WO2022268080A1 - Trk激酶抑制剂化合物及其用途 - Google Patents

Trk激酶抑制剂化合物及其用途 Download PDF

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WO2022268080A1
WO2022268080A1 PCT/CN2022/100186 CN2022100186W WO2022268080A1 WO 2022268080 A1 WO2022268080 A1 WO 2022268080A1 CN 2022100186 W CN2022100186 W CN 2022100186W WO 2022268080 A1 WO2022268080 A1 WO 2022268080A1
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alkyl
group
ethoxy
difluorophenyl
imidazol
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PCT/CN2022/100186
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English (en)
French (fr)
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路良
黄海
张龙争
赵赛赛
张霁旋
王晓龙
朱俊杰
廖新伟
陈佳昕
凌杉村
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河南迈英诺医药科技有限公司
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Priority to US18/572,862 priority Critical patent/US20240317760A1/en
Priority to EP22827573.1A priority patent/EP4357347A1/en
Priority to JP2023579048A priority patent/JP2024524236A/ja
Publication of WO2022268080A1 publication Critical patent/WO2022268080A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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 present application provides a class of novel compounds with pharmaceutical activity, which can be used to inhibit TRK kinase activity.
  • the present application also relates to a composition comprising the compound, and the use of the compound and the composition in the preparation of a medicament for treating diseases or conditions related to TRK kinase or NTRK gene.
  • Protein kinase (Protein Kinase, PK) is a key regulator of cell growth, proliferation and survival, and the dysfunction of protein kinase is a hallmark of many diseases. Most of the oncogenes and proto-oncogenes associated with human cancer encode PK. As a kind of protein kinase, TRK kinase (Tropomyosin receptor kinase, tropomyosin receptor kinase) has attracted the attention of researchers in recent years.
  • TRK kinase Tropomyosin receptor kinase, tropomyosin receptor kinase
  • TRK kinases belong to the family of receptor tyrosine kinases.
  • the Trk family mainly includes three members TRKA, TRKB and TRKC, which are respectively encoded by the neurotrophic receptor tyrosine kinase (NTRK) genes: NTRK1 gene, NTRK2 gene, NTRK3 gene.
  • NTRK neurotrophic receptor tyrosine kinase
  • Previous studies have confirmed that receptors for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor 4/5 (NT-4/5), and neurotrophic factor 3 (NT-3)
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT-4/5 neurotrophic factor 4/5
  • NT-3 neurotrophic factor 3
  • TRK kinases are constitutively activated in human malignancies through multiple mechanisms.
  • the most recognized mechanism is NTRK gene fusion, in which the 3′ NTRK gene region rearranges intrachromosomally or interchromosomally, and then fuses with the sequence of the 5′ partner gene, resulting in a high risk of tumorigenesis.
  • the activation or dysregulation of TRK kinase and NTRK gene fusion have been proven to be closely related to the occurrence, development and progression of various tumors or cancers; for patients with NTRK fusion gene expression, TRK is an important target for tumor therapy. Therefore, small-molecule TRK kinase inhibitors are considered to be a broad-spectrum anticancer drug with great potential.
  • TRK inhibitors have been shown to be effective in preclinical animal models of pain and preclinical animal models of inflammation.
  • Larotrectinib also known as LOXO-101 or Vitrakvi
  • Larotrectinib is the first approved TRK inhibitor anticancer drug. It has shown obvious curative effect in the treatment of some cancers, but its price is extremely expensive, and there are insurmountable drug resistance problems after long-term use.
  • the second TRK inhibitor drug approved for marketing is Entrectinib, also known as Rozlytrek, which also shows good broad-spectrum anticancer activity.
  • the application provides a compound of formula (I) as a TRK kinase inhibitor
  • R 1 and R 2 are each independently selected from H, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and halogen;
  • R 3 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 alicyclic and 4-6 heteroalicyclic;
  • R 6 is 1, 2 or 3, and each R 6 is independently selected from H, halogen, -CN, -OH, -NO 2 , -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 alicyclic and 4-6 heteroalicyclic;
  • X is a link, O, S or (NR 4 ), wherein R 4 is selected from: H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 alicyclic Base and 4-6 membered heteroalicyclic group;
  • R 7 and R 8 are each independently selected from: H, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or R 7 , R 8 and the N atoms connected to them jointly form 3-6 membered ring;
  • n 1, 2 or 3;
  • R 5 is selected from H, halogen, -OH, -NO 2 , -CN, -SF 5 , -SH, -SC 1-4 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 alicyclic , 3-10 heteroalicyclic, C 6-12 bicyclic aliphatic Cyclic group, 6-12 membered bicyclic heteroalicyclic group, C 8-15 membered tricyclic heteroalicyclic group, 8-15 membered tricyclic heteroalicyclic group, C 5-8 aryl group, 5-10 membered heteroaryl group, C 7-11 bicyclic aryl, 7-11 bicyclic heteroaryl, -C 1-4 alkyl-(C 3-7 alicyclic), -C 1-4 alkyl-(3-10 heteroaryl Cyclic group), -C 1-4 alkyl-(
  • R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected at each occurrence from: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 Alicyclic group, 3-10 membered heteroalicyclic group, C 5-8 aryl group, 5-7 membered heteroaryl group, C 7-11 bicyclic aryl group, 7-11 membered bicyclic heteroaryl group, -C 1-4 Alkyl- (C 3-7 alicyclic group), -C 1-4 alkyl-(3-10 membered heteroalicyclic group), -C 1-4 alkyl-(C 6-12 bicyclic alicyclic group) , -C 1-4 alkyl-(6-12 membered bicyclic heteroalicyclic group), -C 1-4 alkyl-(C 8-15 membered tricyclic alicyclic group), -C 1-4 alkyl- (8-15 membered tricyclic heteroalicyclic group), -C 1-4
  • optical isomer means that when a compound has one or more chiral centers, each chiral center can have an R configuration or an S configuration, and the various isomers thus constituted are optical isomers. Construct. Optical isomers include all diastereoisomers, enantiomers, mesoforms, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatographic columns or by chiral synthesis.
  • Geometric isomer means that when a double bond exists in the compound, the compound may exist as a cis-isomer, a trans-isomer, an E-isomer and a Z-isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.
  • tautomer refers to isomers that result from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that: tautomers can transform into each other, and may reach an equilibrium state and coexist in a certain state.
  • isotopes suitable for inclusion in the compounds of the present application include isotopes of hydrogen, such as 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C, 13 C, and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O, 17 O, and 18 O; Isotopes such as35S .
  • isotopes of hydrogen such as 2 H(D) and 3 H(T)
  • isotopes of carbon such as 11 C, 13 C, and 14 C
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • Such isotopically labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes deuterium (ie D) and carbon-14 (ie 14 C) are particularly useful for this purpose in view of the ease of introduction and the convenience of the means of detection.
  • the compounds of the present application are isotopically labeled compounds, wherein H is optionally substituted with D at each occurrence.
  • the isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.
  • the compounds of the present application may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to a human.
  • the term refers to the use in mammals, preferably humans, certified by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA), etc.
  • the pharmaceutically acceptable salts include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , camphorsulfonate, citrate, cyclamate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, six Fluorophosphate, 2-(4-Hydroxybenzyl)benzoate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, 2-Isethionate, Lactate , malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfon
  • Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Half-salts of acids and bases, such as the hemisulfate and hemicalcium salts, may also be formed.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
  • the compounds of the present application may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • Compounds may also exist in one or more crystalline states, ie, polymorphs, or they may exist as amorphous solids. All such forms are included within the scope of this application.
  • the present application also includes prodrugs of the compounds of the present application.
  • prodrug refers to a derivative that is converted into the compound of the present application by reacting with enzymes, gastric acid, etc. under physiological conditions in vivo, such as oxidation, reduction, hydrolysis, etc. catalyzed by enzymes. Therefore, some derivatives of the compounds of the present application may themselves have little or no pharmacological activity, and when administered into or onto the body, can be converted into the compounds of the present application with the desired activity.
  • the present application also includes metabolites of the compounds of the present application.
  • the term "metabolite” refers to all molecules derived from any of the compounds of the present application in a cell or organism, preferably a human.
  • substituted means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group are independently replaced by a corresponding number of substituents.
  • the term “optional” or “optionally” means that the event it describes can or cannot occur.
  • a group “optionally substituted” means that the group can be unsubstituted or substituted.
  • halogen refers to -F, -Cl, -Br, or -I.
  • alkyl refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, an alkyl group has 1-8, or 1-6, or 1-4, or 1-3 carbon atoms.
  • C 1-8 alkyl refers to a straight or branched chain radical having 1 to 8 carbon atoms.
  • C 1-8 alkyl includes in its definition the terms “C 1-6 alkyl", “C 1-3 alkyl” and "C 1-4 alkyl” and the like .
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, iso Pentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3- Dimethylbutyl, hexyl, etc.
  • Alkyl groups may be optionally substituted with one or more (eg, 1 to 5) suitable substituents.
  • alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • an alkenyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkenyl refers to a straight or branched unsaturated radical having 2 to 8 carbon atoms (having at least one carbon-carbon double bond). The double bond may or may not be the point of attachment to another group.
  • Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like.
  • An alkenyl group may be optionally substituted with one or more (eg, 1 to 5) suitable substituents.
  • the alkenyl group may exist in the pure E form, in the pure Z form, or any mixture thereof.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • an alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms.
  • C 2-8 alkynyl refers to a straight or branched unsaturated radical having 2 to 8 carbon atoms (having at least one carbon-carbon triple bond). The triple bond may or may not be the point of attachment to another group.
  • Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like.
  • An alkynyl group may be optionally substituted with one or more (eg, 1 to 5) suitable substituents.
  • C 3-8 alicyclic group refers to an alicyclic group having 3-8 ring-forming carbon atoms.
  • C 3-7 alicyclic group refers to an alicyclic group having 3-7 ring-forming carbon atoms.
  • C 3-6 alicyclic group refers to an alicyclic group having 3-6 ring-forming carbon atoms.
  • the alicyclic group may be a monocyclic ring.
  • the definition of cycloaliphatic also includes unsaturated non-aromatic cycloaliphatic groups.
  • cycloaliphatic groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentenyl, cycloheptene base and cyclooctenyl.
  • Alicyclic groups are optionally substituted with one or more suitable substituents.
  • C 6-12 bicyclic alicyclic group is an alicyclic group containing two rings having 6-12 ring-forming carbon atoms. Bicyclic alicyclic groups may be fused and may also include bridged bicyclic alicyclic systems.
  • C 8-15 membered tricyclic alicyclic group is an alicyclic group containing three rings having 8 to 15 ring-forming carbon atoms.
  • the tricyclic alicyclic groups may be fused or bridged.
  • n-membered heteroalicyclic group refers to an alicyclic group having m ring-forming carbon atoms and (n-m) ring-forming heteroatoms selected from O, S, and N.
  • the term “4-8 membered heteroalicyclic group” means that the heteroalicyclic substituent contains a total of 4 to 8 ring atoms, at least one of which is a heteroatom
  • the term “4-6 membered heteroalicyclic group” means The heteroalicyclic substituent contains a total of 4 to 6 ring atoms, at least one of which is a heteroatom
  • the term “3-10 membered heteroalicyclic” means that the heteroalicyclic substituent contains a total of 3 to 10 ring atoms, At least one of them is a heteroatom.
  • n-membered bicyclic heteroalicyclic group refers to a bicyclic heteroalicyclic group having m ring-forming carbon atoms and (n-m) ring-forming heteroatoms selected from O, S and N.
  • heteroalicyclic groups include, but are not limited to, azetidinyl, thietanyl, dihydrofuryl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, Tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, oxazolidinyl, ox
  • C 5-8 aryl refers to an aryl group having an aromatic ring containing 5-8 carbon atoms, such as phenyl.
  • n-membered heteroaryl refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (n-m) heteroatoms forming an aromatic ring selected from O, S and N.
  • 5-7 membered heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl.
  • a heteroaryl group can be optionally substituted with one or more suitable substituents.
  • C 7-11 bicyclic aryl refers to a bicyclic aryl group having 7-11 carbon atoms, such as naphthyl, indenyl and the like. Bicyclic aryl groups are optionally substituted with one or more suitable substituents.
  • n-membered bicyclic heteroaryl refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclic ring and (n-m) heteroatoms forming an aromatic bicyclic ring selected from From O, S and N.
  • 7-11 membered bicyclic heteroaryl groups include, but are not limited to, quinolinyl, isoquinolyl, indolyl, purinyl, benzothiazolyl, and the like.
  • a bicyclic heteroaryl can be optionally substituted with one or more suitable substituents.
  • 11-15 membered tricyclic group includes, but is not limited to, acridinyl and the like.
  • the 11-15 membered tricyclic group may be optionally substituted with one or more suitable substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom) .
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom replaced).
  • C 1-4 haloalkyl refers to a C 1-4 alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group has one or more halogen substituents substituted by halogen atoms);
  • C 1-3 haloalkyl refers to a C 1-3 alkyl group (up to perhaloalkyl, i.e., each of the alkyl groups) having one or more halogen substituents hydrogen atoms are all replaced by halogen atoms);
  • C 1-2 haloalkyl refers to a C 1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, ie, each hydrogen atom of the alkyl group is replaced by a halogen atom).
  • C haloalkyl refers to a methyl group having 1 , 2 or 3 halo substituents.
  • haloalkyl groups include : CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl , and the like.
  • alkoxy refers to an alkyl group single bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. Alkoxy can be described as alkyl-O-.
  • C 1-6 alkoxy refers to a straight or branched alkoxy group containing 1 to 6 carbon atoms. The term “C 1-6 alkoxy” includes within its definition the term "C 1-3 alkoxy”.
  • Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like. Alkoxy groups are optionally substituted with one or more suitable substituents.
  • 3-14 membered ring refers to a saturated or unsaturated ring system having 3-14 ring-forming atoms.
  • 3-6 membered ring refers to a saturated or unsaturated ring system having 3-6 ring-forming atoms
  • 3-8 membered ring refers to a saturated or unsaturated ring system having 3-8 ring-forming atoms. unsaturated ring system.
  • the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent enumeration of all integers within the range one by one, and the range is only used as a simplified representation.
  • "4-6 yuan” means 4, 5 or 6 yuan; "5-7 yuan” means 5, 6 or 7 yuan; “7-11 yuan” means 7, 8, 9, 10 or 11 yuan; “4 -8 yuan” means 4, 5, 6, 7 or 8 yuan; "3-10 yuan” means 3, 4, 5, 6, 7, 8, 9 or 10 yuan; “3-14 yuan” means 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 members; “C 1-3 “ means 1 (C 1 ), 2 (C 2 ) or 3 carbon atoms (C 3 ); “C 1-4 " means 1 (C 1 ), 2 (C 2 ), 3 carbon atoms (C 3 ) or 4 carbon atoms (C 4 atoms
  • R 1 is selected from H, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and halogen.
  • R 1 is H.
  • R 1 is halogen, for example R 1 is selected from F, Cl, Br, I.
  • R is C 1-4 alkyl or C 1-4 haloalkyl, such as optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • R 1 is C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy.
  • R 1 is CN
  • R 1 may be combined in any manner with any of the embodiments of R 2 , R 3 , R 5 , R 6 , X, L and n as described above and below.
  • R 2 is selected from H, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and halogen.
  • R is H.
  • R 2 is halogen, for example R 2 is selected from F, Cl, Br, I.
  • R is C 1-4 alkyl or C 1-4 haloalkyl, such as optionally substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • R 2 is C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy.
  • R 2 is CN
  • R 2 may be combined in any manner with any of the embodiments of R 1 , R 3 , R 5 , R 6 , X, L and n as described above and below.
  • R 1 and R 2 can be the same.
  • both R1 and R2 are halogen, such as Cl or F ; for another example, both R1 and R2 are H.
  • both R and R are F.
  • both R and R are H.
  • R1 and R2 can be different.
  • R 3 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 alicyclic and 4-6 heteroalicyclic group.
  • R 3 is H.
  • R 3 is C 1-3 alkyl or C 1-3 haloalkyl, for example, R 3 is selected from the group optionally substituted with one or more halogen atoms (eg, fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • R 3 is C 1-3 alkoxy, for example, R 3 is selected from methoxy, ethoxy, propoxy, isopropoxy.
  • R 3 is C 3-6 alicyclic group, for example, R 3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclo Pentenyl etc.
  • R 3 is a 4-6 membered heteroalicyclic group, and the heteroatoms can be selected from O, S and N.
  • R is selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuryl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl , piperidinyl, morpholinyl, piperazinyl.
  • R 3 is methyl
  • R 3 may be combined in any manner with any of the embodiments of R 1 , R 2 , R 5 , R 6 , X, L and n as described above and below.
  • R 6 is H.
  • R 6 is halogen, for example R 6 is selected from F, Cl, Br, I.
  • R 6 is -CN, -OH, or -NO 2 .
  • R 6 is C 1-3 alkyl or C 1-3 haloalkyl, for example R 6 is selected from the group optionally substituted by one or more halogen atoms (eg fluorine, chlorine, bromine, iodine) Methyl, ethyl, propyl, isopropyl.
  • halogen atoms eg fluorine, chlorine, bromine, iodine
  • R 6 is C 1-3 alkoxy, for example R 6 is selected from methoxy, ethoxy, propoxy, isopropoxy.
  • R 6 is a C 3-6 alicyclic group, for example, R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • R 6 is a 4-6 membered heteroalicyclic group (heteroatoms can be selected from O, S and N), for example, R 6 is selected from oxetanyl, thietanyl, nitrogen Heterobutanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.
  • heteroatoms can be selected from O, S and N
  • R 6 is selected from oxetanyl, thietanyl, nitrogen Heterobutanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.
  • R 6 is dimethylamino, diethylamino, methylethylamino.
  • R 6 is 1.
  • R 6 may be combined in any manner with any of the embodiments of R 1 , R 2 , R 3 , R 5 , X, L and n as described above and below.
  • X is a linker, O, S or (NR 4 ), wherein R 4 is selected from: H, C 1-4 alkyl, C 1-4 haloalkyl, C 1- 4 alkoxy, C 3-6 alicyclic and 4-6 heteroalicyclic (heteroatoms can be selected from O, S and N).
  • X is a linkage (ie, X is absent, and the chemical groups on both sides of X are directly connected).
  • X is -O-.
  • X is -S-.
  • X is imino, ie -(NH)-.
  • X is -(N( CH3 ))-.
  • X is selected from a linker, -O-, and -(NH)-.
  • n 1, 2 or 3.
  • n 1
  • n is 2.
  • n 3.
  • n may be combined in any manner with any of the embodiments of R 1 , R 2 , R 3 , R 5 , R 6 , L and X as described above and below.
  • L is a linker (ie L is absent, in which case R5 is directly linked to N).
  • L is -(CR a R b )-, wherein R a and R b are each independently selected from: H, C 1-4 alkyl (eg methyl, ethyl, propyl, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, etc.), C 1-4 haloalkyl group (such as methyl, ethyl, Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), C 1-4 alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, etc.), C 3-6 alicyclic group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadie
  • L can be -CH 2 -, -C(CH 3 ) 2 -, -CH(CH 3 )-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene, etc. Wait.
  • any of the above embodiments of L may be combined in any manner with any of the embodiments of R 1 , R 2 , R 3 , R 5 , R 6 , n and X as described above and below.
  • R 5 may be any substituent commonly used in organic chemistry, which is not particularly limited.
  • R 5 is C 1-6 alkyl, for example R 5 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl Base, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2 ,3-Dimethylpropyl, 2,3-dimethylbutyl, hexyl.
  • R 5 is C 3-7 alicyclic group, for example R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexadiene base, cyclopentenyl, cycloheptenyl.
  • R is a 3-10 membered heteroalicyclic group, for example, R is selected from azetidinyl, thietidinyl , dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophene base, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuryl, octahydrobenzoimidazolyl, octahydrobenzothiazolyl, imidazole Alkyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl
  • R5 is H, halogen, -OH, -NO2 , -CN, -SF5 , or -SH.
  • R 5 is selected from -SC 1-4 alkyl, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -8 alkenyl, C 2-8 alkynyl.
  • R is selected from C 5-8 aryl (such as phenyl), 5-10 membered heteroaryl (such as furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, Pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.), -C 1-4 alkyl-(C 5-8 aryl), -C 1-4 alkyl-(5-10 yuan heteroaryl).
  • C 5-8 aryl such as phenyl
  • 5-10 membered heteroaryl such as furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, Pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclobutyl groups.
  • the methyl, ethyl, propyl, isopropyl or cyclobutyl groups may optionally be substituted with 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, Cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, the substituents can optionally be substituted by 0, 1 or 2 substituents independently selected from the following groups : Methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.
  • R is selected from ( 1 -hydroxycyclopropyl)ethyl, 3-hydroxycyclobutyl, 2-cyanoethyl, 2-hydroxyethyl, 2-cyano- 1-cyclopentylethyl, 1-cyanopropane, 2-morpholinoethyl, ethyl, and (1-methylpiperidin-4-yl)methyl.
  • R 5 is selected from halogen, such as F.
  • R is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidinyl, and the piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl Pyridyl and azetidinyl may optionally be substituted with 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclobutyl groups, said methyl, ethyl, propyl, isopropyl or cyclobutyl groups
  • the group can be optionally substituted by 0, 1 or 2 substituents each independently selected from the following group: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piper
  • the substituent can optionally be replaced by 0, 1 or 2 substituents independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, - Oh.
  • R is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl.
  • R is selected from 3,5 - dimethylpiperazinyl, morpholinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl Base, 4-hydroxypiperidinyl, 1-methylpiperidinyl, 1-ethylpiperidin-4-yl, 1-methylazetidin-3-yl.
  • R is selected from H, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, hydroxyl, cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, morpholinomethyl, hydroxycyclobutyl, hydroxycyclohexyl, cyanoethoxy, cyanomethyl, pyridin-3-yl, 1-methyl-1H-pyrazole-4- Base, 1-methyl-1H-pyrazol-3-yl, 4-methylpiperazin-1-yl, 1-methylpiperidin-4-yl, morpholinyl, pyrrolidin-3-yl, 3 -Hydroxypyrrolidin-1-yl, 3-cyanopyrrolidin-1-yl.
  • R 5 may be combined in any manner with any of the embodiments of R 1 , R 2 , R 3 , R 6 , X, L and n as described above and below.
  • the present application also relates to compounds shown in formula (Ia):
  • X is -O- or -(NH)-; the definitions and preferences of L, n, R 3 , R 5 , and R 6 are the same as those of the compound of formula (I).
  • the present application also relates to compounds shown in formula (Ib):
  • the present application also relates to compounds shown in formula (Ic):
  • X is -O- or -(NH)-; the definitions and preferences of n, R 3 , R 5 , R 6 , R a , R b are the same as those of the compound of formula (I).
  • the present application also relates to compounds shown in formula (IIa):
  • n, R 5 , R 6 , R a , R b are the same as those of the compound of formula (I).
  • the present application also relates to compounds shown in formula (IIb):
  • n, R 5 , R 6 , R a , R b are the same as those of the compound of formula (I).
  • the compound of the present application is selected from the specific compounds shown in the examples of the present application.
  • the compound of the present application can be synthesized by conventional organic synthesis methods according to the specific structure of the compound by those skilled in the art.
  • the compound of formula (I) can be prepared by the method shown in the following synthetic scheme (I) or (II).
  • the compound of formula (I) can be prepared by the method shown in the above synthetic route (I).
  • G in the intermediate Int-2 is selected from halogen, hydroxyl, methanesulfonyl (OMs), p-toluenesulfonyl (OTs) and the like.
  • PG1, PG2, and PG3 are amino protecting groups, such as tetrahydropyran (THP), benzyl (Bn), p-methoxybenzyl (PMB), SEM, Boc, etc.
  • the intermediate Int-3 can be obtained by the Mitsunobu reaction between Int-1 and Int-2.
  • the condensation reaction of intermediate Int-3 with intermediate Int-4 leads to compound Int-5.
  • Int-5 Under oxidative conditions such as but not limited to Swern oxidation or IBX oxidation, Int-5 is converted to intermediate Int-6. After conversion of the protecting group, the intermediate Int-6 can be converted to Int-8.
  • compound Int-7 can be prepared by the method shown in the above synthetic route (II).
  • the condensation reaction of intermediate Int-1 and intermediate Int-4 leads to compound Int-9.
  • Int-9 is converted to intermediate Int-10.
  • the intermediate Int-6 can be converted to Int-11.
  • PG1, PG2, and PG3 are amino protecting groups such as, but not limited to, tetrahydropyran (THP), benzyl (Bn), p-methoxybenzyl (PMB), SEM, Boc, and the like.
  • G in the intermediate Int-2 is selected from halogen, hydroxyl, methanesulfonyl (OMs), p-toluenesulfonyl (OTs) and the like.
  • OMs methanesulfonyl
  • OTs p-toluenesulfonyl
  • G is halogen, OMs, or OTs
  • the SN2 coupling reaction of intermediates Int-11 and Int-2 under basic conditions can generate intermediate Int-7.
  • G is OH the intermediate Int-7 can be obtained by the Mitsunobu reaction between Int-11 and Int-2.
  • the compounds of the present application have been proven to have TRK kinase inhibitory activity, can effectively inhibit TRKA, TRKB and/or TRKC, and are comparable to or better than the inhibitory activity or selectivity of larotrectinib or entrectinib, so they are broad-spectrum.
  • TRK kinase inhibitory activity can effectively inhibit TRKA, TRKB and/or TRKC, and are comparable to or better than the inhibitory activity or selectivity of larotrectinib or entrectinib, so they are broad-spectrum.
  • the present application provides a pharmaceutical composition, which contains the above-mentioned compound of the present application or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or vehicles.
  • compositions of the present application can be prepared in a manner well known in the art of pharmacy and can be administered by a variety of routes depending on whether local or systemic treatment is desired and on the site to be treated. Administration can be topical (including ophthalmic and to the mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal, epidermal and dermal), ophthalmic, oral or parenteral.
  • topical including ophthalmic and to the mucous membranes, including intranasal, vaginal and rectal delivery
  • pulmonary for example, by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal, epidermal and dermal
  • ophthalmic oral or parenteral.
  • Methods for ocular delivery may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic insert surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (eg, intrathecal or intracerebroventricular) administration.
  • Parenteral administration can be in the form of a single bolus dose, or can be by, for example, a continuous infusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • the preparation may be tabletted, placed in a hard gel capsule in powder or granule form, or in troche or lozenge form.
  • Solid carriers may include conventional excipients such as binders, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablets may, if desired, be film coated by conventional techniques.
  • a liquid carrier the preparation may be in the form of a syrup, emulsion, ointment, soft gel capsule, sterile vehicle for injection, aqueous or non-aqueous liquid suspension, or may be presented with water or other suitable liquid before use. Dried product of carrier reconstitution.
  • Liquid formulations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicles (including edible oils), preservatives and flavoring and/or coloring agents.
  • the carrier will usually comprise sterile water, at least in large part, but saline solutions, dextrose solutions, and the like may also be used.
  • Injectable suspensions may also be used, in which case conventional suspending agents may be employed.
  • Conventional preservatives, buffering agents and the like can also be added to parenteral dosage forms.
  • Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing the appropriate amount of active ingredient (ie, a compound of the application).
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable Organic esters (eg, ethyl oleate).
  • compositions may also contain various excipients, for example, preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms can be ensured by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, and the like). Isotonic agents, for example, sugars, sodium chloride, and the like can also be included. Prolonged absorption of the injectable pharmaceutical dosage forms can be brought about by the use of agents delaying absorption (for example, aluminum monostearate and gelatin).
  • agents delaying absorption for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or mixing agents (for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) Moisturizers (eg, glycerol); (d) disintegrants (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solutions Blocking agents (e.g., paraffin); (f) absorption enhancers (e.g., quaternary ammonium compounds); (I) wetting
  • Solid compositions of a similar type can also be employed as fillers in soft-filled and hard-filled gelatin capsules using, for example, lactose as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms eg, tablets, dragees, capsules, pills, and granules
  • coatings and shells eg, enteric coatings and others known in the art. They may contain opacifying agents, they may also release the active compound or combination of active compounds in a certain part of the intestinal tract in a delayed manner.
  • examples of usable embedding compositions are polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs.
  • liquid dosage forms can contain inert diluents (for example, water or other solvents), solubilizers and emulsifiers (for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene, etc.) commonly used in the art.
  • Methanol Benzyl Benzoate, Propylene Glycol, 1,3 Butanediol, Dimethylformamide
  • Oil specifically, Cottonseed Oil, Groundnut Oil, Corn Oil, Olive Oil, Castor Oil, Sesame Oil
  • compositions can also include, for example, wetting agents, emulsifying and suspending agents, perfuming, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Tragacanth or a mixture of these substances, etc.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Tragacanth or a mixture of these substances, etc.
  • Dosage forms for topical administration of a compound of the present application include ointments, powders, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any required preservatives, buffers or propellants.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also included within the scope of this application.
  • the amount of the compound of the present application in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art according to needs, for example, the compound of the present application can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.
  • the application provides the compound of the application or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable Use of a salt, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as described above in the preparation of a medicament for treating a disease or disorder associated with TRK kinase or NTRK gene.
  • the application also provides a method for treating a disease or disorder associated with TRK kinase or NTRK gene, the method comprising administering a therapeutically effective amount of the compound of the application or its isotope-labeled compound or its optical isomer to a patient in need thereof isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as described above.
  • the patient is preferably a mammal, more preferably a human patient.
  • the route of administration can be oral, external (including but not limited to external application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical, and intravenous) administration, bronchial administration, or nasal administration.
  • the diseases or diseases related to TRK kinase or NTRK gene are caused by TRK kinase activity disorder and/or related to NTRK gene fusion, such as but not limited to: cancer, pain, inflammation, neurodegenerative diseases and cell proliferation disease.
  • TRK kinase activity disorder and/or related to NTRK gene fusion such as but not limited to: cancer, pain, inflammation, neurodegenerative diseases and cell proliferation disease.
  • the compound of the present application can be used, for example, to inhibit the proliferation and metastasis of cancer cells, to relieve pain, to reduce inflammation, to treat or alleviate neurodegenerative diseases, and the like.
  • the disease or disorder associated with a TRK kinase or NTRK gene is cancer.
  • Exemplary cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer (e.g., larynx, hypopharynx, nasopharynx, oropharynx , lip, and oral cavity), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung cancer, small cell carcinoma, and non-small cell carcinoma, Bronchial cancer, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (such as exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancer (eg, squamous cell carcinoma, Kaposi's s
  • Additional exemplary cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin or non-Hodgkin lymphoma, myeloproliferative neoplasms (eg, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Wadenstrom's macroglobulinemia, hair Cellular lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt lymphoma.
  • leukemia or lymphoma multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute
  • Additional exemplary cancers include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.
  • the disease or disease associated with TRK kinase or NTRK gene is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, membrane Adenocarcinoma, pancreatic cancer, esophageal cancer, gastric cancer, lymphoma, leukemia, nasopharyngeal cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.
  • the diseases or diseases related to TRK kinase or NTRK gene are solid tumors, such as melanoma, breast tumor, and neuroblastoma, glioblastoma, Ewing sarcoma, retina Blastoma, etc.
  • the disease or disorder associated with TRK kinase or NTRK gene is a cell proliferation disease, such as, but not limited to, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis , atherosclerosis and diseases associated with vascular smooth cell proliferation and neointimal formation, such as restenosis after angioplasty or surgery, pulmonary fibrosis, arthritis, glomerulonephritis, retinopathy (including diabetes and neonatal retinopathy and age-related macular degeneration), graft vascular disease (such as may occur after blood vessel or organ transplantation), acromegaly and conditions secondary to acromegaly, etc.
  • a cell proliferation disease such as, but not limited to, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis , atherosclerosis and diseases associated with vascular smooth cell proliferation and n
  • the disease or disease associated with TRK kinase or NTRK gene is inflammation, including but not limited to: (1) degenerative inflammation; (2) exudative inflammation (serous inflammation, fibrinous inflammation) , suppurative inflammation, hemorrhagic inflammation, necrotic inflammation, catarrhal inflammation); (3) proliferative inflammation; (4) specific inflammation (tuberculosis, syphilis, leprosy, lymphogranuloma, etc.).
  • the disease or condition associated with TRK kinase or NTRK gene is pain, including but not limited to inflammatory pain, arthritis pain, complex regional pain syndrome, low back pain, musculoskeletal pain, Neuropathic pain, chronic pain, cancer-related pain, acute pain, postoperative pain, etc.
  • the disease or disorder associated with TRK kinase or NTRK gene is a neurodegenerative disease, including but not limited to Alzheimer's disease and Parkinson's disease.
  • the "therapeutically effective dose” of the compound of the present application for treating the above diseases can be reasonably determined by experienced physicians or researchers according to the patient's condition, physical condition, disease severity, administration route and other factors.
  • Synthetic intermediate 1-12 tert-butyl 3-azido-4-((methylsulfonyl)oxy)pyrrolidinyl-1-carboxylate
  • Synthetic compound 1 N-(1-(1-(3,5-difluorophenyl)ethyl)-3-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole- 2-yl)-1H-indazol-5-amine
  • Dissolve intermediate 1-7 (10.0 mg, 0.05 mmol) in 2 ml of methanol, add 1 ml of concentrated hydrochloric acid, react at 50 ° C for 5 hours, concentrate, dissolve in 5 ml of methanol, add 0.5 ml of ammonia water, concentrate, prepare a plate for purification, and obtain the final
  • the product was 2.1mg, and the yield was 38.3%.
  • Synthetic compound 2 N-(3,5-difluorobenzyl)-3-(5-(piperidin-4-ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4- d] imidazol-2-yl)-1H-indazol-5-amine
  • the concentrate was dissolved in 4ml of methanol, 2ml of concentrated hydrochloric acid was added, reacted at 50°C for 3 hours, concentrated, dissolved in 5ml of methanol, added with 0.5ml of ammonia water, concentrated, purified on a preparative plate, and 5.6mg of the final product was obtained with a yield of 24.6%.
  • Synthetic compound 4 5-(1-(3,5-difluorophenyl)ethoxy)3-(5-(1-methylpiperidin-4-yl)-1,4,5,6-tetra Hydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole
  • the purified product was dissolved in 2ml of methanol, 1ml of concentrated hydrochloric acid was added, reacted at 50°C for 5 hours, concentrated, dissolved in 5ml of methanol, added with 0.5ml of ammonia water, concentrated, purified on a preparative plate, and 1.9mg of the final product was obtained.
  • the total yield is 15.8%.
  • Synthetic compound 5 2-(5-(1-(3,5-difluorophenyl)ethoxy)-1H-indazol-3-yl)-N,N-dimethyl-4,6-di Hydropyrrolo[3,4-d]imidazole-5(1H)carboxamide
  • Synthetic compound 6 2-(dimethylamino)ethyl 2-(5-(1-(3,5-difluorophenyl)ethoxy)-1H-indazol-3-yl)-4,6 -Dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate
  • intermediate 4-7 (30.0mg, 0.05mmol), HATU (29.1mg, 0.10mmol), N,N-diisopropylethylamine (13.2mg, 0.10mmol) and 1-methyl Piperidine-4-carboxylic acid (14.0mg, 0.10mmol) was dissolved in 20ml DCM, stirred for 2h. Water was added to quench the reaction. It was extracted twice with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • the obtained product was dissolved in 2ml of methanol and 1ml of concentrated hydrochloric acid, reacted at 50°C for 2 hours, concentrated, dissolved in 3ml of methanol, added 1ml of ammonia water, concentrated, and purified by preparative plate to obtain 8mg of the final product, with a yield of 43.7%.
  • reaction solution was cooled to room temperature, triethylamine (419 mg, 4.14 mmol) and acetic anhydride (211 mg, 2.07 mmol) were added to the reaction solution, and the reaction was carried out at 80°C for 16 hours.
  • Triethylamine 419 mg, 4.14 mmol
  • acetic anhydride 211 mg, 2.07 mmol
  • Add water to the reaction solution extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify on a silica gel column to obtain 145 mg of intermediate 8-1 with a yield of 73.1%.
  • Synthetic intermediate 8-2 5-(1-(3,5-difluorophenyl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3- Urethane
  • Synthetic intermediate 8-3 tert-butyl 3-(5-(1-(3,5-difluorophenyl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazole-3-carboximido)-4,4-diethoxypiperidine-1-carboxylate
  • Synthetic intermediate 8-4 2-(5-(1-(3,5-difluorophenyl)ethoxy)-1H-indazol-3-yl)-4,5,6,7-tetrahydro -3H-Imidazol[4,5-c]pyridine
  • Synthetic compound 8 2-(5-(1-(3,5-difluorophenyl)ethoxy)-1H-indazol-3-yl)-5-(1-methylpiperidin-4-yl )-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine
  • Dissolve intermediate 8-4 (15.0mg, 0.04mmol) in 5ml NMP, add 0.1ml acetic acid to the solution, stir at 55°C for 10 minutes, cool to room temperature, add 1-methylpiperidin-4-one (4.3 mg, 0.04mmol), react at room temperature for 16 hours, add sodium triacetoxyborohydride (16.0mg, 0.08mmol) and react at room temperature for 2 hours, add 0.5ml ammonia water to adjust the pH, add water to the mixture, and extract twice with ethyl acetate , the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by a preparative plate to obtain 4.2 mg of the final product, with a yield of 22.5%.
  • Synthetic compound 9-8 5-((tert-butyldimethylsilyl)oxy)-3-(5-(((1-methylpiperidin-4-yl)methyl)-1-( (2-(Trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole
  • Synthetic compound 9-9 3-(5-((1-methylpiperidin-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1,4,5,6-Tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol
  • the obtained product was dissolved in 2ml of methanol and 1ml of concentrated hydrochloric acid, reacted at 50°C for 2 hours, concentrated, dissolved in 3ml of methanol, added with 1ml of ammonia water, concentrated, and purified on a preparative plate to obtain 2.2mg of the final product, yield 17%.
  • Synthetic intermediate 11-1 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl Base)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • Example 12 The compound of Example 12 was prepared according to the synthetic route of Example 11 using suitable starting materials, as follows.
  • Embodiment 13 and embodiment 14 are identical to Embodiment 13 and embodiment 14:
  • Embodiment 15 to embodiment 28 are identical to Embodiment 15 to embodiment 28:
  • Example 15 to Example 28 were prepared according to the synthesis route of Example 4 using suitable starting materials, as follows.
  • Example 29 The compound of Example 29 was prepared according to the synthesis route of Example 5 using suitable starting materials, as follows.
  • Embodiment 30 and embodiment 31 are identical to Embodiment 30 and embodiment 31:
  • Example 32 was prepared according to the synthetic route of Example 9 using suitable starting materials, as follows.
  • the compound of Example 33 was prepared according to the synthetic route of Example 10 using suitable starting materials, as follows.
  • Embodiment 34 to embodiment 46 are identical to Embodiment 34 to embodiment 46:
  • Example 34 to Example 46 were prepared according to the synthetic route of Example 4 using suitable starting materials, as follows.
  • Embodiment 47 to embodiment 48 are identical to Embodiment 47 to embodiment 48:
  • Example 47 to Example 48 were prepared according to the synthetic route of Example 9 using suitable starting materials, as follows.
  • Positive control IC 50 is within 3 times of previous average
  • the tested compounds of each example showed similar or better inhibitory activity to LOXO-101 for TRKA, TRKB, TRKC kinases.

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Abstract

本申请涉及TRK激酶抑制剂化合物及其用途。具体地，本申请公开了如式(I)所示的化合物、或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物。本申请还涉及所述化合物在医学方面的应用。

Description

TRK激酶抑制剂化合物及其用途 技术领域
本申请提供了一类具有药学活性的新颖化合物，所述化合物可用于抑制TRK激酶活性。本申请还涉及包含所述化合物的组合物，以及所述化合物和所述组合物在制备用于治疗与TRK激酶或NTRK基因相关的疾病或病症的药物中的用途。
背景技术
蛋白激酶(Protein Kinase，PK)为细胞生长、增殖和存活的关键调节因子，蛋白激酶的功能失常是许多疾病的标志。与人类癌症有关的致癌基因和原癌基因有一大部分编码PK。作为蛋白激酶的一种，TRK激酶(Tropomyosin receptor kinase，原肌球蛋白受体激酶)近年来引起人研究人员的注意。
TRK激酶属于隶属于受体酪氨酸激酶家族。Trk家族主要包括3个成员TRKA、TRKB和TRKC，其分别由神经营养受体酪氨酸激酶(Neurotrophic receptor tyrosine kinase，NTRK)基因：NTRK1基因、NTRK2基因、NTRK3基因编码。以往的研究证实，作为神经生长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养因子4/5(NT-4/5)、以及神经营养因子3(NT-3)受体的这些TRK激酶可以调节神经元细胞的信号维持、神经元细胞的信号传导、细胞的增殖、分化、代谢、甚至凋亡。TRK激酶在人类恶性肿瘤中通过多种机制被组成性激活。最公认的机制是NTRK基因融合，其中3′NTRK基因区域在染色体内或染色体间重排，然后与5′融合伙伴基因的序列，导致肿瘤发生的高风险。TRK激酶的活化或失调、以及NTRK基因融合已经被证实与多种肿瘤或癌症的发生、发展和恶化密切相关；对于具有NTRK融合基因表达的患者，TRK是肿瘤治疗的重要靶点。因此，小分子TRK激酶抑制剂被认为是一种很有潜力的广谱抗 癌药物。此外，已经证明TRK抑制剂在临床前疼痛动物模型和临床前炎症动物模型是有效的。
拉罗替尼(Larotrectinib)，又称LOXO-101或Vitrakvi，是首个被批准上市的TRK抑制剂抗癌药物。其在一些癌症的治疗中已经显示出明显疗效，但是其价格极其昂贵，且长期服用后有难以克服的抗药性问题。第二个被批准上市的TRK抑制剂药物是恩曲替尼(Entrectinib)，又称Rozlytrek，同样显示了良好的广谱抗癌活性。
拉罗替尼和恩曲替尼的成功使研究人员认识到了TRK抑制剂在癌症治疗中重要性和前景。但是，目前仍存在对于其他替代TRK抑制剂的迫切需求。
发明内容
在第一个方面，本申请提供了作为TRK激酶抑制剂的式(I)的化合物，
Figure PCTCN2022100186-appb-000001
或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中：
R 1、R 2各自独立地选自H、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和卤素；
R 3选自H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
R 6的个数为1、2或3个，且每个R 6各自独立地选自H、卤素、-CN、-OH、-NO 2、-NR 7R 8、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
X为连接键、O、S或(NR 4)，其中R 4选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
R 7和R 8各自独立地选自：H、C 1-6烷基、C 1-4卤代烷基、C 1-4烷氧基，或者R 7、R 8以及与它们相连的N原子共同形成3-6元环；
n＝1、2或3；
L为(C＝O)、(O＝S＝O)、CR aR b或连接键，其中R a和R b各自独立地选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基，或者R a、R b以及与它们相连的碳原子共同形成3-6元环；
R 5选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3- 7脂环基、3-10元杂脂环基、C 6-12双环脂环基、6-12元双环杂脂环基、C 8-15元三环脂环基、8-15元三环杂脂环基、C 5-8芳基、5-10元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)、-C 1-4烷基-(5-10元杂芳基)、-N(R 10)(R 11)、-N(R 10)(C(＝O)R 11)、-N(R 10)(C(＝O)-OR 11)、-N(R 12)(C(＝O)-N(R 10)(R 11))、-C(＝O)-N(R 10)(R 11)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 10)(S(＝O) 2R 11)、-S(＝O) 2-N(R 10)(R 11)、-SR 12和-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3-7脂环基、3-10元杂脂环基、C 6-12双环脂环基、6-12元双环杂脂环基，C 8-15元三环脂环基、8-15元三环杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1- 4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R 5a取代，且R 5a 独立选自卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3- 7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、-N(R 13)(R 14)、-N(R 13)(C(＝O)R 14)、-N(R 13)(C(＝O)-OR 14)、-N(R 15)(C(＝O)-N(R 13)(R 14))、-C(＝O)-N(R 13)(R 14)、-C(＝O)-R 15、-C(＝O)-OR 15、-OC(＝O)R 15、-N(R 13)(S(＝O) 2R 14)、-S(＝O) 2-N(R 13)(R 14)、-SR 15和-OR 15；
且R 10、R 11、R 12、R 13、R 14、和R 15各自在每次出现时独立地选自：H、C 1-6烷基、C 1-6卤代烷基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1- 4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、-NO 2、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、C 1- 4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；或者R 10、R 11以及与它们相连的原子共同形成3-14元环；或者R 13、R 14以及与它们相连的原子共同形成3-14元环。
除非另有指明，本文所述的“式(I)所示的化合物”、“式(I)的化合物”或“本申请的化合物”或类似术语也涵盖其任意光学异构体、几何异构体、互变异构体或异构体的混合物。
术语“光学异构体”意指，当化合物具有一个或更多个手性中心时，每个手性中心可以存在R构型或S构型，由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如，通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指，当化合物中存在双键时，该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解：互变异构体之间可以互相转变，在在某一状态下可能会达到一种平衡状态而共存。
除非另有指明，本文所述的“式(I)所示的化合物”、“式(I)的化合物”或“本申请的化合物”等术语也涵盖该化合物中一个或者多个原子被其同位素原子代替而得到的同位素标记化合物。
适用于包含在本申请的化合物中的同位素的实例包括氢的同位素，诸如 2H(D)和 3H(T)；碳的同位素，诸如 11C、 13C和 14C；氯的同位素，诸如 36Cl；氟的同位素，诸如 18F；碘的同位素，诸如 123I和 125I；氮的同位素，诸如 13N和 15N；氧的同位素，诸如 15O、 17O和 18O；以及硫的同位素，诸如 35S。
所述同位素标记化合物(例如包含放射性同位素的那些)可用于药物和/或底物组织分布研究。考虑到引入的容易性和检测手段的方便性，放射性同位素氘(即D)和碳-14(即 14C)对于该目的是特别有用的。
利用诸如氘(即D)的较重同位素进行取代可以提供某些治疗方面的益处并且因此在某些情况下可以是优选的，所述治疗方面的益处例如是由更大的代谢作用稳定性(例如，增长的体内半衰期或者减小的剂量要求)带来的。因此，在一些实施方式中，本申请的化合物是同位素标记化合物，其中H在每次出现时任选地被D取代。
利用正电子放射同位素(诸如 11C、 18F、 15O和 13N)进行取代可以用于正电子放射受体图像(Positron Emission Topography(PET))研究，用于检测底物受体占用状态。
所述同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂来进行制备。
本申请的化合物可以以其药学上可接受的盐的形式存在。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
所述药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于：乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于：铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。关于合适的盐的综述，参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahl and Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
此外，本申请化合物可以以非溶剂化形式以及与药学上可接受的溶剂如水、乙醇等的溶剂化形式存在。化合物也可以以一种或多种结晶状态存在，即多晶型，或者它们可以作为无定形固体存在。所有这些形式都包含在本申请的范围内。
本申请还包括本申请的化合物的前药。术语“前药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本申请化合物的衍生物。因此，本申请化合物的某些衍生物本身可能具有很少或没有药理学活性，当给药至体内或身体上时，可以转化成具有所需活性的本申请化合物。
本申请还包括本申请的化合物的代谢物。术语“代谢物”是指在细胞或有机体优选人中源自本申请任意化合物的所有分子。
在本文中使用时，术语“被取代”是指基团中的一个或多个(优选1至5个，更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时，术语“独立地”是指当取代基的个数超过一个时，这些取代基可以相同也可以不同。
在本文中使用时，术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如，一个基团“任选地被取代”表示：该基团可以是未被取代的，也可以是被取代的。
术语“卤素”或“卤”是指-F,-Cl,-Br,或-I。
在本文中使用时，术语“烷基”是指饱和的脂族烃，包括直链及支链。在一些实施方式中，烷基基团具有1-8个、或1-6个、或1-4个、或1-3个碳原子。例如，术语“C 1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C 1-8烷基”在其定义中包括术语“C 1-6烷基”、“C 1-3烷基”和“C 1- 4烷基”等。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“烯基”是指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链及支链。在一些实施方式中，烯基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C 2-8烯基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳双键)。所述双键可以是或者可以不是另一基团的连接点。烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-2-丙烯基、丁烯基、戊烯基、3-己烯基等。烯基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。当式(I)的化合物含有烯基基团时，该烯基基团可以纯E形式、纯Z形式、或其任何混合物存在。
在本文中使用时，术语“炔基”是指具有至少一个碳-碳三键的脂族烃， 包括具有至少一个碳-碳三键的直链及支链。在一些实施方式中，炔基基团具有2-8个碳原子、2-6个碳原子、3-6个碳原子、或2-4个碳原子。例如，术语“C 2-8炔基”是指具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳三键)。所述三键可以是或者可以不是另一基团的连接点。炔基包括但不限于乙炔基、1-丙炔基、2-丙炔基、2-甲基-2-丙炔基、丁炔基、戊炔基、3-己炔基等。炔基基团可任选地被一或多个(例如，1至5个)适当的取代基所取代。
在本文中使用时，术语“C 3-8脂环基”是指具有3-8个形成环的碳原子的脂环基。术语“C 3-7脂环基”是指具有3-7个形成环的碳原子的脂环基。术语“C 3-6脂环基”是指具有3-6个形成环的碳原子的脂环基。所述脂环基可以是单环环。脂环基的定义还包括不饱和的非芳族脂环基。脂环基的实例为，例如环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环辛基、环己二烯基、环戊烯基、环庚烯基和环辛烯基。脂环基可任选地被一或多个适当的取代基所取代。
本文中使用时，术语“C 6-12双环脂环基”是具有6-12个形成环的碳原子的含有两个环的脂环基。双环脂环基可稠合，也可包括桥连双环脂环基系统。
本文中使用时，术语“C 8-15元三环脂环基”是具有8-15个形成环的碳原子的含有三个环的脂环基。三环脂环基可稠合，也可桥连。
在本文中使用时，术语“n元杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的脂环基，所述杂原子选自O、S及N。例如，术语“4-8元杂脂环基”是指杂脂环基取代基含有总共4至8个环原子，其中至少一个是杂原子；术语“4-6元杂脂环基”是指杂脂环基取代基含有总共4至6个环原子，其中至少一个是杂原子；术语“3-10元杂脂环基”是指杂脂环基取代基含有总共3至10个环原子，其中至少一个是杂原子。术语“n元双环杂脂环基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的双环杂脂环基，所述杂原子选自O、S及N。杂脂环基的实例包括，但不限于，氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢 噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基(chromanyl)、异苯并二氢吡喃基(isochromanyl)、二氢苯并二噁英基(dihydrobenzodioxinyl)、苯并二氧杂环戊烯基(benzodioxolyl)、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基(isochromyl)、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酰基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基等。杂脂环基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“C 5-8芳基”是指具有含5-8个碳原子的芳环的芳基，例如苯基。
在本文中使用时，术语“n元杂芳基”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基，所述杂原子选自O、S及N。例如，5-7元杂芳基包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基。杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“C 7-11双环芳基”是指具有7-11个碳原子的双环芳基，例如萘基、茚基等。双环芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“n元双环杂芳基”是指具有m个形成芳族双环的碳原子和(n-m)个形成芳族双环的杂原子的双环杂芳基，所述杂原子选自O、S及N。例如，7-11元双环杂芳基包括但不限于喹啉基、异喹啉基、吲哚基、嘌呤基、苯并噻唑基等。双环杂芳基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“11-15元三环基”包括但不限于吖啶基等。11-15元三环基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“卤代烷基”是指具有一或多个卤素取代基的 烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。例如，术语“C 1-6卤代烷基”是指具有一或多个卤素取代基的C 1-6烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。另举一例，术语“C 1-4卤代烷基”是指具有一或多个卤素取代基的C 1-4烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；术语“C 1-3卤代烷基”是指具有一或多个卤素取代基的C 1-3烷基基团(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)；且术语“C 1-2卤代烷基”是指具有一或多个卤素取代基的C 1-2烷基基团(即，甲基或乙基)(至多全卤代烷基，即，烷基基团的每个氢原子均被卤素原子所取代)。再另举一例，术语“C 1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括：CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl等。
在本文中使用时，术语“烷氧基”是指单键连接至氧原子的烷基。烷氧基与分子的连接点是通过氧原子。烷氧基可被描述为烷基-O-。术语“C 1-6烷氧基”是指包含1-6个碳原子的直链或支链的烷氧基。术语“C 1-6烷氧基”在其定义中包括术语“C 1-3烷氧基”。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、己氧基等。烷氧基可任选地被一或多个适当的取代基所取代。
在本文中使用时，术语“3-14元环”是指具有3-14个成环原子的饱和或不饱和环体系。类似地，术语“3-6元环”是指具有3-6个成环原子的饱和或不饱和环体系，术语“3-8元环”是指具有3-8个成环原子的饱和或不饱和环体系。
本文中，与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举，而范围仅是作为一种简化的表示法。例如：“4-6元”表示4、5或6元；“5-7元”表示5、6或7元；“7-11元”表示7、8、9、10或11元；“4-8元”表示4、5、6、7或8元；“3-10元”表示3、4、5、6、7、8、9或10元；“3-14元”表示3、4、5、6、7、8、9、10、11、12、13或14元；“C 1-3”表示1个(C 1)、2个(C 2)或3个碳原子(C 3)；“C 1-4”表示1个(C 1)、2个(C 2)、3个碳原子(C 3)或4个碳原子(C 4)； “C 3-6”表示3个(C 3)、4个(C 4)、5个(C 5)或6个碳原子(C 6)；“C 3- 8”表示3个(C 3)、4个(C 4)、5个(C 5)、6个(C 6)、7个(C 7)或8个碳原子(C 8)；“C 5-7”表示5个(C 5)、6个(C 6)或7个碳原子(C 7)；“C 7-11”表示7个(C 7)、8个(C 8)、9个(C 9)、10个(C 10)或11个碳原子(C 11)。因此，与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围，且每一个子范围也视为被本文公开。
在如上所述的式(I)中，R 1选自H、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和卤素。
在一些实施方式中，R 1为H。
在一些实施方式中，R 1为卤素，例如R 1选自F、Cl、Br、I。
在一些实施方式中，R 1为C 1-4烷基或C 1-4卤代烷基，例如任选地被任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基、正丁基、异丁基。
在一些实施方式中，R 1为C 1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基。
在一些实施方式中，R 1为CN。
应当理解，任何上述R 1的实施方式可以与如上文和下文所述的任何R 2、R 3、R 5、R 6、X、L和n的实施方式以任意方式组合在一起。
在如上所述的式(I)中，R 2选自H、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和卤素。
在一些实施方式中，R 2为H。
在一些实施方式中，R 2为卤素，例如R 2选自F、Cl、Br、I。
在一些实施方式中，R 2为C 1-4烷基或C 1-4卤代烷基，例如任选地被任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基、正丁基、异丁基。
在一些实施方式中，R 2为C 1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基。
在一些实施方式中，R 2为CN。
应当理解，任何上述R 2的实施方式可以与如上文和下文所述的任何R 1、R 3、R 5、R 6、X、L和n的实施方式以任意方式组合在一起。
在一些实施方式中，R 1和R 2可以是相同的。例如，R 1和R 2均为卤素，例如Cl或F；再例如，R 1和R 2均为H。在一个优选的实施方式中，R 1和R 2均为F。在一个优选的实施方式中，R 1和R 2均为H。
在另一些实施方式中，R 1和R 2可以是不同的。
在如上所述的式(I)中，R 3选自H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基。
在一些实施方式中，R 3为H。
在一些实施方式中，R 3为C 1-3烷基或C 1-3卤代烷基，例如，R 3选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中，R 3为C 1-3烷氧基，例如，R 3选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中，R 3为C 3-6脂环基，例如，R 3选自环丙基、环丁基、环戊基、环己基、环己烯基、环己二烯基、环戊烯基等。
在一些实施方式中，R 3为4-6元杂脂环基，杂原子可以选自O、S及N。例如，R 3选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中，R 3为甲基。
应当理解，任何上述R 3的实施方式可以与如上文和下文所述的任何R 1、R 2、R 5、R 6、X、L和n的实施方式以任意方式组合在一起。
在如上所述的式(I)中，R 6的个数可以为1、2或3个，其中每个R 6各自独立地选自H、卤素、-CN、-OH、-NO 2、-NR 7R 8、C 1-4烷基、C 1-4卤 代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基(杂原子可以选自O、S及N)，其中R 7和R 8各自独立地选自：H、C 1-6烷基、C 1-4卤代烷基、C 1- 4烷氧基；或者R 7、R 8以及与它们相连的N原子共同形成3-6元环，例如此时R 7、R 8均为(CH 2) n(n＝1、2、3、4、5等)或R 7、R 8以及与它们相连的N原子共同构成5元或6元含N芳香环。
在一些优选的实施方式中，R 6为H。
在一些实施方式中，R 6为卤素，例如R 6选自F、Cl、Br、I。
在一些实施方式中，R 6为-CN、-OH或-NO 2。
在一些实施方式中，R 6为C 1-3烷基或C 1-3卤代烷基，例如R 6选自任选地被一个或多个卤素原子(例如氟、氯、溴、碘)取代的甲基、乙基、丙基、异丙基。
在一些实施方式中，R 6为C 1-3烷氧基，例如R 6选自甲氧基、乙氧基、丙氧基、异丙氧基。
在一些实施方式中，R 6为C 3-6脂环基，例如R 6选自环丙基、环丁基、环戊基、环己基、环己烯基。
在一些实施方式中，R 6为4-6元杂脂环基(杂原子可以选自O、S及N)，例如R 6选自氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基。
在一些实施方式中，R 6为-NR 7R 8，其中R 7和R 8各自独立地选自：H、C 1-3烷基(例如甲基、乙基、丙基、异丙基等)、C 1-3卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基)、C 1-3烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基)；或者R 7、R 8以及与它们相连的N原子共同形成3-6元环，例如此时R 7、R 8均为(CH 2) n(n＝1、2、3、4、5等)或R 7、R 8以及与它们相连的N原子共同构成5元或6元含N芳香环，例如形成为吡咯、吡啶、嘧啶、咪唑、吡唑、吡咯烷、六氢吡啶等。
在一些实施方式中，R 6为二甲氨基、二乙氨基、甲基乙基氨基。
在一些优选的实施方式中，R 6为1个。
应当理解，任何上述R 6的实施方式可以与如上文和下文所述的任何R 1、R 2、R 3、R 5、X、L和n的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，X为连接键、O、S或(NR 4)，其中R 4选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基(杂原子可以选自O、S及N)。
在一些实施方式中，X为连接键(即X不存在，此时X两侧的化学基团直接相连)。
在一些实施方式中，X为-O-。
在一些实施方式中，X为-S-。
在一些实施方式中，X为亚氨基，即-(NH)-。
在一些实施方式中，X为-(N(CH 3))-。
在一些优选实施方式中，X选自连接键、-O-和-(NH)-。
应当理解，任何上述X的实施方式可以与如上文和下文所述的任何R 1、R 2、R 3、R 5、R 6、L和n的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，n为1、2或3。
在一些实施方式中，n为1。
在一些实施方式中，n为2。
在一些实施方式中，n为3。
应当理解，任何上述n的实施方式可以与如上文和下文所述的任何R 1、R 2、R 3、R 5、R 6、L和X的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，L为(C＝O)、(O＝S＝O)、CR aR b或连接键，其中R a和R b各自独立地选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3- 6脂环基和4-6元杂脂环基(杂原子可以选自O、S及N)，或者R a、R b以及与它们相连的碳原子共同形成3-6元环，例如此时R a、R b均为(CH 2) n(n＝1、2、3、4、5等)从而形成3-6元饱和脂环或R a、R b以及与它们相连的C原子共同构成3-6元不饱和脂环或6元芳香环。
在一些实施方式中，L为-(C＝O)-。
在一些实施方式中，L为-(O＝S＝O)-。
在一些实施方式中，L为连接键(即L不存在，此时R 5与N直接相连)。
在一些实施方式中，L为-(CR aR b)-，其中R a和R b各自独立地选自：H、C 1-4烷基(例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等)、C 1-4卤代烷基(例如被被一个或多个选自氟、氯、溴、碘的卤原子取代的甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等)、C 1-4烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等)、C 3-6脂环基(例如环丙基、环丁基、环戊基、环己基、环己烯基、环己二烯基、环戊烯基等)和4-6元杂脂环基(例如氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、哌嗪基等)，或者R a、R b以及与它们相连的碳原子共同形成3-6元环(优选3-6元脂环族环)。例如，L可以为-CH 2-、-C(CH 3) 2-、-CH(CH 3)-、亚环丙基、亚环丁基、亚环戊基、亚环己基、亚苯基等等。
应当理解，任何上述L的实施方式可以与如上文和下文所述的任何R 1、R 2、R 3、R 5、R 6、n和X的的实施方式以任意方式组合在一起。
在如上所述的式(I)中，R 5可以是有机化学中常见的任何取代基，其并不特别受限。
在一些实施方式中，R 5为C 1-6烷基，例如R 5选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基。
在一些实施方式中，R 5为C 3-7脂环基，例如R 5选自环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环己二烯基、环戊烯基、环庚烯基。
在一些实施方式中，R 5为3-10元杂脂环基，例如R 5选自氮杂环丁烷基、硫杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、 四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻喃基、四氢噻嗪基、四氢噻二嗪基、四氢噁唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、苯并二氢吡喃基、异苯并二氢吡喃基、二氢苯并二噁英基、苯并二氧杂环戊烯基、苯并噁嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基、二氢-1H-异吲哚基、氧杂环庚烷基、硫杂环庚烷基、氮杂环庚烷基。
在一些实施方式中，R 5为H、卤素、-OH、-NO 2、-CN、-SF 5或-SH。
在一些实施方式中，R 5选自-S-C 1-4烷基、C 1-6烷基、C 1-6卤代烷基、C 1- 6烷氧基、C 1-6卤代烷氧基、C 2-8烯基、C 2-8炔基。
在一些实施方式中，R 5选自C 5-8芳基(例如苯基)、5-10元杂芳基(例如呋喃基、噻吩基、吡咯基、噻唑基、吡唑基、咪唑基、吡啶基、吡喃基、哒嗪基、嘧啶基、吡嗪基等)、-C 1-4烷基-(C 5-8芳基)、-C 1-4烷基-(5-10元杂芳基)。
在一些实施方式中，R 5选自-N(R 10)(R 11)、-N(R 10)(C(＝O)R 11)、-N(R 10)(C(＝O)-OR 11)、-N(R 12)(C(＝O)-N(R 10)(R 11))、-C(＝O)-N(R 10)(R 11)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 10)(S(＝O) 2R 11)、-S(＝O) 2-N(R 10)(R 11)、-SR 12和-OR 12，其中R 10、R 11、R 12各自在每次出现时独立地选自：H、C 1-6烷基、C 1-6卤代烷基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、-NO 2、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O- C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；或者R 10、R 11以及与它们相连的原子共同形成3-14元环(例如，R 10、R 11均为(CH 2) n(n＝1、2、3、4、5、6、7、8等)或R 10、R 11以及与它们相连的原子共同构成5至14元芳香环)。
上述对于R 5列举的任意示例基团都应被理解为是任选地被取代的；即在适当的时候，上述对于R 5给出的任意基团可以任选地被0、1、2、3或4个R 5a取代，且R 5a独立选自卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、-N(R 13)(R 14)、-N(R 13)(C(＝O)R 14)、-N(R 13)(C(＝O)-OR 14)、-N(R 15)(C(＝O)-N(R 13)(R 14))、-C(＝O)-N(R 13)(R 14)、-C(＝O)-R 15、-C(＝O)-OR 15、-OC(＝O)R 15、-N(R 13)(S(＝O) 2R 14)、-S(＝O) 2-N(R 13)(R 14)、-SR 15和-OR 15，其中R 13、R 14、和R 15各自在每次出现时独立地选自：H、C 1-6烷基、C 1-6卤代烷基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、-NO 2、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、C 1-4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；或者R 13、R 14以及与它们相连的原子共同形成3-14元环(例如，R 13、R 14均为(CH 2) n(n＝1、2、3、4、5、6、7、8等)或R 13、R 14以及与它们相连的原子共同构成5至14元芳香环)。
在一些优选的实施方式中，R 5选自甲基、乙基、丙基、异丙基、环丁基基团。所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1 或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基，所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。例如，在一些优选的实施方式中，R 5选自(1-羟基环丙基)乙基、3-羟基环丁基、2-氰基乙基、2-羟乙基、2-氰基-1-环戊基乙基、1-氰基丙烷、2-吗啉代乙基、乙基和(1-甲基哌啶-4-基)甲基。
在一些优选的实施方式中，R 5选自卤素，例如F。
在一些优选的实施方式中，R 5选自哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基，所述哌嗪基、吗啉基、吡咯烷基、哌啶基和氮杂环丁烷基可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。在一些优选的实施方式中，R 5选自甲基、乙基、丙基、异丙基、环丁基基团，所述甲基、乙基、丙基、异丙基或环丁基基团可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH、吗啉基、哌啶基，所述取代基又可以任选地被0、1或2个各自独立选自以下群组的取代基所取代：甲基、乙基、环戊基、环丙基、-CN、-OH。
在一些优选的实施方式中，R 5选自哌嗪基、吗啉基、吡咯烷基、哌啶基、氮杂环丁烷基。例如，在一些优选的实施方式中，R 5选自3,5-二甲基哌嗪基、吗啉基、3-羟基吡咯烷基、4-甲基哌嗪基、4-乙基哌嗪基、4-羟基哌啶基、1-甲基哌啶基、1-乙基哌啶-4-基、1-甲基氮杂环丁烷-3-基。
在一些优选的实施方式中，R 5选自H、甲基、乙基、正丙基、异丙基、丁基、甲氧基、乙氧基、羟基、环丙基、环丁基、环戊基、环己基、吗啉代甲基、羟基环丁基、羟基环己基、氰基乙氧基、氰基甲基、吡啶-3-基、1-甲基-1H-吡唑-4-基、1-甲基-1H-吡唑-3-基、4-甲基哌嗪-1-基、1-甲基哌啶-4-基、吗啉基、吡咯烷-3-基、3-羟基吡咯烷-1-基、3-氰基吡咯烷-1-基。
应当理解，任何上述R 5的实施方式可以与如上文和下文所述的任何R 1、R 2、R 3、R 6、X、L和n的实施方式以任意方式组合在一起。
在一些优选的实施方式中，本申请还涉及式(Ia)所示的化合物：
Figure PCTCN2022100186-appb-000002
其中，X为-O-或-(NH)-；L、n、R 3、R 5、R 6的定义以及优选项与式(I)化合物相同。
在一些优选的实施方式中，本申请还涉及式(Ib)所示的化合物：
Figure PCTCN2022100186-appb-000003
其中，L、n、R 5、R 6的定义以及优选项与式(I)化合物相同。
在一些优选的实施方式中，本申请还涉及式(Ic)所示的化合物：
Figure PCTCN2022100186-appb-000004
其中，X为-O-或-(NH)-；n、R 3、R 5、R 6、R a、R b的定义以及优选项与式(I)化合物相同。
在一些优选的实施方式中，本申请还涉及式(IIa)所示的化合物：
Figure PCTCN2022100186-appb-000005
其中，n、R 5、R 6、R a、R b的定义以及优选项与式(I)化合物相同。
在一些优选的实施方式中，本申请还涉及式(IIb)所示的化合物：
Figure PCTCN2022100186-appb-000006
其中，n、R 5、R 6、R a、R b的定义以及优选项与式(I)化合物相同。
在一些更优选的实施方式中，本申请的化合物选自本申请各实施例所示的具体化合物。
本申请的化合物可以由本领域技术人员根据化合物具体结构由常规的有机合成方法合成得到。例如，式(I)化合物可以通过下述合成路线(I)或(II)所示的方法来制备。
合成路线(I)
Figure PCTCN2022100186-appb-000007
例如，式(I)化合物可以通过上述合成路线(I)所示的方法来制备。中间体Int-2中的G选自卤素、羟基、甲磺酰基(OMs)、对甲苯磺酰基 (OTs)等。PG1,PG2,和PG3为氨基保护基，例如四氢吡喃(THP)、苄基(Bn)、对甲氧基苄基(PMB)、SEM、Boc等。当G为卤素、OMs、或者OTs，中间体Int-1和Int-2在碱性条件下的SN2偶联反应可以生成中间体Int-3。当G为OH，中间体Int-3可以通过Int-1和Int-2之间的Mitsunobu反应来获得。中间体Int-3与中间体Int-4的缩合反应生成化合物Int-5。在氧化条件下(例如但不限于Swern氧化或者IBX氧化)，Int-5转化为中间体Int-6。经过保护基的转换，中间体Int-6可以转换为Int-8。在典型的成酰胺反应条件下(例如但不限于在DIPEA/HATU的存在下)，或者成磺酰胺的反应条件下，或者生成脲的反应条件下，或者SN2偶联反应条件下，或者生成氨基甲酸酯的反应条件下，Int-8与合适的起始原料反应，再将保护基脱除，可以得到目标化合物式(I)。
合成路线(II)
Figure PCTCN2022100186-appb-000008
或者，化合物Int-7可以通过上述合成路线(II)所示的方法来制备。中间体Int-1与中间体Int-4的缩合反应生成化合物Int-9。在氧化条件下(例如但不限于Swern氧化或者IBX氧化)，Int-9转化为中间体Int-10。经过保护基的转换，中间体Int-6可以转换为Int-11。PG1,PG2,和PG3为 氨基保护基，例如但不限于四氢吡喃(THP)、苄基(Bn)、对甲氧基苄基(PMB)、SEM、Boc等。中间体Int-2中的G选自卤素、羟基、甲磺酰基(OMs)、对甲苯磺酰基(OTs)等。当G为卤素、OMs、或者OTs，中间体Int-11和Int-2在碱性条件下的SN2偶联反应可以生成中间体Int-7。当G为OH，中间体Int-7可以通过Int-11和Int-2之间的Mitsunobu反应来获得。
另外，本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线，对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
本申请的化合物已被证明具有TRK激酶抑制活性，可以有效抑制TRKA、TRKB和/或TRKC，并且与拉罗替尼或恩曲替尼的抑制活性或选择性相当或更好，因此为广谱抗癌药物、止疼药和抗炎药等的开发提供了更多的选择和可能性。
在第二个方面，本申请提供了一种药物组合物，其含有如上文所述的本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可以按制药领域中熟知的方式制备，并且可以通过多种途径施用，这取决于期望局部治疗还是全身性治疗并且取决于有待治疗的部位。给药可以是局部的(包括眼科的和至粘膜，包括鼻内、阴道和直肠递送)、肺部的(例如，通过吸入或吹入粉末或气溶胶，包括通过喷雾器；气管内、鼻内、表皮和经皮肤)、眼部的、经口的或肠胃外的。用于眼部递送的方法可以包括局部给药(滴眼剂)，结膜下、眼周或玻璃体内注射或者通过用手术方法放置在结膜囊中的气囊式导管或眼科插入件引入。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内(例如，鞘内或脑室内)给药。肠胃外给药可以处于单次推注剂量的形式，或者可以例如通过连续灌注泵。用于局部给药的医药组合物和配制物可以包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体以及粉剂。
如果使用固体载剂，则该制剂可以成片，以粉末或颗粒形式置于硬质凝胶胶囊中，或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂，诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂，则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的，或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂，诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予，通常载体至少大部分包括无菌水，但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液，在这种情况下，可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液、悬浮液或乳液和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如，橄榄油)和可注射有机酯(例如，油酸乙酯)。
这些组合物还可以包含各种赋形剂，例如，防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如，对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂，例如，糖、氯化钠等。可以通过使用延迟吸收试剂(例如，单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中，将活性化合物与至少一种惰性赋型剂(或载体)(例如，柠檬酸钠或磷酸二钙)混合，其中还可以包括：(a)填料或混合剂(例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)；(b)粘结剂(例如，羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶)；(c)保湿剂(例如，丙三醇)；(d)崩解剂(例如，琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠)； (e)溶液阻滞剂(例如，石蜡)；(f)吸收促进剂(例如，季铵化合物)；(I)润湿剂(例如，十六烷醇和单硬脂酸丙三醇酯)；(h)吸附剂(例如，高岭土和斑脱土)和(i)润滑剂(例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如，药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如，肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂，它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式，如果适当的话，可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外，液体剂型可以包含本领域中通常所用的惰性稀释剂(例如，水或其它溶剂)、增溶剂和乳化剂(例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3丁二醇、二甲基甲酰铵)、油(具体为，棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂，组合物还可以包括，例如，润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物，悬浮液可以包含悬浮剂，例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物在药物组合物和剂型中的量可以由本领域技术人员根据需要适当地确定，例如本申请的化合物可以治疗有效量存在于药物组合物或剂型中。
在第三个方面，本申请提供了本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，或如上文所述的药物组合物在制备用于治疗与TRK激酶或NTRK基因相关的疾病或病症的药物中的用途。
本申请也提供了治疗与TRK激酶或NTRK基因相关的疾病或病症的方法，所述方法包括向有此需要的患者施用治疗有效量的本申请的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，或如上文所述的药物组合物。其中，所述患者优选是哺乳动物，更优选是人类患者。其中给药途径可以是口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。
所述与TRK激酶或NTRK基因相关的疾病或病症，例如是由TRK激酶活性失调引起的和/或与NTRK基因融合相关疾病，例如但不限于：癌症、疼痛、炎症、神经变性疾病和细胞增殖疾病。本申请的化合物可例如用于抑制癌细胞的增殖、转移等，用于缓解疼痛，用于消炎，用于治疗或缓解神经变性疾病等等。
在一些实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症是癌症。
示例性癌症包括膀胱癌、乳腺癌、子宫颈癌、结肠直肠癌、小肠癌、结肠癌、直肠癌、肛门癌、子宫内膜癌、头颈癌(例如，喉、喉咽、鼻咽、口咽、唇部和口腔的癌症)、肾癌、肝癌(例如，肝细胞癌、胆管细胞癌)、肺癌(例如，腺癌、小细胞肺癌和非小细胞肺癌、小细胞癌和非小细胞癌、支气管癌、支气管腺瘤、胸膜肺母细胞瘤)、卵巢癌、前列腺癌、睾丸癌、子宫癌、食管癌、胆囊癌、胰腺癌(例如外分泌胰腺癌)、甲状腺癌、副甲状腺癌、皮肤癌(例如，鳞状细胞癌、卡波西肉瘤、梅克尔(Merkel)细胞皮肤癌)以及脑癌(例如，星状细胞瘤、神经管胚细胞瘤、室管膜瘤、神经外 胚层肿瘤、松果体肿瘤)。
另外的示例性癌症包括造血系统恶性肿瘤，如白血病或淋巴瘤、多发性骨髓瘤、慢性淋巴细胞性淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、皮肤T细胞淋巴瘤、急性骨髓性白血病、霍奇金或非霍奇金淋巴瘤、骨髓增生性肿瘤(例如，真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化)、瓦登斯特隆巨球蛋白血症、毛细胞淋巴瘤、慢性骨髓性淋巴瘤、急性淋巴母细胞性淋巴瘤、AIDS相关的淋巴瘤以及柏基特淋巴瘤。
另外的示例性癌症包括眼睛肿瘤、神经胶母细胞瘤、黑色素瘤、横纹肌肉瘤、淋巴肉瘤以及骨肉瘤。
在一些优选的实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、胰腺癌、食道癌、胃癌、淋巴癌、白血病、鼻咽癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌以及横纹肌肉瘤。
在一些优选的实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症为实体瘤，如黑素瘤、乳腺瘤、以及神经母细胞瘤、胶质母细胞瘤、尤因肉瘤、视网膜母细胞瘤等。
在另一些实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症是细胞增殖疾病，例如，但不限于良性前列腺增生，家族性腺瘤病，息肉病，神经纤维瘤病，银屑病，动脉粥样硬化和与血管平滑细胞增殖和新生内膜形成有关的疾病，例如血管成形术或手术后的再狭窄、肺纤维化、关节炎、肾小球肾炎，视网膜病变(包括糖尿病性和新生儿视网膜病变和老年性黄斑变性)，移植血管疾病(例如可能在血管或器官移植后发生)，肢端肥大症和肢端肥大症继发性病症等。
在另一些实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症是炎症，包括但不限于：(1)变质性炎症；(2)渗出性炎症(浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎)；(3)增生性炎症；(4)特异性炎症(结核、梅毒、麻疯、淋巴肉芽肿等)。
在另一些实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病 症是疼痛，包括但不限于炎性疼痛、关节炎疼痛、复杂区域性疼痛综合征、腰尻痛、肌肉骨骼痛、神经性疼痛、慢性疼痛、癌症相关疼痛、急性疼痛、术后疼痛等。
在另一些实施方式中，所述与TRK激酶或NTRK基因相关的疾病或病症是神经变性疾病，包括但不限于阿尔茨海默病和帕金森病。
用于治疗上述疾病的本申请化合物的“治疗有效量”可有有经验的医师或研究人员根据患者的病情、身体状况、疾病严重程度、给药途径等因素予以合理地确定。
下面结合具体实施例对本申请做进一步的说明和描述。
实施例
以下在本文中阐述的实施例仅仅为了说明目的，用以举例说明本发明的各个方面以及实施方式，并不意欲以任何方式限制本发明所要求保护的范围。
除非另有声明，所有原料和试剂均从商业途径获得。合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。所有未特别注明的反应条件和测试条件均为本领域中通常使用的常规反应条件和测试条件，可通过参考相关技术文献或仪器说明书等获得。
实施例1:N-(1-(1-(3,5-二氟苯基)乙基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2- 基)-1H-吲唑-5-胺
Figure PCTCN2022100186-appb-000009
化合物1的合成路线：
Figure PCTCN2022100186-appb-000010
中间体1-8的合成路线
Figure PCTCN2022100186-appb-000011
合成方法：
合成中间体1-1:5-硝基-1H-吲唑-3-甲醛
亚硝酸钠(1.7g,24.70mmol)溶于9ml DMF和5ml水中，冷却到0℃，缓慢滴加3N HCl(7.2ml,21.61mmol)，滴加完反应10分钟。在0℃下，向反应液中加入5-硝基-1H-吲哚(501mg,3.10mmol)的DMF(6ml)溶液，滴加完，加热到80℃反应过夜。用乙酸乙酯萃取3次，合并有机相，用水洗3次，饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得370mg中间体1-1，收率62.6％。
1H NMR(400MHz,DMSO)δ14.71(brs,1H),10.26(s,1H),8.95(d,J＝8.0Hz,1H),8.33(dd,J＝8.0Hz,J＝12.0Hz,1H),7.93(d,J＝16.0Hz,1H).
合成中间体1-2:5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将中间体1-1(370mg,1.94mmol)溶于30ml DCM中，加入对甲苯磺酸(333mg,1.94mmol)，搅拌2分钟，向反应液中加入3,4-二氢-2H-吡喃(326mg,3.87mmol)，室温反应2小时。向反应液中加水，用DCM萃取2次，合并有机相，分别用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得380mg中间体1-2，收率71.3％。
1H NMR(400MHz,CDCl 3)δ10.30(s,1H),9.26(d,J＝4.0Hz,1H),8.39-8.36(m,1H),7.82(d,J＝8.0Hz,1H),5.93-5.90(m,1H),4.04-3.99(m,1H),3.86-3.80(m,1H),2.60-2.52(m,1H),2.23-2.20(m,2H),1.84-1.78(m,3H).
合成中间体1-9：2,5-二氢-1H-吡咯-1甲酸叔丁酯
将3-吡咯啉(10.0g,0.15mol)溶于400ml二氯甲烷和三乙胺(40.6ml,0.29mol)中，冷却到0度，缓慢加入(Boc) 2O(37.9g,0.17mol)，室温反应过夜，加入水，用二氯甲烷萃取2次，合并有机相，用水洗3次，饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-9，收率91.0％。
合成中间体1-10：6-氧杂-3-氮杂双环并[3.1.0]己烷-3-甲酸叔丁酯
将中间体1-9(24.5g,0.15mol)溶于450ml二氯甲烷中，冷却到0度，分批缓慢加入间氯过氧苯甲酸(37.5g,0.22mol)，室温反应过夜，加入饱和硫代硫酸钠(40ml)，搅拌30分钟，水相用二氯甲烷萃取2次，用饱和碳酸钾溶液，水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-10，收率84.9％。
1H NMR(400MHz,CDCl 3)δ3.85(d,J＝12.0Hz,1H),3.77(d,J＝12.0Hz,1H),3.69-3.67(m,2H),3.36-3.30(m,2H),1.45(s,9H).
合成中间体1-11：3-叠氮基-4-羟基吡咯烷基-1-甲酸叔丁酯
将中间体1-10(20.8g,0.12mol)溶于150ml 1,4-二氧六环和50ml水中，加入叠氮化钠(24.0g,0.37mol)，加热到106度反应18小时，冷却到室温，加入饱和食盐水100ml，用二氯甲烷萃取(250ml x 4),合并有机相，用饱和食盐水洗，无水硫酸钠干燥，浓缩，得中间体1-11，收率100％。 1H NMR(400MHz,CDCl 3)δ4.27-4.24(m,1H),3.94(s,1H),3.73-3.59(m,2H),3.41-3.36(m,2H),1.47(s,9H).
合成中间体1-12：3-叠氮基-4-((甲磺酰基)氧基)吡咯烷基-1-甲酸叔丁酯
将中间体1-11(28.0g,0.12mol)溶于350ml二氯甲烷和三乙胺(37.3g,0.37mol)中，冷却到0度，缓慢滴加甲磺酰氯(16.9g,0.15mol)，滴加完后，室温反应2小时，加入水淬灭反应，用二氯甲烷萃取2次，合并有机相，用饱和碳酸氢钠溶液，水和饱和食盐水洗，无水硫酸钠干燥，浓缩，得中间体1-12，收率98.0％。
合成中间体1-13：3,4-二叠氮基吡咯烷基-1-甲酸叔丁酯
将中间体1-12(36.9g,0.12mol)溶于250ml DMF中，加入叠氮化钠(23.5g,0.36mol)，加热到90度，反应2天，冷却到室温，加入750ml水,用甲基叔丁基醚萃取(400ml*4)，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，硅胶柱纯化，得中间体1-13，收率62.2％。
合成中间体1-8：3,4-二氨基吡咯烷基-1-甲酸叔丁酯
将中间体1-13(18.9g,0.08mol)溶于200ml甲醇中，加入10％Pd/C,氢气置换3次，加热到40度，反应2天，过滤，浓缩，得中间体1-8，收率78％。 1H NMR(400MHz,CDCl 3)δ3.51-3.49(m,2H),3.40-3.36(m,2H),3.21-3.11(m,2H),1.47(s,9H).
合成中间体1-3:2-(5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-2(300mg,1.09mmol)溶于20ml叔丁醇中，加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(219mg,1.09mmol)，碘(415mg,1.63mmol)，碳 酸钾(452mg,3.27mmol)，升温70℃反应3小时。反应完成后，降至室温，加5％的硫代硫酸钠水溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得410mg中间体1-3，收率82.4％。
合成中间体1-4:2-(5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-3(400mg,0.88mmol)溶于5ml DMSO中，加入IBX(491mg,1.75mmol)，升温50℃反应3小时。反应完成后，降至室温，加水淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得270mg中间体1-4，收率67.8％。
合成中间体1-5:2-(5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-4(270mg,0.59mmol)溶于25ml THF中，降温至0℃，加入NaH(60％)(35.6mg,0.89mmol)，搅拌10mim，加入SEMCl(149mg,0.89mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得209mg中间体1-5，收率60.2％。
1H NMR(400MHz,CDCl 3)δ9.51(d,J＝8.0Hz,1H),8.33(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),5.99-5.94(m,1H),5.90-5.87(m,1H),5.81-5.79(m,1H),4.63-4.52(m,4H),4.00-3.98(m,1H),3.79-3.77(m,1H),3.62-3.56(m,2H),2.55-2.52(m,1H),2.20-2.17(m,2H),1.79-1.76(m,3H),1.54(s,9H),0.95-0.89(m,2H),-0.08(s,9H).
合成中间体1-6:2-(5-胺基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-5(200mg,0.34mmol)溶于60ml甲醇中，加入10％Pd/C(20mg)，氢气置换3次，室温反应3小时。反应完成后，过滤，浓缩，得173mg中间体1-6，收率91.2％。
合成中间体1-7:2-(5-((1-(3,5-二氟苯基)乙基)胺基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-6(20.0mg,0.04mmol)和3,5-二氟苯乙酮(6.8mg,0.04mmol)溶于5ml甲苯中，加入1滴冰醋酸，加热至80℃反应过夜，冷却到室温向反应液中加入三乙酰基硼氢化钠(9.9mg,0.05mmol)，室温反应3小时，加水淬灭，用EA萃取，用饱和食盐水洗涤，浓缩纯化得9mg中间体1-7，收率35.9％。
合成化合物1:N-(1-(1-(3,5-二氟苯基)乙基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺
将中间体1-7(10.0mg,0.05mmol)溶于2ml甲醇中，加入1ml浓盐酸，50℃反应5小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物2.1mg,收率38.3％。
1H NMR(400MHz,CD 3OD)δ7.33(d,J＝8.0Hz,1H),7.18(d,J＝4.0Hz,1H),7.10-7.06(m,2H),6.98(dd,J＝4.0Hz,J＝8.0Hz,1H),6.74-6.69(m,1H),4.70-4.65(m,1H),4.18(s,4H),1.55(d,J＝8.0Hz,3H).
实施例2:N-(3,5-二氟苄基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d] 咪唑-2-基)-1H-吲唑-5-胺
Figure PCTCN2022100186-appb-000012
化合物2的合成路线：
Figure PCTCN2022100186-appb-000013
合成方法：
合成中间体2-1:2-(5-((3,5-二氟苄基)胺基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体1-6(80.0mg,0.14mmol)和3,5-二氟苯甲醛(24.6mg,0.17mmol)溶于5ml甲苯中，加入1滴冰醋酸，加热至80℃反应过夜，冷却到室温向反应液中加入三乙酰基硼氢化钠(45.9mg,0.22mmol)，室温反应3小时，加水淬灭，用EA萃取，用饱和食盐水洗涤，浓缩纯化得79mg中间体2-1，收率80.5％。
合成中间体2-2:N-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺
将中间体2-1(79.0mg,0.12mmol)溶于20ml DCM中，加入ZnBr2(105.0mg,0.46mmol)，室温下搅拌。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得60.2mg中间体2-2，收率89.4％。
合成中间体2-3:4-((2-(5-((3,5-二氟苄基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-羧酸叔丁酯
将中间体2-2(67.5mg,0.12mmol)和4-甲酰基哌啶-1-羧酸叔丁酯(29.7mg,0.14mmol)溶于10ml DCM中，室温搅拌10分钟，加入三乙酰基硼氢化钠(37.0mg,0.17mmol)，室温反应3小时，加水淬灭，用DCM萃取，用饱和食盐水洗涤，浓缩纯化得24.9mg中间体2-3，收率27.5％。
合成化合物2:N-(3,5-二氟苄基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺
将中间体2-3(24.9mg,0.03mmol)溶于2ml甲醇中，加入1ml浓盐酸，50℃反应5小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物5.1mg,收率34.4％。
1H NMR(400MHz,CD 3OD)δ7.37(d,J＝8.0Hz,1H),7.30(d,J＝4.0Hz,1H),7.08(dd,J＝4.0Hz,J＝16.0Hz,2H),7.01(dd,J＝4.0Hz,J＝8.0Hz,1H),6.80-6.75(m,1H),4.46(s,2H),3.90(s,4H),3.19-3.15(m,2H),2.78-2.72(m,4H),2.06-2.04(m,1H),1.96-1.91(m,2H),1.81-1.78(m,1H),1.62-1.57(m,1H).
实施例3：5-(3,5-二氟苄基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪 唑-2-基)-1H-吲唑
Figure PCTCN2022100186-appb-000014
化合物3的合成路线：
Figure PCTCN2022100186-appb-000015
合成方法：
合成中间体3-1:5-溴-1H-吲唑-3-甲醛
将亚硝酸钠(1.41g,20.4mmol)溶于10ml水中，加入10ml DMF，0℃滴加3M HCl(2.29ml,6.89mmol)，搅拌10分钟，向反应液中加入5-溴吲哚(500mg,2.55mmol)的DMF(10ml)溶液，室温反应3小时。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体3-1 410mg，收率71.4％。
1H NMR(400MHz,CDCl 3)δ10.28(s,1H),8.53(d,J＝1.1Hz,1H),7.61(dd,J＝8.9,1.8Hz,1H),7.49(d,J＝8.8,1H).
合成中间体3-2:5-溴-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将中间体3-1(300mg,1.33mmol)溶于20ml DCM中，加入对甲苯磺酸(279mg,1.46mmol)，搅拌2分钟，向反应液中加入3,4-二氢-2H-吡喃(168 mg,2.0mmol)的DCM(3ml)溶液，室温反应1小时。向反应液中加水，用DCM萃取2次，合并有机相，分别用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体3-2 300mg，收率72.8％。
合成中间体3-3:5-溴-3-(二甲氧基甲基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体3-2(50.0mg,0.16mmol)，原甲酸三甲酯(20.6mg,0.19mmol)和对甲苯磺酸(2.8mg,0.02mmol)溶于5ml甲醇中，室温反应2小时，加水淬灭，用EA萃取，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩纯化得23mg中间体3-3，收率40.0％。
1H NMR(400MHz,CDCl 3)δ8.13(d,J＝4.0Hz,1H),7.52-7.46(m,2H),5.74(s,1H),5.72-5.69(m,1H),4.08-4.04(m,1H),3.78-3.72(m,1H),3.47(s,6H),2.52-2.48(m,1H),2.15-2.04(m,2H),1.80-1.71(m,3H).
合成中间体3-4:3-(二甲氧基甲基)-1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲唑
将中间体3-3(20.0mg,0.06mmol)，频哪醇硼酸酯(28.6mg,0.11mmol)，Pd(dppf)Cl2(4.1mg,0.006mmol)和醋酸钾(16.6mg,0.17mmol)溶于10ml1,4-二氧六环中，氮气置换3次，加热到100℃反应过夜，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩薄层析，得15mg中间体3-4，收率66.2％。
1H NMR(400MHz,CDCl 3)δ8.45(s,1H),7.82(dd,J＝4.0Hz,J＝8.0Hz,1H),7.58(dd,J＝8.0,4.0Hz,1H),5.81(s,1H),5.76(dd,J＝8.0,4.0Hz,1H),4.11-4.07(m,1H),3.78-3.75(m,1H),3.48(s,6H),2.60-2.51(m,1H),2.16-2.03(m,2H),1.79-1.60(m,3H),1.38(s,12H).
合成中间体3-5:5-(3,5-二氟苄基)-3-(二甲氧基甲基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体3-4(175mg,0.44mmol)，3,5-二氟溴苄(180mg,0.87mmol)，Pd(PPh 3) 4(50.2mg,0.04mmol)和碳酸钠(138mg,1.31mmol)溶于10ml四氢呋喃和2ml的水中，氮气置换3次，加热到65℃反应过夜，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩柱层析，得148mg中间体3-5，收率84.5％。
合成中间体3-6:5-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将中间体3-5(50mg,0.12mmol),对甲苯磺酸(47.3mg,0.25mmol)溶于10ml乙腈中，室温反应。反应完成后加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩柱层析，得27mg中间体3-6，收率61.0％。
1H NMR(400MHz,CDCl 3)δ10.27(s,1H),8.18(s,1H),7.64(d,J＝8.4Hz,1H),7.31-7.28(m,1H),6.74-6.63(m,3H),5.84(dd,J＝8.9,2.9Hz,1H),4.11(s,2H),4.06-3.99(m,1H),3.83-3.77(m,1H),2.63-2.55(m,1H),2.26-2.14(m,2H),1.85-1.74(m,3H).
合成中间体3-7:2-(5-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体3-6(50mg,0.14mmol)溶于10ml叔丁醇中，加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(28.2mg,0.14mmol)，碘(53.4mg,0.21mmol)，碳酸钾(58.2mg,0.42mmol)，升温70℃反应3小时。反应完成后，降至室温，加5％的硫代硫酸钠水溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体3-7 68mg，收率90.2％。
合成中间体3-8:2-(5-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体3-7(65mg,0.12mmol)溶于10ml DMSO中，加入IBX(67.7mg,0.24mmol)，升温50℃反应3小时。反应完成后，降至室温，加水淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体3-8 34mg，收率52.5％。
1H NMR(400MHz,CDCl 3)δ8.33(s,1H),7.53(d,J＝8.8Hz,1H),7.24(dd,J＝8.8,1.7Hz,1H),6.74-6.71(m,1H),6.67-6.60(m,2H),5.72(dd,J＝9.6,2.6Hz,1H),4.60-4.54(m,4H),4.13(s,2H),4.10-4.06(m,1H),3.81-3.75(m,1H),2.62-2.54(m,1H),2.16-2.06(m,2H),1.85-1.70(m,3H),1.55(s,9H).
合成中间体3-9:2-(5-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体3-8(19.8mg,0.04mmol)溶于5ml THF中，降温至0℃，加入NaH(60％)(1.9mg,0.05mmol)，搅拌15mim，加入SEMCl(6.7mg,0.04mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体3-9 18.1mg，收率73.4％。
合成中间体3-10:5-(3,5-二氟苄基)-1-(四氢-2H-吡喃-2-基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯[3,4-d]咪唑-2-基)-1H-吲唑
将中间体3-9(182mg,0.27mmol)溶于20ml DCM中，加入ZnBr 2(24mg,1.10mmol)，室温下搅拌。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得中间体3-10 140mg，收率90.3％。
合成化合物3:5-(3,5-二氟苄基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体3-10(30.0mg,0.05mmol)5ml DCM中，向溶液中加入TEA(8.0mg,0.08mmol)，甲磺酰氯(7.3mg,0.06mmol)。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩。将浓缩物溶于4ml甲醇中，加入2ml浓盐酸，50℃反应3小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物5.6mg,收率24.6％。
1H NMR(400MHz,CD 3OD)δ8.18(s,1H),7.53(d,J＝8.4Hz,1H),7.32(dd,J＝8.7,4.0Hz,1H),6.91-6.85(m,2H),6.78-6.73(m,1H),4.66-4.52(m,4H),3.65(s,2H),3.01(s,3H).
实施例4:5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡 咯并[3,4-d]咪唑-2-基)-1H-吲唑
Figure PCTCN2022100186-appb-000016
化合物4的合成路线：
Figure PCTCN2022100186-appb-000017
合成方法：
合成中间体4-1:1-(3,5-二氟苯基)乙醇
将3,5-二氟苯乙酮(2.1g,13.50mmol)溶于20ml甲醇中，0℃分批加入氰基硼氢化钠(1.3g,20.21mmol)，加完转移至室温搅拌1小时，反应完毕。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品中间体4-1 2.13g，收率100.1％。
合成中间体4-2:1-(3,5-二氟苯基)甲磺酸乙酯
将中间体4-1(2.13g,13.50mmol)溶于20ml二氯甲烷中，加入三乙胺(4.1g,40.41mmol)，0℃滴加甲磺酰氯(1.9g,16.20mmol)，加完转移至室温搅拌1小时，反应完毕。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得粗品中间体4-2 3.2g，收率100％。
合成中间体4-3:5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将中间体4-2(2.2g,9.30mmol)和5-羟基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛(2.3g,18.61mmol)溶于20ml DMF中，加入碳酸铯(6.1g,0.82mmol)，60℃反应2小时，反应完毕。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体4-3 3.1g，收率86.2％。
1H NMR(400MHz,CDCl 3)δ10.19(s,1H),7.72-7.45(m,2H),7.19-7.16(m,1H),7.00-6.92(m,2H),6.73-6.67(m,1H),5.81-5.77(m,1H),5.43(q,J＝6.3Hz,1H),4.03-3.98(m,1H),3.81-3.75(m,1H),2.56-2.49(m,1H),2.26-2.03(m,2H),1.82-1.71(m,3H),1.67(d,J＝6.3Hz,3H).
合成中间体4-4:2-(5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体4-3(3.1g,8.01mmol)溶于30ml叔丁醇中，加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(1.6g,8.01mmol)，碘(3.1g,12.11mmol)，碳酸钾(3.3g,24.02mmol)，升温70℃反应3小时。反应完成后，降至室温，加5％的硫代硫酸钠水溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体4-4 3.6g，收率79.1％。
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.49(dd,J＝9.1Hz,3.2Hz,1H),7.11(dd,J＝9.1Hz,2.4Hz,1H),7.00(d,J＝7.3Hz,2H),6.69(t,J＝9.0Hz,1H),5.70-5.67(m,1H),5.49-5.44(m,1H),5.00-4.80(m,1H),4.52-4.31(m,1H),4.03-3.99(m,1H),3.77-3.66(m,5H),2.56-2.47(m,1H),2.18-2.10(m,1H),2.06-2.02(m,1H),1.79-1.72(m,3H),1.66-1.64(m,3H),1.45(s,9H).
合成中间体4-5:2-(5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4,6-二氢吡咯[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体4-4(1.3g,2.31mmol)溶于10ml DMSO中，加入IBX(1.3g,4.60mmol)，升温50℃反应3小时。反应完成后，降至室温，加水淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体4-5 560mg，收率43.2％。
合成中间体4-6:2-(5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体4-5(790mg,1.40mmol)溶于10ml THF中，降温至0℃，加入NaH(60％)(96.4mg,4.20mmol)，搅拌15mim，加入SEMCl(280mg,1.68mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体4-6 810mg，收率83.3％。
合成中间体4-7:5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体4-6(810.0mg,1.20mmol)溶于20ml DCM中，加入ZnBr 2(1.1g,4.70mmol)，室温下搅拌。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得中间体4-7 660mg，收率95.2％。
合成化合物4:5-(1-(3,5-二氟苯基)乙氧基)3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体4-7(15.0mg,0.03mmol)和1-甲基哌啶-4-酮(4.3mg,0.04mmol),溶于5ml DCM中，室温搅拌10分钟，加入三乙酰氧基硼氢化钠(8.01mg,0.04mmol),室温搅拌3小时。反应完成后，加水淬灭，用DCM萃取，用饱和食盐水洗涤，浓缩。硅胶板纯化，将纯化所得产物溶于2ml甲醇中，加入1ml浓盐酸，50℃反应5小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物1.9mg,两步总收率15.8％。
1H NMR(400MHz,CD 3OD)δ7.67(d,J＝4.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.19(dd,J＝4.0Hz,J＝8.0Hz,1H),7.10(dd,J＝4.0Hz,J＝8.0Hz,2H),6.84-6.79(m,1H),5.61-5.56(m,1H),4.36(s,4H),3.71-3.59(m,2H),3.19-3.15(m,3H),2.93(s,3H),2.48-2.47(m,2H),2.06-2.02(m,2H),1.67(d,J＝8.0Hz,3H).
实施例5:2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-N，N-二甲基-4,6- 二氢吡咯并[3,4-d]咪唑-5(1H)甲酰胺
Figure PCTCN2022100186-appb-000018
化合物5的合成路线：
Figure PCTCN2022100186-appb-000019
合成方法：
合成化合物5:2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-N,N-二甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)甲酰胺
将中间体4-7(30.0mg,0.05mmol)溶于10ml的二氯甲烷，向体系中加入三光气(15.3mg,0.05mmol),将体系降温至0℃，滴加三乙胺(10.4mg,0.10mmol)，反应0.5h，向体系中加入盐酸二甲胺(5.05mg,0.06mmol)，升至室温反应。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩。将浓缩物溶于4ml甲醇中，加入2ml浓盐酸， 50℃反应5小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物4.8mg,收率20.4％。
1H NMR(400MHz,CD 3OD)δ7.69(d,J＝2.3Hz,1H),7.46(d,J＝9.0Hz,1H),7.17(dd,J＝9.0,2.4Hz,1H),7.13-7.08(m,2H),6.84-6.78(m,1H),5.58(q,J＝6.4Hz,1H),4.71-4.63(m,4H),2.99(s,6H),1.66(d,J＝6.4Hz,3H).
实施例6：2-(二甲基氨基)乙基2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3- 基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯
Figure PCTCN2022100186-appb-000020
化合物6的合成路线：
Figure PCTCN2022100186-appb-000021
合成方法：
合成化合物6：2-(二甲基氨基)乙基2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯
将中间体4-7(50.0mg,0.08mmol)溶于THF中，冷却到0℃，加入三光气(25.1mg,0.08mmol)，反应5分钟，缓慢加入三乙胺(84.2mg,0.80mmol)，室温反应0.5小时，向反应液中加2-(二甲基氨基)乙烷-1-醇(38.1mg,0.42mmol)和DMAP(5.0mg,0.04mmol)，加热到60反应1.5小 时，向反应液中加水，用EA萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶板纯化，将纯化后的浓缩物溶于2ml甲醇中，加入1ml的浓盐酸，50℃反应6小时，浓缩，溶于3ml的甲醇中，加入0.5ml的氨水，浓缩，硅胶板纯化，得到终产物15mg，收率35.0％。
1H NMR(400MHz,CD 3OD)δ7.68(d,J＝4.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.20-7.14(m,1H),7.14-7.08(m,2H),6.85-6.78(m,1H),5.58(q,J＝8.0Hz,1H),4.72-4.50(m,4H),4.35(t,J＝8.0Hz,2H),2.82-2.74(m,2H),2.41(s,6H),1.66(d,J＝8.0Hz,3H).
实施例7：(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并 [3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮
Figure PCTCN2022100186-appb-000022
化合物7的合成路线
Figure PCTCN2022100186-appb-000023
合成方法：
合成化合物7：(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮
在室温条件下，将中间体4-7(30.0mg,0.05mmol),HATU(29.1mg,0.10mmol),N,N-二异丙基乙胺(13.2mg,0.10mmol)和1-甲基哌啶-4-羧酸(14.0mg,0.10mmol)溶于20ml DCM中，搅拌反应2h。加水淬灭反应。 用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。得到的产物溶于2ml甲醇和1ml浓盐酸中，50℃反应2小时，浓缩，溶于3ml甲醇，加1ml氨水，浓缩，制备板纯化，得到最终产物8mg,收43.7％。
1H NMR(400MHz,CD 3OD)δ7.67(d,J＝1.8Hz,1H),7.45(d,J＝9.0Hz,1H),7.21-7.03(m,3H),6.78(t,J＝9.1Hz,1H),5.55(q,J＝6.2Hz,1H),4.80-4.59(m,4H),3.17-3.14(m,2H),2.75-2.65(m,1H),2.48(s,3H),2.46-2.41(m,2H),1.95-1.90(m,4H),1.63(d,J＝6.4Hz,3H).
实施例8：2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4- 基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
Figure PCTCN2022100186-appb-000024
化合物8的合成路线：
Figure PCTCN2022100186-appb-000025
合成方法：
合成中间体8-1：5-(1-(3,5-二氟苯基)-4-基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-腈
将5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛(200mg,0.52mmol)和三乙胺(157mg,1.55mmol)溶于10ml乙腈中，向溶液中加入盐酸羟胺(53.9mg,0.78mmol),60℃反应3小时。将反应液冷却至室温，向反应液加入三乙胺(419mg,4.14mmol)和乙酸酐(211mg,2.07mmol)，80℃反应16小时。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体8-1 145mg，收率73.1％。
1H NMR(400MHz,CDCl 3)δ7.64-7.60(m,1H),7.19-7.17(m,1H),6.98-6.97(m,1H),6.93-6.89(m,2H),6.73-6.68(m,1H),5.77-5.73(m,1H),5.34(q,J＝6.4Hz,1H),3.94-3.88(m,1H),3.76-3.71(m,1H),2.49-2.41(m,1H),2.14-2.06(m,2H),1.77-1.68(m,3H),1.65(d,J＝6.4Hz,3H).
合成中间体8-2：5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-氨基甲酸酯
将中间体8-1(135mg,0.35mmol)溶于10ml甲醇中，向反应液加入甲醇钠(57.1mg,1.06mmol),室温反应16小时，将反应液浓缩除去甲醇，浓缩物中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到中间体8-2粗品120mg,收率82.0％。
合成中间体8-3：叔丁基3-(5-(1-(3,5-二氟苯基)乙氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-羧酰亚胺基)-4，4-二乙氧基哌啶-1-羧酸酯
将中间体8-2(110mg,0.26mmol)和3-氨基-4,4-二乙氧基哌啶-1-羧酸叔丁酯(91.6mg,0.32mmol)溶于10ml乙醇中，向反应液加入醋酸(31.8mg,0.53mmol),50℃反应16小时，将反应液浓缩除去乙醇，浓缩物用适量甲苯带一下，浓缩得到中间体8-3粗品208mg。
合成中间体8-4：2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑[4,5-c]吡啶
将中间体8-3(200mg,0.22mmol)溶于10ml乙醇中，向反应液加入5ml浓盐酸,40℃反应16小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，硅胶柱纯化，得到中间体8-4 78mg,收率66.2％。
合成化合物8：2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶
将中间体8-4(15.0mg,0.04mmol)溶于5ml NMP中，向溶液中加入0.1ml醋酸,55℃搅拌10分钟，冷却至室温，加入1-甲基哌啶-4-酮(4.3mg,0.04mmol)，室温反应16小时，加入三乙酰氧基硼氢化钠(16.0mg,0.08mmol)室温反应2小时，加0.5ml氨水调pH，向混合物中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，制备板纯化，得最终产物4.2mg，收率22.5％。
1H NMR(400MHz,CD 3OD)δ7.68(d,J＝2.4Hz,1H),7.45(d,J＝9.0Hz,1H),7.16(dd,J＝9.0,2.4Hz,1H),7.12-7.10(m,2H),6.83-6.79(m,1H),5.58(q,J＝6.3Hz,1H),3.80(s,2H),3.17-3.10(m,2H),3.04-3.01(m,2H),2.84-2.80(m,2H),2.73-2.70(m,1H),2.43(s,3H),2.36-2.19(m,2H),2.10-2.03(m,2H),1.84-1.75(m,2H),1.65(d,J＝6.3Hz,3H).
实施例9:(S)-5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)- 1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
Figure PCTCN2022100186-appb-000026
化合物9的合成路线：
Figure PCTCN2022100186-appb-000027
合成方法：
合成中间体9-1:5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛
将5-羟基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-甲醛(427mg,1.73mmol)和咪唑(177mg,2.60mmol)溶于20ml二氯甲烷中，0℃滴加TBSCl(0.33ml,1.91mmol)，加完转移至室温搅拌1小时，反应完毕。向反应液中加水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品中间体9-1 540mg，收率86.4％。
合成中间体9-2:2-(5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-3a,4,6,6a-四氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体9-1(540mg,1.49mmol)溶于20ml叔丁醇中，加入3,4-二氨基吡咯烷-1-羧酸叔丁酯(362mg,1.79mmol)，碘(570mg,2.25mmol)，碳酸钾(621mg,4.49mmol)，升温70℃反应3小时。反应完成后，降至室温，加5％的硫代硫酸钠水溶液淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体9-2 530mg，收率65.3％。
合成中间体9-3:2-(5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体9-2(530mg,0.99mmol)溶于10ml DMSO中，加入IBX(548mg,1.96mmol)，升温50℃反应3小时。反应完成后，降至室温，加水淬灭反应，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体9-3 362mg，收率68.4％。
合成中间体9-4:2-(5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸叔丁酯
将中间体9-3(362mg,0.67mmol)溶于10ml THF中，降温至0℃，加入NaH(60％w/w,32.1mg,1.33mmol)，搅拌15min，加入SEMCl(0.14ml,0.80mmol)。加入完毕后升至室温搅拌，反应完成后，加水淬灭，加EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体9-4 365mg，收率81.5％。
合成中间体9-5:5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体9-4(180mg,0.27mmol)溶于10ml DCM中，加入ZnBr 2(303mg,1.34mmol)，室温下搅拌。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得中间体9-5 153mg，收率99.9％。
合成中间体9-6:4-((2-(5-((叔丁基二甲基甲硅烷基)氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-甲酸叔丁酯
将中间体9-5(153mg,0.27mmol)和4-甲酰基哌啶-1-羧酸叔丁酯(68.7mg,0.32mmol)溶于10ml二氯甲烷中，室温搅拌1小时，加入氰基硼氢化钠(25.3mg,0.40mmol)，搅拌1小时，反应完成后，加水淬灭，加二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体9-6 165mg，收率80.1％。
合成中间体9-7:5-((叔丁基二甲基甲硅烷基)氧基)-3-(5-(哌啶-4-基甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯[3，4-d]咪唑-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体9-6(165mg,0.22mmol)溶于10ml DCM中，加入ZnBr 2(248mg,1.10mmol)，室温下搅拌。反应完成后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得中间体9-7 130mg，收率90.6％。
合成化合物9-8:5-((叔丁基二甲基甲硅烷基)氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体9-7(130mg,0.19mmol)和30％甲醛水溶液(17.5mg,0.58mmol)溶于5ml DCM中，搅拌1小时，向溶液中加入三乙酰基硼氢化钠(80.5mg,0.38mmol)。反应完成后，加水淬灭，用DCM萃取，合并有机相，用饱和食盐水洗涤，浓缩，硅胶柱纯化，得中间体9-8 75.5mg，收率56.9％。
合成化合物9-9:3-(5-((1-甲基哌啶-4-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-醇
将中间体9-8(40.0mg,0.06mmol)溶于5ml四氢呋喃中，降温至0℃向溶液中加入TBAF的四氢呋喃溶液(1M)(0.12ml,0.12mmol)，搅拌30分 钟反应完毕，加水淬灭，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，浓缩，得粗品中间体9-9 30.1mg，收率90.1％。
合成中间体9-10:5-((S)-1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑
将中间体9-9(30.1mg,0.05mmol)和(R)-1-(3,5-二氟苯基)甲磺酸乙酯(12.5mg,0.05mmol)溶于10ml DMF中，加入碳酸铯(35.8mg,0.11mmol)，60℃反应2小时，反应完毕。向反应液中加水，用乙酸乙酯萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体9-10 19.2mg，收率51.3％。
合成化合物9:(S)-5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体9-10(19.2mg,0.02mmol)溶于4ml甲醇中，加入2ml浓盐酸，50℃反应5小时，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物6.2mg,收率46.3％。
1H NMR(400MHz,CD 3OD)δ7.64(s,1H),7.46(d,J＝9.0Hz,1H),7.15(dd,J＝9.1,2.4Hz,1H),7.10-7.05(m,2H),6.81-6.76(m,1H),5.55(q,J＝6.4Hz,1H),4.38(s,4H),3.56(d,J＝12.4Hz,2H),3.27-3.20(m,2H),3.16-3.06(m,2H),2.89(s,3H),2.21-2.18(m,3H),1.76-1.62(m,5H).
实施例10：1-甲基哌啶-4-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)- 4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯
Figure PCTCN2022100186-appb-000028
化合物10的合成路线：
Figure PCTCN2022100186-appb-000029
合成方法：
合成化合物10：1-甲基哌啶-4-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯
将1-甲基哌啶-4-醇(11.0mg,0.10mmol)溶于10ml DCM中，冷却到0℃，加入三光气(15.0mg,0.05mmol)，反应5分钟，向溶液中滴加三乙胺(41.2mg,0.40mmol),搅拌0.5h。向反应液中加入中间体4-7(30.0mg,0.05mmol)，反应16h。加水淬灭反应。用DCM萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。得到的产物溶于2ml甲醇和1ml浓盐酸中，50℃反应2小时，浓缩，溶于3ml甲醇，加1ml氨水，浓缩，制备板纯化，得到最终产物2.2mg,收17％。
1H NMR(400MHz,CD 3OD)δ7.69(d,J＝2.2Hz,1H),7.47(d,J＝9.1Hz,1H),7.18-7.09(m,3H),6.83-6.79(m,1H),5.58(q,J＝6.2Hz,1H),4.87-4.83(m,1H),4.63-4.58(m,4H),2.87-2.79(m,2H),2.62-2.52(m,2H),2.43(s,3H),2.08-2.02(m,2H),1.93-1.84(m,2H),1.66(d,J＝6.4Hz,3H)。
实施例11:N-(1-(3,5-二氟苯基)乙基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯 并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺
Figure PCTCN2022100186-appb-000030
化合物11的合成路线：
Figure PCTCN2022100186-appb-000031
合成方法：
合成中间体11-1：5-硝基-1-(四氢-2H-吡喃-2-基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑
将中间体1-5(1.40g,2.39mmol)溶于10ml DCM中，加入溴化锌(1.08g,4.79mmol)，氮气置换，室温下反应4小时。反应完成后，加水淬灭，加 DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体11-1 780mg，收率67.21％。LC-MS m/z(ESI)[M+H]+针对C 23H 33N 6O 4Si的计算值为:484.2；测量值为:484.2。
合成中间体11-2：4-((2-(5-硝基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-羧酸叔丁酯
将中间体11-1(780mg,1.61mmol)溶于10ml 1,2-二氯乙烷中，加入4-甲酰基哌啶-1-羧酸叔丁酯(686mg,3.22mmol)，室温搅拌2h后，加入三乙酰基硼氢化钠(683mg,3.22mmol)，室温搅拌1h后，加水淬灭，加DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体11-2 650mg，收率59.01％。LC-MS m/z(ESI)[M+H]+针对C 34H 52N 7O 6Si的计算值为:682.4；测量值为:682.4。
合成中间体11-3：4-((2-(5-氨基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-羧酸叔丁酯
将中间体11-2(200mg,0.29mmol)溶于5ml乙酸乙酯，加入钯碳(10％w/w,100mg)，氢气置换气体，在氢气提供气体环境下室温反应18h，18h后抽滤，浓缩，硅胶柱纯化，得中间体11-3 110mg，收率57.49％。LC-MS m/z(ESI)[M+H]+针对C 34H 54N 7O 4Si的计算值为:652.4；测量值为:652.4。
合成中间体11-4：4-((2-(5-((1-(3,5-二氟苯基)乙基)氨基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-羧酸叔丁酯
将中间体11-3(110mg,0.17mmol)溶于5ml甲苯，加入1-(3,5-二氟苯基)乙-1-酮(52.6mg,0.34mmol)，90℃反应18h，降温至40℃，加入氰基硼氢化钠(31.8mg,0.51mmol)，反应4h，加水淬灭，EA萃取，水洗有机相，干燥，浓缩，硅胶柱纯化，的中间体11-4 36mg，收率27.0％。LC-MS m/z(ESI)[M+H]+针对C 42H 60F 2N 7O 4Si的计算值为:792.4；测量值为:792.4。
合成化合物11：N-(1-(3,5-二氟苯基)乙基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺
将中间体11-4(36mg,0.05mmol)溶于4ml甲醇，再加入2ml浓盐酸，50℃反应3h，浓缩，溶于5ml甲醇，加0.5ml氨水，浓缩，制备板纯化，得到最终产物7mg,收率32.2％。LC-MS m/z(ESI)[M+H]+针对C 26H 30F 2N 7的计算值为:478.3；测量值为:478.3.
实施例12:
实施例12化合物根据实施例11的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000032
实施例13和实施例14:
实施例13、14的化合物根据实施例3的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000033
Figure PCTCN2022100186-appb-000034
实施例15至实施例28:
实施例15至实施例28的化合物根据实施例4的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000035
Figure PCTCN2022100186-appb-000036
Figure PCTCN2022100186-appb-000037
Figure PCTCN2022100186-appb-000038
Figure PCTCN2022100186-appb-000039
Figure PCTCN2022100186-appb-000040
实施例29:
实施例29化合物根据实施例5的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000041
实施例30和实施例31:
实施例30、31的化合物根据实施例6的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000042
Figure PCTCN2022100186-appb-000043
实施例32:
实施例32化合物根据实施例9的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000044
Figure PCTCN2022100186-appb-000045
实施例33：
实施例33化合物根据实施例10的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000046
实施例34至实施例46:
实施例34至实施例46的化合物根据实施例4的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000047
Figure PCTCN2022100186-appb-000048
Figure PCTCN2022100186-appb-000049
Figure PCTCN2022100186-appb-000050
Figure PCTCN2022100186-appb-000051
实施例47至实施例48:
实施例47至实施例48的化合物根据实施例9的合成路线，使用合适的起始原料进行制备，具体如下。
Figure PCTCN2022100186-appb-000052
Figure PCTCN2022100186-appb-000053
活性测试实验：对TRKA/B/C激酶抑制活性的测定
1.材料和设备
Figure PCTCN2022100186-appb-000054
2.实验步骤
2.1制备1x激酶反应缓冲液:
1倍体积的5X激酶反应缓冲液和4倍体积的水；5mM MgCl 2；1mM DTT。
2.2激酶和底物准备:
2.5X底物混合物配制
Figure PCTCN2022100186-appb-000055
2.3化合物筛选:
1)在稀释板中用DMSO对化合物进行4倍梯度稀释，化合物起始浓度为1000nM。
2)将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。
3)用1X的酶反应缓冲液配制准备2X激酶。
4)向反应板中每孔加入2μl激酶(步骤3中配制)。
5)向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟。
6)用1X的酶反应缓冲液配制4x ATP&sub混合液，向反应板中加入1μl 4x ATP&sub混合液。
7)用封板膜封住板子1000g离心30秒，室温反应60分钟。
8)转移4μl ADP-Glo到384反应板中1000rpm/min,离心1min，25℃孵育40min。
9)转移8μl Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。
10)使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
3.数据分析
3.1抑制率计算如下:
化合物抑制率(％inh)＝100％-(化合物-阳性对照)/(阴性对照-阳性对照)*100％
3.2计算IC 50并绘制化合物的抑制曲线：
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：用Graphpad 6.0软件进行数据分析。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*Hill Slope))
X:化合物浓度log值 Y:抑制率(％inhibition)
3.3结果验证
数据从Biotek中导出，人工分析。比值转化为抑制率，IC 50通过抑制率由Prism GraphPad 6.0计算。IC 50通过比值再次计算，以验证结果准确性。
3.4质量控制
Z factor>0.5；S/B>2
阳性对照IC 50在历次平均值3倍以内
4.结果
测试结果见下面的表1。
表1：各实施例化合物对TRKA/B/C激酶的抑制作用
Figure PCTCN2022100186-appb-000056
Figure PCTCN2022100186-appb-000057
Figure PCTCN2022100186-appb-000058
测试的各实施例化合物对于TRKA、TRKB、TRKC激酶均显示出与LOXO-101相似或更好的抑制活性。
虽然已经阐明并描述了本发明的特定实施方式，但并不意味着这些实施方式阐明了并描述了本发明的所有可能形式。更确切地，用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是，在不脱离本公开的一般范围的情况下，可以进行各种其他改变和修改。因此，在所附权利要求中，旨在包括在本发明范围内的所有这些改变和修改。

Claims (13)

  1. 一种式(I)的化合物：
    Figure PCTCN2022100186-appb-100001
    或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中：
    R 1、R 2各自独立地选自H、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和卤素；
    R 3选自H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
    R 6的个数为1、2或3个，且每个R 6各自独立地选自H、卤素、-CN、-OH、-NO 2、-NR 7R 8、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
    X为连接键、O、S或(NR 4)，其中R 4选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基；
    R 7和R 8各自独立地选自：H、C 1-6烷基、C 1-4卤代烷基、C 1-4烷氧基，或者R 7、R 8以及与它们相连的N原子共同形成3-6元环；
    n＝1、2或3；
    L为(C＝O)、(O＝S＝O)、CR aR b或连接键，其中R a和R b各自独立地选自：H、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6脂环基和4-6元杂脂环基，或者R a、R b以及与它们相连的碳原子共同形成3-6元环；
    R 5选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷 基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3- 7脂环基、3-10元杂脂环基、C 6-12双环脂环基、6-12元双环杂脂环基、C 8-15元三环脂环基、8-15元三环杂脂环基、C 5-8芳基、5-10元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)、-C 1-4烷基-(5-10元杂芳基)、-N(R 10)(R 11)、-N(R 10)(C(＝O)R 11)、-N(R 10)(C(＝O)-OR 11)、-N(R 12)(C(＝O)-N(R 10)(R 11))、-C(＝O)-N(R 10)(R 11)、-C(＝O)-R 12、-C(＝O)-OR 12、-OC(＝O)R 12、-N(R 10)(S(＝O) 2R 11)、-S(＝O) 2-N(R 10)(R 11)、-SR 12和-OR 12，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3-7脂环基、3-10元杂脂环基、C 6-12双环脂环基、6-12元双环杂脂环基，C 8-15元三环脂环基、8-15元三环杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1- 4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R 5a取代，且R 5a独立选自卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-8烯基、C 2-8炔基、C 3- 7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、-N(R 13)(R 14)、-N(R 13)(C(＝O)R 14)、-N(R 13)(C(＝O)-OR 14)、-N(R 15)(C(＝O)-N(R 13)(R 14))、-C(＝O)-N(R 13)(R 14)、-C(＝O)-R 15、-C(＝O)-OR 15、-OC(＝O)R 15、-N(R 13)(S(＝O) 2R 14)、-S(＝O) 2-N(R 13)(R 14)、-SR 15和-OR 15；
    且R 10、R 11、R 12、R 13、R 14、和R 15各自在每次出现时独立地选自：H、C 1-6烷基、C 1-6卤代烷基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1- 4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 6-12双环脂环基)、-C 1-4烷基-(6-12元双环杂脂环基)、-C 1-4烷基-(C 8-15元三环脂环基)、-C 1-4烷基-(8-15元三环杂脂环基)、-C 1-4烷基-(C 5-8芳基)和-C 1-4烷基-(5-10元杂芳基)，其中该群组内 的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-CN、-NO 2、-SF 5、-SH、-S-C 1-4烷基、氧代、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基、C 7-11双环芳基、7-11元双环杂芳基、C 1- 4羟烷基、-S-C 1-4烷基、-C(＝O)H、-C(＝O)-C 1-4烷基、-C(＝O)-O-C 1-4烷基、-C(＝O)-NH 2、-C(＝O)-N(C 1-4烷基) 2、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；或者R 10、R 11以及与它们相连的原子共同形成3-14元环；或者R 13、R 14以及与它们相连的原子共同形成3-14元环。
  2. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中n＝1或2。
  3. 根据权利要求1或2所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中X为-O-或-NH-。
  4. 根据权利要求1-3中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R 1和R 2各自独立地选自：H、F、Cl和Br。
  5. 根据权利要求1-4中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中L为-(C＝O)-、-(O＝S＝O)-、-CH 2-、-C(CH 3) 2-、-CH(CH 3)-或连接键。
  6. 根据权利要求1-5中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R 6为H。
  7. 根据权利要求1-6中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R 5选自H、卤素、-OH、-NO 2、-CN、-SF 5、-SH、-S-C 1-4烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6 卤代烷氧基、C 3-6脂环基、4-6元杂脂环基、C 5-8芳基、5-10元杂芳基、-C 1- 4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 5-8芳基)、-C 1-4烷基-(5-10元杂芳基)、-N(R 10)(R 11)，其中所述-S-C 1-4烷基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-6脂环基、4-6元杂脂环基、C 5-8芳基、5-10元杂芳基、-C 1-4烷基-(C 3-7脂环基)、-C 1-4烷基-(3-10元杂脂环基)、-C 1-4烷基-(C 5-8芳基)、-C 1-4烷基-(5-10元杂芳基)各自任选地被0、1、2、3或4个R 5a取代，且R 5a独立选自卤素、-OH、-NO 2、-CN、氧代、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-7脂环基、3-10元杂脂环基、C 5-8芳基、5-7元杂芳基；
    且R 10、R 11和R 12各自在每次出现时独立地选自：H、C 1-6烷基、C 1-6卤代烷基、C 3-7脂环基、3-10元杂脂环基，其中该群组内的各个选项任选地被0、1、2、3或4个各自独立选自以下群组的取代基所取代：卤素、-OH、-NH 2、氧代、C 1-4烷基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；或者R 10、R 11以及与它们相连的原子共同形成3-8元环。
  8. 根据权利要求7所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中R 5选自H、卤素、-OH、甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基和吡唑基，其中的甲基、乙基、丙基、丁基、戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、哌嗪基、哌啶基、吗啉基、吡咯烷基、吡咯基、吗啉基、吡啶基、吡唑基各自任选地被1或2个R 5a取代，且R 5a独立选自卤素、-OH、-NO 2、-CN、氧代、C 1-4烷基、C 1-4卤代烷基和C 1-4烷氧基。
  9. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中所述化合物选自：
    N-(1-(1-(3,5-二氟苯基)乙基)-3-(1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺；
    N-(3,5-二氟苄基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺；
    5-(3,5-二氟苄基)-3-(5-(甲基磺酰基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-N，N-二甲基-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)甲酰胺；
    2-(二甲基氨基)乙基2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯；
    (2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(1-甲基哌啶-4-基)甲酮；
    2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-5-(1-甲基哌啶-4-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶；
    (S)-5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    1-甲基哌啶-4-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯；
    N-(1-(3,5-二氟苯基)乙基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺；
    N-(1-(1-，3,5-二氟苯基)乙基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑-5-胺；
    环丙基(2-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲酮；
    5-(3,5-二氟苄基)-3-(5-(1-甲基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(哌啶-4-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-乙基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    2-(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-N，N-二甲基乙-1-胺；
    1-(4-((2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-基)乙-1-酮；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基吡咯烷-3-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(2-(1-甲基哌啶-4-基)乙基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-异丙基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-(1-甲基哌啶-4-基)乙基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(哌啶-3-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(哌啶-2-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-((1-甲基氮杂环丁烷-3-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    3-(5-((1-环丁基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-异丙基-4-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    (2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)(4-甲基哌嗪-1-基)甲酮；
    1-甲基吡咯烷-3-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯；
    1-甲基氮杂环丁烷-3-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯；
    (R)-5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    1-甲基哌啶-3-基-2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-羧酸酯；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-(1-甲基氮杂环丁烷-3-基)乙基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    4-(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-N,N-二甲基环己烷-1-胺；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-(甲基磺酰基)哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑；
    4-((2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)甲基)哌啶-1-羧酸甲酯；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-乙基哌啶-4-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(2-甲基-2-氮杂螺[3.3]庚烷-6-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(7-甲基-7-氮杂螺[3.5]壬烷-2-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-甲基吡咯烷-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(吡咯烷-2-基甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑；
    5-(1-(3,5-二氟苯基)乙氧基)-3-(5-(1-乙基哌啶-3-基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H吲唑；
    3-(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-N,N-二甲基环丁烷-1-胺；
    3-(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-N,N-二甲基环己烷-1-胺；
    3-(2-(5-(1-(3,5-二氟苯基)乙氧基)-1H-吲唑-3-基)-4,6-二氢吡咯并[3,4-d]咪唑-5(1H)-基)-N，N-二甲基环戊烷-1-胺；
    3-氟-5-(1-(3-(5-((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲哚-5-基)氧基)乙基)苯甲腈；
    5-(1-(3,5-二氟苯基)丙氧基)-3-(5-((1-甲基哌啶-4-基)甲基)-1,4,5,6-四氢吡咯并[3,4-d]咪唑-2-基)-1H-吲唑。
  10. 根据权利要求1所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，其中所述式(I)化合物为下面式(Ia)所示的化合物：
    Figure PCTCN2022100186-appb-100002
    其中，X为-O-或-(NH)-；L、n、R 3、R 5、R 6如权利要求1所定义；
    或下面式(Ib)所示的化合物：
    Figure PCTCN2022100186-appb-100003
    其中，L、n、R 5、R 6如权利要求1所定义；
    或下面式(Ic)所示的化合物：
    Figure PCTCN2022100186-appb-100004
    其中，X为-O-或-(NH)-；n、R 3、R 5、R 6、R a、R b如权利要求1所定义；
    或下面式(IIa)所示的化合物：
    Figure PCTCN2022100186-appb-100005
    其中，n、R 5、R 6、R a、R b如权利要求1所定义；
    或下面式(IIb)所示的化合物：
    Figure PCTCN2022100186-appb-100006
    其中，n、R 5、R 6、R a、R b如权利要求1所定义。
  11. 一种药物组合物，其包含根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物，以及一种或多种药学上可接受的载体、佐剂或赋形剂。
  12. 根据权利要求1-10中任一项所述的化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前药、或其代谢物或者根据权利要求15所述的药物组合物在制备用于治疗与TRK激酶或NTRK基因相关的疾病或病症的药物中的用途。
  13. 根据权利要求12所述的用途，其中所述与TRK激酶或NTRK基因相关的疾病和病症选自：癌症、疼痛、炎症、神经变性疾病和细胞增殖疾病，优选地选自肝细胞癌、乳腺癌、膀胱癌、结肠直肠癌、黑色素瘤、间皮瘤、肺癌、前列腺癌、膜腺癌、胰腺癌、食道癌、胃癌、淋巴癌、白血病、鼻咽癌、睾丸癌、甲状腺癌、鳞状细胞癌、神经胶母细胞瘤、成神经细胞瘤、子宫癌、横纹肌肉瘤。
PCT/CN2022/100186 2021-06-21 2022-06-21 Trk激酶抑制剂化合物及其用途 WO2022268080A1 (zh)

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