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WO2022068772A1 - Dérivé de benzimidazole, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé de benzimidazole, son procédé de préparation et son utilisation médicale 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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WIPO (PCT)
Prior art keywords
methyl
mmol
oxetan
benzo
ylmethyl
Prior art date
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Ceased
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PCT/CN2021/120978
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English (en)
Chinese (zh)
Inventor
吴俊军
陆银锁
肖瑛
周鹏
滕耀辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Salubris Pharmaceuticals Co Ltd
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Priority to CN202180030750.1A priority Critical patent/CN115515956B/zh
Publication of WO2022068772A1 publication Critical patent/WO2022068772A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

L'invention concerne un composé représenté par la formule (I), son procédé de préparation et son utilisation en médecine. En particulier, l'invention concerne un composé représenté par la formule (I) ou un stéréoisomère, un tautomère et un sel pharmaceutiquement acceptable de celui-ci. Les composés sont des agonistes de récepteurs du peptide 1 apparenté au glucagon (GLP-1R). La présente invention concerne également une composition pharmaceutique comprenant les composés et l'utilisation des composés dans des médicaments pour le traitement de maladies telles que le diabète.
PCT/CN2021/120978 2020-09-29 2021-09-27 Dérivé de benzimidazole, son procédé de préparation et son utilisation médicale Ceased WO2022068772A1 (fr)

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WO2022192430A1 (fr) * 2021-03-11 2022-09-15 Gilead Sciences, Inc. Composés modulateurs de glp-1r
WO2022192428A1 (fr) * 2021-03-11 2022-09-15 Gilead Sciences, Inc. Composés modulateurs de glp-1r
WO2022246019A1 (fr) 2021-05-20 2022-11-24 Eli Lilly And Company Agonistes macrocycliques du récepteur du peptide 1 de type glucagon
WO2023057414A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certaines octahydrofuro 3,4-b]pyrazines utilisées en tant que modulateurs du récepteur glp-1
WO2023057427A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes utilisés en tant que modulateurs du récepteur glp-1
WO2023057429A1 (fr) 2021-10-05 2023-04-13 Astrazeneca Ab Certains 2,5-diazabicyclo[4.2.0]octanes et octahydrofuro[3,4-b]pyrazines utilisés en tant que modulateurs du récepteur glp-1
WO2023090859A1 (fr) * 2021-11-17 2023-05-25 일동제약(주) Procédé de préparation d'un dérivé d'isoxazole et nouvel intermédiaire associé
WO2023111145A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab Certains 3-azabicyclo[3.1.0] hexanes utilisés en tant que modulateurs du récepteur de glp-1
WO2023111144A1 (fr) 2021-12-16 2023-06-22 Astrazeneca Ab 3-azabicyclo [3.1.0] hexanes en tant que modulateurs du récepteur glp-1
US11702404B2 (en) 2019-10-25 2023-07-18 Gilead Sciences, Inc. GLP-1R modulating compounds
US11851419B2 (en) 2020-11-20 2023-12-26 Gilead Sciences, Inc. GLP-1R modulating compounds
US11858918B2 (en) 2021-04-21 2024-01-02 Gilead Sciences, Inc. GLP-1R modulating compounds
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
WO2024063143A1 (fr) 2022-09-22 2024-03-28 塩野義製薬株式会社 Composé à cycle condensé ayant un effet agoniste du récepteur glp-1
WO2024102625A1 (fr) 2022-11-11 2024-05-16 Eli Lilly And Company Agonistes de récepteur du peptide 1 de type glucagon
WO2024107781A1 (fr) 2022-11-16 2024-05-23 Eli Lilly And Company Agonistes du récepteur du glucagon-like peptide 1
US12121511B2 (en) 2020-01-29 2024-10-22 Gilead Sciences, Inc. GLP-1R modulating compounds
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
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RU2853119C2 (ru) * 2022-05-20 2025-12-19 Чэнду Дьяо Цзюхун Фармасьютикал Фэктори Бензимидазольное или азабензимидазольное соединение, способ его получения и его применение
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WO2024107781A1 (fr) 2022-11-16 2024-05-23 Eli Lilly And Company Agonistes du récepteur du glucagon-like peptide 1
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WO2025189141A1 (fr) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Méthodes de traitement de l'obésité et d'augmentation de la perte de poids

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