和氯化铵溶液至pH为中性，乙酸乙酯(10毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：二氯甲烷/甲醇＝19/1)。得白色固体(S)-2-((4-(6-((7-氰基喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯53毫克(收率：49.5％)。LC-MS：RT＝1.89min,[M+H] +＝645.36。 The reaction was completed, cooled to room temperature, slowly added saturated ammonium chloride solution until the pH became neutral, extracted with ethyl acetate (10 mL×3 times), combined organic phases, washed with saturated brine (20 mL×3 times), and anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1). A white solid (S)-2-((4-(6-((7-cyanoquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester 53 mg (yield: 49.5%). LC-MS: RT=1.89 min, [M+H] + =645.36.
步骤D：合成(S)-2-((4-(6-(((1H-吲哚-5-基)甲基)氨基)吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-(((1H-Indol-5-yl)methyl)amino)pyridin-2-yl)piperidin-1-yl)methyl) -1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000565
Figure PCTCN2021120978-appb-000565
将(S)-2-((4-(6-((7-氰基喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯(53毫克，0.08毫摩尔)，溶于混合溶剂(2毫升，二氯甲烷/三氟乙酸＝6/1)中，加毕，室温下搅拌3小时。(S)-2-((4-(6-((7-cyanoquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (53 mg, 0.08 mmol) in mixed solvent (2 mL, di Chloromethane/trifluoroacetic acid=6/1), the addition was completed, and the mixture was stirred at room temperature for 3 hours.
反应结束，反应液减压浓缩，所得残余物经高效液相制备仪器制备纯化后得到22毫克白色固体(S)-2-((4-(6-((7-氰基喹啉-4-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-苯并[d]咪唑-6-羧酸(收率：66.0％)。LC-MS：RT＝1.73min,[M+H] +＝589.29。 The reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by high-performance liquid chromatography to obtain 22 mg of white solid (S)-2-((4-(6-((7-cyanoquinoline-4- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid (yield: 66.0%). LC-MS: RT=1.73 min, [M+H] + =589.29.
实施例106Example 106
合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)methoxy )pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000566
Figure PCTCN2021120978-appb-000566
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2,2-二氟乙基)-6-甲基-1H-吡唑并[3,4-b]吡啶Step A: Synthesis of 1-(2,2-difluoroethyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine
Figure PCTCN2021120978-appb-000567
Figure PCTCN2021120978-appb-000567
室温下，向含有6-甲基-1H-吡唑并[3,4-b]吡啶(1.0克，7.51毫摩尔)的N,N-二甲基甲酰胺(12.0毫升)中，加入1,1-二氟-2-碘乙烷(2.16克，11.27毫摩尔)和碳酸钾(2.07克，15.02毫摩尔)，80 摄氏度反应4小时。To 6-methyl-1H-pyrazolo[3,4-b]pyridine (1.0 g, 7.51 mmol) in N,N-dimethylformamide (12.0 mL) at room temperature was added 1 , 1-Difluoro-2-iodoethane (2.16 g, 11.27 mmol) and potassium carbonate (2.07 g, 15.02 mmol) were reacted at 80 degrees Celsius for 4 hours.
反应结束，冷却至室温，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到1.18克无色液体1-(2,2-二氟乙基)-6-甲基-1H-吡唑并[3,4-b]吡啶(收率：79.4％)。LC-MS:RT＝1.79min,[M+H] +＝198.19。 The reaction was completed, cooled to room temperature, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). 1.18 g of colorless liquid 1-(2,2-difluoroethyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine was obtained (yield: 79.4%). LC-MS: RT=1.79 min, [M+H] + =198.19.
步骤B：合成6-(溴甲基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶Step B: Synthesis of 6-(bromomethyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridine
Figure PCTCN2021120978-appb-000568
Figure PCTCN2021120978-appb-000568
室温下，向含有1-(2,2-二氟乙基)-6-甲基-1H-吡唑并[3,4-b]吡啶(1.18克，5.96毫摩尔)的四氯化碳(12.0毫升)中，加入N-溴代丁二酰亚胺(1.27克，7.15毫摩尔)和偶氮二异丁腈(98.5毫克，0.6毫摩尔)，70摄氏度反应4小时。To a solution containing 1-(2,2-difluoroethyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine (1.18 g, 5.96 mmol) in carbon tetrachloride ( 12.0 mL), N-bromosuccinimide (1.27 g, 7.15 mmol) and azobisisobutyronitrile (98.5 mg, 0.6 mmol) were added, and the reaction was carried out at 70 degrees Celsius for 4 hours.
反应结束，过滤，滤液减压浓缩得到1.17克淡黄色液体6-(溴甲基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶，直接用于下一步。LC-MS:RT＝1.91min,[M+H] +＝276.04。 The reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.17 g of pale yellow liquid 6-(bromomethyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridine, used directly in the next step. LC-MS: RT=1.91 min, [M+H] + =276.04.
步骤C：合成(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)乙酸甲酯Step C: Synthesis of methyl (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acetate
Figure PCTCN2021120978-appb-000569
Figure PCTCN2021120978-appb-000569
室温下，向含有6-(溴甲基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶(1.17克，4.24毫摩尔)的N,N-二甲基甲酰胺(15.0毫升)中，加入醋酸钾(832.2毫克，8.48毫摩尔)，60摄氏度反应2小时。To a solution containing 6-(bromomethyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridine (1.17 g, 4.24 mmol) in N, To N-dimethylformamide (15.0 mL), potassium acetate (832.2 mg, 8.48 mmol) was added, and the reaction was carried out at 60 degrees Celsius for 2 hours.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)。得到700.0毫克无色液体(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)乙酸甲酯(收率：64.6％)。LC-MS:RT＝1.81min,[M+H] +＝256.17。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (50 mL×3 times), the organic phases were combined, washed with saturated brine (30 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 700.0 mg of methyl (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acetate was obtained as a colorless liquid (yield: 64.6%). LC-MS: RT=1.81 min, [M+H] + =256.17.
步骤D：合成(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)甲醇Step D: Synthesis of (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)methanol
Figure PCTCN2021120978-appb-000570
Figure PCTCN2021120978-appb-000570
室温下，向含有(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)乙酸甲酯(700.0毫克，2.74毫摩尔)的甲醇(12.0毫升)中，加入氢氧化钠水溶液(3.0毫升,2.0摩尔每毫升)，室温反应1小时。To methyl (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acetate (700.0 mg, 2.74 mmol) in methanol at room temperature (12.0 mL), sodium hydroxide aqueous solution (3.0 mL, 2.0 mol per mL) was added, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸除甲醇，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)。得到521.0毫克白色固体(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)甲醇(收率：78.9％)。LC-MS:RT＝1.59min,[M+H] +＝214.13。 After the reaction was completed, methanol was evaporated, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 521.0 mg of white solid (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)methanol was obtained (yield: 78.9%). LC-MS: RT=1.59 min, [M+H] + =214.13.
步骤E：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- tert-butyl carboxylate
Figure PCTCN2021120978-appb-000571
Figure PCTCN2021120978-appb-000571
室温下，向含有(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)甲醇(50.0毫克，0.24毫摩尔)的1,4-二氧六环(10.0毫升)中，加入(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(116.4毫克，0.24毫摩尔)、碳酸铯(114.9毫克，0.75毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(19.5毫克，0.023毫摩尔)，100摄氏度反应2小时。To 1,4 containing (1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)methanol (50.0 mg, 0.24 mmol) at room temperature - dioxane (10.0 mL), add (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxacycle Butan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (116.4 mg, 0.24 mmol), cesium carbonate (114.9 mg, 0.75 mmol) and methanesulfonic acid (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II) (19.5 mg, 0.023 mmol) was reacted at 100 degrees Celsius for 2 hours.
反应结束，加水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到120.0毫克黄色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：75.0％)。LC-MS:RT＝1.89min,[M+H] +＝674.40。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtained 120.0 mg of yellow solid (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 - tert-butyl carboxylate (yield: 75.0%). LC-MS: RT=1.89 min, [M+H] + =674.40.
步骤F：合成(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid
Figure PCTCN2021120978-appb-000572
Figure PCTCN2021120978-appb-000572
室温下，将(S)-2-((4-(6-((6-氟异喹啉-1-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-苯并[d]咪唑-6-羧酸叔丁酯(120.0毫克，0.18毫摩尔)加入二氯甲烷(3.0毫升)中，滴加三氟乙酸(1.0毫升)，室温反应3小时。At room temperature, (S)-2-((4-(6-((6-fluoroisoquinolin-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) - tert-butyl 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (120.0 mg, 0.18 mmol) was added to dichloromethane (3.0 mL) ), trifluoroacetic acid (1.0 mL) was added dropwise, and the mixture was reacted at room temperature for 3 hours.
反应结束，蒸干二氯甲烷并用油泵抽干三氟乙酸，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/15)。得到90.0毫克白色固体(S)-2-((4-(6-((1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-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-苯并[d]咪唑-6-羧酸(收率：80.8％)。LC-MS:RT＝1.73min,[M+H] +＝618.37。 After the reaction was completed, dichloromethane was evaporated to dryness and trifluoroacetic acid was drained by oil pump, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/15). Obtained 90.0 mg of white solid (S)-2-((4-(6-((1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl) )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 80.8%). LC-MS: RT=1.73 min, [M+H] + =618.37.
实施例107Example 107
合成(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((7-Chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(( oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000573
Figure PCTCN2021120978-appb-000573
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(7-氯喹啉-4-基)甲醇Step A: Synthesis of (7-chloroquinolin-4-yl)methanol
Figure PCTCN2021120978-appb-000574
Figure PCTCN2021120978-appb-000574
冰浴下，向含有7-氯喹啉-4-羧酸(220.0毫克，1.06毫摩尔)的四氢呋喃(3.0毫升)中加入硼烷的四氢呋喃溶液(2.1毫升)，室温下反应4.0小时。To a solution of 7-chloroquinoline-4-carboxylic acid (220.0 mg, 1.06 mmol) in tetrahydrofuran (3.0 mL) was added a solution of borane in tetrahydrofuran (2.1 mL) under ice bath, and the reaction was carried out at room temperature for 4.0 hours.
反应结束，加水淬灭，二氯甲烷(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。得到80.0毫克白色固体(7-氯喹啉-4-基)甲醇(收率：38.9％)。LC-MS:RT＝0.53min,[M+H] +＝194.07。 The reaction was completed, quenched by adding water, extracted with dichloromethane (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 80.0 mg of white solid (7-chloroquinolin-4-yl)methanol was obtained (yield: 38.9%). LC-MS: RT=0.53 min, [M+H] + =194.07.
步骤B：合成4-(6-(((7-氯喹啉-4-基)甲氧基)吡啶-2-基)哌啶)-1-甲酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-(((7-chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidine)-1-carboxylate
Figure PCTCN2021120978-appb-000575
Figure PCTCN2021120978-appb-000575
室温下，将4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(84.3毫克，0.28毫摩尔)、(7-氯喹啉-4-基)甲醇(55.0毫克，0.28毫摩尔)和碳酸铯(138.8毫克，0.43毫摩尔)加入二氧六环(10.0毫升)中，再依次加入2-二环己基磷-2,4,6-三异丙基联苯(17.4毫克，0.03毫摩尔)、三(二亚苄基丙酮)二钯(25.6毫克，0.03毫摩尔)，N 2保护下，95摄氏度反应3.0小时。 At room temperature, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (84.3 mg, 0.28 mmol), (7-chloroquinolin-4-yl)methanol (55.0 mg, 0.28 mmol) and cesium carbonate (138.8 mg, 0.43 mmol) were added to dioxane (10.0 mL), followed by 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (17.4 mg) , 0.03 mmol), tris(dibenzylideneacetone)dipalladium (25.6 mg, 0.03 mmol), under N 2 protection, reacted at 95 degrees Celsius for 3.0 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)，得到30.0毫克淡黄色固体4-(6-(((7-氯喹啉-4-基)甲氧基)吡啶-2-基)哌啶)-1-甲酸叔丁酯(收率：23.0％)。LC-MS:RT＝1.93min,[M+H] +＝454.27。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 30.0 mg of 4-(6-(((7-chloroquinolin-4-yl)methan as a pale yellow solid oxy)pyridin-2-yl)piperidine)-1-carboxylic acid tert-butyl ester (yield: 23.0%). LC-MS: RT=1.93 min, [M+H] + =454.27.
步骤C：合成7-氯-4-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉Step C: Synthesis of 7-chloro-4-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline
Figure PCTCN2021120978-appb-000576
Figure PCTCN2021120978-appb-000576
室温下，将4-(6-(((7-氯喹啉-4-基)甲氧基)吡啶-2-基)哌啶)-1-甲酸叔丁酯(30.0毫克，0.07毫摩尔)加入二氧六环的盐酸溶液(1.00毫摩尔/毫升，5毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(6-(((7-chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidine)-1-carboxylate (30.0 mg, 0.07 mmol) was added A solution of dioxane in hydrochloric acid (1.00 mmol/mL, 5 mL) was allowed to react at room temperature for 1 h under the protection of N 2 .
反应结束，减压浓缩。得到23.0毫克乳白色固体7-氯-4-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(收率：99.4％)直接用于下步反应。LC-MS:RT＝1.73min,[M+H] +＝354.15。 After the reaction was completed, it was concentrated under reduced pressure. 23.0 mg of milky white solid 7-chloro-4-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (yield: 99.4%) was used directly in the following step reaction. LC-MS: RT=1.73 min, [M+H] + =354.15.
步骤D：合成(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((7-chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000577
Figure PCTCN2021120978-appb-000577
室温下，将7-氯-4-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)喹啉(23.0毫克，0.07毫摩尔)、(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(21.9毫克，0.07毫摩尔)和碳酸铯(46.0毫克，0.14毫摩尔)加入N,N-二甲基甲酰胺(10.0毫升)中，最后加入N,N-二异丙基乙胺，N 2保护下，50摄氏度反应4.0小时。 7-Chloro-4-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)quinoline (23.0 mg, 0.07 mmol), (S) - 2-(Chloromethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (21.9 mg, 0.07 mmol ) and cesium carbonate (46.0 mg, 0.14 mmol) were added to N,N-dimethylformamide (10.0 mL), and finally N,N-diisopropylethylamine was added, and the reaction was carried out at 50°C under N2 protection for 4.0 Hour.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到30.0毫克淡黄色固体(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：70.5％)。LC-MS:RT＝2.00min,[M+H] +＝654.35。 The reaction was completed, quenched by adding water, and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 30.0 mg of pale yellow solid ( S)-2-((4-(6-((7-Chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxa Cyclobutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 70.5%). LC-MS: RT=2.00 min, [M+H] + =654.35.
步骤E：合成(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((7-chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000578
Figure PCTCN2021120978-appb-000578
室温下，向含有(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸叔丁酯(30.0毫克，0.05毫摩尔)的二氯甲烷(8.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应6.0小时。at room temperature, to a compound containing (S)-2-((4-(6-((7-chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (30.0 mg, 0.05 mmol) in dichloromethane (8.0 mL) Trifluoroacetic acid (1.0 mL) was added dropwise to the mixture, and the mixture was reacted at room temperature for 6.0 hours.
反应结束，加水淬灭，用碳酸氢钠水溶液(0.5摩尔/升)调pH至6，二氯甲烷(30毫升×3次)萃取，合并有机相，碳酸氢钠溶液(30毫升×2次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝10：1)得到10.2毫克淡黄色固体(S)-2-((4-(6-((7-氯喹啉-4-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-苯并[d]咪唑-6-羧酸(收率：38.0％)。LC-MS:RT＝1.79min,[M+H] +＝598.29。 The reaction was completed, quenched by adding water, adjusted to pH 6 with aqueous sodium bicarbonate solution (0.5 mol/L), extracted with dichloromethane (30 mL × 3 times), combined with organic phases, sodium bicarbonate solution (30 mL × 2 times) Washed, dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10: 1) to obtain 10.2 mg of pale yellow solid (S)-2-((4-(6-(( 7-Chloroquinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H- Benzo[d]imidazole-6-carboxylic acid (yield: 38.0%). LC-MS: RT=1.79 min, [M+H] + =598.29.
实施例108Example 108
合成(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-Methylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000579
Figure PCTCN2021120978-appb-000579
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-氨基-3-(羟基甲基)吡啶-1-鎓盐Step A: Synthesis of 1-amino-3-(hydroxymethyl)pyridine-1-onium salt
Figure PCTCN2021120978-appb-000580
Figure PCTCN2021120978-appb-000580
将(E)-N-(2,4,6-三甲基苯磺酰基)氧基乙酰亚胺酸乙酯(1.9克，6.75毫摩尔)溶于二氧六环(6毫升)，加入高氯酸(2毫升)，室温下搅拌0.5小时，反应结束后，加入5毫升水淬灭，过滤干燥得白色固体，溶解于二氯甲烷(10毫升)中，加入吡啶-3-基甲醇(500毫克，4.5毫摩尔)，室温下搅拌2小时。Ethyl (E)-N-(2,4,6-trimethylbenzenesulfonyl)oxyacetimidate (1.9 g, 6.75 mmol) was dissolved in dioxane (6 mL) and added with high Chloric acid (2 mL), stirred at room temperature for 0.5 hours, after the reaction was completed, 5 mL of water was added to quench, filtered and dried to obtain a white solid, which was dissolved in dichloromethane (10 mL), and pyridin-3-ylmethanol (500 mL) was added. mg, 4.5 mmol) and stirred at room temperature for 2 hours.
反应结束后，浓缩得白色固体粗品直接用于下一步。After the reaction was completed, the crude product was concentrated to obtain a white solid, which was directly used in the next step.
步骤B：合成4-(羟甲基)-2-甲基吡唑并[1,5-a]吡啶-3-羧酸乙酯Step B: Synthesis of ethyl 4-(hydroxymethyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000581
Figure PCTCN2021120978-appb-000581
将上步固体粗品(4.5毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，加入碳酸钾(1.2克，9毫摩尔)和丁-2-炔酸乙酯(504毫克，4.5毫摩尔)，室温下反应16小时。The crude solid from the previous step (4.5 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.2 g, 9 mmol) and ethyl but-2-ynoate (504 mg) were added. , 4.5 mmol), and reacted at room temperature for 16 hours.
反应结束，加入饱和氯化钠淬灭，乙酸乙酯萃取(10毫升×2次)，合并有机相，无水硫酸钠干燥，过滤后浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到200毫克黄色色油状液体4-(羟甲基)-2-甲基吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：28％)。LC-MS:RT＝1.85min,[M+H] + ＝235.27。 After the reaction was completed, saturated sodium chloride was added for quenching, extracted with ethyl acetate (10 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent: Ethyl acetate/n-hexane=1/1) to obtain 200 mg of ethyl 4-(hydroxymethyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate as a yellow oily liquid (received rate: 28%). LC-MS: RT=1.85 min, [M+H] + =235.27.
步骤C：合成(2-甲基吡唑并[1,5-a]吡啶-4-基)甲醇Step C: Synthesis of (2-Methylpyrazolo[1,5-a]pyridin-4-yl)methanol
Figure PCTCN2021120978-appb-000582
Figure PCTCN2021120978-appb-000582
将4-(羟甲基)-2-甲基吡唑并[1,5-a]吡啶-3-羧酸乙酯(200毫克，0.85毫摩尔)溶于硫酸(50％，3毫升)中，100摄氏度下微波反应1小时。Ethyl 4-(hydroxymethyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 0.85 mmol) was dissolved in sulfuric acid (50%, 3 mL) , microwave reaction at 100 degrees Celsius for 1 hour.
反应结束，加入1摩尔稀盐酸中和至PH等于6，乙酸乙酯(50毫升)萃取，无水硫酸钠干燥，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到得到100毫克白色固体(2-甲基吡唑并[1,5-a]吡啶-4-基)甲醇(收率：72％)。LC-MS:RT＝1.87min,[M+H] +＝163.17。 After the reaction was completed, 1 mole of dilute hydrochloric acid was added to neutralize the pH to 6, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/1) to obtain 100 mg of white solid (2-methylpyrazolo[1,5-a]pyridin-4-yl)methanol (yield: 72%). LC-MS: RT=1.87 min, [M+H] + =163.17.
步骤D：合成(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((2-methylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000583
Figure PCTCN2021120978-appb-000583
将(2-甲基吡唑并[1,5-a]吡啶-4-基)甲醇(50毫克，0.31毫摩尔)，(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基(甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(150毫克，0.31毫摩尔)，钯催化剂(15毫克)，碳酸铯(195毫克，0.6毫摩尔)溶于二氧六环中，升温至100摄氏度搅拌16小时。(2-Methylpyrazolo[1,5-a]pyridin-4-yl)methanol (50 mg, 0.31 mmol), (S)-2-(chloromethyl)-1-((oxa Cyclobutan-2-yl(methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (150 mg, 0.31 mmol), palladium catalyst (15 mg), cesium carbonate (195 mg, 0.6 mmol) was dissolved in dioxane, heated to 100 degrees Celsius and stirred for 16 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到40毫克黄色油状液体(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：25％)。LC-MS:RT＝1.81min,[M+H] +＝623.25。 After the reaction was completed, suction filtration with celite, rinsed with dichloromethane, concentrated the filtrate, and the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 40 mg of yellow oily liquid (S )-2-((4-(6-((2-Methylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 25%). LC-MS: RT=1.81 min, [M+H] + =623.25.
步骤E：合成(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((2-methylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000584
Figure PCTCN2021120978-appb-000584
将(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯(40毫克，0.06毫摩尔)溶于二氯甲烷(5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((2-Methylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (40 mg, 0.06 mmol) in In dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束，浓缩，所得粗品高效液相纯化得到13毫克白色固体(S)-2-((4-(6-((2-甲基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸(收率：36％)。LC-MS:RT＝1.65min,[M+H] +＝566.35。 The reaction was completed, concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 13 mg of white solid (S)-2-((4-(6-((2-methylpyrazolo[1,5-a]pyridin-4-yl) )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-ylmethyl))-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 36%). LC-MS: RT=1.65 min, [M+H] + =566.35.
实施例109Example 109
合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinolin-4-yl)methan) Oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000585
Figure PCTCN2021120978-appb-000585
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-甲基-7-(三氟甲基)喹啉Step A: Synthesis of 4-methyl-7-(trifluoromethyl)quinoline
Figure PCTCN2021120978-appb-000586
Figure PCTCN2021120978-appb-000586
室温下，将4-(氯甲基)-7-(三氟甲基)喹啉(900.0毫克，3.90毫摩尔)、2,4,6-三甲基-1,3,5,2,4,6-三氧三硼硼烷(1.1毫升，0.30毫摩尔)和碳酸铯(1.9克，5.82毫摩尔)加入二氧六环(10.0毫升)中，最后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(285.4毫克，0.39毫摩尔)，N 2保护下，100摄氏度反应3.5小时。 At room temperature, 4-(chloromethyl)-7-(trifluoromethyl)quinoline (900.0 mg, 3.90 mmol), 2,4,6-trimethyl-1,3,5,2,4 ,6-Trioxaborolane (1.1 mL, 0.30 mmol) and cesium carbonate (1.9 g, 5.82 mmol) were added to dioxane (10.0 mL), followed by [1,1'-bis(bis(bis(bis(bis)) Phenylphosphino)ferrocene]palladium dichloride (285.4 mg, 0.39 mmol) was reacted under N2 protection at 100 degrees Celsius for 3.5 hours.
反应结束，加水淬灭，二氯甲烷(50毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝5：1)得到280.0毫克无色油状4-甲基-7-(三氟甲基)喹啉(收率：33.4％)。LC-MS:RT＝1.94min,[M+H] +＝212.33。 The reaction was completed, quenched by adding water, and extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1) to obtain 280.0 mg of colorless oil 4-Methyl-7-(trifluoromethyl)quinoline (yield: 33.4%). LC-MS: RT=1.94 min, [M+H] + =212.33.
步骤B：合成4-(溴甲基)-7-(三氟甲基)喹啉Step B: Synthesis of 4-(bromomethyl)-7-(trifluoromethyl)quinoline
Figure PCTCN2021120978-appb-000587
Figure PCTCN2021120978-appb-000587
室温下，将4-甲基-7-(三氟甲基)喹啉(280.0毫克，1.33毫摩尔)溶于四氯化碳(10.0毫升)中，再依次加入N-溴代琥珀酰亚胺(283.2毫克，1.59毫摩尔)、偶氮二异丁腈(21.8毫克，0.133毫摩尔)，N 2保护下，70摄氏度过夜反应。 4-Methyl-7-(trifluoromethyl)quinoline (280.0 mg, 1.33 mmol) was dissolved in carbon tetrachloride (10.0 mL) at room temperature, followed by the addition of N-bromosuccinimide (283.2 mg, 1.59 mmol), azobisisobutyronitrile (21.8 mg, 0.133 mmol), and react overnight at 70°C under N2 protection.
TLC监测原料消失，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝4/1)，得到380.0毫克淡黄色固体4-(溴甲基)-7-(三氟甲基)喹啉(收率：98.8％)。TLC monitored the disappearance of the raw materials, quenched with water, extracted with ethyl acetate (30 mL×3 times), combined the organic phases, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/1) to obtain 380.0 mg of 4-(bromomethyl)-7-(trifluoromethyl)quinoline as a pale yellow solid (Yield: 98.8%).
步骤C：合成(7-(三氟甲基)喹啉-4-基)乙酸甲酯Step C: Synthesis of Methyl (7-(trifluoromethyl)quinolin-4-yl)acetate
Figure PCTCN2021120978-appb-000588
Figure PCTCN2021120978-appb-000588
室温下，将4-(溴甲基)-7-(三氟甲基)喹啉(380.0毫克，1.31毫摩尔)加入N,N-二甲基甲酰胺(5.0毫升)中，再加入醋酸钾(257.1毫克，2.62毫摩尔)，N 2保护下，70摄氏度反应1.0小时。 4-(Bromomethyl)-7-(trifluoromethyl)quinoline (380.0 mg, 1.31 mmol) was added to N,N-dimethylformamide (5.0 mL) followed by potassium acetate at room temperature (257.1 mg, 2.62 mmol), under N 2 protection, react at 70 degrees Celsius for 1.0 hours.
反应结束，加水淬灭，乙酸乙酯(50毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝3：1)得到200.0毫克白固(7-(三氟甲基)喹啉-4-基)乙酸甲酯(收率：56.5％)。LC-MS:RT＝1.97min,[M+H] +＝270.16。 The reaction was completed, quenched by adding water, and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain 200.0 mg of white solid ( Methyl 7-(trifluoromethyl)quinolin-4-yl)acetate (yield: 56.5%). LC-MS: RT=1.97 min, [M+H] + =270.16.
步骤D：合成(7-(三氟甲基)喹啉-4-基)甲醇Step D: Synthesis of (7-(trifluoromethyl)quinolin-4-yl)methanol
Figure PCTCN2021120978-appb-000589
Figure PCTCN2021120978-appb-000589
室温下，向含有(7-(三氟甲基)喹啉-4-基)乙酸甲酯(200.0毫克，0.74毫摩尔)的甲醇(10.0毫升)中滴加氢氧化钠(160.0毫克，4.00毫摩尔)水溶液(2.0毫升)，室温下反应3.0小时。To methyl (7-(trifluoromethyl)quinolin-4-yl)acetate (200.0 mg, 0.74 mmol) in methanol (10.0 mL) was added dropwise sodium hydroxide (160.0 mg, 4.00 mmol) at room temperature mol) aqueous solution (2.0 mL), and reacted at room temperature for 3.0 hours.
反应结束，加水淬灭，二氯甲烷(20毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝3：1)得到85.0毫克白固(7-(三 氟甲基)喹啉-4-基)甲醇(收率：50.0％)。LC-MS:RT＝1.75min,[M+H] +＝228.13。 The reaction was completed, quenched by adding water, and extracted with dichloromethane (20 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain 85.0 mg of white solid ( 7-(trifluoromethyl)quinolin-4-yl)methanol (yield: 50.0%). LC-MS: RT=1.75 min, [M+H] + =228.13.
步骤E：合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinoline-4- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000590
Figure PCTCN2021120978-appb-000590
室温下，将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(109.4毫克，0.22毫摩尔)、(7-(三氟甲基)喹啉-4-基)甲醇(50.0毫克，0.22毫摩尔)和碳酸铯(107.5毫克，0.33毫摩尔)加入二氧六环(10.0毫升)中，再加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(18.6毫克，0.02毫摩尔)，N 2保护下，100摄氏度反应5.0小时。 At room temperature, (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (109.4 mg, 0.22 mmol), (7-(trifluoromethyl)quinolin-4-yl)methanol (50.0 mg, 0.22 mmol) and cesium carbonate (107.5 mg, 0.33 mmol) were added to dioxane (10.0 mL) followed by methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri- Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2 -yl)palladium(II) (18.6 mg, 0.02 mmol), under N, 100 Celsius reaction for 5.0 hours.
反应结束，加水淬灭，二氯甲烷(30毫升×3次)萃取。合并有机相，饱和食盐水(30毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝20：1)得到50.0毫克淡黄色油状固体(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：33.1％)。LC-MS:RT＝1.97min,[M+H] +＝688.37。 The reaction was completed, quenched by adding water, and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed with saturated brine (30 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 50.0 mg of a pale yellow oily solid (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinolin-4-yl)methoxy (yield: 33.1%). LC-MS: RT=1.97 min, [M+H] + =688.37.
步骤F：合成(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinoline-4-) yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000591
Figure PCTCN2021120978-appb-000591
室温下，向含有(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(50.0毫克，0.07毫摩尔)的二氯甲烷(4.0毫升)中滴加三氟乙酸(1.0毫升)，室温下反应1.0小时。At room temperature, the solution containing (S)-1-((oxetan-2-yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinoline-4) -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (50.0 mg, 0.07 mmol) in Trifluoroacetic acid (1.0 mL) was added dropwise to chloromethane (4.0 mL), and the mixture was reacted at room temperature for 1.0 hour.
反应结束，加水淬灭，用碳酸氢钠水溶液(0.5摩尔/升)调pH至6，二氯甲烷(30毫升×3次)萃取，合并有机相，碳酸氢钠水溶液(30毫升×2次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：二氯甲烷：甲醇＝10：1)得到27.4毫克白色固体(S)-1-((氧杂环丁烷-2-基)甲基)-2-((4-(6-((7-(三氟甲基)喹啉-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：59.4％)。LC-MS:RT＝1.82min,[M+H] +＝632.30。 1H NMR(400MHz,DMSO)δ9.07(d,J＝4.4Hz,1H),8.41(dd,J＝21.2,4.9Hz,3H),7.97(dd,J＝8.6,1.7Hz,1H),7.91(dd,J＝8.5,1.5Hz,1H),7.83–7.72(m,3H),6.98(d,J＝7.8Hz,1H),6.86(d,J＝8.3Hz,1H),5.98(s,2H),5.12–4.97(m,2H),4.91–4.73(m,3H),4.48(q,J＝8.7Hz,1H),4.33(dd,J＝8.6,6.5Hz,1H),4.04(dd,J＝14.3,6.9Hz,1H),2.77–2.61(m,1H),2.37–2.27(m,1H),2.12–1.79(m,5H),1.35–1.04(m,3H)。 The reaction was completed, quenched by adding water, adjusted to pH 6 with aqueous sodium bicarbonate solution (0.5 mol/L), extracted with dichloromethane (30 mL × 3 times), combined with organic phases, aqueous sodium bicarbonate solution (30 mL × 2 times) Washed, dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10: 1) to obtain 27.4 mg of white solid (S)-1-((oxetane-2- yl)methyl)-2-((4-(6-((7-(trifluoromethyl)quinolin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 59.4%). LC-MS: RT=1.82 min, [M+H] + =632.30. 1 H NMR (400MHz, DMSO) δ 9.07 (d, J=4.4Hz, 1H), 8.41 (dd, J=21.2, 4.9Hz, 3H), 7.97 (dd, J=8.6, 1.7Hz, 1H), 7.91(dd,J=8.5,1.5Hz,1H),7.83–7.72(m,3H),6.98(d,J=7.8Hz,1H),6.86(d,J=8.3Hz,1H),5.98(s ,2H),5.12–4.97(m,2H),4.91–4.73(m,3H),4.48(q,J=8.7Hz,1H),4.33(dd,J=8.6,6.5Hz,1H),4.04( dd, J=14.3, 6.9 Hz, 1H), 2.77–2.61 (m, 1H), 2.37–2.27 (m, 1H), 2.12–1.79 (m, 5H), 1.35–1.04 (m, 3H).
实施例110Example 110
合成(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Methylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000592
Figure PCTCN2021120978-appb-000592
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成吡唑并[1,5-a]吡啶-5-羧酸甲酯Step A: Synthesis of methyl pyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000593
Figure PCTCN2021120978-appb-000593
将吡唑并[1,5-a]吡啶-5-羧酸(550毫克，3.39毫摩尔)溶于二氯甲烷(10毫升)中，滴入两滴N,N-二甲基甲酰胺，然后边搅拌边滴加草酰氯(1毫升)，在室温下反应0.5小时。Pyrazolo[1,5-a]pyridine-5-carboxylic acid (550 mg, 3.39 mmol) was dissolved in dichloromethane (10 mL), two drops of N,N-dimethylformamide were added dropwise, Then, oxalyl chloride (1 ml) was added dropwise with stirring, and the reaction was carried out at room temperature for 0.5 hour.
将甲醇(5毫升)滴入反应中，搅拌十分钟，加入稀氢氧化钠溶液中和至中性，二氯甲烷(20毫升×2次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到534毫克白色固体吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：89％)。LC-MS:RT＝1.77min,[M+H] +＝177.09。 Methanol (5 mL) was added dropwise to the reaction, stirred for ten minutes, added with dilute sodium hydroxide solution to neutralize to neutrality, extracted with dichloromethane (20 mL × 2 times), combined and dried organic phases, and the obtained crude product was concentrated with silica gel. Purification by column chromatography (eluent: ethyl acetate/n-hexane=1/1) gave 534 mg of methyl pyrazolo[1,5-a]pyridine-5-carboxylate as a white solid (yield: 89%) . LC-MS: RT=1.77 min, [M+H] + =177.09.
步骤B：合成3-溴吡唑并[1,5-a]吡啶-5-羧酸甲酯Step B: Synthesis of methyl 3-bromopyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000594
Figure PCTCN2021120978-appb-000594
将吡唑并[1,5-a]吡啶-5-羧酸甲酯(150毫克，0.85毫摩尔)溶于乙腈(10毫升)中，滴入两滴乙酸，加入N-溴代丁二酰亚胺(151毫克，3.39毫摩尔)，反应升温至60摄氏度。Methyl pyrazolo[1,5-a]pyridine-5-carboxylate (150 mg, 0.85 mmol) was dissolved in acetonitrile (10 mL), two drops of acetic acid were added dropwise, N-bromosuccinyl was added imine (151 mg, 3.39 mmol) and the reaction was warmed to 60°C.
反应结束，加入饱和氯化钠淬灭，乙酸乙酯(30毫升)萃取，水洗涤两次，无水硫酸钠干燥，过滤后浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到160毫克白色固体3-溴吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：74％)。LC-MS:RT＝1.82min。After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate). ester/n-hexane=1/1) to obtain 160 mg of methyl 3-bromopyrazolo[1,5-a]pyridine-5-carboxylate as a white solid (yield: 74%). LC-MS: RT=1.82 min.
步骤C：合成3-甲基吡唑并[1,5-a]吡啶-5-羧酸甲酯Step C: Synthesis of methyl 3-methylpyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000595
Figure PCTCN2021120978-appb-000595
将3-溴吡唑并[1,5-a]吡啶-5-羧酸甲酯(160毫克，0.63毫摩尔)，三甲基环三硼氧烷(2毫升，3.5M四氢呋喃溶液)，钯催化剂(46毫克)和碳酸钾(134毫克，1.26毫摩尔)溶于混合溶剂(5毫升，二氧六环/水＝4/1)中，100摄氏度微波1小时。Methyl 3-bromopyrazolo[1,5-a]pyridine-5-carboxylate (160 mg, 0.63 mmol), trimethylcyclotriboroxane (2 mL, 3.5M in tetrahydrofuran), palladium The catalyst (46 mg) and potassium carbonate (134 mg, 1.26 mmol) were dissolved in a mixed solvent (5 mL, dioxane/water=4/1) and microwaved at 100°C for 1 hour.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到75毫克黄色固体3-甲基吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：63％)。LC-MS:RT＝1.86min,[M+H] +＝191.12。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 75 mg of yellow solid 3- Methylpyrazolo[1,5-a]pyridine-5-carboxylate (yield: 63%). LC-MS: RT=1.86 min, [M+H] + =191.12.
步骤D：合成(3-甲基吡唑并[1,5-a]吡啶-5-基)甲醇Step D: Synthesis of (3-Methylpyrazolo[1,5-a]pyridin-5-yl)methanol
Figure PCTCN2021120978-appb-000596
Figure PCTCN2021120978-appb-000596
室温下，将3-甲基吡唑并[1,5-a]吡啶-5-羧酸甲酯(120毫克，0.63毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(53毫克，1.26毫摩尔)，在室温下搅拌0.5小时。Methyl 3-methylpyrazolo[1,5-a]pyridine-5-carboxylate (120 mg, 0.63 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature and cooled to zero in an ice bath Celsius, lithium tetrahydroaluminum (53 mg, 1.26 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour.
反应结束，加入饱和氯化钠淬灭，乙酸乙酯(20毫升)萃取，水洗涤两次，无水硫酸钠干燥，过滤后浓缩得到74毫克白色固体(3-甲基吡唑并[1,5-a]吡啶-5-基)甲醇(收率：73％)。LC-MS:RT＝1.57min,[M+H] +＝163.15。 The reaction was completed, quenched by adding saturated sodium chloride, extracted with ethyl acetate (20 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 74 mg of white solid (3-methylpyrazolo[1, 5-a]pyridin-5-yl)methanol (yield: 73%). LC-MS: RT=1.57 min, [M+H] + =163.15.
步骤E：合成(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((3-methylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine Perid-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000597
Figure PCTCN2021120978-appb-000597
将(3-甲基吡唑并[1,5-a]吡啶-5-基)甲醇(80毫克，0.49毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(243毫克，0.49毫摩尔)，钯催化剂(41毫克)和碳酸铯(319毫克，0.98毫摩尔)溶于二氧六环(10毫升)中，升温至100摄氏度搅拌2小时。(3-Methylpyrazolo[1,5-a]pyridin-5-yl)methanol (80 mg, 0.49 mmol), (S)-2-((((4-(6-chloropyridine-2 -yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (243 mg, 0.49 mmol), palladium catalyst (41 mg) and cesium carbonate (319 mg, 0.98 mmol) were dissolved in dioxane (10 mL), and the temperature was raised to 100 degrees Celsius and stirred for 2 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到100毫克白色固体(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：33％)。LC-MS:RT＝1.88min,[M+H] +＝623.34。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 100 mg of white solid (S )-2-((4-(6-((3-Methylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 33%). LC-MS: RT=1.88 min, [M+H] + =623.34.
步骤F：(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Step F: (S)-2-((4-(6-((3-Methylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000598
Figure PCTCN2021120978-appb-000598
将(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(100毫克，0.16毫摩尔)溶于二氯甲烷(2.5毫升)中，室温下加入三氟乙酸(2毫升)，反应1小时。(S)-2-((4-(6-((3-Methylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (100 mg, 0.16 mmol) in In dichloromethane (2.5 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束，浓缩，所得粗品高效液相纯化得到31毫克白色固体(S)-2-((4-(6-((3-甲基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸(收率：34％)。LC-MS:RT＝1.72min,[M+H] +＝567.33。 1H NMR(500MHz,DMSO-d 6)δ8.54(d,J＝7.2Hz,1H),8.24(s,1H),7.79(dd,J＝8.7,1.6Hz,2H),7.69–7.58(m,3H),6.85(dd,J＝10.5,4.6Hz,2H),6.70(d,J＝8.1Hz,1H),5.45–5.31(m,2H),5.17–5.04(m,1H),4.77(dd,J＝15.2,7.1Hz,1H),4.64(dd,J＝15.3,2.7Hz,1H),4.45(dd,J＝13.6,7.7Hz,1H),4.36(dt,J＝9.1,5.9Hz,1H),3.94(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),3.00(d,J＝11.2Hz,1H),2.86(d,J＝10.9Hz,1H),2.65(ddd,J＝26.2,12.9,7.1Hz,2H),2.46–2.39(m,1H),2.28–2.20(m,1H),2.15(d,J＝8.7Hz,4H),1.86–1.66(m,4H)。 The reaction was completed, concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 31 mg of white solid (S)-2-((4-(6-((3-methylpyrazolo[1,5-a]pyridin-5-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (yield: 34%). LC-MS: RT=1.72 min, [M+H] + =567.33. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.54 (d, J=7.2Hz, 1H), 8.24 (s, 1H), 7.79 (dd, J=8.7, 1.6Hz, 2H), 7.69-7.58 ( m, 3H), 6.85 (dd, J=10.5, 4.6Hz, 2H), 6.70 (d, J=8.1Hz, 1H), 5.45–5.31 (m, 2H), 5.17–5.04 (m, 1H), 4.77 (dd, J=15.2, 7.1Hz, 1H), 4.64 (dd, J=15.3, 2.7Hz, 1H), 4.45 (dd, J=13.6, 7.7Hz, 1H), 4.36 (dt, J=9.1, 5.9 Hz,1H),3.94(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),3.00(d,J＝11.2Hz,1H),2.86(d,J＝10.9Hz, 1H), 2.65 (ddd, J=26.2, 12.9, 7.1Hz, 2H), 2.46–2.39 (m, 1H), 2.28–2.20 (m, 1H), 2.15 (d, J=8.7Hz, 4H), 1.86 -1.66 (m, 4H).
实施例111Example 111
合成(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000599
Figure PCTCN2021120978-appb-000599
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-氯吡唑并[1,5-a]吡啶-5-羧酸甲酯Step A: Synthesis of methyl 3-chloropyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000600
Figure PCTCN2021120978-appb-000600
将吡唑并[1,5-a]吡啶-5-羧酸甲酯(100毫克，0.56毫摩尔)溶于乙腈(5毫升)中，滴入两滴乙酸，加入N-氯代丁二酰亚胺(300毫克，2.24毫摩尔)，升温至60摄氏度反应。Methyl pyrazolo[1,5-a]pyridine-5-carboxylate (100 mg, 0.56 mmol) was dissolved in acetonitrile (5 mL), two drops of acetic acid were added dropwise, N-chlorosuccinyl was added imine (300 mg, 2.24 mmol), warmed to 60 degrees Celsius to react.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(30毫升)萃取，水洗两次，无水硫酸钠干燥，过滤后浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到160毫克白色固体3-氯吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：74％)。LC-MS:RT＝1.97min,[M+H] +＝211.01。 The reaction was completed, quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate) /n-hexane=1/1) to obtain 160 mg of methyl 3-chloropyrazolo[1,5-a]pyridine-5-carboxylate as a white solid (yield: 74%). LC-MS: RT=1.97 min, [M+H] + =211.01.
步骤B：合成(3-氯吡唑并[1,5-a]吡啶-5-基)甲醇Step B: Synthesis of (3-chloropyrazolo[1,5-a]pyridin-5-yl)methanol
Figure PCTCN2021120978-appb-000601
Figure PCTCN2021120978-appb-000601
室温下，将3-氯吡唑并[1,5-a]吡啶-5-羧酸甲酯(120毫克，0.57毫摩尔)溶于四氢呋喃(5毫升)中，在冰浴中冷却至零摄氏度，加入四氢铝锂(60毫克，1.14毫摩尔)，在室温下搅拌0.5小时。Methyl 3-chloropyrazolo[1,5-a]pyridine-5-carboxylate (120 mg, 0.57 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature and cooled to zero degrees Celsius in an ice bath , Lithium tetrahydroaluminum (60 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 0.5 h.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(20毫升)萃取，水洗两次，无水硫酸钠干燥，过滤后浓缩得到100毫克白色固体(3-氯吡唑并[1,5-a]吡啶-5-基)甲醇(收率：96％)。LC-MS:RT＝1.70min,[M+H] +＝183.08。 The reaction was completed, quenched by adding saturated sodium chloride, extracted with ethyl acetate (20 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of white solid (3-chloropyrazolo[1,5- a] Pyridin-5-yl)methanol (yield: 96%). LC-MS: RT=1.70 min, [M+H] + =183.08.
步骤C：合成4-(6-((3-氯吡唑并[1,5-a]吡啶-5-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step C: Synthesis of tert-butyl 4-(6-((3-chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000602
Figure PCTCN2021120978-appb-000602
将(3-氯吡唑并[1,5-a]吡啶-5-基)甲醇(80毫克，0.44毫摩尔)，4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯(149毫克，0.44毫摩尔)，钯催化剂(41毫克)，BINAP(55毫克，0.09毫摩尔)和碳酸铯(287毫克，088毫摩尔)溶于二氧六环(10毫升)中，升温至100摄氏度搅拌8小时。(3-Chloropyrazolo[1,5-a]pyridin-5-yl)methanol (80 mg, 0.44 mmol), tert-4-(6-bromopyridin-2-yl)piperidine-1-carboxylic acid Butyl ester (149 mg, 0.44 mmol), palladium catalyst (41 mg), BINAP (55 mg, 0.09 mmol) and cesium carbonate (287 mg, 088 mmol) in dioxane (10 mL), The temperature was raised to 100°C and stirred for 8 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到42毫克淡黄色固体4-(6-((3-氯吡唑并[1,5-a]吡啶-5-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：22％)。LC-MS:RT＝2.34min,[M-100] +＝343.19。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 42 mg of pale yellow solid 4- (6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 22%) . LC-MS: RT=2.34 min, [M-100] + =343.19.
步骤D：合成3-氯-5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶Step D: Synthesis of 3-chloro-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine
Figure PCTCN2021120978-appb-000603
Figure PCTCN2021120978-appb-000603
将4-(6-((3-氯吡唑并[1,5-a]吡啶-5-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(42毫克,0.10毫摩尔)溶于盐酸的二氧六环溶液(5毫升)中，室温搅拌。4-(6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (42 mg, 0.10 mmol) was dissolved in hydrochloric acid in dioxane (5 mL) and stirred at room temperature.
反应结束，减压浓缩得到30毫克淡黄色固体3-氯-5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶(收率：87％)。After the reaction was completed, it was concentrated under reduced pressure to obtain 30 mg of pale yellow solid 3-chloro-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5 -a]pyridine (yield: 87%).
步骤E：合成(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯Step E: Synthesis of (S)-2-((4-(6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000604
Figure PCTCN2021120978-appb-000604
室温下，将3-氯-5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶(50毫克，0.15毫摩尔)碳酸钾(40毫克，0.29毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，再加入2-(1-氯甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(49毫克,0.15毫摩尔)，室温反应。3-Chloro-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridine (50 mg, 0.15 mmol) potassium carbonate (40 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by addition of 2-(1-chloromethyl)-1-((((S) -Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (49 mg, 0.15 mmol), react at room temperature.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(30毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到60毫克白色固体(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：64％)。LC-MS:RT＝1.88min,[M+H] +＝643.31。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 10/1) gave 60 mg of white solid (S)-2-((4-(6-((3-chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (received rate: 64%). LC-MS: RT=1.88 min, [M+H] + =643.31.
步骤F：合成(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000605
Figure PCTCN2021120978-appb-000605
将(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(60毫克，0.10毫摩尔)溶于二氯甲烷(4毫升)中，室温下加入三氟乙酸(2毫升)，反应1小时。(S)-2-((4-(6-((3-Chloropyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (60 mg, 0.10 mmol) was dissolved in To dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was reacted for 1 hour.
反应结束，浓缩，所得粗品高效液相纯化得到38毫克白色固体(S)-2-((4-(6-((3-氯吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸(收率：69％)。LC-MS:RT＝1.77min,[M+H] +＝587.27。 1H NMR(500MHz,DMSO-d 6)δ8.70(d,J＝7.2Hz,1H),8.36(s,1H),8.14(s,1H),7.89(d,J＝8.3Hz,1H),7.77(d,J＝8.1Hz,1H),7.74–7.62(m,2H),7.03(dd,J＝7.2,1.6Hz,1H),6.93(d,J＝7.2Hz,1H),6.79(d,J＝8.2Hz,1H),5.46(s,2H),5.04(d,J＝6.9Hz,1H),4.81(dd,J＝15.6,6.8Hz,2H),4.67(d,J＝13.8Hz,1H),4.48(dd,J＝13.8,7.3Hz,1H),4.34(dd,J＝14.7,5.9Hz,1H),4.04(s,1H),3.61(s,2H),3.12(s,1H),2.89(s,1H),2.70(dt,J＝15.9,8.0Hz,1H),2.33(s,1H),2.25–1.83(m,5H)。 The reaction was completed, concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 38 mg of white solid (S)-2-((4-(6-((3-chloropyrazolo[1,5-a]pyridin-5-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- Carboxylic acid (yield: 69%). LC-MS: RT=1.77 min, [M+H] + =587.27. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.70 (d, J=7.2 Hz, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.89 (d, J=8.3 Hz, 1H) ,7.77(d,J＝8.1Hz,1H),7.74–7.62(m,2H),7.03(dd,J＝7.2,1.6Hz,1H),6.93(d,J＝7.2Hz,1H),6.79( d, J＝8.2Hz, 1H), 5.46(s, 2H), 5.04(d, J＝6.9Hz, 1H), 4.81(dd, J＝15.6, 6.8Hz, 2H), 4.67(d, J＝13.8 Hz, 1H), 4.48(dd, J=13.8, 7.3Hz, 1H), 4.34(dd, J=14.7, 5.9Hz, 1H), 4.04(s, 1H), 3.61(s, 2H), 3.12(s , 1H), 2.89 (s, 1H), 2.70 (dt, J=15.9, 8.0 Hz, 1H), 2.33 (s, 1H), 2.25–1.83 (m, 5H).
实施例112Example 112
合成(S)-2-((4-(6-(苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-(benzo[d]isoxazol-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000606
Figure PCTCN2021120978-appb-000606
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成苯并[d]异恶唑-3-基甲醇Step A: Synthesis of Benzo[d]isoxazol-3-ylmethanol
Figure PCTCN2021120978-appb-000607
Figure PCTCN2021120978-appb-000607
零摄氏度下，向含有苯并[d]异噁唑-3-羧酸乙酯(400毫克，2.09毫摩尔)的四氢呋喃(5毫升) 中，加入四氢锂铝(79.4毫克，2.09毫摩尔)，搅拌10分钟后，升至25摄氏度反应1小时。To ethyl benzo[d]isoxazole-3-carboxylate (400 mg, 2.09 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum tetrahydride (79.4 mg, 2.09 mmol) at zero degrees Celsius , after stirring for 10 minutes, it was raised to 25 degrees Celsius and reacted for 1 hour.
反应结束，缓慢加饱和十水硫酸钠(5毫升)淬灭，过滤，滤液用乙酸乙酯(50毫升×3次)萃取，合并有机相，饱和食盐水(50毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)。得到250毫克黄色油状物苯并[d]异噁唑-3-基甲醇(收率：80.3％)。LC-MS:RT＝1.63min,[M+H] +＝150.06。 The reaction was completed, slowly added saturated sodium sulfate decahydrate (5 mL) to quench, filtered, the filtrate was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, washed with saturated brine (50 mL × 3 times), no It was dried over sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 250 mg of benzo[d]isoxazol-3-ylmethanol was obtained as a yellow oil (yield: 80.3%). LC-MS: RT=1.63 min, [M+H] + =150.06.
步骤B：合成(S)-2-((4-(6-((苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸甲酯Step B: Synthesis of (S)-2-((4-(6-((benzo[d]isoxazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000608
Figure PCTCN2021120978-appb-000608
将苯并[d]异噁唑-3-基甲醇(24毫克，0.16毫摩尔)，(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(73毫克，0.16毫摩尔)溶于1,4-二氧六环(3毫升)中，依次加入1,1'-联萘-2,2'-双二苯膦(20毫克，0.03毫摩尔)，三(二亚苄基茚丙酮)二钯(15毫克，0.016毫摩尔)，叔丁醇钠(31毫克，0.32毫摩尔)，加毕，氮气保护下，迅速升温至100摄氏度，搅拌1小时。Benzo[d]isoxazol-3-ylmethanol (24 mg, 0.16 mmol), (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl) Methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (73 mg, 0.16 mmol) in 1,4 - dioxane (3 mL), followed by adding 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20 mg, 0.03 mmol), tris(dibenzylideneindenone)dipalladium (15 mg, 0.016 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), after the addition was completed, the temperature was rapidly increased to 100 degrees Celsius under nitrogen protection, and stirred for 1 hour.
反应结束，冷却至室温，缓慢加入饱和氯化铵溶液至pH为中性，乙酸乙酯(10毫升×3次)萃取，合并有机相，饱和食盐水(20毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶层析柱纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)。得白色固体(S)-2-((4-(6-((苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸甲酯40毫克(收率：44.1％)。LC-MS：RT＝1.84min,[M+H] +＝568.33。 The reaction was completed, cooled to room temperature, slowly added saturated ammonium chloride solution until the pH became neutral, extracted with ethyl acetate (10 mL×3 times), combined organic phases, washed with saturated brine (20 mL×3 times), and anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). A white solid was obtained (S)-2-((4-(6-((benzo[d]isoxazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 40 mg (yield: 44.1%). LC-MS: RT=1.84 min, [M+H] + =568.33.
步骤C：合成(S)-2-((4-(6-((苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸Step C: Synthesis of (S)-2-((4-(6-((benzo[d]isoxazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000609
Figure PCTCN2021120978-appb-000609
零摄氏度下，向含有(S)-2-((4-(6-(苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸甲酯(40毫克,0.07毫摩尔)的四氢呋喃(3毫升)和甲醇(1毫升)混合溶液中，滴加氢氧化锂(307毫克,7.30毫摩尔)的水溶液(1毫升)，于25摄氏度下反应0.5小时。At zero degrees Celsius, to a compound containing (S)-2-((4-(6-(benzo[d]isoxazol-3-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methan yl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (40 mg, 0.07 mmol) in tetrahydrofuran (3 mL) To the mixed solution with methanol (1 mL), an aqueous solution (1 mL) of lithium hydroxide (307 mg, 7.30 mmol) was added dropwise, and the reaction was carried out at 25 degrees Celsius for 0.5 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10。得到25毫克白色固体(S)-2-((4-(6-((苯并[d]异噁唑-3-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-苯并[d]咪唑-6-羧酸甲酯(收率：41.6％)。LC-MS:RT＝1.77min,[M+H] +＝554.29。 1H NMR(400MHz,DMSO-d 6)δ12.71(s,1H),8.26(s,1H),8.01(d,J＝0.7Hz,1H),7.80(d,J＝8.5Hz,1H),7.76(s,1H),7.72(d,J＝8.3Hz,1H),7.63(t,J＝7.7Hz,2H),7.22(dd,J＝8.3,1.1Hz,1H),6.86(d,J＝7.2Hz,1H),6.68(d,J＝8.1Hz,1H),5.48(q,J＝12.3Hz,2H),5.10(d,J＝5.3Hz,1H),4.93–4.85(m,1H),4.78(dd,J＝15.2,7.3Hz,1H),4.63(d,J＝5.8Hz,1H),4.44(dd,J＝13.9,7.4Hz,1H),4.35(dt,J＝8.9,5.8Hz,1H),4.23(s,1H),3.95(d,J＝14.0Hz,1H),3.77(d,J＝13.7Hz,1H),3.02(s,1H),2.85(s,1H),2.73–2.60(m,2H),2.21(d,J＝37.5Hz,2H),1.89–1.68(m,4H)。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 mL×2 times), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting Reagent: methanol/dichloromethane = 1/10. Obtained 25 mg of white solid (S)-2-((4-(6-((benzo[d]isoxazol-3-yl)methoxy)pyridine -2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( Yield: 41.6%). LC-MS: RT=1.77 min, [M+H] + =554.29. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.71 (s, 1H), 8.26 (s, 1H) ),8.01(d,J＝0.7Hz,1H),7.80(d,J＝8.5Hz,1H),7.76(s,1H),7.72(d,J＝8.3Hz,1H),7.63(t,J =7.7Hz,2H),7.22(dd,J=8.3,1.1Hz,1H),6.86(d,J=7.2Hz,1H),6.68(d,J=8.1Hz,1H),5.48(q,J =12.3Hz,2H),5.10(d,J=5.3Hz,1H),4.93-4.85(m,1H),4.78(dd,J=15.2,7.3Hz,1H),4.63(d,J=5.8Hz ,1H),4.44(dd,J＝13.9,7.4Hz,1H),4.35(dt,J＝8.9,5.8Hz,1H),4.23(s,1H),3.95(d,J＝14.0Hz,1H) ,3.77(d,J=13.7Hz,1H),3.02(s,1H),2.85(s,1H),2.73–2.60(m,2H),2.21(d,J=37.5Hz,2H),1.89– 1.68 (m, 4H).
实施例113Example 113
合成(S)-2-((4-(6-((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((benzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000610
Figure PCTCN2021120978-appb-000610
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-2-((4-(6-((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯Step A: Synthesis of (S)-2-((4-(6-((benzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000611
Figure PCTCN2021120978-appb-000611
将(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80毫克,0.18毫摩尔)溶于1,4-二氧六环(5.0毫升)中,将苯并[d]噁唑-2-基甲醇(53毫克,0.36毫摩尔),碳酸铯(120毫克,0.30毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(20毫克,0.020毫摩尔)加入反应瓶中,氮气保护,100摄氏度下搅拌12小时。(S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl) Methyl-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5.0 mL) and benzo[d]oxazole-2 -ylmethanol (53 mg, 0.36 mmol), cesium carbonate (120 mg, 0.30 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl- 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.020 mmol) was added to the reaction flask, under nitrogen protection, at 100 degrees Celsius Stir for 12 hours.
反应结束，垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,乙酸乙酯(20.0毫升×3次)萃取,合并有机相,饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到65毫克黄色固体(S)-2-((4-(6-((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯(收率：63.1％)。LC-MS：RT＝1.79min,[M+H] +＝568.33。 After the reaction was completed, the celite was filtered, the filtrate was slowly added dropwise to saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL×3 times), the organic phases were combined, saturated brine (15.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 65 mg of yellow solid (S)-2-((4-(6-((benzo[d]oxazol-2-yl)methoxy)pyridin-2-yl )piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (yield: 63.1 %). LC-MS: RT=1.79 min, [M+H] + =568.33.
步骤B：合成(S)-2-((4-(6-((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((benzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000612
Figure PCTCN2021120978-appb-000612
将(S)-2-((4-(6-(((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯(65毫克,0.11毫摩尔)溶于乙腈/水(4/1,5毫升)中,然后将1,5,7-三叠氮双环(4.4.0)癸-5-烯(70毫克,0.5摩尔)加入反应液中,室温搅拌2小时。(S)-2-((4-(6-(((benzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Methyl 1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (65 mg, 0.11 mmol) in acetonitrile/water (4/1 , 5 mL), and then 1,5,7-triazidebicyclo(4.4.0)dec-5-ene (70 mg, 0.5 mol) was added to the reaction solution, and stirred at room temperature for 2 hours.
LC-MS监测至反应完全，加15％柠檬酸水溶液(15.0毫升)淬灭,乙酸乙酯(30.0毫升×3次)萃取,合并有机相,浓缩,残余物经高效液相制备纯化得到3毫克白色固体(S)-2-((4-(6-((苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸(收率：4.9％)。LC-MS：RT＝1.73min,[M+H] +＝554.33。 LC-MS was monitored to complete the reaction, quenched by adding 15% aqueous citric acid solution (15.0 mL), extracted with ethyl acetate (30.0 mL × 3 times), the organic phases were combined, concentrated, and the residue was purified by HPLC to obtain 3 mg White solid (S)-2-((4-(6-((benzo[d]oxazol-2-ylmethoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 4.9%). LC-MS: RT=1.73 min, [M+ H] + =554.33.
实施例114Example 114
合成(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000613
Figure PCTCN2021120978-appb-000613
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-环丙基吡唑并[1,5-a]吡啶-5-羧酸甲酯Step A: Synthesis of methyl 3-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxylate
Figure PCTCN2021120978-appb-000614
Figure PCTCN2021120978-appb-000614
将3-溴吡唑并[1,5-a]吡啶-5-羧酸甲酯(300毫克，1.17毫摩尔)，环丙基硼酸(101毫克，1.17毫摩尔)，钯催化剂(100毫克)和碳酸钾(323毫克，2.34毫摩尔)溶于混合溶剂(12毫升，二氧六环/水＝4/1)中，100摄氏度微波1小时。Methyl 3-bromopyrazolo[1,5-a]pyridine-5-carboxylate (300 mg, 1.17 mmol), cyclopropylboronic acid (101 mg, 1.17 mmol), palladium catalyst (100 mg) and potassium carbonate (323 mg, 2.34 mmol) were dissolved in a mixed solvent (12 mL, dioxane/water=4/1), and microwaved at 100 degrees Celsius for 1 hour.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到150毫克黄色油状液体3-环丙基吡唑并[1,5-a]吡啶-5-羧酸甲酯(收率：59％)。LC-MS:RT＝2.04min,[M+H] +＝217.14。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 150 mg of yellow oily liquid 3 -Cyclopropylpyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (yield: 59%). LC-MS: RT=2.04 min, [M+H] + =217.14.
步骤B：合成(3-环丙基吡唑并[1,5-a]吡啶-5-基)甲醇Step B: Synthesis of (3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methanol
Figure PCTCN2021120978-appb-000615
Figure PCTCN2021120978-appb-000615
室温下，将3-环丙基吡唑并[1,5-a]吡啶-5-羧酸甲酯(150毫克，0.54毫摩尔)溶于四氢呋喃(7毫升)中，在冰浴中冷却至0摄氏度，加入四氢铝锂(45毫克，1.08毫摩尔)，在室温下搅拌0.5小时。Methyl 3-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxylate (150 mg, 0.54 mmol) was dissolved in tetrahydrofuran (7 mL) at room temperature and cooled in an ice bath to At 0 degrees Celsius, lithium tetrahydroaluminum (45 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(20毫升)萃取，水洗两次，无水硫酸钠干燥，过滤后浓缩得到100毫克白色固体(3-环丙基吡唑并[1,5-a]吡啶-5-基)甲醇(收率：98％)。The reaction was completed, quenched by adding saturated sodium chloride, extracted with ethyl acetate (20 mL), washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of white solid (3-cyclopropylpyrazolo[1, 5-a]pyridin-5-yl)methanol (yield: 98%).
步骤C：合成(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯Step C: Synthesis of (S)-2-((4-(6-((3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000616
Figure PCTCN2021120978-appb-000616
将(3-环丙基吡唑并[1,5-a]吡啶-5-基)甲醇(100毫克，0.53毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(262毫克，0.53毫摩尔)，钯催化剂(50毫克)和碳酸铯(345毫克，1.06毫摩尔)溶于二氧六环(5毫升)中，升温至100摄氏度搅拌2小时。(3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methanol (100 mg, 0.53 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (262 mg, 0.53 mmol), palladium catalyst (50 mg) and cesium carbonate (345 mg, 1.06 mmol) were dissolved in dioxane (5 mL), and the temperature was raised to 100 degrees Celsius and stirred for 2 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到90毫克白色固体(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：26％)。LC-MS:RT＝1.89min,[M+H] +＝649.41。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 90 mg of white solid (S )-2-((4-(6-((3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (yield: 26%). LC-MS: RT=1.89 min, [M+H] + =649.41.
步骤D：合成(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000617
Figure PCTCN2021120978-appb-000617
将(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸叔丁酯(90毫克，0.14毫摩尔)溶于二氯甲烷(2.5毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((3-Cyclopropylpyrazolo[1,5-a]pyridin-5-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (90 mg, 0.14 mmol) It was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束，浓缩，所得粗品高效液相纯化得到70毫克白色固体(S)-2-((4-(6-((3-环丙基吡唑并[1,5-a]吡啶-5-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-苯并[d]咪唑-6-羧酸(收率：84％)。LC-MS:RT＝1.73min,[M+H] +＝593.35。 1H NMR(500MHz,DMSO-d 6)δ8.53(d,J＝7.2Hz,1H),8.24(s,1H),7.79(dd,J＝8.4,1.4Hz,1H),7.73(s,1H),7.69(s,1H),7.66–7.59(m,2H),6.85(dd,J＝9.7,4.4Hz,2H),6.70(d,J＝8.2Hz,1H),5.47–5.33(m,2H),5.10(d,J＝7.1Hz,1H),4.76(dd,J＝15.1,7.2Hz,1H),4.63(dd,J＝15.1,2.6Hz,1H),4.45(dd,J＝13.6,7.7Hz,1H),4.36(dt,J＝9.1,5.9Hz,1H),3.94(d,J＝13.5Hz,1H),3.76(d,J＝13.3Hz,1H),3.00(d,J＝11.5Hz,1H),2.86(d,J＝11.2Hz,1H),2.65(ddd,J＝26.6,16.1,7.3Hz,2H),2.46–2.39(m,1H),2.27–2.12(m,2H),1.89–1.68(m,5H),0.79–0.68(m,2H),0.60–0.48(m,2H)。 The reaction was completed, concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 70 mg of white solid (S)-2-((4-(6-((3-cyclopropylpyrazolo[1,5-a]pyridine-5- yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid (yield: 84%). LC-MS: RT=1.73 min, [M+H] + =593.35. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.53 (d, J=7.2 Hz, 1H), 8.24 (s, 1H), 7.79 (dd, J=8.4, 1.4 Hz, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 7.66–7.59 (m, 2H), 6.85 (dd, J=9.7, 4.4Hz, 2H), 6.70 (d, J=8.2Hz, 1H), 5.47–5.33 (m ,2H),5.10(d,J＝7.1Hz,1H),4.76(dd,J＝15.1,7.2Hz,1H),4.63(dd,J＝15.1,2.6Hz,1H),4.45(dd,J＝ 13.6,7.7Hz,1H),4.36(dt,J=9.1,5.9Hz,1H),3.94(d,J=13.5Hz,1H),3.76(d,J=13.3Hz,1H),3.00(d, J=11.5Hz, 1H), 2.86 (d, J=11.2Hz, 1H), 2.65 (ddd, J=26.6, 16.1, 7.3Hz, 2H), 2.46–2.39 (m, 1H), 2.27–2.12 (m , 2H), 1.89–1.68 (m, 5H), 0.79–0.68 (m, 2H), 0.60–0.48 (m, 2H).
实施例115Example 115
合成(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxygen Hetetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000618
Figure PCTCN2021120978-appb-000618
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(6-((苯并呋喃-2-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000619
Figure PCTCN2021120978-appb-000619
将苯并呋喃-2-基甲醇300毫克，2.0毫摩尔)溶于四氢呋喃(8.0毫升)中，零摄氏度下分批加入钠氢(120.0毫克，3毫摩尔)，搅拌10分钟后，加入4-(6-氟吡啶-2-基)哌啶-1-甲酸叔丁酯(676毫克，2.4毫摩尔)，室温反应18小时。Dissolve benzofuran-2-ylmethanol 300 mg, 2.0 mmol) in tetrahydrofuran (8.0 mL), add sodium hydrogen (120.0 mg, 3 mmol) in portions at zero degrees Celsius, stir for 10 minutes, add 4- (6-Fluoropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (676 mg, 2.4 mmol), reacted at room temperature for 18 hours.
反应结束，加水淬灭，二氯甲烷(10毫升×3次)萃取，合并有机相，饱和食盐水(6毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝10：1)得到380毫克无色油状物4-(6-(苯并呋喃-2-基甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：46.5％)。LC-MS:RT＝2.38min,[M+H] +＝409.32。 The reaction was completed, quenched by adding water, extracted with dichloromethane (10 mL×3 times), the organic phases were combined, washed with saturated brine (6 mL×2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10:1) to obtain 380 mg of colorless oily substance 4-(6-(benzofuran-2-ylmethoxy)pyridin-2-yl)piperidine-1 - tert-butyl formate (yield: 46.5%). LC-MS: RT=2.38 min, [M+H] + =409.32.
步骤B：合成2-((苯并呋喃-2-基)甲氧基)-6-(哌啶-4-基)吡啶Step B: Synthesis of 2-((benzofuran-2-yl)methoxy)-6-(piperidin-4-yl)pyridine
Figure PCTCN2021120978-appb-000620
Figure PCTCN2021120978-appb-000620
室温下，将4-(6-((苯并呋喃-2-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(380.0毫克，0.93毫摩尔)溶于乙醇(2毫升)中，冰浴下加入4摩尔的盐酸乙醇溶液(4毫升)，室温反应1小时。反应结束，旋干溶剂，得到130毫克白色固体2-((苯并呋喃-2-基)甲氧基)-6-(哌啶-4-基)吡啶(收率：45.3％)。LC-MS:RT＝1.72min,[M+H] +＝309.21。 At room temperature, tert-butyl 4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (380.0 mg, 0.93 mmol) was dissolved in ethanol ( 2 mL), 4 mol of ethanolic hydrochloric acid solution (4 mL) was added under ice bath, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried to obtain 130 mg of white solid 2-((benzofuran-2-yl)methoxy)-6-(piperidin-4-yl)pyridine (yield: 45.3%). LC-MS: RT=1.72 min, [M+H] + =309.21.
步骤C：合成(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of (S)-2-((4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000621
Figure PCTCN2021120978-appb-000621
室温下，将2-((苯并呋喃-2-基)甲氧基)-6-(哌啶-4-基)吡啶(130毫克，0.37毫摩尔)，碳酸钾(116毫克)溶于N,N-二甲基甲酰胺(4.0毫升)中，搅拌10分钟后，加入(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(124.3毫克，0.42毫摩尔)，氮气保护下，25摄氏度反应12小时。At room temperature, 2-((benzofuran-2-yl)methoxy)-6-(piperidin-4-yl)pyridine (130 mg, 0.37 mmol), potassium carbonate (116 mg) was dissolved in N , N-dimethylformamide (4.0 mL), and after stirring for 10 minutes, (S)-2-(chloromethyl)-1-((oxetan-2-yl)methyl)- 1H-Benzo[d]imidazole-6-carboxylic acid tert-butyl ester (124.3 mg, 0.42 mmol) was reacted at 25 degrees Celsius for 12 hours under nitrogen protection.
反应结束，加水淬灭，乙酸乙酯(10毫升×3次)萃取。合并有机相，饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：乙酸乙酯)得到80毫克淡黄色固体(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸甲酯(收率：38.2％)。LC-MS:RT＝1.87min,[M+H] +＝567.37。 The reaction was completed, quenched by adding water, and extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 80 mg of pale yellow solid (S)-2-( (4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl )methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 38.2%). LC-MS: RT=1.87 min, [M+H] + =567.37.
步骤D：合成(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸Step D: Synthesis of (S)-2-((4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000622
Figure PCTCN2021120978-appb-000622
室温下，将(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸甲酯(80毫克，0.14毫摩尔),1,3,4,6,7,8-六氢-2H-嘧啶[1,2-a]嘧啶(94.6毫克，0.68毫摩尔)溶于乙腈(6.0毫升)和水(1.2毫升)，室温反应12小时。At room temperature, (S)-2-((4-(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (80 mg, 0.14 mmol), 1,3,4,6,7, 8-Hexahydro-2H-pyrimidine[1,2-a]pyrimidine (94.6 mg, 0.68 mmol) was dissolved in acetonitrile (6.0 mL) and water (1.2 mL) and reacted at room temperature for 12 hours.
反应结束，用15％的柠檬酸调至pH＝6，乙酸乙酯(10毫升×3次)萃取。合并有机相，饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，过滤，旋干得到粗产品，用制备型高效液相色谱纯化得到18.43毫克(S)-2-((4-(6-((苯并呋喃-2-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-苯并[d]咪唑-6-羧酸(收率：22.5％)。LC-MS:RT＝1.82min,[M+H] +＝553.31。 1H NMR(500MHz,DMSO)δ12.71(s,1H),9.30(s,1H),8.65(s,1H),8.26(d,J＝1.0Hz,1H),8.16(t,J＝8.7Hz,2H),7.88–7.76(m,2H),7.75–7.57(m,3H),6.88(d,J＝7.3Hz,1H),6.64(d,J＝8.2Hz,1H),5.84–5.76(m,2H),5.16–5.06(m,1H),4.80(dd,J＝15.2,7.3Hz,1H),4.66(dd,J＝15.2,2.7Hz,1H),4.43(dd,J＝13.3,8.1Hz,1H),4.35(dt,J＝9.0,5.8Hz,1H),3.96(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),3.01(d,J＝11.1Hz,1H),2.87(d,J＝11.2Hz,1H),2.76–2.58(m,2H),2.43(dd,J＝18.9,7.9Hz,1H),2.22(dt,J＝20.9,10.1Hz,2H),1.91–1.66(m,4H)。 After the reaction was completed, the pH was adjusted to 6 with 15% citric acid, and extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain 18.43 mg of (S)-2-((4 -(6-((benzofuran-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 22.5%). LC-MS: RT=1.82 min, [M+H] + =553.31. 1 H NMR(500MHz, DMSO)δ12.71(s,1H),9.30(s,1H),8.65(s,1H),8.26(d,J=1.0Hz,1H),8.16(t,J=8.7 Hz, 2H), 7.88–7.76 (m, 2H), 7.75–7.57 (m, 3H), 6.88 (d, J=7.3Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 5.84–5.76 (m, 2H), 5.16–5.06 (m, 1H), 4.80 (dd, J=15.2, 7.3Hz, 1H), 4.66 (dd, J=15.2, 2.7Hz, 1H), 4.43 (dd, J=13.3 ,8.1Hz,1H),4.35(dt,J＝9.0,5.8Hz,1H),3.96(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),3.01(d,J =11.1Hz,1H),2.87(d,J=11.2Hz,1H),2.76–2.58(m,2H),2.43(dd,J=18.9,7.9Hz,1H),2.22(dt,J=20.9, 10.1Hz, 2H), 1.91–1.66 (m, 4H).
实施例116Example 116
合成(S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000623
Figure PCTCN2021120978-appb-000623
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-氨基-5-(羟甲基)-2-甲氧基吡啶-1-鎓盐Step A: Synthesis of 1-amino-5-(hydroxymethyl)-2-methoxypyridine-1-onium salt
Figure PCTCN2021120978-appb-000624
Figure PCTCN2021120978-appb-000624
将(E)-N-(2,4,6-三甲基苯磺酰基)氧基乙酰亚胺酸乙酯(2克，7.2毫摩尔)溶于二氧六环(6毫升)，加入高氯酸(2毫升)，室温下搅拌0.5小时，反应结束后加入5毫升水淬灭，过滤干燥得白色固体，溶解于二氯甲烷(10毫升)中，加入(6-甲氧基吡啶-3-基)甲醇(500毫克，3.6毫摩尔)，室温下搅拌2小时。Ethyl (E)-N-(2,4,6-trimethylbenzenesulfonyl)oxyacetimidate (2 g, 7.2 mmol) was dissolved in dioxane (6 mL) and added with high Chloric acid (2 mL), stirred at room temperature for 0.5 hours, quenched by adding 5 mL of water after the reaction, filtered and dried to obtain a white solid, dissolved in dichloromethane (10 mL), added (6-methoxypyridine-3 -yl) methanol (500 mg, 3.6 mmol), stirred at room temperature for 2 hours.
反应结束后，浓缩得白色固体粗品直接用于下一步。After the reaction was completed, the crude product was concentrated to obtain a white solid, which was directly used in the next step.
步骤B：合成4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸乙酯Step B: Synthesis of 4-(hydroxymethyl)-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester
Figure PCTCN2021120978-appb-000625
Figure PCTCN2021120978-appb-000625
将上步固体粗品(3.6毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，加入碳酸钾(994毫克，7.2毫摩尔)和丙炔酸乙酯(352毫克，3.6毫摩尔)，室温下反应16小时。The crude solid from the previous step (3.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (994 mg, 7.2 mmol) and ethyl propiolate (352 mg, 3.6 mmol) were added. mol) for 16 hours at room temperature.
反应结束后，加饱和氯化钠淬灭，乙酸乙酯萃取(10毫升×2次)，合并有机相，无水硫酸钠干燥，过滤后浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到220毫克黄色色油状液体4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：28％)。LC-MS:RT＝1.88min,[M+H] +＝251.15。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (10 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent). : ethyl acetate/n-hexane=1/1) to obtain 220 mg of ethyl 4-(hydroxymethyl)-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate as a yellow oily liquid (Yield: 28%). LC-MS: RT=1.88 min, [M+H] + =251.15.
步骤C：合成4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸Step C: Synthesis of 4-(hydroxymethyl)-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000626
Figure PCTCN2021120978-appb-000626
将4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸乙酯(220毫克，0.88毫摩尔)溶于乙醇(5毫升)和水(1毫升)中，室温下加入氢氧化钾(148毫克，2.64毫摩尔)，反应1小时。Ethyl 4-(hydroxymethyl)-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (220 mg, 0.88 mmol) was dissolved in ethanol (5 mL) and water ( 1 mL), potassium hydroxide (148 mg, 2.64 mmol) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束，加入1摩尔稀盐酸中和至PH等于6，乙酸乙酯(50毫升)萃取，无水硫酸钠干燥得到150毫克黄色固体4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸(收率：77％)。LC-MS:RT＝1.70min,[M+H] +＝223.07。 After the reaction was completed, 1 mole of dilute hydrochloric acid was added to neutralize to pH 6, extracted with ethyl acetate (50 mL), and dried over anhydrous sodium sulfate to obtain 150 mg of yellow solid 4-(hydroxymethyl)-7-methoxypyrazolo [1,5-a]pyridine-3-carboxylic acid (yield: 77%). LC-MS: RT=1.70 min, [M+H] + =223.07.
步骤D：合成(7-甲氧基吡唑并[1,5-a]吡啶-4-基)甲醇Step D: Synthesis of (7-Methoxypyrazolo[1,5-a]pyridin-4-yl)methanol
Figure PCTCN2021120978-appb-000627
Figure PCTCN2021120978-appb-000627
将4-(羟甲基)-7-甲氧基吡唑并[1,5-a]吡啶-3-羧酸(150毫克，0.68毫摩尔)溶于邻二氯苯(5毫升)，在120摄氏度下反应16小时。反应完后，浓缩，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到100毫克白色固体(7-甲氧基吡唑并[1,5-a]吡啶-4-基)甲醇(收率：83％)。LC-MS:RT＝1.80min,[M+H] +＝179.13。 4-(Hydroxymethyl)-7-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (150 mg, 0.68 mmol) was dissolved in o-dichlorobenzene (5 mL) in The reaction was carried out at 120 degrees Celsius for 16 hours. After completion of the reaction, it was concentrated, and the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=1/3) to obtain 100 mg of white solid (7-methoxypyrazolo[1,5-a] Pyridin-4-yl)methanol (yield: 83%). LC-MS: RT=1.80 min, [M+H] + =179.13.
步骤E：合成(S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of (S)-methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000628
Figure PCTCN2021120978-appb-000628
将(7-甲氧基吡唑并[1,5-a]吡啶-4-基)甲醇(50毫克，0.28毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(127毫克，0.28毫摩尔)，钯催化剂(24毫克)，碳酸铯(182毫克，0.56毫摩尔)溶于二氧六环中，升温至100摄氏度搅拌16小时。(7-Methoxypyrazolo[1,5-a]pyridin-4-yl)methanol (50 mg, 0.28 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (127 mg, 0.28 mmol), palladium catalyst (24 mg), cesium carbonate (182 mg, 0.56 mmol) were dissolved in dioxane, and the temperature was raised to 100 degrees Celsius and stirred for 16 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩滤液，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到30毫克白色固体(S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯(收率：18％)。LC-MS:RT＝1.87min,[M+H]+＝597.35After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, and the filtrate was concentrated. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 30 mg of white solid (S) -Methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 18%). LC-MS: RT=1.87min, [M+H]+=597.35
步骤F：合成(S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridine-2 -yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000629
Figure PCTCN2021120978-appb-000629
将S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯(30毫克，0.05毫摩尔)溶于乙腈(5毫升)和水(1毫升)中，室温下加入1,3,4,6,7,8-六氢-2H-嘧啶[1,2-a]嘧啶(30毫克，0.2毫摩尔)，反应4小时。S)-methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine Methyl pyridin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.05 mmol ) was dissolved in acetonitrile (5 mL) and water (1 mL), and 1,3,4,6,7,8-hexahydro-2H-pyrimidine[1,2-a]pyrimidine (30 mg, 0.2 mmol) for 4 hours.
反应结束，浓缩，所得粗品高效液相纯化得到12毫克白色固体(S)-甲基-2-((4-(6-((7-甲氧基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸(收率：41％)。LC-MS:RT＝1.80min,[M+H] +＝583.27。 The reaction was completed, concentrated, and the obtained crude product was purified by high performance liquid phase to obtain 12 mg of white solid (S)-methyl-2-((4-(6-((7-methoxypyrazolo[1,5-a]pyridine) -4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d ] Imidazole-6-carboxylic acid (yield: 41%). LC-MS: RT=1.80 min, [M+H] + =583.27.
实施例117Example 117
合成(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxygen Hetetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000630
Figure PCTCN2021120978-appb-000630
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成苯并呋喃-3-基甲醇Step A: Synthesis of Benzofuran-3-ylmethanol
Figure PCTCN2021120978-appb-000631
Figure PCTCN2021120978-appb-000631
将苯并呋喃-3-甲醛(250.0毫克，1.7毫摩尔)溶于甲醇(5.0毫升)中，零摄氏度下分批加入硼氢化钠(96.6毫克，2.6毫摩尔)，逐渐升至室温，室温反应1小时。Dissolve benzofuran-3-carbaldehyde (250.0 mg, 1.7 mmol) in methanol (5.0 mL), add sodium borohydride (96.6 mg, 2.6 mmol) in portions at zero degrees Celsius, gradually warm to room temperature, and react at room temperature 1 hour.
反应结束，加1.0摩尔的稀盐酸淬灭，二氯甲烷(6毫升×3次)萃取，合并有机相，饱和食盐水(4毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩得到251.0毫克无色液体苯并呋喃-3-基甲醇(收率：99.1％)。The reaction was completed, quenched by adding 1.0 mol of dilute hydrochloric acid, extracted with dichloromethane (6 mL×3 times), the organic phases were combined, washed with saturated brine (4 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure 251.0 mg of colorless liquid benzofuran-3-ylmethanol was obtained (yield: 99.1%).
步骤B：合成4-(6-((苯并呋喃-3-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯Step B: Synthesis of tert-butyl 4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
Figure PCTCN2021120978-appb-000632
Figure PCTCN2021120978-appb-000632
将苯并呋喃-3-基甲醇(221.0毫克，1.5毫摩尔)溶于四氢呋喃(8.0毫升)中，零摄氏度下分批加入钠氢(120.0毫克，3毫摩尔)，搅拌10分钟后，加入4-(6-氟吡啶-2-基)哌啶-1-甲酸叔丁酯(546.0毫克，1.9毫摩尔)，室温反应12小时。Benzofuran-3-ylmethanol (221.0 mg, 1.5 mmol) was dissolved in tetrahydrofuran (8.0 mL), and sodium hydrogen (120.0 mg, 3 mmol) was added in portions at zero degrees Celsius. After stirring for 10 minutes, 4 -(6-Fluoropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (546.0 mg, 1.9 mmol), reacted at room temperature for 12 hours.
反应结束，加水淬灭，二氯甲烷(10毫升×3次)萃取，合并有机相，饱和食盐水(6毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝10：1)得到188.0毫克无色油状物4-(6-((苯并呋喃-3-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(收率：35.4％)。LC-MS:RT＝2.37min,[M-56+H] +＝353.24。 The reaction was completed, quenched by adding water, extracted with dichloromethane (10 mL×3 times), the organic phases were combined, washed with saturated brine (6 mL×2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10:1) to obtain 188.0 mg of 4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidine as a colorless oil - tert-butyl 1-carboxylate (yield: 35.4%). LC-MS: RT=2.37 min, [M-56+H] + =353.24.
步骤C：合成2-((苯并呋喃-3-基)甲氧基)-6-(哌啶-4-基)吡啶Step C: Synthesis of 2-((benzofuran-3-yl)methoxy)-6-(piperidin-4-yl)pyridine
Figure PCTCN2021120978-appb-000633
Figure PCTCN2021120978-appb-000633
室温下，将4-(6-((苯并呋喃-3-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(188.0毫克，0.46毫摩尔)溶于二氧六环(2毫升)中，冰浴下加入4摩尔的盐酸二氧六环溶液(4毫升)，室温反应1小时。反应结束，旋干溶剂，得到158.4毫克白色固体2-((苯并呋喃-3-基)甲氧基)-6-(哌啶-4-基)吡啶(收率：100％)。LC-MS:RT＝1.72min,[M+H] +＝309.21。 Dissolve tert-butyl 4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (188.0 mg, 0.46 mmol) in dioxygen at room temperature Hexane (2 mL) was added with 4 moles of dioxane hydrochloride solution (4 mL) under ice bath, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried to obtain 158.4 mg of white solid 2-((benzofuran-3-yl)methoxy)-6-(piperidin-4-yl)pyridine (yield: 100%). LC-MS: RT=1.72 min, [M+H] + =309.21.
步骤D：合成(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸甲酯Step D: Synthesis of (S)-2-((4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000634
Figure PCTCN2021120978-appb-000634
室温下，将2-((苯并呋喃-3-基)甲氧基)-6-(哌啶-4-基)吡啶(158.4毫克，0.46毫摩尔)，N,N-二异丙基乙胺(0.4毫升)溶于N,N-二甲基甲酰胺(4.0毫升)中，搅拌10分钟后，加入(S)-2-(氯甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(134.3毫克，0.55毫摩尔)，N 2保护下，25度反应12小时。 At room temperature, 2-((benzofuran-3-yl)methoxy)-6-(piperidin-4-yl)pyridine (158.4 mg, 0.46 mmol), N,N-diisopropylethyl The amine (0.4 mL) was dissolved in N,N-dimethylformamide (4.0 mL), and after stirring for 10 min, (S)-2-(chloromethyl)-1-((oxetane- 2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (134.3 mg, 0.55 mmol), under N 2 protection, reacted at 25 degrees for 12 hours.
反应结束，加水淬灭，乙酸乙酯(10毫升×3次)萃取。合并有机相，饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，最后硅胶柱层析纯化(洗脱剂：正己烷：乙酸乙酯＝0：1)得到116.0毫克淡黄色固体(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸甲酯(收率：44.5％)。LC-MS:RT＝1.82min,[M+H] +＝567.37 The reaction was completed, quenched by adding water, and extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=0:1) to obtain 116.0 mg of pale yellow solid (S)-2-((4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxa Cyclobutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 44.5%). LC-MS: RT=1.82min, [M+H] + =567.37
步骤E：合成(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000635
Figure PCTCN2021120978-appb-000635
室温下，将(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸甲酯(96毫克0.17毫摩尔),1,3,4,6,7,8-六氢-2H-嘧啶[1,2-a]嘧啶(94.6毫克，0.68毫摩尔)溶于乙腈(6.0毫升)和水(1.2毫升)，室温反应12小时。(S)-2-((4-(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1- Methyl ((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (96 mg 0.17 mmol), 1,3,4,6,7,8 - Hexahydro-2H-pyrimidine[1,2-a]pyrimidine (94.6 mg, 0.68 mmol) was dissolved in acetonitrile (6.0 mL) and water (1.2 mL) and reacted at room temperature for 12 hours.
反应结束，用15％的柠檬酸调至pH＝6，乙酸乙酯(10毫升×3次)萃取。合并有机相，饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，过滤，旋干得到粗产品，用制备型高效液相色谱纯化得到36.95毫克(S)-2-((4-(6-((苯并呋喃-3-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-苯并[d]咪唑-6-羧酸(收率：39.3％)。LC-MS:RT＝1.81min,[M+H] +＝553.35。 1H NMR(400MHz,DMSO):δ＝12.79(s,1H),8.26(d,J＝1.0Hz,1H),8.08(s,1H),7.80(dd,J＝8.4,1.5Hz,1H),7.69(d,J＝7.5Hz,1H),7.66–7.56(m,3H),7.36–7.30(m,1H),7.26(dd,J＝10.8,4.1Hz,1H),6.88(d,J＝7.3Hz,1H),6.65(d,J＝8.1Hz,1H),5.59–5.42(m,2H),5.16–5.06(m,1H),4.79(dd,J＝15.2,7.2Hz,1H),4.65(dd,J＝15.2,2.6Hz,1H),4.48–4.30(m,2H),3.96(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.03(d,J＝11.2Hz,1H),2.88(d,J＝11.1Hz,1H),2.74–2.59(m,2H),2.43(dd,J＝18.8,8.0Hz,1H),2.30–2.14(m,2H),1.92–1.68(m,4H)。 After the reaction was completed, the pH was adjusted to 6 with 15% citric acid, and extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain 36.95 mg of (S)-2-((4 -(6-((benzofuran-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 39.3%). LC-MS: RT=1.81 min, [M+H] + =553.35. 1 H NMR (400MHz, DMSO): δ=12.79 (s, 1H), 8.26 (d, J=1.0 Hz, 1H), 8.08 (s, 1H), 7.80 (dd, J=8.4, 1.5 Hz, 1H) ,7.69(d,J＝7.5Hz,1H),7.66-7.56(m,3H),7.36-7.30(m,1H),7.26(dd,J＝10.8,4.1Hz,1H),6.88(d,J =7.3Hz,1H),6.65(d,J=8.1Hz,1H),5.59-5.42(m,2H),5.16-5.06(m,1H),4.79(dd,J=15.2,7.2Hz,1H) ,4.65(dd,J＝15.2,2.6Hz,1H),4.48–4.30(m,2H),3.96(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.03( d, J=11.2Hz, 1H), 2.88 (d, J=11.1Hz, 1H), 2.74–2.59 (m, 2H), 2.43 (dd, J=18.8, 8.0Hz, 1H), 2.30–2.14 (m , 2H), 1.92–1.68 (m, 4H).
实施例118Example 118
合成(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡咯并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-(2-methoxy-2-oxoethyl)pyrrolo[1,5-a]pyridin-4-yl)methoxy )pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000636
Figure PCTCN2021120978-appb-000636
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-氨基-3-(羟甲基)吡啶-1-鎓盐Step A: Synthesis of 1-amino-3-(hydroxymethyl)pyridine-1-onium salt
Figure PCTCN2021120978-appb-000637
Figure PCTCN2021120978-appb-000637
室温下，先将(E)-N-((2,4,6-三甲基苯磺酰基)氧基)乙酰亚胺酸乙酯(7.80克，27.52毫摩尔)溶于二氧六环(10毫升)中，再加入高氯酸(3.5毫升)反应至有大量白色沉淀，加水过滤，固体抽干后用二氯甲烷(20毫升)溶解，无水硫酸钠干燥。然后在过滤后溶液中加入吡啶-3-基甲醇(2克，18.35毫摩尔)，室温下反应2小时后直接旋干备用。At room temperature, ethyl (E)-N-((2,4,6-trimethylbenzenesulfonyl)oxy)acetimidate (7.80 g, 27.52 mmol) was first dissolved in dioxane ( 10 mL), and then added perchloric acid (3.5 mL) to react until there was a large amount of white precipitate, add water to filter, the solid was drained and dissolved in dichloromethane (20 mL), and dried over anhydrous sodium sulfate. Then, pyridin-3-ylmethanol (2 g, 18.35 mmol) was added to the filtered solution, and the solution was reacted at room temperature for 2 hours and then directly rotated to dryness for use.
步骤B：合成4-(羟甲基)-2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-3-羧酸甲酯Step B: Synthesis of methyl 4-(hydroxymethyl)-2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000638
Figure PCTCN2021120978-appb-000638
将前一步所得鎓盐(2.30克，18.35毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入3-氧代戊二酸二甲酯(3.20克，18.35毫摩尔)和碳酸钾(5克，36.70毫摩尔)，升温至50摄氏度反应过夜。The onium salt obtained in the previous step (2.30 g, 18.35 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of dimethyl 3-oxoglutarate (3.20 g, 18.35 mmol). ) and potassium carbonate (5 g, 36.70 mmol), heated to 50 degrees Celsius and reacted overnight.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(20毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到550毫克淡黄色油状液体4-(羟甲基)-2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-3-羧酸甲酯(收率：11％)。LC-MS:RT＝1.61min,[M+H] +＝279.15。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (20 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/1) Obtained 550 mg of pale yellow oily liquid 4-(hydroxymethyl)-2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridine-3-carboxylate Methyl acid (yield: 11%). LC-MS: RT=1.61 min, [M+H] + =279.15.
步骤C：合成2-(羧甲基)-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸Step C: Synthesis of 2-(carboxymethyl)-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000639
Figure PCTCN2021120978-appb-000639
室温下，将4-(羟甲基)-2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-3-羧酸甲酯(469毫克,1.68毫摩尔)溶于混合溶剂(4毫升，乙醇/水＝3/1)中，加入氢氧化钾(188毫克，3.36毫摩尔)，室温反应。At room temperature, methyl 4-(hydroxymethyl)-2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (469 mg, 1.68 mmol) was dissolved in a mixed solvent (4 mL, ethanol/water=3/1), potassium hydroxide (188 mg, 3.36 mmol) was added, and the reaction was carried out at room temperature.
反应结束后，用稀盐酸调节pH＝5-6，直接旋干备用。LC-MS:RT＝1.49min,[M+H] +＝251.13。 After the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid, and it was directly spin-dried for use. LC-MS: RT=1.49 min, [M+H] + =251.13.
步骤D：合成2-(4-(羟甲基)吡唑并[1,5-a]吡啶-2基)乙羧Step D: Synthesis of 2-(4-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2yl)ethylcarboxylate
Figure PCTCN2021120978-appb-000640
Figure PCTCN2021120978-appb-000640
将粗品2-(羧甲基)-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸溶于二氯乙烷(15毫升，乙醇/水＝3/1)中，升温至100摄氏度过夜。The crude 2-(carboxymethyl)-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid was dissolved in dichloroethane (15 mL, ethanol/water=3/1 ), the temperature was raised to 100°C overnight.
反应结束后，直接旋干备用。LC-MS:RT＝1.43min,[M+H] +＝207.12。 After the reaction, it was directly spin-dried for use. LC-MS: RT=1.43 min, [M+H] + =207.12.
步骤E：合成2-(4-(羟甲基)吡唑并[1,5-a]吡啶-2基)乙羧甲酯Step E: Synthesis of methyl 2-(4-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2yl)ethylcarboxylate
Figure PCTCN2021120978-appb-000641
Figure PCTCN2021120978-appb-000641
将粗品2-(4-(羟甲基)吡唑并[1,5-a]吡啶-2基)乙羧(400毫克，1.93毫摩尔)溶于甲醇(15毫升)中，再加入浓硫酸(2毫升)，升温至80摄氏度反应。The crude 2-(4-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2yl)ethanecarboxylate (400 mg, 1.93 mmol) was dissolved in methanol (15 mL) and concentrated sulfuric acid was added (2 ml), and the temperature was raised to 80 degrees Celsius for the reaction.
反应结束，用稀释的氢氧化钠溶液中和，乙酸乙酯(10毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到200毫克淡黄色固体2-(4-(羟甲基)吡唑并[1,5-a]吡啶-2基)乙羧甲酯。LC-MS:RT＝1.65min,[M+H] +＝221.13。 After the reaction was completed, it was neutralized with dilute sodium hydroxide solution, extracted with ethyl acetate (10 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane). alkane=1/1) to give 200 mg of methyl 2-(4-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2yl)ethylcarboxylate as a pale yellow solid. LC-MS: RT=1.65 min, [M+H] + =221.13.
步骤F：合成4-(6-((2-(2-乙氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁基酯Step F: Synthesis of 4-(6-((2-(2-ethoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridine-2 -yl)piperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021120978-appb-000642
Figure PCTCN2021120978-appb-000642
将2-(4-(羟甲基)吡唑并[1,5-a]吡啶-2基)乙羧甲酯(100毫克，0.45毫摩尔)，4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯(154毫克，0.45毫摩尔)，钯催化剂(38毫克)，碳酸铯(293毫克，0.90毫摩尔)溶于二氧六环(15毫升)中，升温至100摄氏度搅拌8小时。2-(4-(Hydroxymethyl)pyrazolo[1,5-a]pyridin-2-yl)ethylcarboxymethyl (100 mg, 0.45 mmol), 4-(6-bromopyridin-2-yl ) piperidine-1-carboxylate tert-butyl ester (154 mg, 0.45 mmol), palladium catalyst (38 mg), cesium carbonate (293 mg, 0.90 mmol) was dissolved in dioxane (15 mL), warmed to Stir at 100°C for 8 hours.
反应结束，用硅藻土抽滤，二氯甲烷淋洗，浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到150毫克淡黄色固体4-(6-((2-(2-乙氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁基酯(收率：22％)。LC-MS:RT＝2.29min,[M+H] +＝481.31。 After the reaction was completed, suction filtration was performed with celite, rinsed with dichloromethane, the organic phase was concentrated, and the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 150 mg of pale yellow solid 4 -(6-((2-(2-Ethoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine - tert-butyl 1-carboxylate (yield: 22%). LC-MS: RT=2.29 min, [M+H] + =481.31.
步骤G：合成2-(4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶-2-基)乙酸甲酯Step G: Synthesis of 2-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-2-yl) methyl acetate
Figure PCTCN2021120978-appb-000643
Figure PCTCN2021120978-appb-000643
将4-(6-((2-(2-乙氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁基酯(80毫克,0.17毫摩尔)溶于盐酸的二氧六环溶液(3毫升)中，室温搅拌。4-(6-((2-(2-ethoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl) tert-Butyl piperidine-1-carboxylate (80 mg, 0.17 mmol) was dissolved in hydrochloric acid in dioxane (3 mL) and stirred at room temperature.
反应完全，减压旋干得到85毫克淡黄色固体2-(4-((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶-2-基)乙酸甲酯。LC-MS:RT＝1.66min,[M+H] +＝381.25。 After the reaction was completed, it was spin-dried under reduced pressure to obtain 85 mg of pale yellow solid 2-(4-((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5- a]Methyl pyridin-2-yl)acetate. LC-MS: RT=1.66 min, [M+H] + =381.25.
步骤H：合成(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯Step H: Synthesis of (S)-2-((4-(6-((2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 - tert-butyl carboxylate
Figure PCTCN2021120978-appb-000644
Figure PCTCN2021120978-appb-000644
将2-(4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)吡唑并[1,5-a]吡啶-2-基)乙酸甲酯(85毫克，0.22毫摩尔)碳酸钾(61毫克，0.44毫摩尔)溶于N,N-二甲基甲酰胺(5毫升)中，再加入2-((S)-1-氯乙基)-1-((S)-氧杂环丁烷-2-基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(75毫克,0.22毫摩尔)，室温反应。Methyl 2-(4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyrazolo[1,5-a]pyridin-2-yl)acetate (85 mg, 0.22 mmol) potassium carbonate (61 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (5 mL) followed by 2-((S)-1-chloroethyl) -1-((S)-oxetan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (75 mg, 0.22 mmol), reacted at room temperature.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(30毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到50毫克白色固体(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯(收率：34％)。LC-MS:RT＝1.89min,[M+H] +＝681.44。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 10/1) to give 50 mg of white solid (S)-2-((4-(6-((2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]) Pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[ d] tert-butyl imidazole-6-carboxylate (yield: 34%). LC-MS: RT=1.89 min, [M+H] + =681.44.
步骤I：合成(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Step I: Synthesis of (S)-2-((4-(6-((2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl )methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -carboxylic acid
Figure PCTCN2021120978-appb-000645
Figure PCTCN2021120978-appb-000645
将(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸叔丁酯(50毫克，0.08毫摩尔)溶于二氯甲烷(3毫升)中，室温下加入三氟乙酸(1毫升)，反应1小时。(S)-2-((4-(6-((2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl)methoxy yl)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-Butyl ester (50 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the reaction was carried out for 1 hour.
反应结束，浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到25毫克白色固体(S)-2-((4-(6-((2-(2-甲氧基-2-氧代乙基)吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸(收率：69％)。LC-MS:RT＝1.77min,[M+H] +＝625.83。 1H NMR(500MHz,DMSO-d 6)δ8.72(d,J＝6.8Hz,1H),8.35(s,1H),7.89–7.59(m,5H),7.06(t,J＝7.0Hz,1H),6.92(d,J＝6.6Hz,1H),6.65(d,J＝8.0Hz,1H),5.72(s,2H),5.03(s,1H),4.80(dd,J＝15.2,6.9Hz,2H),4.66(d,J＝14.1Hz,1H),4.47(d,J＝5.7Hz,1H),4.32(s,1H),3.76(s,2H),3.52(s,3H), 2.88(s,2H),2.71(d,J＝9.9Hz,2H),2.32(s,2H),2.07(s,4H),1.23(dd,J＝6.6,2.9Hz,2H). The reaction was completed, concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 25 mg of white solid (S)-2-((4-(6-((2- (2-Methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 69%). LC-MS: RT=1.77 min, [M+H] + =625.83. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.72 (d, J=6.8 Hz, 1H), 8.35 (s, 1H), 7.89-7.59 (m, 5H), 7.06 (t, J=7.0 Hz, 1H), 6.92(d, J＝6.6Hz, 1H), 6.65(d, J＝8.0Hz, 1H), 5.72(s, 2H), 5.03(s, 1H), 4.80(dd, J＝15.2, 6.9 Hz, 2H), 4.66(d, J=14.1Hz, 1H), 4.47(d, J=5.7Hz, 1H), 4.32(s, 1H), 3.76(s, 2H), 3.52(s, 3H), 2.88(s, 2H), 2.71(d, J=9.9Hz, 2H), 2.32(s, 2H), 2.07(s, 4H), 1.23(dd, J=6.6, 2.9Hz, 2H).
实施例119Example 119
合成(S)-2-((4-(6-((2-环丙基吡咯并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrrolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000646
Figure PCTCN2021120978-appb-000646
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成3-环丙基丙炔酸乙酯Step A: Synthesis of Ethyl 3-Cyclopropylpropiolate
Figure PCTCN2021120978-appb-000647
Figure PCTCN2021120978-appb-000647
将环丙基乙炔(2.2克，33.28毫摩尔)溶于四氢呋喃(20毫升)中，冷却至零下78摄氏度，加入正丁基锂(13.3毫升)搅拌0.5小时，再加入氰基甲酸乙酯(3.30克，33.28毫摩尔)，反应1小时。Cyclopropylacetylene (2.2 g, 33.28 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to minus 78 degrees Celsius, n-butyllithium (13.3 mL) was added and stirred for 0.5 h, then ethyl cyanoformate (3.30 g, 33.28 mmol), and reacted for 1 hour.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(10毫升×2次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：正己烷)得到3.2克淡黄色油状液体3-环丙基丙炔酸乙酯(收率：69％)。LC-MS:RT＝1.93min,[M+H] +＝139.06。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (10 mL×2 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: n-hexane) to obtain 3.2 g of pale Yellow oily liquid 3-cyclopropylpropioic acid ethyl ester (yield: 69%). LC-MS: RT=1.93 min, [M+H] + =139.06.
步骤B：合成1-氨基-3-(羟甲基)吡啶-1-鎓盐Step B: Synthesis of 1-amino-3-(hydroxymethyl)pyridine-1-onium salt
Figure PCTCN2021120978-appb-000648
Figure PCTCN2021120978-appb-000648
室温下，先将(E)-N-((2,4,6-三甲基苯磺酰基)氧基)乙酰亚胺酸乙酯(7.80克，27.52毫摩尔)溶于二氧六环(10毫升)中，再加入高氯酸(3.5毫升)反应至有大量白色沉淀，加水过滤，固体抽干后用二氯甲烷(20毫升)溶解，无水硫酸钠干燥。向滤液中加入吡啶-3-基甲醇(2克，18.35毫摩尔)，室温下反应2小时后直接旋干备用。At room temperature, ethyl (E)-N-((2,4,6-trimethylbenzenesulfonyl)oxy)acetimidate (7.80 g, 27.52 mmol) was first dissolved in dioxane ( 10 mL), and then added perchloric acid (3.5 mL) to react until there was a large amount of white precipitate, add water to filter, the solid was drained and dissolved in dichloromethane (20 mL), and dried over anhydrous sodium sulfate. Pyridin-3-ylmethanol (2 g, 18.35 mmol) was added to the filtrate, and the mixture was reacted at room temperature for 2 hours and then directly rotated to dryness for use.
步骤C：合成2-环丙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯Step C: Synthesis of ethyl 2-cyclopropyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000649
Figure PCTCN2021120978-appb-000649
将前一步所得鎓盐(2.89克，23.19毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入3-环丙基丙炔酸乙酯(3.20克，23.19毫摩尔)和碳酸钾(6.40克，46.38毫摩尔)，升温至50摄氏度反应过夜。The onium salt obtained in the previous step (2.89 g, 23.19 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of ethyl 3-cyclopropylpropiolate (3.20 g, 23.19 mmol). ) and potassium carbonate (6.40 g, 46.38 mmol), warmed to 50 degrees Celsius and reacted overnight.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(30毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到562毫克淡黄色固体2-环丙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：9％)。LC-MS:RT＝1.89min,[M+H] +＝261.17。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/1) 562 mg of ethyl 2-cyclopropyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was obtained as a pale yellow solid (yield: 9%). LC-MS: RT=1.89 min, [M+H] + =261.17.
步骤D：合成2-环丙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸Step D: Synthesis of 2-Cyclopropyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000650
Figure PCTCN2021120978-appb-000650
将2-环丙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(562毫克,2.16毫摩尔)溶于混合溶剂(4毫升，乙醇/水＝3/1)中，加入氢氧化钾(242毫克，4.32毫摩尔)，室温反应。Ethyl 2-cyclopropyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (562 mg, 2.16 mmol) was dissolved in a mixed solvent (4 mL, ethanol/ Water = 3/1), potassium hydroxide (242 mg, 4.32 mmol) was added, and the mixture was reacted at room temperature.
反应结束后，用稀盐酸调节pH＝5-6，直接旋干备用。LC-MS:RT＝1.66min,[M+H] +＝233.15。 After the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid, and it was directly spin-dried for use. LC-MS: RT=1.66 min, [M+H] + =233.15.
步骤E：合成(2-环丙基吡唑并[1,5-a]吡啶-4-基)甲醇Step E: Synthesis of (2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methanol
Figure PCTCN2021120978-appb-000651
Figure PCTCN2021120978-appb-000651
将粗品2-环丙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸溶于二氯乙烷(15毫升，乙醇/水＝3/1)中，升温至100摄氏度过夜。The crude 2-cyclopropyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid was dissolved in dichloroethane (15 mL, ethanol/water=3/1) , warmed to 100 °C overnight.
反应结束后-，直接旋干，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)得到562毫克白色固体(2-环丙基吡唑并[1,5-a]吡啶-4-基)甲醇。After the reaction was completed, it was directly rotated to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 562 mg of white solid (2-cyclopropylpyrazolo[1, 5-a]pyridin-4-yl)methanol.
步骤F：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯Step F: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl) Methyl piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate
Figure PCTCN2021120978-appb-000652
Figure PCTCN2021120978-appb-000652
将(2-环丙基吡唑并[1,5-a]吡啶-4-基)甲醇(75毫克，0.40毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(180毫克，0.40毫摩尔)，钯催化剂(34毫克)和碳酸铯(261毫克，0.80毫摩尔)溶于二氧六环(5毫升)中，升温至100摄氏度搅拌2小时。(2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methanol (75 mg, 0.40 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (180 mg, 0.40 mmol), palladium catalyst (34 mg) and cesium carbonate (261 mg, 0.80 mmol) were dissolved in dioxane (5 mL), and the temperature was raised to 100 degrees Celsius and stirred for 2 hours.
反应结束，硅藻土抽滤，二氯甲烷淋洗，浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到27毫克白色固体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯(收率：26％)。LC-MS:RT＝1.84min,[M+H] +＝607.37。 After the reaction was completed, celite was suction filtered, rinsed with dichloromethane, the organic phase was concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 27 mg of white solid (S )-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (yield: 26%). LC-MS: RT=1.84 min, [M+H] + =607.37.
步骤G：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸Step G: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000653
Figure PCTCN2021120978-appb-000653
将(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸甲酯(92毫克，0.15毫摩尔)溶于混合溶剂(5毫升，乙腈/水＝4/1)中，再加入1,5,7-三叠氮双环(4,4,0)癸-5-烯(84毫克，0.61毫摩尔)，反应4小时。(S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (92 mg, 0.15 mmol) in In a mixed solvent (5 mL, acetonitrile/water=4/1), 1,5,7-triazidebicyclo(4,4,0)dec-5-ene (84 mg, 0.61 mmol) was added, The reaction was carried out for 4 hours.
反应结束，加柠檬酸淬灭，乙酸乙酯萃取(10毫升×3次)，合并有机相，无水硫酸钠干燥，过滤后浓缩，浓缩所得粗品用高效液相纯化得到18毫克白色固体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-4-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-苯并[d]咪唑-6-羧酸(收率：84％)。LC-MS:RT＝1.79min,[M+H] +＝593.36。 1H NMR(500MHz,DMSO-d 6)δ8.47(d,J＝6.9Hz,1H),8.26(s,1H),7.79(dd,J＝8.4,1.4Hz,1H),7.69–7.57(m,2H),7.19(d,J＝6.8Hz,1H),6.87(d,J＝7.2Hz,1H),6.78–6.64(m,2H),6.37(s,1H),5.57–5.41(m,2H),5.09(d,J＝7.4Hz,1H),4.78(dd,J＝15.4,7.3 Hz,1H),4.64(d,J＝12.6Hz,1H),4.47–4.31(m,2H),3.94(d,J＝13.5Hz,1H),3.76(d,J＝13.5Hz,1H),2.98(d,J＝11.3Hz,1H),2.83(d,J＝11.3Hz,1H),2.70–2.56(m,2H),2.42(s,1H),2.26–2.11(m,2H),2.02(ddd,J＝13.3,8.4,5.0Hz,1H),1.83–1.60(m,4H),0.99–0.87(m,2H),0.82–0.70(m,2H)。 The reaction was completed, quenched by adding citric acid, extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained from the concentration was purified by high performance liquid phase to obtain 18 mg of white solid (S )-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 84%). LC-MS: RT=1.79 min, [M+H] + =593.36. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.47 (d, J=6.9Hz, 1H), 8.26 (s, 1H), 7.79 (dd, J=8.4, 1.4Hz, 1H), 7.69-7.57 ( m, 2H), 7.19 (d, J=6.8Hz, 1H), 6.87 (d, J=7.2Hz, 1H), 6.78–6.64 (m, 2H), 6.37 (s, 1H), 5.57–5.41 (m ,2H),5.09(d,J＝7.4Hz,1H),4.78(dd,J＝15.4,7.3 Hz,1H),4.64(d,J＝12.6Hz,1H),4.47–4.31(m,2H) ,3.94(d,J＝13.5Hz,1H),3.76(d,J＝13.5Hz,1H),2.98(d,J＝11.3Hz,1H),2.83(d,J＝11.3Hz,1H),2.70 –2.56(m,2H),2.42(s,1H),2.26–2.11(m,2H),2.02(ddd,J=13.3,8.4,5.0Hz,1H),1.83–1.60(m,4H),0.99 -0.87(m,2H),0.82-0.70(m,2H).
实施例120Example 120
合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)pyridin-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000654
Figure PCTCN2021120978-appb-000654
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯Step A: Synthesis of ethyl 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000655
Figure PCTCN2021120978-appb-000655
向含有1-氨基-3-(羟甲基)吡唑-1-鎓(1.1克,8.8毫摩尔)的N,N-二甲基甲酰胺(10.0毫升)中，加入2-戊炔酸乙酯(1.11克,8.8毫摩尔)和碳酸钾(1.82克,13.2毫摩尔)，于室温下反应过夜。To 1-amino-3-(hydroxymethyl)pyrazol-1-onium (1.1 g, 8.8 mmol) in N,N-dimethylformamide (10.0 mL) was added ethyl 2-pentynoate The ester (1.11 g, 8.8 mmol) and potassium carbonate (1.82 g, 13.2 mmol) were reacted overnight at room temperature.
反应结束，加水淬灭，乙酸乙酯(50毫升×2次)萃取，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到980毫克白色固体2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：46.6％)。LC-MS:RT＝1.92min,[M+H] +＝249.23。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (50 mL × 2 times), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane = 1/2) to obtain 980 mg of ethyl 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate as a white solid (received rate: 46.6%). LC-MS: RT=1.92 min, [M+H] + =249.23.
步骤B：合成2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸Step B: Synthesis of 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000656
Figure PCTCN2021120978-appb-000656
将2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(400毫克,1.61毫摩尔)溶解于5毫升乙醇中，加入氢氧化钾(269毫克,4.81毫摩尔)，1毫升水于室温下反应4小时。Ethyl 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (400 mg, 1.61 mmol) was dissolved in 5 mL of ethanol and potassium hydroxide was added (269 mg, 4.81 mmol), 1 mL of water was reacted at room temperature for 4 hours.
反应结束，加入稀盐酸中和，二氯甲烷(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩得粗品经柱层析分离制备得350毫克淡黄色固体2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸(收率：98.3％)。LC-MS:RT＝1.87min,[M+H] +＝221.13。 After the reaction was completed, dilute hydrochloric acid was added to neutralize, extracted with dichloromethane (30 mL×2 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product through column Chromatographic separation prepared 350 mg of 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as a pale yellow solid (yield: 98.3%). LC-MS: RT=1.87 min, [M+H] + =221.13.
步骤C：合成2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶Step C: Synthesis of 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine
Figure PCTCN2021120978-appb-000657
Figure PCTCN2021120978-appb-000657
将2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸(350毫克,1.58毫摩尔)溶解于10毫升1,2-二氯乙烷中，于75摄氏度下反应12小时。反应结束，反应液直接旋干拌样经柱层析分离制备得266毫克淡黄色固体2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶(收率：95.3％)。LC-MS:RT＝2.03min,[M+H] +＝177.19。 2-Ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (350 mg, 1.58 mmol) was dissolved in 10 mL of 1,2-dichloroethane , at 75 degrees Celsius for 12 hours. After the reaction was completed, the reaction solution was directly rotated to dry and mixed with a sample and separated by column chromatography to obtain 266 mg of pale yellow solid 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine (yield: 95.3 %). LC-MS: RT=2.03 min, [M+H] + =177.19.
步骤D：合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)pyridine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000658
Figure PCTCN2021120978-appb-000658
室温下，向含有(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(125毫克，0.254毫摩尔)，2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶(45毫克，0.254毫摩尔)的1,4-二氧六环(5毫升)中，加入碳酸铯(166毫克，0.508毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(21.5毫克，0.0254毫摩尔)，100摄氏度反应4小时。at room temperature, to a compound containing (S)-2-((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl) Methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (125 mg, 0.254 mmol), 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a ] pyridine (45 mg, 0.254 mmol) in 1,4-dioxane (5 mL), cesium carbonate (166 mg, 0.508 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21.5 mg, 0.0254 mM) mol), reacted at 100 degrees Celsius for 4 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1)。得到86毫克淡黄色固体(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：56.9％)。LC-MS:RT＝1.96min,[M+H] +＝595.31。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 ml × 3 times), combined with the organic phases, washed with saturated brine (30 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue using a silica gel column. Purification by chromatography (eluent: ethyl acetate/n-hexane=5/1). 86 mg of pale yellow solid (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl was obtained )pyridin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 56.9 %). LC-MS: RT=1.96 min, [M+H] + =595.31.
步骤E：合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)pyridine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000659
Figure PCTCN2021120978-appb-000659
将(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(86毫克,0.144毫摩尔)溶于4毫升无水二氯甲烷中，加入2毫升三氟乙酸于室温下反应40分钟。(S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)pyridin-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (86 mg, 0.144 mmol) was dissolved in In 4 ml of anhydrous dichloromethane, 2 ml of trifluoroacetic acid was added and the reaction was carried out at room temperature for 40 minutes.
反应结束，倒入20毫升碳酸氢钠溶液中，二氯甲烷(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝10/1)得到42毫克淡白色固体(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-4-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：50.3％)。 1H NMR(400MHz,DMSO)δ12.75(s,1H),8.51(d,J＝6.9Hz,1H),8.25(s,1H),7.79(dd,J＝8.4,1.5Hz,1H),7.66–7.59(m,2H),7.21(d,J＝6.8Hz,1H),6.87(d,J＝7.3Hz,1H),6.76(t,J＝6.9Hz,1H),6.68(d,J＝8.1Hz,1H),6.45(s,1H),5.51(s,2H),5.12–5.06(m,1H),4.80–4.74(m,1H),4.63(dd,J＝15.2,2.6Hz,1H),4.43(dd,J＝13.3,8.0Hz,1H),4.36–4.32(m,1H),3.94(d,J＝13.5Hz,1H),3.76(d,J＝13.6Hz,1H),2.98(d,J＝10.4Hz,1H),2.83(d,J＝10.8Hz,1H),2.72(dd,J＝15.2,7.6Hz,2H),2.68–2.53(m,2H),2.32-2.44(m,1H),2.25–2.13(m,2H),1.81–1.60(m,4H),1.22(t,J＝7.6Hz,3H)。LC-MS:RT＝1.77min,[M+H] +＝581.37。 After the reaction was completed, poured into 20 mL of sodium bicarbonate solution, extracted with dichloromethane (30 mL × 2 times), combined the organic phases, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 10/1) to obtain 42 mg of pale white solid (S)-2-((4-(6-((2-ethylpyridine) azolo[1,5-a]pyridin-4-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-((oxetan-2-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 50.3%). 1 H NMR (400MHz, DMSO) δ12.75(s, 1H), 8.51(d, J=6.9Hz, 1H), 8.25(s, 1H), 7.79(dd, J=8.4, 1.5Hz, 1H), 7.66–7.59(m, 2H), 7.21(d, J=6.8Hz, 1H), 6.87(d, J=7.3Hz, 1H), 6.76(t, J=6.9Hz, 1H), 6.68(d, J =8.1Hz,1H),6.45(s,1H),5.51(s,2H),5.12-5.06(m,1H),4.80-4.74(m,1H),4.63(dd,J=15.2,2.6Hz, 1H), 4.43 (dd, J=13.3, 8.0Hz, 1H), 4.36–4.32 (m, 1H), 3.94 (d, J=13.5Hz, 1H), 3.76 (d, J=13.6Hz, 1H), 2.98(d,J＝10.4Hz,1H),2.83(d,J＝10.8Hz,1H),2.72(dd,J＝15.2,7.6Hz,2H),2.68-2.53(m,2H),2.32-2.44 (m, 1H), 2.25–2.13 (m, 2H), 1.81–1.60 (m, 4H), 1.22 (t, J=7.6Hz, 3H). LC-MS: RT=1.77 min, [M+H] + =581.37.
实施例121Example 121
合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)pyridin-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000660
Figure PCTCN2021120978-appb-000660
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯Step A: Synthesis of ethyl 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000661
Figure PCTCN2021120978-appb-000661
向含有1-氨基-3-(羟甲基)吡唑-1-鎓(1.0克,8.0毫摩尔)的N,N-二甲基甲酰胺(10.0毫升)中，加入2-戊炔酸乙酯(1.0克,8.0毫摩尔)和碳酸钾(1.65克,12.0毫摩尔)，于室温下反应过夜。To 1-amino-3-(hydroxymethyl)pyrazol-1-onium (1.0 g, 8.0 mmol) in N,N-dimethylformamide (10.0 mL) was added ethyl 2-pentynoate The ester (1.0 g, 8.0 mmol) and potassium carbonate (1.65 g, 12.0 mmol) were reacted overnight at room temperature.
反应结束，加水淬灭，乙酸乙酯(50毫升×2次)萃取，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/2)得到760毫克白色固体2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：38.1％)。LC-MS:RT＝1.94min,[M+H] +＝249.23。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (50 mL×2 times), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane = 1/2) to obtain 760 mg of ethyl 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate as a white solid (received rate: 38.1%). LC-MS: RT=1.94 min, [M+H] + =249.23.
步骤B：合成2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸Step B: Synthesis of 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000662
Figure PCTCN2021120978-appb-000662
将2-乙基-4-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(400毫克,1.61毫摩尔)溶解于5毫升乙醇中，加入氢氧化钾(269毫克,4.81毫摩尔)，1毫升水于55摄氏度下反应12小时。Ethyl 2-ethyl-4-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (400 mg, 1.61 mmol) was dissolved in 5 mL of ethanol and potassium hydroxide was added (269 mg, 4.81 mmol), 1 ml of water was reacted at 55 degrees Celsius for 12 hours.
反应结束，加稀盐酸中和，二氯甲烷(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩得粗品经柱层析分离制备得314毫克淡黄色固体2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸(收率：88.3％)。LC-MS:RT＝1.89min,[M+H] +＝221.13。 After the reaction was completed, diluted hydrochloric acid was added to neutralize, extracted with dichloromethane (30 mL×2 times), the organic phases were combined, washed with saturated brine (20 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Chromatographic separation prepared 314 mg of 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as a pale yellow solid (yield: 88.3%). LC-MS: RT=1.89 min, [M+H] + =221.13.
步骤C：合成2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶Step C: Synthesis of 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine
Figure PCTCN2021120978-appb-000663
Figure PCTCN2021120978-appb-000663
将2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸(314毫克,1.42毫摩尔)溶解于5毫升1,2-二氯苯中于120摄氏度下反应3小时。反应结束，直接旋干拌样经柱层析分离制备得157毫克淡黄色固体2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶(收率：62.5％)。LC-MS:RT＝2.06min,[M+H] +＝177.19。 2-Ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (314 mg, 1.42 mmol) was dissolved in 5 mL of 1,2-dichlorobenzene in The reaction was carried out at 120 degrees Celsius for 3 hours. After the reaction was completed, the sample was directly spun dry and was separated by column chromatography to obtain 157 mg of pale yellow solid 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine (yield: 62.5%) . LC-MS: RT=2.06 min, [M+H] + =177.19.
步骤D：合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯Step D: Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)pyridine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester
Figure PCTCN2021120978-appb-000664
Figure PCTCN2021120978-appb-000664
室温下，向含有(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(125毫克，0.254毫摩尔)，2-乙基-6-(羟甲基)吡唑并[1,5-a]吡啶(45毫克，0.254毫摩尔)的1,4-二氧六环(5毫升)中，加入碳酸铯(166毫克，0.508毫摩尔)和甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(21.5毫克，0.0254毫摩尔)，100摄氏度反应4小时。At room temperature, the solution containing (S)-2-(((4-(6-chloropyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl) )methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (125 mg, 0.254 mmol), 2-ethyl-6-(hydroxymethyl)pyrazolo[1,5- a] To a solution of pyridine (45 mg, 0.254 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (166 mg, 0.508 mmol) and methanesulfonic acid (2-dicyclohexylphosphino- 2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21.5 mg, 0.0254 mmol), reacted at 100 degrees Celsius for 4 hours.
反应结束，加水淬灭，乙酸乙酯(30毫升×3次)萃取，合并有机相，饱和食盐水(30毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝5/1)。得到78毫克淡黄色固体(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(收率：51.6％)。LC-MS:RT＝1.98min,[M+H] +＝595.31。 The reaction was completed, quenched by adding water, extracted with ethyl acetate (30 ml × 3 times), combined with the organic phases, washed with saturated brine (30 ml × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue using a silica gel column. Purification by chromatography (eluent: ethyl acetate/n-hexane=5/1). 78 mg of pale yellow solid (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl was obtained )pyridin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (yield: 51.6 %). LC-MS: RT=1.98 min, [M+H] + =595.31.
步骤E：合成(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸Step E: Synthesis of (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)pyridine -1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000665
Figure PCTCN2021120978-appb-000665
将(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸叔丁酯(78毫克,0.131毫摩尔)溶于4毫升无水二氯甲烷中，加入2毫升三氟乙酸于室温下反应40分钟。反应结束，倒入20毫升碳酸氢钠溶液中，二氯甲烷(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝10/1)得到36毫克淡白色固体(S)-2-((4-(6-((2-乙基吡唑并[1,5-a]吡啶-6-基)甲氧基)吡啶-2-基)吡啶-1-基)甲基)-1-((氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(收率：47.3％)。 1H NMR(400MHz,DMSO)δ12.95(s,1H),8.71(s,1H),8.37(s,1H),7.90(d,J＝8.4Hz,1H),7.79(d,J＝8.5Hz,1H),7.68(t,J＝7.8Hz,1H),7.57(d,J＝9.1Hz,1H),7.25(d,J＝9.1Hz,1H),6.92(d,J＝7.3Hz,1H),6.73(d,J＝8.2Hz,1H),6.40(s,1H),5.36(s,2H),5.09–5.00(m,1H),4.82(dd,J＝15.4,7.1Hz,1H),4.71–4.63(m,1H),4.53–4.44(m,1H),4.37–4.30(m,1H),3.66(d,J＝13.5Hz,1H),3.76(d,J＝13.6Hz,1H),2.94(d,J＝10.4Hz,1H),2.83(d,J＝10.8Hz,1H),2.71(dd,J＝15.2,7.6Hz,2H),2.70–2.66(m,2H),2.44–2.22(m,1H),2.21–2.13(m,2H),2.12–2.08(m,4H),1.22(t,J＝7.6Hz,3H)。LC-MS:RT＝1.79min,[M+H] +＝581.37。 (S)-2-((4-(6-((2-ethylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)pyridin-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate tert-butyl ester (78 mg, 0.131 mmol) was dissolved in In 4 ml of anhydrous dichloromethane, 2 ml of trifluoroacetic acid was added and the reaction was carried out at room temperature for 40 minutes. After the reaction was completed, poured into 20 mL of sodium bicarbonate solution, extracted with dichloromethane (30 mL × 2 times), combined the organic phases, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=10/1) to obtain 36 mg of pale white solid (S)-2-((4-(6-((2-ethylpyridine) azolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-((oxetan-2-yl)methyl yl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 47.3%). 1 H NMR (400MHz, DMSO) δ 12.95(s, 1H), 8.71(s, 1H), 8.37(s, 1H), 7.90(d, J=8.4Hz, 1H), 7.79(d, J=8.5 Hz, 1H), 7.68(t, J＝7.8Hz, 1H), 7.57(d, J＝9.1Hz, 1H), 7.25(d, J＝9.1Hz, 1H), 6.92(d, J＝7.3Hz, 1H), 6.73(d, J=8.2Hz, 1H), 6.40(s, 1H), 5.36(s, 2H), 5.09–5.00(m, 1H), 4.82(dd, J=15.4, 7.1Hz, 1H) ), 4.71–4.63 (m, 1H), 4.53–4.44 (m, 1H), 4.37–4.30 (m, 1H), 3.66 (d, J=13.5Hz, 1H), 3.76 (d, J=13.6Hz, 1H), 2.94(d, J＝10.4Hz, 1H), 2.83(d, J＝10.8Hz, 1H), 2.71(dd, J＝15.2, 7.6Hz, 2H), 2.70–2.66(m, 2H), 2.44–2.22 (m, 1H), 2.21–2.13 (m, 2H), 2.12–2.08 (m, 4H), 1.22 (t, J=7.6Hz, 3H). LC-MS: RT=1.79 min, [M+H] + =581.37.
实施例122Example 122
合成2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸Synthesis of 2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000666
Figure PCTCN2021120978-appb-000666
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成吡唑并[1,5-a]吡啶-2-基三氟甲磺酸Step A: Synthesis of Pyrazolo[1,5-a]pyridin-2-yltrifluoromethanesulfonic acid
Figure PCTCN2021120978-appb-000667
Figure PCTCN2021120978-appb-000667
将吡唑并[1,5-a]吡啶-2(1H)-酮(0.5克，3.73毫摩尔)溶于四氢呋喃(10毫升)中，在冰浴中冷却至零摄氏度，加入氢化钠(224毫克，19.5毫摩尔)，在室温下搅拌0.5小时,加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(1.6克，4.48毫摩尔)，室温下搅拌过夜。Pyrazolo[1,5-a]pyridin-2(1H)-one (0.5 g, 3.73 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to zero degrees Celsius in an ice bath, and sodium hydride (224 mmol) was added. mg, 19.5 mmol), stirred at room temperature for 0.5 h, added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.6 g, 4.48 mmol) mol) and stirred overnight at room temperature.
反应结束后，加冰水淬灭，乙酸乙酯(50毫升)萃取，水洗两次，无水硫酸钠干燥，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到0.8克无色油状液体吡唑并[1,5-a]吡啶-2-基三氟甲磺酸(收率：80％)。LC-MS:RT＝2.12min,[M+H]+＝267.13。After the reaction was completed, quenched by adding ice water, extracted with ethyl acetate (50 mL), washed twice with water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/10) to obtain 0.8 g of colorless oily liquid pyrazolo[1,5-a]pyridin-2-yl trifluoromethanesulfonic acid (yield: 80%). LC-MS: RT=2.12 min, [M+H]+=267.13.
步骤B：合成2-环丙基吡唑并[1,5-a]吡啶Step B: Synthesis of 2-Cyclopropylpyrazolo[1,5-a]pyridine
Figure PCTCN2021120978-appb-000668
Figure PCTCN2021120978-appb-000668
将吡唑并[1,5-a]吡啶-2-基三氟甲磺酸(800毫克，3.0毫摩尔)，环丙基硼酸(516毫克，0.39毫摩尔)，四(三苯基膦)钯(50毫克)，碳酸钠(254毫克，0.78毫摩尔)溶于二氧六环(10毫升)中，升温至100摄氏度搅拌16小时。Pyrazolo[1,5-a]pyridin-2-yl trifluoromethanesulfonic acid (800 mg, 3.0 mmol), cyclopropylboronic acid (516 mg, 0.39 mmol), tetrakis(triphenylphosphine) Palladium (50 mg), sodium carbonate (254 mg, 0.78 mmol) were dissolved in dioxane (10 mL), and the temperature was raised to 100°C and stirred for 16 hours.
反应结束，硅藻土抽滤，二氯甲烷淋洗，浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)得到200毫克无色油状液体2-环丙基吡唑并[1,5-a]吡啶(收率：42％)。LC-MS:RT＝2.21min,[M+H]+＝159.23。After the reaction was completed, celite was suction filtered, rinsed with dichloromethane, the organic phase was concentrated, and the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 200 mg of colorless oily liquid 2 -Cyclopropylpyrazolo[1,5-a]pyridine (yield: 42%). LC-MS: RT=2.21 min, [M+H]+=159.23.
步骤C：合成2-环丙基吡唑并[1,5-a]吡啶-7-甲醛Step C: Synthesis of 2-Cyclopropylpyrazolo[1,5-a]pyridine-7-carbaldehyde
Figure PCTCN2021120978-appb-000669
Figure PCTCN2021120978-appb-000669
将2-环丙基吡唑并[1,5-a]吡啶(200毫克，1.26毫摩尔)溶于四氢呋喃(10毫升)中，在干冰乙醇浴中滴加正丁基锂(1毫升，2.52毫摩尔)，搅拌0.5小时,加入甲酸乙酯(1.6克，4.48毫摩尔)，保持温度搅拌0.5小时。2-Cyclopropylpyrazolo[1,5-a]pyridine (200 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL) and n-butyllithium (1 mL, 2.52 mL) was added dropwise in a dry ice ethanol bath. mmol), stirred for 0.5 h, added ethyl formate (1.6 g, 4.48 mmol), and kept stirring for 0.5 h at the temperature.
反应结束后，加冰水淬灭，加入乙酸乙酯(50毫升)萃取，水洗两次，无水硫酸钠干燥，浓缩得粗品200毫克无色油状液体2-环丙基吡唑并[1,5-a]吡啶-7-甲醛，直接用于下一步。After the reaction, add ice water to quench, add ethyl acetate (50 ml) for extraction, wash twice with water, dry over anhydrous sodium sulfate, and concentrate to obtain 200 mg of crude product as colorless oily liquid 2-cyclopropylpyrazolo[1, 5-a]pyridine-7-carbaldehyde, used directly in the next step.
步骤D：合成(2-环丙基吡唑并[1,5-a]吡啶-7-基)甲醇Step D: Synthesis of (2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methanol
Figure PCTCN2021120978-appb-000670
Figure PCTCN2021120978-appb-000670
将2-环丙基吡唑并[1,5-a]吡啶-7-甲醛(200毫克，粗品，1.26毫摩尔)，溶于甲醇(5毫升)中，冰水浴下缓慢加入硼氢化钠(98毫克，2.52毫摩尔)，搅拌0.5小时。2-Cyclopropylpyrazolo[1,5-a]pyridine-7-carbaldehyde (200 mg, crude, 1.26 mmol) was dissolved in methanol (5 mL), and sodium borohydride ( 98 mg, 2.52 mmol) and stirred for 0.5 h.
反应结束，加0.5毫升水淬灭，干燥，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)得到40毫克无色油状液体(2-环丙基吡唑并[1,5-a]吡啶-7-基)甲醇(收率：17％)。LC-MS:RT＝1.88min,[M+H]+＝189.07。After the reaction was completed, 0.5 ml of water was added for quenching and drying. The obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=1/3) to obtain 40 mg of colorless oily liquid (2-cyclopropylpyrazole) and [1,5-a]pyridin-7-yl)methanol (yield: 17%). LC-MS: RT=1.88 min, [M+H]+=189.07.
步骤E：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl) Methyl piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate
Figure PCTCN2021120978-appb-000671
Figure PCTCN2021120978-appb-000671
将(2-环丙基吡唑并[1,5-a]吡啶-7-基)甲醇(40毫克，0.21毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(96毫克，0.21毫摩尔)，钯催化剂(18毫克)，碳酸铯(137毫克，0.42毫摩尔)溶于二氧六环中，升温至100摄氏度搅拌8小时。(2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methanol (40 mg, 0.21 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (96 mg, 0.21 mmol), palladium catalyst (18 mg), cesium carbonate (137 mg, 0.42 mmol) were dissolved in dioxane, and the temperature was raised to 100 degrees Celsius and stirred for 8 hours.
反应结束后，用硅藻土抽滤，用二氯甲烷洗涤后浓缩有机相，所得粗品用柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到60毫克白色固体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸甲酯(收率：47％)。LC-MS:RT＝1.80min,[M+H]+＝607.37。After the reaction was completed, suction filtration with celite, washed with dichloromethane, and then concentrated the organic phase, the obtained crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 60 mg of white solid ( S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl)piperidine-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 47%). LC-MS: RT=1.80 min, [M+H]+=607.37.
步骤F：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000672
Figure PCTCN2021120978-appb-000672
将(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸甲酯(60毫克，0.1毫摩尔)溶于乙腈(5毫升)和水(1毫升)中，室温下加入1,3,4,6,7,8-六氢-2H-嘧啶[1,2-a]嘧啶(55毫克，0.4毫摩尔)，反应4小时。(S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-7-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 0.1 mmol) in In acetonitrile (5 mL) and water (1 mL), 1,3,4,6,7,8-hexahydro-2H-pyrimidine[1,2-a]pyrimidine (55 mg, 0.4 mmol) was added at room temperature ) for 4 hours.
反应结束后，浓缩，所得粗品高效液相纯化得到15毫克白色固体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-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-苯并[d]咪唑-6-羧酸(收率：25％)。LC-MS:RT＝1.80min,[M+H] +＝593.27。 After the reaction, concentrated, the obtained crude product was purified by high performance liquid phase to obtain 15 mg of white solid (S)-2-((4-(6-((2-cyclopropylpyrazolo[1,5-a]pyridine-7 -yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-carboxylic acid (yield: 25%). LC-MS: RT=1.80 min, [M+H] + =593.27.
1H NMR(400MHz,DMSO)δ8.22(s,1H),7.78(dd,J＝8.4,1.5Hz,1H),7.71–7.64(m,1H),7.59(d,J＝8.4Hz,1H),7.50(d,J＝7.9Hz,1H),7.14(dd,J＝8.8,6.9Hz,1H),6.90(d,J＝7.2Hz,1H),6.83(d,J＝6.8Hz,1H),6.77(d,J＝8.0Hz,1H),6.32(s,1H),5.76(s,2H),5.07(d,J＝7.5Hz,1H),4.74(dd,J＝15.4,7.3Hz,1H),4.60(d,J＝12.6Hz,1H),4.43(dd,J＝13.4,7.9Hz,1H),4.33(dt,J＝9.0,6.0Hz,1H),3.91(d,J＝13.5Hz,1H),3.74(d,J＝13.5Hz,1H),2.95(d,J＝11.1Hz,1H),2.80(d,J＝11.4Hz,1H),2.62(dd,J＝19.9,11.4Hz,2H),2.41(d,J＝9.1Hz,1H),2.25–2.04(m,3H),1.80–1.57(m,4H),0.96(ddd,J＝8.4,6.4,3.9Hz,2H),0.81–0.69(m,2H)。 1 H NMR (400MHz, DMSO) δ 8.22 (s, 1H), 7.78 (dd, J=8.4, 1.5Hz, 1H), 7.71-7.64 (m, 1H), 7.59 (d, J=8.4Hz, 1H) ),7.50(d,J＝7.9Hz,1H),7.14(dd,J＝8.8,6.9Hz,1H),6.90(d,J＝7.2Hz,1H),6.83(d,J＝6.8Hz,1H) ),6.77(d,J＝8.0Hz,1H),6.32(s,1H),5.76(s,2H),5.07(d,J＝7.5Hz,1H),4.74(dd,J＝15.4,7.3Hz ,1H),4.60(d,J＝12.6Hz,1H),4.43(dd,J＝13.4,7.9Hz,1H),4.33(dt,J＝9.0,6.0Hz,1H),3.91(d,J＝ 13.5Hz, 1H), 3.74 (d, J=13.5Hz, 1H), 2.95 (d, J=11.1Hz, 1H), 2.80 (d, J=11.4Hz, 1H), 2.62 (dd, J=19.9, 11.4Hz, 2H), 2.41 (d, J=9.1Hz, 1H), 2.25–2.04 (m, 3H), 1.80–1.57 (m, 4H), 0.96 (ddd, J=8.4, 6.4, 3.9Hz, 2H ), 0.81–0.69 (m, 2H).
实施例123Example 123
合成(S)-2-((4-(6-((2-环丙基吡咯并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrrolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000673
Figure PCTCN2021120978-appb-000673
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-氨基-3-(羟甲基)吡啶-1-鎓盐Step A: Synthesis of 1-amino-3-(hydroxymethyl)pyridine-1-onium salt
Figure PCTCN2021120978-appb-000674
Figure PCTCN2021120978-appb-000674
室温下，先将(E)-N-((2,4,6-三甲基苯磺酰基)氧基)乙酰亚胺酸乙酯(7.80克，27.52毫摩尔)溶于二氧六环(10毫升)中，再加入高氯酸(3.5毫升)反应至有大量白色沉淀，加水过滤，固体抽干后用二氯甲烷(20毫升)溶解，无水硫酸钠干燥。然后在过滤后溶液中加入吡啶-3-基甲醇(2克，18.35毫摩尔)，室温下反应2个小时后直接旋干备用。At room temperature, ethyl (E)-N-((2,4,6-trimethylbenzenesulfonyl)oxy)acetimidate (7.80 g, 27.52 mmol) was first dissolved in dioxane ( 10 mL), and then added perchloric acid (3.5 mL) to react until there was a large amount of white precipitate, add water for filtration, the solid was drained and dissolved in dichloromethane (20 mL), and dried over anhydrous sodium sulfate. Then, pyridin-3-ylmethanol (2 g, 18.35 mmol) was added to the filtered solution, and the mixture was reacted at room temperature for 2 hours and then directly rotated to dryness for use.
步骤B：合成2-环丙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯Step B: Synthesis of ethyl 2-cyclopropyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate
Figure PCTCN2021120978-appb-000675
Figure PCTCN2021120978-appb-000675
将前一步所得鎓盐(2.89克，23.19毫摩尔)溶于N,N-二甲基甲酰胺(20毫升)中，再加入3-环丙基丙炔酸乙酯(3.20克，23.19毫摩尔)和碳酸钾(6.40克，46.38毫摩尔)，升温至50摄氏度反应过夜。The onium salt obtained in the previous step (2.89 g, 23.19 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of ethyl 3-cyclopropylpropiolate (3.20 g, 23.19 mmol). ) and potassium carbonate (6.40 g, 46.38 mmol), warmed to 50 degrees Celsius and reacted overnight.
反应结束，加饱和氯化钠淬灭，乙酸乙酯(30毫升×3次)萃取，合并并干燥有机相，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到562毫克淡黄色固体2-环丙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(收率：7％)。LC-MS:RT＝1.86min,[M+H] +＝261.17。 After the reaction was completed, it was quenched by adding saturated sodium chloride, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined and dried, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/1) 562 mg of ethyl 2-cyclopropyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate was obtained as a pale yellow solid (yield: 7%). LC-MS: RT=1.86 min, [M+H] + =261.17.
步骤C：合成2-环丙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸Step C: Synthesis of 2-cyclopropyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021120978-appb-000676
Figure PCTCN2021120978-appb-000676
将2-环丙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸乙酯(451毫克,1.73毫摩尔)溶于混合溶剂(4毫升，乙醇/水＝3/1)中，加入氢氧化钾(194毫克，3.47毫摩尔)，室温反应。Ethyl 2-cyclopropyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (451 mg, 1.73 mmol) was dissolved in a mixed solvent (4 mL, ethanol/ Water = 3/1), potassium hydroxide (194 mg, 3.47 mmol) was added, and the mixture was reacted at room temperature.
反应结束后，用稀盐酸调节pH＝5-6，直接旋干备用。LC-MS:RT＝1.59min,[M+H] +＝233.15。 After the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid, and it was directly spin-dried for use. LC-MS: RT=1.59 min, [M+H] + =233.15.
步骤D：合成(2-环丙基吡唑并[1,5-a]吡啶-6-基)甲醇Step D: Synthesis of (2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methanol
Figure PCTCN2021120978-appb-000677
Figure PCTCN2021120978-appb-000677
将粗品2-环丙基-6-(羟甲基)吡唑并[1,5-a]吡啶-3-羧酸溶于二氯乙烷(15毫升，乙醇/水＝3/1)中，升温至100摄氏度过夜。The crude 2-cyclopropyl-6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid was dissolved in dichloroethane (15 mL, ethanol/water=3/1) , warmed to 100 °C overnight.
反应结束，直接旋干，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)得到60毫克白色固体(2-环丙基吡唑并[1,5-a]吡啶-6-基)甲醇。After the reaction was completed, it was directly rotated to dryness, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 60 mg of white solid (2-cyclopropylpyrazolo[1,5- a] Pyridin-6-yl)methanol.
步骤E：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸甲酯Step E: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl) Methyl piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate
Figure PCTCN2021120978-appb-000678
Figure PCTCN2021120978-appb-000678
将(2-环丙基吡唑并[1,5-a]吡啶-6-基)甲醇(60毫克，0.32毫摩尔)，(S)-2-(((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(138毫克，0.317毫摩尔)，钯催化剂(27毫克)和碳酸铯(207毫克，0.63毫摩尔)溶于二氧六环(5毫升)中，升温至100摄氏度搅拌2小时。(2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methanol (60 mg, 0.32 mmol), (S)-2-((((4-(6-chloropyridine- 2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (138 mg, 0.317 mmol), palladium catalyst (27 mg) and cesium carbonate (207 mg, 0.63 mmol) were dissolved in dioxane (5 mL), and the temperature was raised to 100 degrees Celsius and stirred for 2 hours.
反应结束，硅藻土抽滤，二氯甲烷淋洗，浓缩有机相，所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝10/1)得到72毫克淡黄色油状液体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸甲酯(收率：37％)。LC-MS:RT＝1.73min,[M+H] +＝607.39。 After the reaction was completed, celite was suction filtered, rinsed with dichloromethane, the organic phase was concentrated, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=10/1) to obtain 72 mg of pale yellow oily liquid (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)piperidine-1 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (yield: 37%). LC-MS: RT=1.73 min, [M+H] + =607.39.
步骤F：合成(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸Step F: Synthesis of (S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl) Piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000679
Figure PCTCN2021120978-appb-000679
将(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸甲酯(72毫克，0.12毫摩尔)溶于混合溶剂(5毫升，乙腈/水＝4/1)中，再加入1,5,7-三叠氮双环(4,4,0)癸-5-烯(66毫克，0.48毫摩尔)，反应4小时。(S)-2-((4-(6-((2-Cyclopropylpyrazolo[1,5-a]pyridin-6-yl)methoxy)pyridin-2-yl)piperidine- 1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (72 mg, 0.12 mmol) in In a mixed solvent (5 mL, acetonitrile/water=4/1), 1,5,7-triazidebicyclo(4,4,0)dec-5-ene (66 mg, 0.48 mmol) was added, The reaction was carried out for 4 hours.
反应结束，加柠檬酸淬灭，乙酸乙酯萃取(10毫升×3次)，合并有机相，无水硫酸钠干燥，过滤后浓缩，浓缩所得粗品用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到20毫克白色固体(S)-2-((4-(6-((2-环丙基吡唑并[1,5-a]吡啶-6-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-苯并[d]咪唑-6-羧酸(收率：28％)。LC-MS:RT＝1.82min,[M+H] +＝593.34。 1H NMR(500MHz,DMSO-d 6)δ8.64(s,1H),8.25(s,1H),7.79(dd,J＝8.4,1.4Hz,1H),7.71–7.58(m,2H),7.49(d,J＝9.0Hz,1H),7.22(dd,J＝9.1,1.3Hz,1H),6.86(d,J＝7.2Hz,1H),6.65(d,J＝8.1Hz,1H),6.27(s,1H),5.31(s,2H),5.10(d,J＝7.3Hz,1H),4.80(dd,J＝15.2,7.2Hz,1H),4.66(dd,J＝15.0,2.4Hz,1H),4.45(dd,J＝13.5,7.8Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.01(d,J＝11.5Hz,1H),2.86(d,J＝11.7Hz,1H),2.75–2.57(m,2H),2.46-2.39(m,1H),2.29–2.12(m,2H),2.00(ddd,J＝13.3,8.5,5.0Hz,1H),1.93–1.66(m,4H),1.05–0.86(m,2H),0.83–0.67(m,2H)。 The reaction was completed, quenched by adding citric acid, extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained from the concentration was purified by silica gel column chromatography (eluent: two Methyl chloride/methanol=10/1) to give 20 mg of white solid (S)-2-((4-(6-((2-cyclopropylpyrazolo[1,5-a]pyridin-6-yl)) Methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6- Carboxylic acid (yield: 28%). LC-MS: RT=1.82 min, [M+H] + =593.34. 1 H NMR (500MHz, DMSO-d 6 )δ8.64(s,1H),8.25(s,1H),7.79(dd,J=8.4,1.4Hz,1H),7.71-7.58(m,2H), 7.49(d,J＝9.0Hz,1H),7.22(dd,J＝9.1,1.3Hz,1H),6.86(d,J＝7.2Hz,1H),6.65(d,J＝8.1Hz,1H), 6.27(s, 1H), 5.31(s, 2H), 5.10(d, J=7.3Hz, 1H), 4.80(dd, J=15.2, 7.2Hz, 1H), 4.66(dd, J=15.0, 2.4Hz) ,1H),4.45(dd,J＝13.5,7.8Hz,1H),4.35(dt,J＝9.0,5.9Hz,1H),3.95(d,J＝13.5Hz,1H),3.78(d,J＝ 13.5Hz, 1H), 3.01 (d, J=11.5Hz, 1H), 2.86 (d, J=11.7Hz, 1H), 2.75–2.57 (m, 2H), 2.46–2.39 (m, 1H), 2.29– 2.12 (m, 2H), 2.00 (ddd, J=13.3, 8.5, 5.0 Hz, 1H), 1.93–1.66 (m, 4H), 1.05–0.86 (m, 2H), 0.83–0.67 (m, 2H).
实施例124Example 124
合成(S)-2-((4-(6-((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸Synthesis of (S)-2-((4-(6-((5-Fluorobenzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000680
Figure PCTCN2021120978-appb-000680
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-(氯甲基)-5-氟苯并[d]噁唑Step A: Synthesis of 2-(chloromethyl)-5-fluorobenzo[d]oxazole
Figure PCTCN2021120978-appb-000681
Figure PCTCN2021120978-appb-000681
将2-氨基-4-氟苯酚(500毫克,4.0毫摩尔)溶于2-氯-1,1,1-三甲氧基乙烷(2.0毫升)中,氮气保护,85摄氏度下搅拌2小时。2-Amino-4-fluorophenol (500 mg, 4.0 mmol) was dissolved in 2-chloro-1,1,1-trimethoxyethane (2.0 mL) under nitrogen protection and stirred at 85°C for 2 hours.
反应结束，待冷却至室温,加水(20.0毫升),乙酸乙酯(20.0毫升×3次)萃取,合并有机相,饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到600毫克黄色固体2-(氯甲基)-5-氟苯并[d]噁唑(收率：100％)。LC-MS：RT＝1.93min,[M+H] +＝186.05。 After the reaction was completed, after cooling to room temperature, water (20.0 mL) was added, extracted with ethyl acetate (20.0 mL×3 times), the organic phases were combined, saturated brine (15.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography to obtain 600 mg of yellow solid 2-(chloromethyl)-5-fluorobenzo[d]oxazole (yield: 100%). LC-MS: RT=1.93 min, [M+H] + =186.05.
步骤B：合成5-氟苯并[d]噁唑-2-基甲醇Step B: Synthesis of 5-fluorobenzo[d]oxazol-2-ylmethanol
Figure PCTCN2021120978-appb-000682
Figure PCTCN2021120978-appb-000682
将2-氨基-4-氟苯酚(500毫克,4.0毫摩尔)溶于N,N-二甲基甲酰胺(5.0毫升)中,加乙酸钠(640毫克,8.0毫摩尔),50摄氏度下搅拌2小时。加10％氢氧化钠水溶液(15.0毫升)，室温搅拌2小时。Dissolve 2-amino-4-fluorophenol (500 mg, 4.0 mmol) in N,N-dimethylformamide (5.0 mL), add sodium acetate (640 mg, 8.0 mmol), and stir at 50°C 2 hours. A 10% aqueous sodium hydroxide solution (15.0 mL) was added, and the mixture was stirred at room temperature for 2 hours.
反应结束，乙酸乙酯(20.0毫升×3次)萃取,合并有机相,饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到400毫克黄色固体2-(氯甲基)-5-氟苯并[d]噁唑(收率：89.1％)。LC-MS：RT＝1.66min,[M+H] +＝168.09。 The reaction was completed, extracted with ethyl acetate (20.0 mL×3 times), the organic phases were combined, saturated brine (15.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 400 mg of 2-(chloromethyl)-5-fluorobenzo[d]oxazole as a yellow solid (yield: 89.1%). LC-MS: RT=1.66 min, [M+H] + =168.09.
步骤C：合成(S)-2-((4-(6-(((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯Step C: Synthesis of (S)-2-((4-(6-(((5-fluorobenzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester
Figure PCTCN2021120978-appb-000683
Figure PCTCN2021120978-appb-000683
将(S)-2-((4-(6-氯吡啶-2-基)哌啶-1-基)甲基)-1-()氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(150毫克,0.33毫摩尔)溶于1,4-二氧六环(5.0毫升)中,将5-氟苯并[d]噁唑-2-基甲醇(110毫克,0.66毫摩尔),碳酸铯(200毫克,0.66毫摩尔),甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(30毫克,0.030毫摩尔)加入反应瓶中,氮气保护后,100摄氏度下搅拌12小时。(S)-2-((4-(6-Chloropyridin-2-yl)piperidin-1-yl)methyl)-1-()oxetan-2-yl)methyl)- Methyl 1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.33 mmol) was dissolved in 1,4-dioxane (5.0 mL), 5-fluorobenzo[d]oxazole -2-ylmethanol (110 mg, 0.66 mmol), cesium carbonate (200 mg, 0.66 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropane Base-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30 mg, 0.030 mmol) was added to the reaction flask, after nitrogen protection, Stir at 100 degrees Celsius for 12 hours.
反应结束，垫硅藻土过滤,滤液缓慢滴加到饱和氯化铵水水溶液(20.0毫升)中,乙酸乙酯(20.0毫升×3次)萃取,合并有机相,饱和食盐水(15.0毫升×3次),无水硫酸钠干燥,减压浓缩。所得残余物经硅胶柱层析纯化得到75毫克黄色固体(S)-2-((4-(6-((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯(收率：38.9％)。LC-MS：RT＝1.81min,[M+H] +＝586.31。 After the reaction was completed, the celite was filtered, the filtrate was slowly added dropwise to saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL×3 times), the organic phases were combined, saturated brine (15.0 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 75 mg of yellow solid (S)-2-((4-(6-((5-fluorobenzo[d]oxazol-2-yl)methoxy)pyridine- 2-yl)piperidin-1-yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (received rate: 38.9%). LC-MS: RT=1.81 min, [M+H] + =586.31.
步骤B：合成(S)-2-((4-(6-((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸Step B: Synthesis of (S)-2-((4-(6-((5-fluorobenzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl )methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTCN2021120978-appb-000684
Figure PCTCN2021120978-appb-000684
将(S)-2-((4-(6-((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸甲酯(75毫克,0.20毫摩尔)溶于乙腈/水(4/1,5毫升)中,然后将1,5,7-三叠氮双环(4.4.0)癸-5-烯(70毫克,0.5摩尔)加入反应液中,室温搅拌2小时后,LC-MS监测至反应完全。(S)-2-((4-(6-((5-Fluorobenzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl )-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (75 mg, 0.20 mmol) in acetonitrile/water (4 /1,5 mL), then 1,5,7-triazidebicyclo(4.4.0)dec-5-ene (70 mg, 0.5 mol) was added to the reaction solution, and after stirring at room temperature for 2 hours, LC- MS monitored until the reaction was complete.
加15％柠檬酸水溶液(15.0毫升)淬灭,乙酸乙酯(30.0毫升X3次)萃取,合并有机相,旋干,残余物经高效液相制备纯化得到15毫克白色固体(S)-2-((4-(6-((5-氟苯并[d]噁唑-2-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-苯并[d]咪唑-6-羧酸(收率：13.1％)。LC-MS：RT＝1.77min,[M+H] +＝572.29。 Add 15% citric acid aqueous solution (15.0 mL) to quench, extract with ethyl acetate (30.0 mL × 3 times), combine the organic phases, spin dry, and the residue is purified by HPLC to obtain 15 mg of white solid (S)-2- ((4-(6-((5-Fluorobenzo[d]oxazol-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((oxygen Hetetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (yield: 13.1%). LC-MS: RT=1.77 min, [M+H] + =572.29.
实施例125：人源GLP1R细胞中化合物体外cAMP信号活化的测量Example 125: Measurement of Compound In Vitro cAMP Signaling Activation in Human GLP1R Cells
1、细胞培养1. Cell culture
将稳定表达人GLP1 R的细胞系(hGLP1R-U2OS)用于该试验中。细胞采用生长培养基(完全培养基，DMEM+10％FBS+500μg/ml G418(Promega))，于37℃、5％CO 2饱和湿度的培养箱中培养。 A cell line stably expressing human GLP1 R (hGLP1R-U2OS) was used in this assay. Cells were cultured in a growth medium (complete medium, DMEM+10% FBS+500 μg/ml G418 (Promega)) at 37° C. in an incubator with 5% CO 2 saturated humidity.
2、cAMP测定2. Determination of cAMP
以1.0×10 4个细胞/孔(5μl)(细胞工作液为：DMEM+0.1％BSA+1mM IBMX(毕得医药))，将hGLP1R-U2OS接种于384孔板中，置于37℃的培养箱中静置30min，备用。将试剂盒中Stimulation Buffer 1(1X)逐级稀释待测化合物，将稀释好的待测化合物加入培养板中，5μl/孔，置于37℃的培养箱中孵育30min，然后，依次加入5μl/孔Lysis&Detection缓冲液配置的cAMP-d2和5μl/孔的Anti cAMP-Cryptate工作液，于室温孵育60min，最后进行检测。 Inoculate hGLP1R-U2OS in 384-well plate with 1.0×10 4 cells/well (5 μl) (cell working solution: DMEM + 0.1% BSA + 1 mM IBMX (Bide Pharmaceuticals)), and culture at 37° C. Let stand for 30min in the box and set aside. Dilute the test compound stepwise with Stimulation Buffer 1 (1X) in the kit, add the diluted test compound to the culture plate, 5μl/well, incubate in a 37°C incubator for 30min, and then add 5μl/well in turn. Well Lysis&Detection buffer prepared cAMP-d2 and 5μl/well Anti cAMP-Cryptate working solution, incubated at room temperature for 60min, and finally detected.
3、数据处理3. Data processing
计算每个孔供体与受体发射信号的比率：HTRF率＝665nm信号/620nm信号*104，然后将HTRF率转化为反应率(％)，通过Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))的四参数方程创建各实施例化合物的浓度-响应曲线，并且计算半数最大(50％)有效浓度(EC 50)，结果见表一。 Calculate the ratio of donor to acceptor emission signals for each well: HTRF rate = 665nm signal/620nm signal*104, then convert the HTRF rate to reaction rate (%) by Y=Bottom+(Top-Bottom)/(1+ The four-parameter equation of 10^((LogIC50-X)*HillSlope)) was used to create the concentration-response curve of each example compound, and the half-maximum (50%) effective concentration (EC 50 ) was calculated. The results are shown in Table 1.
表一：本发明化合物对人GLP-1 R的EC 50 Table 1: EC 50 of the compounds of the present invention to human GLP-1 R
实施例Example EC 50(nM) EC50 (nM)
11 0.480.48
22 1.941.94
33 5.565.56
44 1.571.57
55 2.592.59
77 2.862.86
1111 2.012.01
1414 3.053.05
1515 0.990.99
1616 1.881.88
1818 8.008.00
1919 6.076.07
2020 6.926.92
21twenty one 1.701.70
23twenty three 7.447.44
24twenty four 4.494.49
2727 2.762.76
2929 6.696.69
3030 4.334.33
3131 2.432.43
3434 1.071.07
3535 1.841.84
3636 6.236.23
3838 2.762.76
3939 1.191.19
4040 4.614.61
4141 2.292.29
4242 4.764.76
4343 0.290.29
4444 2.062.06
4545 3.713.71
4646 <0.015<0.015
4949 0.250.25
5050 1.291.29
5151 1.571.57
5252 7.557.55
5353 0.760.76
5454 9.429.42
5555 6.686.68
5858 4.254.25
5959 2.292.29
6161 6.756.75
6262 1.621.62
6767 4.094.09
6868 4.434.43
6969 2.192.19
7070 1.041.04
7171 1.221.22
7272 0.160.16
7373 1.821.82
7474 4.824.82
7575 2.982.98
7676 3.003.00
7777 4.384.38
7878 2.602.60
8080 2.952.95
8181 5.535.53
8383 3.533.53
8484 2.382.38
8686 1.701.70
8888 0.830.83
9292 0.460.46
9393 0.240.24
9696 1.921.92
9898 0.810.81
9999 7.597.59
101101 5.285.28
102102 3.673.67
105105 8.468.46
106106 3.693.69
107107 5.305.30
110110 4.444.44
112112 2.392.39
113113 2.092.09
114114 5.675.67
119119 3.803.80
120120 6.976.97
124124 1.061.06
结论：本发明化合物对人GLP-1 R具有明显的激动活性。Conclusion: The compound of the present invention has obvious agonistic activity on human GLP-1 R.
实施例126：本发明化合物大鼠药代动力学研究Example 126: Pharmacokinetic study of compounds of the present invention in rats
1、实验材料1. Experimental materials
SD大鼠：雄性，180-250g，购于北京维通利华实验动物技术有限公司。SD rats: male, 180-250 g, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，普萘洛尔(内标)均为市售可得。Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are commercially available.
仪器：赛默飞LC-MS(U300 UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。Instrument: Thermo Fisher Scientific LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
2、实验方法2. Experimental method
称取化合物溶于DMSO-PEG-400-生理盐水(5：60：35，v/v/v)体系中，大鼠静脉或灌胃给药后，于15min、30min、1h、2h、5h、7h、24h(iv组加采5min)采集静脉血200μL于肝素化EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为0.3、1、3、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆(静脉给药5min、15min、30min、1h血浆稀释10倍)，加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：The compounds were weighed and dissolved in DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system, and after intravenous or intragastric administration to rats, 15min, 30min, 1h, 2h, 5h, 200 μL of venous blood was collected in heparinized EP tubes at 7 h and 24 h (in addition to 5 min in iv group), centrifuged at 12000 rpm for 2 min, and the plasma was frozen at -80°C for testing. Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile and dilute to make standard series solutions. Accurately aspirate 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex and mix to prepare plasma samples with plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng/mL. A two-sample analysis was performed at one concentration, and a standard curve was established. Take 30 μL of plasma (intravenous administration of 5min, 15min, 30min, 1h plasma diluted 10 times), add 200μL of acetonitrile solution of internal standard propranolol (50ng/mL), vortex to mix, add 100μL of purified water, vortex again Spin and mix, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:
色谱柱：赛默飞HYPERSIL GOLD C-18 UPLC柱，100*2.1mm，1.7μm。Chromatographic column: Thermo Scientific HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.7μm.
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱Mobile phase: water (0.1% formic acid)-acetonitrile for gradient elution according to the following table
时间(min)time (min) 水(含0.1％甲酸)Water (with 0.1% formic acid) 乙腈Acetonitrile
00 90％90% 10％10%
0.60.6 90％90% 10％10%
11 10％10% 90％90%
2.62.6 10％10% 90％90%
2.612.61 90％90% 10％10%
44 90％90% 10％10%
3、数据处理3. Data processing
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数，结果见表二。After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate pharmacokinetic parameters by non-compartmental model method. The results are shown in Table 2.
表二：本发明化合物对大鼠药代动力学结果Table 2: Pharmacokinetic results of the compounds of the present invention on rats
Figure PCTCN2021120978-appb-000685
Figure PCTCN2021120978-appb-000685
Figure PCTCN2021120978-appb-000686
Figure PCTCN2021120978-appb-000686
结论：从表二中可以看出本发明化合物相对于参照化合物在大鼠口服吸收较好，具有较好的暴露量和生物利用度。Conclusion: It can be seen from Table 2 that the compound of the present invention is better orally absorbed in rats than the reference compound, and has better exposure and bioavailability.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (17)

  1. 式(I)的化合物：Compounds of formula (I):
    Figure PCTCN2021120978-appb-100001
    Figure PCTCN2021120978-appb-100001
    或其立体异构体、互变异构体、药学上可接受的盐，其中：or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
    A选自8～10元稠芳环；A is selected from 8-10-membered fused aromatic rings;
    R 1选自氢、卤素、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、1个或多个R 7取代的烷基、1个或多个R 8取代的芳基和杂芳基； R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    W为O或NH；W is O or NH;
    R 2选自氢、卤素、氰基； R 2 is selected from hydrogen, halogen, cyano;
    R 3选自氟、羟基、氰基、C 1-3烷基、OC 1-3烷基、C 3-4环烷基、或2个R 3一起环化成C 3-4螺环烷基，其中C 1-3烷基和OC 1-3烷基、环烷基或螺环烷基在化合价容许时可经0～3个氟原子或经0～1个羟基取代； R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
    q为0、1、2；q is 0, 1, 2;
    X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
    Y为CH或N；Y is CH or N;
    R 4为-C 1-3烷基、-C 0-3亚烷基-C 3-6环烷基、-C 0-3亚烷基-R 5或-C 1-3亚烷基-R 6，其中所述的烷基在化合价容许时可经0至3个独立地选自0至3个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代，及其中所述的亚烷基和环烷基在化合价容许时可独立地经0至2个独立地选自0至2个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代； R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituent substitution of -C 0-1 alkylene-OR O or -N(R N ) 2 , and the alkylene and cycloalkyl groups described therein may be independently replaced by 0 to 2 when the valence allows Substituents selected from 0 to 2 F atoms or through 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O or -N(R N ) 2 Substituent substitution;
    R 5为4至6元杂环烷基，其中该杂环烷基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
    0至1个氧代(＝O)，0 to 1 oxo (=O),
    0至1个-CN，0 to 1 -CN,
    0至2个F原子，或0 to 2 F atoms, or
    0至2个独立地选自-C 1-3烷基或-OC 1-3烷基的取代基，其中C 1-3烷基和OC 1-3烷基的烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 substituents independently selected from -C 1-3 alkyl or -OC 1-3 alkyl, wherein the alkyl of C 1-3 and OC 1-3 alkyl may be modified by valence when allowed. Substituted with 0 to 3 substituents independently selected from:
    0至3个F原子，0 to 3 F atoms,
    0至1个-CN，或0 to 1 -CN, or
    0至1个-OR O； 0 to 1 -OR O ;
    R 6为5至6元杂芳基，其中该杂芳基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
    0至2个卤素，0 to 2 halogens,
    0至1个选自-OR O和-N(R N) 2的取代基，或 0 to 1 substituent selected from -OR O and -N(R N ) 2 , or
    0至2个-C 1-3烷基，其中该烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 -C 1-3 alkyl groups, wherein the alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
    0至3个F原子，或0 to 3 F atoms, or
    0至1个-OR O； 0 to 1 -OR O ;
    各R O独立地为H或-C 1-3烷基，其中C 1-3烷基可经0至3个F原子取代； Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
    各R N独立地为H或-C 1-3烷基； each R N is independently H or -C 1-3 alkyl;
    Z 1、Z 2和Z 3各自独立地为-CR Z或N，各R Z独立地为H、F、Cl或-CH 3； Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
    R 7选自卤素、氰基、羟基、环烷基、杂环烷基、砜基； R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
    R 8选自卤素、氰基、烷基、卤代烷基，烷氧基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、砜基。 R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
  2. 根据权利要求1所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述化合物如式(II)所示：The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that the compound is represented by formula (II):
    Figure PCTCN2021120978-appb-100002
    其中：
    Figure PCTCN2021120978-appb-100002
    in:
    A选自8～10元稠芳环；A is selected from 8-10-membered fused aromatic rings;
    R 1选自氢、卤素、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、1个或多个R 7取代的烷基、1个或多个R 8取代的芳基和杂芳基； R 1 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 or more R 7 , aryl and heteroaryl substituted with one or more R 8 ;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    W为O或NH；W is O or NH;
    R 3选自氟、羟基、氰基、C 1-3烷基、OC 1-3烷基、C 3-4环烷基、或2个R 3一起环化成C 3-4螺环烷基，其中C 1-3烷基和OC 1-3烷基、环烷基或螺环烷基在化合价容许时可经0～3个氟原子或经0～1个羟基取代； R 3 is selected from fluorine, hydroxyl, cyano, C 1-3 alkyl, OC 1-3 alkyl, C 3-4 cycloalkyl, or 2 R 3 are cyclized together to form C 3-4 spirocycloalkyl, Wherein C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl or spirocycloalkyl can be substituted by 0 to 3 fluorine atoms or 0 to 1 hydroxyl group when the valence allows;
    q为0、1、2；q is 0, 1, 2;
    X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
    Y为CH或N；Y is CH or N;
    R 4为-C 1-3烷基、-C 0-3亚烷基-C 3-6环烷基、-C 0-3亚烷基-R 5或-C 1-3亚烷基-R 6，其中所述的烷基在化合价容许时可经0至3个独立地选自0至3个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代，及其中所述的亚烷基和环烷基在化合价容许时可独立地经0至2个独立地选自0至2个F原子的取代基或经0至1个选自-C 0-1亚烷基-CN、-C 0-1亚烷基-OR O或-N(R N) 2的取代基取代； R 4 is -C 1-3 alkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-R 5 or -C 1-3 alkylene-R 6 , wherein the alkyl group can be independently selected from 0 to 3 substituents of 0 to 3 F atoms through 0 to 3 substituents or through 0 to 1 selected from -C 0-1 alkylene-CN, Substituent substitution of -C 0-1 alkylene-OR O or -N(R N ) 2 , and the alkylene and cycloalkyl groups described therein may be independently replaced by 0 to 2 when the valence allows Substituents selected from 0 to 2 F atoms or through 0 to 1 selected from -C 0-1 alkylene-CN, -C 0-1 alkylene-OR O or -N(R N ) 2 Substituent substitution;
    R 5为4至6元杂环烷基，其中该杂环烷基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 5 is a 4- to 6-membered heterocycloalkyl group, wherein the heterocycloalkyl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
    0至1个氧代(＝O)，0 to 1 oxo (=O),
    0至1个-CN，0 to 1 -CN,
    0至2个F原子，或0 to 2 F atoms, or
    0至2个独立地选自-C 1-3烷基或-OC 1-3烷基的取代基，其中C 1-3烷基和OC 1-3烷基的烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 substituents independently selected from -C 1-3 alkyl or -OC 1-3 alkyl, wherein the alkyl of C 1-3 and OC 1-3 alkyl may be modified by valence when allowed. Substituted with 0 to 3 substituents independently selected from:
    0至3个F原子，0 to 3 F atoms,
    0至1个-CN，或0 to 1 -CN, or
    0至1个-OR O； 0 to 1 -OR O ;
    R 6为5至6元杂芳基，其中该杂芳基在化合价容许时可经0至2个独立地选自下列的取代基取代： R 6 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group may be substituted, as valence permits, with 0 to 2 substituents independently selected from the following:
    0至2个卤素，0 to 2 halogens,
    0至1个选自-OR O和-N(R N) 2的取代基，或 0 to 1 substituent selected from -OR O and -N(R N ) 2 , or
    0至2个-C 1-3烷基，其中该烷基在化合价容许时可经0至3个独立地选自下列的取代基取代： 0 to 2 -C 1-3 alkyl groups, wherein the alkyl group may be substituted, as valency allows, with 0 to 3 substituents independently selected from the following:
    0至3个F原子，或0 to 3 F atoms, or
    0至1个-OR O； 0 to 1 -OR O ;
    各R O独立地为H或-C 1-3烷基，其中C 1-3烷基可经0至3个F原子取代； Each R O is independently H or -C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
    各R N独立地为H或-C 1-3烷基； each R N is independently H or -C 1-3 alkyl;
    Z 1、Z 2和Z 3各自独立地为-CR Z或N，各R Z独立地为H、F、Cl或-CH 3； Z 1 , Z 2 and Z 3 are each independently -CR Z or N, and each R Z is independently H, F, Cl or -CH 3 ;
    R 7选自卤素、氰基、羟基、环烷基、杂环烷基、砜基； R 7 is selected from halogen, cyano, hydroxyl, cycloalkyl, heterocycloalkyl, sulfone;
    R 8选自卤素、氰基、烷基、卤代烷基，烷氧基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基、砜基。 R 8 is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, sulfone.
  3. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述烷基选自C 1-6的烷基，所述C 1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异 丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1,2-二甲基丙基、异戊基、新戊基、正己基、异己基、仲己基、叔己基、新己基、2-甲基戊基、1，2-二甲基丁基、1-乙基丁基。 The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from C 1-6 alkanes base, the C 1-6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-amyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl , 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl.
  4. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述烷氧基选自C 1-6的烷氧基，所述C 1-6的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1,2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、仲己氧基、叔己氧基、新己氧基、2-甲基戊氧基、1，2-二甲基丁氧基、1-乙基丁氧基；所述烷氧烷基选自C 1-4的烷氧C 1-4的烷基，进一步选自甲氧甲基、甲氧乙基、甲氧丙基、甲氧丁基、乙氧甲基、乙氧乙基、乙氧丙基、乙氧丁基、丙氧甲基、丙氧乙基、丙氧丙基、丙氧丁基、丁氧甲基、丁氧乙基、丁氧丙基、丁氧丁基等。 The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butyl Oxy, n-pentyloxy, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-amyloxy, 1,2-dimethylpropoxy, isopentyloxy, Neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethyl butoxy; the alkoxyalkyl group is selected from C 1-4 alkoxy C 1-4 alkyl group, further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl , ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl , Butoxypropyl, Butoxybutyl, etc.
  5. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述卤素选自氟、氯、溴、碘，卤代烷基指烷基一个以上的氢原子被卤素取代，卤代烷氧基指烷氧基一个以上的氢原子被卤素取代，杂环烷基是指烷基一个以上的氢原子被杂环取代。The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine , haloalkyl means that one or more hydrogen atoms of an alkyl group are substituted by halogen, haloalkoxy means that one or more hydrogen atoms of an alkoxy group are substituted by halogen, and heterocycloalkyl means that one or more hydrogen atoms of an alkyl group are substituted by a heterocycle.
  6. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述稠芳环选自萘或者稠芳杂环，所述稠芳杂环指芳环或杂芳环与杂芳环稠合而成，所述杂芳环上的杂原子选自氮、氧、硫，所述杂原子为一个或者多个。The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the fused aromatic ring is selected from naphthalene or fused aromatic heterocyclic ring, the fused aromatic heterocyclic ring refers to an aromatic ring or a heteroaromatic ring and a heteroaromatic ring fused, the heteroatom on the heteroaromatic ring is selected from nitrogen, oxygen, sulfur, and the heteroatom is one or more .
  7. 根据权利要求6所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述稠芳杂环选自吲唑、喹啉、异喹啉、喹喔啉、吲哚、异吲哚、噌啉、喹唑啉、酞嗪、嘌呤、萘啶、蝶啶、苯并呋喃、苯并噻吩、苯并噁唑、苯并噻唑、苯并异噁唑、苯并异噻唑、苯并噁二唑、苯并噻二唑、苯并三唑、苯并三嗪、苯并咪唑、吡嗪并吡唑、吡嗪并嘧啶、吡嗪并哒嗪、吡嗪并三嗪、嘧啶并吡唑、嘧啶并咪唑、嘧啶并三唑、嘧啶并三嗪、嘧啶并哒嗪、哒嗪并咪唑、哒嗪并吡唑、哒嗪并三唑、哒嗪并三嗪、三嗪并咪唑、三嗪并吡唑、三嗪并三唑、吡啶并噁唑、吡啶并噻唑、吡啶并异噁唑、吡啶并异噻唑、吡啶并噁二唑、吡啶并噻二唑、吡啶并呋喃、吡啶并吡咯、吡嗪并噁唑、吡嗪并噻唑、吡嗪并异噁唑、吡嗪并异噻唑、吡嗪并噁二唑、吡嗪并噻二唑、吡嗪并呋喃、吡嗪并吡咯、嘧啶并噁唑、嘧啶并噻唑、嘧啶并异噁唑、嘧啶并异噻唑、嘧啶并噁二唑、嘧啶并噻二唑、嘧啶并呋喃、嘧啶并吡咯、哒嗪并噁唑、哒嗪并噻唑、哒嗪并异噁唑、哒嗪并异噻唑、哒嗪并噁二唑、哒嗪并噻二唑、哒嗪并呋喃、哒嗪并吡咯、三嗪并噁唑、三嗪并噻唑、三嗪并异噁唑、三嗪并异噻唑、三嗪并噁二唑、三嗪并噻二唑、三嗪并呋喃、三嗪并吡咯。The compound according to claim 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the fused aromatic heterocycle is selected from indazole, quinoline, isoquinoline, Quinoxaline, indole, isoindole, cinnoline, quinazoline, phthalazine, purine, naphthyridine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisox azole, benzisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole, benzotriazine, benzimidazole, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine, pyrimidotriazine, pyrimidopyrazole, pyrimidopyrazole, pyrimidotriazole, pyrimidotriazine, pyrimidopyridazine, pyridazinimidazole, pyridazinopyrazole, pyridazinotriazole, pyridazino Triazine, triazinimidazole, triazinopyrazole, triazinotriazole, pyridooxazole, pyridothiazole, pyridoisoxazole, pyridoisothiazole, pyridooxadiazole, pyridothiadi azoles, pyridofurans, pyridopyrroles, pyrazinoxazoles, pyrazinothiazoles, pyrazinoisoxazoles, pyrazinoisothiazoles, pyrazinooxadiazoles, pyrazinothiadiazoles, pyrazine pyrimidofuran, pyrimidopyrrole, pyrimidooxazole, pyrimidothiazole, pyrimidoisoxazole, pyrimidoisothiazole, pyrimidooxadiazole, pyrimidothiadiazole, pyrimidofuran, pyrimidopyrrole, pyridazine oxazoles, pyridazinothiazoles, pyridazinoisoxazoles, pyridazinoisothiazoles, pyridazinooxadiazoles, pyridazinothiadiazoles, pyridazinofurans, pyridazinopyrroles, triazinooxazoles azoles, triazinothiazoles, triazinoisoxazoles, triazinoisothiazoles, triazinooxadiazoles, triazinothiadiazoles, triazinofurans, triazinopyrroles.
  8. 根据权利要求7所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述萘啶选自
    Figure PCTCN2021120978-appb-100003
    所述吡啶并咪唑选自
    Figure PCTCN2021120978-appb-100004
    Figure PCTCN2021120978-appb-100005
    所述吡嗪并咪唑选自
    Figure PCTCN2021120978-appb-100006
    所述吡嗪并三唑选自
    Figure PCTCN2021120978-appb-100007
    所述嘧啶并吡唑选自
    Figure PCTCN2021120978-appb-100008
    所述嘧啶并咪唑选自
    Figure PCTCN2021120978-appb-100009
    所述嘧啶并三唑选自
    Figure PCTCN2021120978-appb-100010
    所述哒嗪并咪唑选自
    Figure PCTCN2021120978-appb-100011
    所述哒嗪并三唑选自
    Figure PCTCN2021120978-appb-100012
    所述三嗪并咪唑选自
    Figure PCTCN2021120978-appb-100013
    Figure PCTCN2021120978-appb-100014
    所述吡啶并哒嗪选自
    Figure PCTCN2021120978-appb-100015
    所述吡啶并吡唑选自
    Figure PCTCN2021120978-appb-100016
    所述吡啶并嘧啶选自
    Figure PCTCN2021120978-appb-100017
    Figure PCTCN2021120978-appb-100018
    所述吡啶并三嗪选自
    Figure PCTCN2021120978-appb-100019
    所述嘧啶并三嗪选自
    Figure PCTCN2021120978-appb-100020
    The compound according to claim 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the naphthyridine is selected from
    Figure PCTCN2021120978-appb-100003
    The pyridoimidazole is selected from
    Figure PCTCN2021120978-appb-100004
    Figure PCTCN2021120978-appb-100005
    The pyrazinimidazole is selected from
    Figure PCTCN2021120978-appb-100006
    The pyrazinotriazole is selected from
    Figure PCTCN2021120978-appb-100007
    The pyrimidopyrazole is selected from
    Figure PCTCN2021120978-appb-100008
    The pyrimimidazole is selected from
    Figure PCTCN2021120978-appb-100009
    The pyrimidotriazole is selected from
    Figure PCTCN2021120978-appb-100010
    The pyridazinimidazole is selected from
    Figure PCTCN2021120978-appb-100011
    The pyridazinotriazole is selected from
    Figure PCTCN2021120978-appb-100012
    The triazineimidazole is selected from
    Figure PCTCN2021120978-appb-100013
    Figure PCTCN2021120978-appb-100014
    The pyridopyridazine is selected from
    Figure PCTCN2021120978-appb-100015
    The pyridopyrazole is selected from
    Figure PCTCN2021120978-appb-100016
    The pyridopyrimidine is selected from
    Figure PCTCN2021120978-appb-100017
    Figure PCTCN2021120978-appb-100018
    The pyridotriazine is selected from
    Figure PCTCN2021120978-appb-100019
    The pyrimidotriazine is selected from
    Figure PCTCN2021120978-appb-100020
  9. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述杂环烷基的杂环选自4至10元杂环，所述4至10元杂环选自
    Figure PCTCN2021120978-appb-100021
    Figure PCTCN2021120978-appb-100022
    所述芳基选自苯基；所述杂芳基选自5至12元杂芳基，所述5至12元杂芳基选自
    Figure PCTCN2021120978-appb-100023
    Figure PCTCN2021120978-appb-100024
    The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the heterocycle of the heterocycloalkyl group is selected from 4 to 10-membered heterocycle, the 4- to 10-membered heterocycle is selected from
    Figure PCTCN2021120978-appb-100021
    Figure PCTCN2021120978-appb-100022
    The aryl group is selected from phenyl; the heteroaryl group is selected from the 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group is selected from
    Figure PCTCN2021120978-appb-100023
    Figure PCTCN2021120978-appb-100024
  10. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述环烷基选自C 3-6的环烷，C 3-6的环烷选自环丙基、环丁基、环戊基、环己基。 The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is selected from C 3-6 Cycloalkane, C 3-6 cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  11. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述A选自
    Figure PCTCN2021120978-appb-100025
    Figure PCTCN2021120978-appb-100026
    The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the A is selected from the group consisting of
    Figure PCTCN2021120978-appb-100025
    Figure PCTCN2021120978-appb-100026
  12. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述A选自
    Figure PCTCN2021120978-appb-100027
    The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the A is selected from the group consisting of
    Figure PCTCN2021120978-appb-100027
    Figure PCTCN2021120978-appb-100028
    Figure PCTCN2021120978-appb-100028
    R 1选自氢、氰基、甲基、乙基、异丙基、环丙基、甲氧基、甲氧乙基、二氟甲基、三氟甲基、氧杂环丁烷-3-基、氟、氯、2，2-二氟乙基、2-氟乙基、三氟乙基、氰基甲基、环丙基甲基、2-甲氧基-2-氧代乙基、氧杂环丁-3-基甲基、
    Figure PCTCN2021120978-appb-100029
    R 1 is selected from hydrogen, cyano, methyl, ethyl, isopropyl, cyclopropyl, methoxy, methoxyethyl, difluoromethyl, trifluoromethyl, oxetane-3- group, fluorine, chlorine, 2,2-difluoroethyl, 2-fluoroethyl, trifluoroethyl, cyanomethyl, cyclopropylmethyl, 2-methoxy-2-oxoethyl, oxetan-3-ylmethyl,
    Figure PCTCN2021120978-appb-100029
    W为O或NH；W is O or NH;
    R 2为氢； R 2 is hydrogen;
    R 3为甲基； R 3 is methyl;
    R 4为氧杂环丁烷-2-基甲基； R 4 is oxetan-2-ylmethyl;
    X-L选自N-CH 2、CHCH 2、或环丙基； XL is selected from N- CH2 , CHCH2 , or cyclopropyl;
    Y为CH或N；Y is CH or N;
    Z 1为CH或N； Z 1 is CH or N;
    Z 2为CH、CF或N； Z 2 is CH, CF or N;
    Z 3为CH、CF或N。 Z 3 is CH, CF or N.
  13. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，选自以下化合物：The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is characterized in that, it is selected from the following compounds:
    Figure PCTCN2021120978-appb-100030
    Figure PCTCN2021120978-appb-100030
    Figure PCTCN2021120978-appb-100031
    Figure PCTCN2021120978-appb-100031
    Figure PCTCN2021120978-appb-100032
    Figure PCTCN2021120978-appb-100032
    Figure PCTCN2021120978-appb-100033
    Figure PCTCN2021120978-appb-100033
    Figure PCTCN2021120978-appb-100034
    Figure PCTCN2021120978-appb-100034
    Figure PCTCN2021120978-appb-100035
    Figure PCTCN2021120978-appb-100035
    Figure PCTCN2021120978-appb-100036
    Figure PCTCN2021120978-appb-100036
    Figure PCTCN2021120978-appb-100037
    Figure PCTCN2021120978-appb-100037
  14. 根据权利要求1或2任一权利要求所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于，所述药学上可接受的盐是指化合物与药学上可接受的酸或碱制备。The compound according to any one of claims 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt refers to the compound with A pharmaceutically acceptable acid or base is prepared.
  15. 根据权利要求1-13任一项所述化合物，或其立体异构体、互变异构体、药学上可接受的盐，其特征在于：所述化合物的一个以上的氢原子上被同位素氘取代。The compound according to any one of claims 1-13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: one or more hydrogen atoms of the compound are deuterium isotopes replace.
  16. 一种药物组合物，其特征在于，包括前述权利要求1-15任一项所述化合物，或其立体异构体、互变异构体、药学上可接受的盐和一种以上药学上可接受的载体。A pharmaceutical composition is characterized in that, comprises the compound described in any one of the preceding claims 1-15, or its stereoisomer, tautomer, pharmaceutically acceptable salt and more than one pharmaceutically acceptable accepted vector.
  17. 根据权利要求1-15任一项所述化合物，或其立体异构体、互变异构体、药学上可接受的盐在制备用于制备治疗GLP-1相关疾病的药物用途，优选糖尿病相关疾病的药物用途。Use of the compound according to any one of claims 1-15, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicine for the treatment of GLP-1-related diseases, preferably diabetes-related Medicinal use of disease.
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