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WO2024213032A1 - Indole compound, preparation method therefor, and use thereof - Google Patents

Indole compound, preparation method therefor, and use thereof Download PDF

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Publication number
WO2024213032A1
WO2024213032A1 PCT/CN2024/087175 CN2024087175W WO2024213032A1 WO 2024213032 A1 WO2024213032 A1 WO 2024213032A1 CN 2024087175 W CN2024087175 W CN 2024087175W WO 2024213032 A1 WO2024213032 A1 WO 2024213032A1
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Prior art keywords
group
membered
alkyl
cycloalkyl
independently
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French (fr)
Chinese (zh)
Inventor
陈德恒
贾海飞
赵乐乐
吴凌云
申华琼
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Neushen Therapeutics Shanghai Co Ltd
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Neushen Therapeutics Shanghai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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    • 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
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the invention relates to an indole compound and a preparation method and application thereof.
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs serotonin and norepinephrine reuptake inhibitors
  • psychedelic drugs such as ketamine, psilocybin, and lysergic acid diethylamide (LSD) have a rapid onset of antidepressant effects and have long-term effects on brain function by regulating neuroplasticity. Therefore, the development of drugs that regulate neuroplasticity has broad application prospects in the treatment of neuropsychiatric diseases.
  • the technical problem to be solved by the present invention is to provide a novel indole compound and its application in view of the lack of compounds for regulating neuronal plasticity in the prior art.
  • the present invention provides a compound with clinically relevant therapeutic efficacy, which is relatively easy to synthesize, has improved physicochemical properties, pharmacokinetic properties or significant antidepressant effects.
  • the present invention solves the above technical problems through the following methods.
  • the present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • X is CH or N
  • R 1 is nitro, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;
  • R 1-1 and R 1-2 are independently deuterium or halogen
  • R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;
  • Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;
  • two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently hydrogen or C 1-6 alkyl
  • Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • Each L 2-1-1 is independently deuterium
  • Each L 2-1-2 is independently C 1-6 alkyl
  • Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;
  • L 1 is an ethylene group substituted by one or more L 1-2 , each L 1-2 are independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring with the carbon atom to which they are commonly attached;
  • R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 ;
  • X is CH or CR X ;
  • RX is halogen or C1-6 alkyl
  • R 1-2 are independently deuterium or halogen
  • RX its adjacent R1 and the carbon atom to which they are each attached together form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring;
  • R2 and R3 are each independently hydrogen, C1-6 alkoxy or halogen
  • R1 and R2 together with the carbon atoms to which they are attached form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring;
  • R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • L 1 is a methylene group substituted by one or more L 1-1 or an ethylene group substituted by one or more L 1-2 ;
  • Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;
  • two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , C 3-6 cycloalkyl substituted by one or more L 2-1-2 , or C 1-6 alkoxy substituted by one or more L 2-1-3 ;
  • Each L 2-1-1 is independently deuterium, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • Each L 2-1-2 is independently C 1-6 alkyl
  • Each L 2-1-3 is independently a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl
  • Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring;
  • heterocyclic hydrocarbon group the type of heteroatoms is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;
  • the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;
  • the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;
  • the heteroatom is N or N and O, and the number of the heteroatoms is independently 1 or 2.
  • certain groups in the compound of formula (I), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention”).
  • the halogen is F, Cl, Br or I.
  • each L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • each " C1-6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • each " C1-6 alkoxy group” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.
  • the C3-12 cycloalkyl is a C3-6 monocyclic cycloalkyl or a C6-12 polycyclic cycloalkyl; the C3-6 monocyclic cycloalkyl may be a C3-6 monocyclic cycloalkyl or a C3-6 monocyclic cycloalkenyl; the C6-12 polycyclic cycloalkyl may be a C6-12 spirocyclic cycloalkyl, a C6-12 paracyclic cycloalkyl or a C6-12 bridged cycloalkyl; the C6-12 spirocyclic cycloalkyl may be a C6-12 spirocyclic cycloalkyl or a C6-12 spirocyclic cycloalkenyl; the C6-12 paracyclic cycloalkyl may be a C6-12 paracyclic cycloalkyl or a C6-12 paracyclic cycloalkyl or a C6-12 paracyclic
  • the 3-12 membered heterocyclic hydrocarbon group is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group;
  • the 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group;
  • the 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 6-12 membered bridged heterocyclic hydrocarbon group;
  • the 6-12 membered spirocyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkenyl group;
  • the halogen is independently F, Cl, Br or I, for example, F.
  • the halogen is independently F, Cl, Br or I, such as F.
  • the halogen is F, Cl, Br or I.
  • the C1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C3-6 cycloalkyl is a C3-6 cycloalkyl or a C3-6 cycloalkenyl, such as a C3-6 cycloalkyl, further such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the described 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, such as a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, further such as an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a dihydrofuranyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydropyridinyl group or a dihydropyranyl group.
  • the above-mentioned halogen is independently F, Cl, Br or I, for example, F.
  • the C 1-6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.
  • the C5-6 carbocyclic ring is a C5-6 saturated carbocyclic ring or a C5-6 carbene ring.
  • the 5-6-membered heterocyclic ring is a 5-6-membered saturated heterocyclic ring or a 5-6-membered heterocyclic alkene, such as dihydrofuran or 1,3-dioxole.
  • the C 3-5 carbocycle is a C 3-5 saturated carbocycle or a C 3-5 carbene ring, such as a C 3-5 saturated carbocycle, further such as cyclopropane, cyclobutane or cyclopentane, preferably cyclopropane.
  • the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.
  • the C 3-5 carbocycle is a C 3-5 saturated carbocycle or a C 3-5 carbene ring, such as a C 3-5 saturated carbocycle, further such as cyclopropane, cyclobutane or cyclopentane, preferably cyclopropane or cyclobutane.
  • the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.
  • the C 3-5 carbocyclic ring is a C 3-5 saturated carbocyclic ring or a C 3-5 carbene ring, for example, a C 3-5 saturated carbocyclic ring, further
  • the steps are for example cyclopropane, cyclobutane or cyclopentane.
  • the above-mentioned 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.
  • the "C 3-12 cycloalkyl” is a C 3-6 monocyclic cycloalkyl or a C 6-12 polycyclic cycloalkyl;
  • the C 3-6 monocyclic cycloalkyl group may be a C 3-6 monocyclic cycloalkyl group or a C 3-6 monocyclic cycloalkenyl group, such as a C 3-6 monocyclic cycloalkyl group, further such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, such as a cyclopentyl group or a cyclohexyl group;
  • the C 6-12 polycyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group, a C 6-12 paracyclic cycloalkyl group or a C 6-12 bridged cycloalkyl group;
  • the C 6-12 spirocyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group or a C 6-12 spirocyclic cycloalkenyl group, such as a C 6-12 spirocyclic cycloalkyl group, further such as a spiro[3.3]heptyl group, a spiro[3.4]octyl group, a spiro[3.5]nonyl group, a spiro[4.5]decyl group or a spiro[5.5]undecyl group;
  • the C 6-12 cycloalkyl group may be a C 6-12 cycloalkyl group or a C 6-12 cycloalkenyl group, such as a C 6-12 cycloalkyl group, further such as a bicyclo[3.1.0]hexyl group or a bicyclo[3.3.0]octyl group, for example
  • the C 6-12 bridged ring cycloalkyl group may be a C 6-12 bridged ring cycloalkyl group or a C 6-12 bridged ring cycloalkenyl group, for example a C 6-12 bridged ring cycloalkyl group, further for example a bicyclo[2.2.2]octanyl group.
  • the "3-12 membered heterocyclic hydrocarbon group” is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group;
  • the 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group; the 3-7 membered monocyclic heterocyclic alkyl group may be a 4-7 membered monocyclic heterocyclic alkyl group, such as azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl or 1,4-oxaazepanyl, such as
  • the 3-7 membered monocyclic heterocycloalkenyl group may be a 4-7 membered monocyclic heterocycloalkenyl group, such as dihydropyrrolyl, preferably
  • the 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 7-12 membered bridged heterocyclic hydrocarbon group;
  • the 6-12 membered spirocyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkenyl group.
  • the spirocyclic heterocycloalkyl group may be a 6-11-membered spirocyclic heterocycloalkyl group in which the heteroatom is N and the number of heteroatoms is 1 or 2, for example, any one of the following:
  • Case 1 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane or 2-azaspiro[3.5]nonane, further such as
  • Case 2 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 9-aza-3-oxaspiro[5.5]undecane, 1-aza-8-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[3.5]nonane, 6-azaspiro[2.5]octane, 8-aza-2-oxaspiro[4.5]decane, 2-aza-6-oxaspiro[3.4]octane, 6-aza-2-oxaspiro[3.3]heptane or 5-azaspiro[2.3]hexane, preferably
  • the 6-12 membered heterocyclic hydrocarbon group may be a 6-12 membered heterocyclic alkyl group or a 6-12 membered heterocyclic alkenyl group
  • the 6-12 membered heterocyclic alkyl group may be a 6-10 membered heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example
  • the 6-12 membered bridged heterocyclic hydrocarbon group may be a 6-12 membered bridged heterocyclic alkyl group or a 6-12 membered bridged heterocyclic alkenyl group; the 6-12 membered bridged heterocyclic alkyl group may be a 6-12 membered bridged heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example, any one of the following:
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • the halogen is independently F, Cl, Br or I.
  • each "C 1-6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.
  • each "C 1-6 alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.
  • each "C 3-6 cycloalkyl group” is independently a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
  • the 3-6 membered heterocyclic hydrocarbon group is each independently a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group
  • the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms as N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • the halogen is F, Cl, Br or I.
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
  • the C 3-6 cycloalkyl group is a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group
  • the C 3-6 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the C 3-6 cycloalkyl groups are each independently C 3-6 cycloalkyl or C 3-6 cycloalkenyl, and the C 3-6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl
  • the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group
  • the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms as N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.
  • the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group
  • the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group whose heteroatoms are N and/or O and the number of heteroatoms is 1 or 2, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.
  • the 3-12-membered nitrogen-containing heterocyclic ring may independently be a 3-7-membered nitrogen-containing monocyclic heterocyclic ring or a 6-12-membered nitrogen-containing polycyclic heterocyclic ring;
  • the 3-7 membered nitrogen-containing monocyclic heterocycle may be a 3-7 membered saturated nitrogen-containing monocyclic heterocycle or a 3-7 membered nitrogen-containing monocyclic heterocycle alkene, and the 3-7 membered nitrogen-containing monocyclic heterocycle may be a 4-6 membered saturated nitrogen-containing monocyclic heterocycle in which the heteroatom is N or N and O and the number of heteroatoms is 1 or 2, such as azetidine, tetrahydropyrrole ring, piperidine ring, morpholine ring or piperazine ring;
  • the 6-12 membered nitrogen-containing polycyclic heterocycle may be a 6-12 membered nitrogen-containing spirocyclic heterocycle, a 6-12 membered nitrogen-containing cyclic heterocycle or a 6-12 membered nitrogen-containing bridged heterocycle;
  • the 6-12 membered nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle or a 6-12 membered nitrogen-containing spiro heterocycle alkene.
  • the 6-12 membered saturated nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azaspiro[2.4]heptane, azaspiro[2.5]octane, azaspiro[3,3]heptane or azaspiro[3,5]nonane, preferably
  • the 6-12 membered nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle or a 6-12 membered nitrogen-containing paracyclic heterocycle alkene
  • the 6-12 membered saturated nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle wherein the heteroatom is N and the number of heteroatoms is 1 or 2, further for example, azabicyclo[3.1.0]hexane or octahydrocyclopentapyrrole;
  • the 6-12 membered nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle or a 6-12 membered nitrogen-containing bridged ring heterocycle alkene.
  • the 6-12 membered saturated nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azabicyclo[2.2.2]octane.
  • X is CH.
  • X is N.
  • RX is a halogen, such as F.
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 , for example, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 .
  • R1 is hydroxyl or C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are respectively attached form a 5-6 membered heterocyclic ring, or RX together with its adjacent R1 and the carbon atom to which they are respectively attached form a 5-6 membered heterocyclic ring.
  • R1 is a C1-6 alkoxy group, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX together with its adjacent R1 and the carbon atom to which they are attached form a 5-6 membered heterocyclic ring.
  • R 1-2 is independently deuterium or halogen; for example, deuterium.
  • R 3 is hydrogen or halogen; for example, hydrogen.
  • R 8 is hydrogen, deuterium or cyano, for example, hydrogen or cyano; for example, hydrogen.
  • L 1 is a connecting bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;
  • Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;
  • two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring.
  • L 1 is a connecting bond or a methylene group substituted by one or more L 1-1 ;
  • Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl; preferably, each L 1-1 is independently hydrogen or deuterium.
  • L1 is a methylene group.
  • each L 2-0 is independently C 1-6 alkyl.
  • each L 2-1 is independently -N(L 2-3 ) 2 .
  • each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 .
  • each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 or C 3-6 cycloalkyl substituted by one or more L 2-1-2 , preferably C 1-6 alkyl.
  • each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 or C 1-6 alkyl substituted by one or more L 2-1-1 ; preferably, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; more preferably, it is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; most preferably, it is C 1-6 alkyl or C 1-6 alkoxy.
  • each L 2-1-1 is independently deuterium or a C 3-6 cycloalkyl group, such as deuterium.
  • each L 2-1-1 is deuterium.
  • each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are commonly connected form a 3-12 membered nitrogen-containing heterocyclic ring; preferably, each L 2-3 is independently a C 1-6 alkyl group.
  • L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • Each L 2-1-1 is independently deuterium
  • Each L 2-1-2 is independently C 1-6 alkyl
  • Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.
  • L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2- 3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • Each L 2-1-1 is independently deuterium
  • Each L 2-1-2 is independently C 1-6 alkyl
  • Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.
  • L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ;
  • Each L 2-1-1 is independently deuterium
  • Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.
  • L2 is a 3-12 membered heteroaryl substituted by 1, 2 or 3 L2-2. Cycloalkyl;
  • Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ;
  • Each L 2-1-1 is independently deuterium.
  • L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2
  • L 2-2 is a C 1-6 alkyl group
  • L 2 is an azetidinyl group substituted by 1, 2 or 3 L 2-2
  • L 2-2 is a C 1-6 alkyl group
  • X is CH or N
  • R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;
  • R 1-2 are independently deuterium or halogen
  • R 8 is hydrogen or cyano
  • L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;
  • Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;
  • two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2- 3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • L 2-1-1 is independently deuterium
  • L 2-1-2 is independently C 1-6 alkyl
  • L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;
  • L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .
  • X is CH or N
  • R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;
  • R 1-2 are independently deuterium
  • R8 is hydrogen
  • L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;
  • Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl
  • L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ;
  • L 2-1-1 is independently deuterium
  • L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;
  • R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .
  • X is CH or N
  • R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;
  • R 1-2 are independently deuterium
  • R8 is hydrogen
  • L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;
  • Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl
  • L 2 is a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; the "3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;
  • Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ;
  • L 2-1-1 is independently deuterium.
  • X is CH or N
  • R1 is C1-6 alkoxy
  • R8 is hydrogen
  • L 1 is a connecting bond or a methylene group substituted by one or more L 1-1 ;
  • Each L 1-1 is independently hydrogen or deuterium
  • L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1 or 2.
  • X is CH
  • R1 is C1-6 alkoxy
  • R8 is hydrogen
  • L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;
  • Each L 1-1 is independently hydrogen or deuterium
  • L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1.
  • X is CH or N
  • R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;
  • R 1-2 are independently deuterium or halogen
  • R 8 is hydrogen or cyano
  • L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;
  • Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;
  • two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-0 is independently C 1-6 alkyl
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;
  • L 2-1-1 is independently deuterium
  • L 2-1-2 is independently C 1-6 alkyl
  • L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;
  • L2 is a C3-12 cycloalkyl substituted by 1, 2 or 3 L2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L2-2 , wherein the " C3-12 cycloalkyl” is a C3-12 monocyclic cycloalkyl.
  • "3-12 membered heterocyclic hydrocarbon group” is a 3-12 membered monocyclic heterocyclic hydrocarbon group;
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;
  • L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;
  • R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .
  • R 1 is a C 1-6 alkoxy group.
  • R 8 is hydrogen
  • L 1 is a connecting bond or an ethylene group substituted by one or more L 1-2 .
  • each L 1-2 is independently hydrogen.
  • L 2 is a C 3-12 cyclic hydrocarbon group substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 .
  • each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.
  • L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;
  • Each L 2-1 is independently -N(L 2-3 ) 2 ;
  • Each L 2-3 is independently C 1-6 alkyl
  • Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.
  • X is CH or CR X ;
  • RX is halogen or C 1-6 alkyl;
  • R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring;
  • R2 is hydrogen, C1-6 alkoxy or halogen
  • R3 is hydrogen or halogen
  • L 1 is a methylene group
  • L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 , each L 2-1-1 is independently C 3-6 cycloalkyl or deuterium.
  • X is CH or CR X ; RX is halogen;
  • R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring;
  • R2 is hydrogen, C1-6 alkoxy or halogen
  • R3 is hydrogen or halogen
  • L 1 is a methylene group
  • L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 alkyl group substituted by one or more L 2-1-1 ; each L 2-1-1 is deuterium.
  • X is CH or CR X ; RX is halogen;
  • R1 is a C1-6 alkoxy group, or RX , its adjacent R1 and the carbon atom to which they are attached together form a 5-6 membered heterocyclic ring;
  • R2 is hydrogen, C1-6 alkoxy or halogen
  • R3 is hydrogen
  • L 1 is a methylene group
  • L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl is N, and the number of heteroatoms is 1 or 2;
  • R2 is hydrogen
  • R3 is hydrogen
  • the number of heteroatoms in the 3-7 membered monocyclic heterocycloalkyl group is 1.
  • X is CH, CF or C-CH 3 , or RX and its adjacent R 1 and the carbon atom to which they are connected together form
  • the carbon atom marked with "a” indicates that it is the carbon atom corresponding to X; preferably, X is CH, or RX and its adjacent R1 and the carbon atom to which they are connected together form
  • the carbon atom labeled "a” indicates that it is the carbon atom corresponding to X.
  • X is CH or CF, or RX and its adjacent R1 and the carbon atom to which they are connected together form The carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.
  • R 1-1 is deuterium or F.
  • R 1 is methoxy
  • R 1 is methoxy
  • R 1 is
  • R 1 is methoxy
  • R1 is hydroxyl or methoxy, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form
  • the carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.
  • the carbon atom marked with "a” represents It is the carbon atom corresponding to X.
  • R1 is a methoxy group, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form
  • the carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.
  • R 8 is hydrogen or cyano.
  • R 8 is hydrogen
  • R2 is hydrogen, methoxy or F, or R1 and R2 together with the carbon atoms to which they are connected form
  • R2 is hydrogen, methoxy or F, or, R1 and R2 together with the carbon atoms to which they are attached form
  • R 3 is hydrogen or F.
  • each L 1-1 and L 1-2 are independently hydrogen, deuterium, F or methyl;
  • two L 1-1 groups on the same carbon atom and the carbon atom to which they are commonly attached form a cyclopropane or cyclobutane;
  • two L 1-2 on the same carbon atom form cyclopropane or cyclobutane with the carbon atom to which they are commonly attached.
  • L1 is a connecting bond, a methylene group, an ethylene group, Preferably, it is a linker, a methylene group, an ethylene group, The # side is connected to L2 .
  • L1 is a connecting bond, a methylene group, an ethylene group, Preferably, it is a linker, a methylene group, an ethylene group, Wherein the # side is connected to L2 ; more preferably, it is a connecting bond, methylene, ethylene, Most preferably, a linker, a methylene group,
  • L1 is Preferably The # side is connected to L2 .
  • L1 is methylene
  • Preferred is methylene
  • each L 2-0 is independently a methyl group.
  • each L 2-1 is -N(CH 3 ) 2 or
  • each L 2-2 is independently methyl, cyclopropyl, methoxy, -N(CH 3 ) 2 ,
  • L 2 is -N(CH 3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably For example
  • L 2 is -N(CH 3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably For example
  • L2 is n is 1, 2, or 3, preferably 1; L2 is preferably For example Further example
  • L2 is n is 1, 2 or 3;
  • L 2 is preferably n is 1, 2 or 3;
  • L2 is N
  • the compound represented by formula (I) is a compound represented by formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6):
  • R 1 , R 8 , L 2 , L 1-1 and L 1-2 are as defined in any of the preceding embodiments.
  • L2 is n is 1, 2 or 3, preferably 1; L2 is preferably
  • L2 is n is 1, 2 or 3, preferably 1; L2 is preferably
  • L2 is n is 1, 2 or 3, preferably 1; L2 is preferably
  • L2 is n is 1, 2 or 3, preferably 1; L2 is preferably
  • L 2 is -N(CH 3 ) 2
  • at least one L 1-2 is deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom form a C 3-5 carbocycle with the carbon atom to which they are connected.
  • L1 is a methylene group
  • L2 is a C3-12 cycloalkyl group substituted by 1, 2 or 3 L2-1 groups , or a 3-12 membered heterocycloalkyl group substituted by 1, 2 or 3 L2-2 groups ; when the carbon atom in L2 is connected to L1 , the carbon atom in L2 connected to L1 is a chiral carbon atom, and the chiral carbon atom is in R configuration, S configuration or a mixture of R configuration and S configuration.
  • the compound represented by formula (I) is a compound represented by formula (IA), (IB) or (IC):
  • R 1 , R 2 , R 3 , X, L 2-2 and R 8 are as defined in any of the preceding embodiments.
  • R 3 is H and X is CH.
  • the compound represented by formula (I) is a compound represented by formula (I-7):
  • R 1 , R 2 , R 3 , X and R 8 are defined as described in any of the previous schemes; preferably, R 3 is H, and X is CH.
  • the present invention also provides a compound as shown below, their pharmaceutically acceptable salts, their solvates or their pharmaceutically acceptable Acceptable salt solvates:
  • Monoformate Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, monoformate, monoformate or The monoformate.
  • the compound represented by formula (I) is any of the following compounds:
  • the stationary phase of the chromatographic column is C18
  • the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min
  • the model of the chromatographic column is: Waters-Xbridge-C18-10 ⁇ m-19*250mm, and more preferably, the retention time of the compound that elutes first is 9min;
  • the stationary phase of the chromatographic column is C18
  • the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min
  • the model of the chromatographic column is: Waters-Xbridge-C18-10 ⁇ m-19*250mm, and more preferably, the retention time of the compound that elutes later is 9.2min;
  • the stationary phase of the chromatographic column is C18
  • the mobile phase is a mixture of A and B, wherein A is acetonitrile
  • B is a 0.1% (v/v) formic acid aqueous solution
  • the volume percentage of A in the mobile phase is 10-20%
  • elution time is 17 min
  • the model of the chromatographic column is: Waters-SunFire-C18-10 ⁇ m-19*250 mm, and more preferably, the retention time of the compound that elutes first is 7.3 min;
  • the stationary phase of the chromatographic column is C18, and the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is 0.1% (v/v) formic acid aqueous solution, the volume percentage of A in the mobile phase is 10-20%, gradient elution, flow rate 20mL/min, elution time is 17min;
  • the model of the chromatographic column is: Waters-SunFire-C18-10 ⁇ m-19*250mm, more preferably, the retention time of the late peak compound is 7.7min;
  • the stationary phase of the chromatographic column is C18
  • the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20mL/min, and elution time is 17min
  • the model of the chromatographic column is: Waters-XBndge-C18-10 ⁇ m-19*250mm, and more preferably, the retention time of the compound that elutes first is 5.7min;
  • the stationary phase of the chromatographic column is C18
  • the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10 mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20 mL/min, and elution time is 17 min
  • the model of the chromatographic column is: Waters-XBndge-C18-10 ⁇ m-19*250 mm, and more preferably, the retention time of the compound that elutes later is 7.5 min.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable carrier, wherein the substance X is the compound described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition, which comprises a substance X and a pharmaceutically acceptable carrier, wherein the substance X is the compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
  • the present invention also provides use of the compound described in any of the above schemes, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a drug for regulating neuronal plasticity.
  • the present invention also provides a use of any of the above compounds as shown in formula (I), their pharmaceutically acceptable salts, their solvates, their pharmaceutically acceptable salt solvates or the above pharmaceutical compositions in the preparation of drugs for regulating neuronal plasticity.
  • the present invention also provides a use of the compound described in any of the above schemes, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a drug for preventing and/or treating depression, schizophrenia, anxiety or post-traumatic stress disorder.
  • the present invention also provides a use of any of the above compounds as shown in formula (I), their pharmaceutically acceptable salts, their solvates, their pharmaceutically acceptable salt solvates or the above pharmaceutical compositions in the preparation of drugs for preventing and/or treating depression, schizophrenia, anxiety or post-traumatic stress disorder.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • the pharmaceutically acceptable salts are formate, glutarate, caprylate, palmitate, and laurate.
  • solvate refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • pharmaceutically acceptable salt solvate refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the amount of the solvent may be stoichiometric or non-stoichiometric.
  • halogen refers to F, Cl, Br, I.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1-6 ). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • alkoxy refers to a group -ORX , wherein RX is alkyl as defined above.
  • cycloalkyl refers to a non-aromatic saturated or partially unsaturated cycloalkyl having a specified number of ring carbon atoms (e.g., C 3-12 or C 3-6 ), including cycloalkyl and cycloalkenyl.
  • the cycloalkyl may be monocyclic or polycyclic, and may be a cyclocyclic, spirocyclic, or bridged ring structure.
  • the cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, or bicyclo[3.3.0]octyl.
  • cycloalkyl refers to a saturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of ring carbon atoms (e.g., C 3-12 or C 3-6 ), wherein the ring atoms consist only of carbon atoms.
  • Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl refers to an unsaturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of carbon atoms (eg, C 3-8 ) and the ring atoms consisting only of carbon atoms, which is not aromatic.
  • heterocyclic hydrocarbon group refers to a non-aromatic saturated or partially unsaturated cyclic group having a specified number of ring atoms (e.g., 3-12 members, 3-6 members, or 3-5 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), including heterocyclic alkyl or heterocyclic alkenyl.
  • the heterocyclic hydrocarbon group may be a monocyclic or polycyclic ring, and may be a cyclic, spirocyclic, or bridged ring structure.
  • Heterocyclic hydrocarbon groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, 1,4-oxazaazacycloheptyl, dihydropyrrolyl, 4-azaspiro[2.4]heptyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, or 2-azabicyclo[2.2.2]octanyl.
  • heterocycloalkyl refers to a saturated monocyclic, spirocyclic, or heterocyclic ring having a specified number of ring atoms (e.g., 3-12, 3-6, or 3-5 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S).
  • ring atoms e.g., 3-12, 3-6, or 3-5 members
  • heteroatoms e.g., 1, 2, or 3
  • a specified type of heteroatoms e.g., 1, 2, or 3 of N, O, and S
  • Heterocycloalkyl includes but is not limited to azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, 1,4-oxazacycloheptyl, 2-azaspiro [3,3] heptyl, 2-azaspiro [3,5] nonyl, or 2-azabicyclo[2.2.2]octanyl.
  • heterocycloalkenyl refers to an unsaturated monocyclic, spirocyclic, bridged or cyclic hydrocarbon ring group having a specified number of ring atoms (e.g., 3-12, 3-6 or 3-5), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), and having no aromaticity.
  • ring atoms e.g., 3-12, 3-6 or 3-5
  • heteroatoms e.g., 1, 2 or 3
  • a specified heteroatom type one or more of N, O and S
  • heterocycle satisfies any of the following conditions, and the rest of the definition is the same as the term “heterocyclic hydrocarbon group”: 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • heterocycloalkene satisfies any of the following conditions, and the rest of the definition is the same as the term “heterocycloalkenyl”: 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • Carbocycle satisfies any of the following conditions, and the rest of the definition is the same as the term “cycloalkyl”: 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • carbene ring satisfies any of the following conditions, and the rest of the definition is the same as the term “cycloalkenyl”: 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
  • alkylene means a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon group by removing two hydrogen atoms; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above, for example, C1-6 alkylene.
  • one or more means 1, 2, 3, 4 or more.
  • pharmaceutically acceptable carrier refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • the wedge-shaped solid line key and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive and progressive effects of the present invention are that the compounds of the present invention are easier to synthesize, have improved physicochemical properties, pharmacokinetic properties or significant antidepressant effects.
  • Figure 1 Results of testing of compounds in promoting synaptic growth in rat primary cortical neurons.
  • Figure 2 Test results of compounds in increasing the number of head movements in mice.
  • Figure 3 Results of testing of compounds in reducing immobility time in forced swimming mice.
  • 6-Methoxyindole (2.40 g, 16.3 mmol) was dissolved in dichloromethane (20 mL), ethyl magnesium bromide in ether solution (19.6 mL, 19.6 mmol, 1 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours.
  • the crude intermediate was dissolved in dichloromethane (20 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours.
  • a saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2).
  • Dissolve compound 12-1 (2.00 g, 8.02 mmol) in dichloromethane (20 mL), add oxalyl chloride (0.76 mL, 8.83 mmol) dropwise at 0°C, stir for 10 minutes, slowly add N,N-dimethylformamide (0.12 mL, 1.60 mmol), stir at 0°C for 1.2 hours, and concentrate the reaction solution under reduced pressure to obtain the reaction solution of the intermediate.
  • reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 6-35%, retention time: 9 min) to obtain the monoformate of compound 13.
  • Dissolve compound 14-1 (1.00 g, 4.32 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.49 mmol) dropwise at 0°C, slowly add N,N-dimethylformamide (31.6 mg, 0.43 mmol), stir at 20°C for 3 hours, and concentrate the reaction solution under reduced pressure to obtain the reaction solution of the intermediate.
  • Dissolve 6-methoxyindole (589 mg, 4.00 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (3.53 mL, 12.0 mmol, 3.4 mol/L) at 0°C, and stir at 0°C for 1 hour.
  • compound 1-1 (2.20 g, 15.0 mmol) was dissolved in tetrahydrofuran (30 mL), methylmagnesium bromide (5.48 mL, 16.4 mmol, 3.0 M) was added, and the mixture was stirred at 25°C for 45 minutes.
  • a solution of 3,4-epoxytetrahydrofuran (1.42 g, 16.4 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 16 hours.
  • reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 4), and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain compound 15-2.
  • the crude product of the target compound was obtained, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 ⁇ m-19*250 mm, mobile phase: acetonitrile-10 mmol/L aqueous ammonium bicarbonate solution, gradient: 20-50%, retention time: 8.0 min) to obtain compound 15.
  • the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-35%, retention time: 10min) to obtain the monoformate of compound 16.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound.
  • the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 ⁇ m-19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 2-32%, flow rate 20 mL/min, elution time 17 min) to obtain the monoformate of compound 20 (retention time: 9 min).
  • 6-Methoxyindole (100 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide in ether solution (0.41 mL, 0.82 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours.
  • the crude intermediate was dissolved in dichloromethane (10 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours.
  • Dissolve compound 24-2 (440 mg, 2.73 mmol) in dichloromethane (2 mL), add ethylmagnesium bromide (1.77 mL, 3.55 mmol, 2.0 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min) to obtain compound 26.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min
  • reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min) to obtain compound 27.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min
  • reaction solution was cooled to room temperature, water (1 mL) was added dropwise, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 40-55%, retention time: 8.0min) to obtain compound 30.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 40-55%, retention time: 8.0min
  • the reaction was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% sodium hydroxide aqueous solution (0.33 mL) and water (0.33 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-7.5mmol/L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 17min) to obtain compound 31.
  • preparative high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-7.5mmol/L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 17min
  • Dissolve compound 32-5 (300 mg, 1.88 mmol) in dichloromethane (5 mL), add ethylmagnesium bromide (4.52 mL, 2.26 mmol, 2 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • the reaction was cooled to room temperature, quenched by adding ice water (0.06 mL), and 15% aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250 mm, mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution, gradient: 15-25%, retention time: 17 min) to obtain compound 32.
  • high performance liquid chromatography Waters-SunFire-C18-10 ⁇ m-19*250 mm, mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution, gradient: 15-25%, retention time: 17 min
  • the monoformate of 33 was further purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 10-20%, flow rate 20mL/min, elution time 17min, retention time: 7.7min).
  • the monoformate of 34 was further purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 10-20%, flow rate 20mL/min, elution time 17min, retention time: 7.3min).
  • the reaction was cooled to room temperature, quenched by adding ice water (0.2 mL), and 15% sodium hydroxide aqueous solution (0.2 mL) and water (0.6 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 37.
  • the reaction was cooled to room temperature, quenched by adding ice water (0.2 mL), and 15% sodium hydroxide aqueous solution (0.2 mL) and water (0.6 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified on a preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 38.
  • Dissolve compound 39-3 (900 mg, 5.99 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.71 mL, 6.71 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • reaction solution was cooled to room temperature, quenched by adding ice water (0.22 mL), and 15% sodium hydroxide aqueous solution (0.66 mL) and water (0.22 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonia aqueous solution, gradient: 25-35%, retention time: 17min) to obtain compound 39.
  • high performance liquid chromatography Waters-SunFire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonia aqueous solution, gradient: 25-35%, retention time: 17min
  • reaction solution was cooled to room temperature, quenched by adding ice water (0.1 mL), and 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.1 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 17.0 min) to obtain compound 40.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 17.0 min
  • Dissolve compound 41-1 (1.80 g, 8.19 mmol) in dichloromethane (15 mL), add ethylmagnesium bromide (8.2 mL, 8.2 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours.
  • Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour.
  • the monoformate of compound 41 was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 17.0min).
  • Dissolve compound 42-1 (1.00 g, 4.55 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (5.05 mL, 5.05 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours.
  • Dissolve the crude intermediate in dichloromethane (10 mL) add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • reaction solution was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% aqueous sodium hydroxide solution (0.33 mL) and water (0.11 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L aqueous ammonium bicarbonate solution, gradient: 25-35%, retention time: 17.0 min) to obtain compound 42.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L aqueous ammonium bicarbonate solution, gradient: 25-35%, retention time: 17.0 min
  • Dissolve compound 43-2 (1.00 g, 5.71 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.85 mL, 6.85 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding ice water (0.27 mL), and 15% sodium hydroxide aqueous solution (0.81 mL) and water (0.27 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 25-40%, retention time: 17.0 min) to obtain the monoformate of compound 43.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 25-40%, retention time: 17.0 min
  • Dissolve compound 44-1 (2.00 g, 9.10 mmol) in dichloromethane (20 mL), add ethylmagnesium bromide (10.1 mL, 10.1 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • the reaction solution was cooled to room temperature, quenched by adding ice water (0.20 mL), and 15% sodium hydroxide aqueous solution (0.60 mL) and water (0.20 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-10%, retention time: 17.0 min) to obtain the monoformate of compound 44.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-10%, retention time: 17.0 min
  • Dissolve compound 45-5 (450 mg, 2.83 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (3.11 mL, 3.11 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours.
  • Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours.
  • the reaction solution was cooled to room temperature, quenched by adding ice water (0.05 mL), and 15% sodium hydroxide aqueous solution (0.15 mL) and water (0.05 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min) to obtain the monoformate of compound 45.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min
  • Dissolve compound 46-6 (1.00 g, 6.05 mmol) in dichloromethane (20 mL), add ethylmagnesium bromide (7.26 mL, 7.26 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour.
  • the reaction solution was cooled to room temperature, quenched by adding ice water (0.15 mL), and 15% sodium hydroxide aqueous solution (0.45 mL) and water (0.15 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 10-20%, retention time: 17.0 min) to obtain the monoformate of compound 46.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 10-20%, retention time: 17.0 min
  • Dissolve compound 47-6 (1.00 g, 6.05 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.66 mL, 6.66 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour.
  • the reaction solution was cooled to room temperature, quenched by adding ice water (0.1 mL), and 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.1 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min) to obtain the monoformate of compound 47.
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min
  • reaction solution was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% sodium hydroxide aqueous solution (0.33 mL) and water (0.11 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L trifluoroacetic acid aqueous solution, gradient: 15-25%, flow rate 20mL/min, elution time 17min) to obtain compound 48 (retention time: 5.7min) or 49 (retention time: 7.5min).
  • high performance liquid chromatography Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L trifluoroacetic acid aqueous solution, gradient: 15-25%, flow rate 20mL/min, elution time 17min
  • Dissolve compound 51-1 (3.00 g, 21.1 mmol) in dichloromethane (50 mL), add ethylmagnesium bromide (25.3 mL, 25.3 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (20 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour.
  • the crude compound 51-4 (100 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.00 g, 8.80 mmol) and triethylsilane (512 mg, 4.40 mmol) were slowly added dropwise.
  • the reaction solution was stirred at 60 ° C for 4 hours under a nitrogen atmosphere.
  • the reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (30 mL) was added, and dichloromethane (50 mL x 3) was used for extraction.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 7.0 min) to obtain the monoformate of compound 51.
  • the activity of the compounds on 5-HT 2A receptor was determined using a stably transfected cell line (HEK293 cells) expressing human 5-HT 2A receptor.
  • Test compounds were diluted to 400-fold concentration of stock solution on 384-well LDV plates using DMSO. The compound solution was then transferred to the 384-well plate.
  • HEK-293/5-HT 2A cells were cultured using DMEM medium (10% FBS), and when the cells reached 80% of the density, the cells were detached using 0.25% Trypsin-EDTA.
  • the experimental samples were prepared from the corresponding examples. The results are shown in the table above.
  • the compounds of the present application showed agonist activity on 5-HT 2A receptors in this test system.
  • a stably transfected cell line expressing human 5-HT 2A receptor (cell line name: 5-HT 2A & beta-arrestin 2OE HEK293T, vector: pLVX-Puro/pCDHBSD, culture medium: DMEM+10% FBS+1% PS+2 ⁇ g/mL puromycin+5 ⁇ g/mL blasticidin), the agonist effect of the compound on the 5-HT 2A receptor was evaluated by the recruitment of beta-arrestin 2.
  • Human 5-HT-2A & beta-arrestin 2 OE HEK293T cells were cultured in DMEM complete medium (DMEM + 10% FBS + 1% P/S + 2 ⁇ g/mL Puromycin Dihydrochloride + 5 ⁇ g/mL Blasticidin S HCl), and digested and plated after the cell density reached about 80%.
  • DMEM complete medium DMEM + 10% FBS + 1% P/S + 2 ⁇ g/mL Puromycin Dihydrochloride + 5 ⁇ g/mL Blasticidin S HCl
  • Sample activity 100% ⁇ (average signal value per well of sample wells – average signal value per well of negative control wells) / (average signal value per well of positive control wells – average signal value per well of negative control wells)
  • the experimental samples were prepared from the corresponding examples. The results are shown in the table above.
  • the compounds of the present application showed agonist activity on 5-HT 2A receptors in the test system.
  • Cortical neurons were isolated from the 18-day-old rat embryonic brain.
  • the detailed neuron culture method is as follows:
  • mice were purchased from Shanghai Experimental Animal Research Center (certificate number: SCXK (Shanghai) 2018-0006, quality control: 20180006050501). Rats at 18 days of gestation were killed with carbon dioxide, and the embryos were removed from the uterus. The brains were then removed and placed in DPBS on ice to separate the cortical tissue. After incubation with 1 mL of papain digestion solution at 37°C for 8 to 10 min, the digestion was terminated with 2 mL of papain inhibitor solution, and the cortical tissue was blown with a pipette until there were no visible tissue chunks. Then, it was filtered through a 70 ⁇ m filter and centrifuged at 1000 rpm for 5 min.
  • the supernatant was removed and resuspended in culture medium. Trypan blue was then used to count the live cells to determine whether the cells were viable. Rate. 2 x 10 ⁇ 5 neuronal cells were inoculated in a 35 mm culture dish with a cell slide coated with 0.1 mg/mL poly-d-lysine hydrochloride, 2 mL of culture medium was added to each dish, and finally placed in a 37°C, 5% CO2/95% O2 incubator for culture. The inoculation time was day 0.
  • Control group treated with 0.1% DMSO;
  • Immunofluorescence images were taken by a Nikon A1 laser confocal microscope; neurites were manually counted and synaptic length was analyzed by FIJI (Image J) software; data were processed by Graphpad Prism 8.3 and Excel.
  • One-way ANOVA analysis was performed to analyze the statistical differences between groups. The significance of the difference was p ⁇ 0.05 for significant difference, p ⁇ 0.01, p ⁇ 0.001, and p ⁇ 0.0001 for very significant difference. * represents p ⁇ 0.05, ** represents p ⁇ 0.01, *** represents p ⁇ 0.001, and **** represents p ⁇ 0.0001.
  • test samples were prepared from the corresponding examples, and the results showed that the compounds of the present application can significantly promote the synaptic growth of primary cortical neurons in rats.
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous, subcutaneous and oral gavage administration were tested by standard protocols.
  • the candidate compound was prepared into a clear solution or suspension with a specified solvent and given a single intravenous injection, subcutaneous injection and oral gavage to three mice.
  • the solvents for intravenous, subcutaneous and oral gavage administration were all 10% sulfobutyl- ⁇ -cyclodextrin aqueous solution.
  • Whole blood samples were collected within 8 hours into commercial EDTA2K anticoagulant tubes, centrifuged to obtain the upper plasma sample, and acetonitrile solution containing internal standard was added to precipitate the protein. The supernatant was centrifuged and added with an equal volume of water. After centrifugation, the supernatant was sampled and the blood drug concentration was quantitatively analyzed by LCMS/MS analysis method and the pharmacokinetic parameters were calculated.
  • test samples were prepared from the corresponding examples, and the results showed that the examples of the present invention had good pharmacokinetic properties in mice.
  • the pharmacokinetic properties of the compounds obtained in the examples of the present invention were evaluated in SD rats.

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Abstract

Disclosed in the present invention are an indole compound, a preparation method therefor, and a use thereof. Specifically, disclosed in the present invention is a compound as represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound as represented by formula (I) in the present invention is easy to synthesize, and has improved physicochemical properties and pharmacokinetic properties or a significant anti-depression effect.

Description

一种吲哚类化合物及其制备方法与应用Indole compound and preparation method and application thereof

本申请要求申请日为2023年4月11日的中国专利申请2023103818868、2023年5月23日的中国专利申请2023105862314、2023年7月3日的中国专利申请202310805991X、2023年9月6日的中国专利申请2023111456680、2023年9月28日的中国专利申请202311273881X、2023年11月16日的中国专利申请2023115312221、2023年12月25日的中国专利申请2023117961217和2024年4月2日的中国专利申请2024103975100的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2023103818868 filed on April 11, 2023, Chinese patent application 2023105862314 filed on May 23, 2023, Chinese patent application 202310805991X filed on July 3, 2023, Chinese patent application 2023111456680 filed on September 6, 2023, Chinese patent application 202311273881X filed on September 28, 2023, Chinese patent application 2023115312221 filed on November 16, 2023, Chinese patent application 2023117961217 filed on December 25, 2023, and Chinese patent application 2024103975100 filed on April 2, 2024. The entire text of the above-mentioned Chinese patent application is cited in this application.

技术领域Technical Field

本发明涉及一种吲哚类化合物及其制备方法与应用。The invention relates to an indole compound and a preparation method and application thereof.

背景技术Background Art

许多精神障碍类疾病与大脑5-羟色胺能系统的功能受损、退化或异常改变相关。因此，针对5-羟色胺能系统调控的药物如选择性5-羟色胺再摄取抑制剂(SSRI)、5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)等药物已广泛应用于抑郁症、焦虑症、精神分裂症等精神障碍类疾病的治疗。但上述疗法起效慢，对部分病人药效不足，以及存在失眠、困倦、血压和体重改变等副作用。Many mental disorders are associated with impaired, degraded or abnormal changes in the brain's serotonergic system. Therefore, drugs that regulate the serotonergic system, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), have been widely used in the treatment of mental disorders such as depression, anxiety, and schizophrenia. However, the above therapies are slow to take effect, are not effective enough for some patients, and have side effects such as insomnia, drowsiness, blood pressure and weight changes.

近年来，临床前和临床研究发现氯胺酮、裸盖菇素和麦角酸二乙胺(LSD)等致幻剂抗抑郁作用起效快，同时通过对神经可塑性的调控对大脑功能产生长期影响。因此，开发调控神经可塑性的药物对神经精神类疾病的治疗具有广阔的应用前景。In recent years, preclinical and clinical studies have found that psychedelic drugs such as ketamine, psilocybin, and lysergic acid diethylamide (LSD) have a rapid onset of antidepressant effects and have long-term effects on brain function by regulating neuroplasticity. Therefore, the development of drugs that regulate neuroplasticity has broad application prospects in the treatment of neuropsychiatric diseases.

发明内容Summary of the invention

本发明要解决的技术问题是针对现有技术中调控神经元可塑性的化合物的缺乏，提供一种新型吲哚类化合物及其应用。本文提供具有临床相关治疗功效的化合物，该化合物较容易合成，具有改进的物理化学性质、药代动力学性质或显著的抗抑郁效果。The technical problem to be solved by the present invention is to provide a novel indole compound and its application in view of the lack of compounds for regulating neuronal plasticity in the prior art. The present invention provides a compound with clinically relevant therapeutic efficacy, which is relatively easy to synthesize, has improved physicochemical properties, pharmacokinetic properties or significant antidepressant effects.

本发明是通过以下方法来解决上述技术问题的。The present invention solves the above technical problems through the following methods.

本发明提供一种如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物：
The present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

所述的如式(I)所示的化合物为以下情形1或情形2：The compound as shown in formula (I) is the following situation 1 or situation 2:

情形1：q为1，Case 1: q is 1,

所述的如式(I)所示的化合物为如下所示的化合物：
The compound shown in formula (I) is the compound shown below:

其中，X为CH或N；Wherein, X is CH or N;

R1为硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C3-12环烃基、3-12元杂环烃基、被1个、2个或3个R1-1取代的C1-6烷基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is nitro, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

每个R1-1和R1-2各自独立地为氘或卤素；Each of R 1-1 and R 1-2 is independently deuterium or halogen;

R8为氢、氘、氰基、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;

每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

或者，相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环或3-5元杂环；Alternatively, L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地为氢或C1-6烷基；Each L 2-0 is independently hydrogen or C 1-6 alkyl;

每个L2-1和L2-2各自独立地为氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium;

每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl;

每个L2-3独立地为氢、氘、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

或者，两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环；Alternatively, two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring;

其中，如式(I)所示的化合物满足以下条件的一种、两种、三种或四种：Wherein, the compound as shown in formula (I) satisfies one, two, three or four of the following conditions:

I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: for L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;

II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基；II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;

III：为L1为被一个或多个L1-2取代的亚乙基，每个L1-2 独立地为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；III: for L 1 is an ethylene group substituted by one or more L 1-2 , each L 1-2 are independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring with the carbon atom to which they are commonly attached;

IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基；IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 ;

情形2：q为3，Case 2: q is 3,

所述的如式(I)所示的化合物为如下所示的化合物：
The compound shown in formula (I) is the compound shown below:

其中，X为CH或CRX；Wherein, X is CH or CR X ;

RX为卤素或C1-6烷基； RX is halogen or C1-6 alkyl;

R1为羟基、-S(＝O)2(C1-6烷基)、氰基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is hydroxy, -S(=O) 2 (C 1-6 alkyl), cyano, C 1-6 alkoxy, or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

R1-2独立地为氘或卤素；R 1-2 are independently deuterium or halogen;

或者，RX与其相邻的R1和它们各自连接的碳原子共同形成C5-6碳环或5-6元杂环；Alternatively, RX, its adjacent R1 and the carbon atom to which they are each attached together form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring;

R2和R3各自独立地为氢、C1-6烷氧基或卤素； R2 and R3 are each independently hydrogen, C1-6 alkoxy or halogen;

或者，R1和R2与它们各自连接的碳原子共同形成C5-6碳环或5-6元杂环；Alternatively, R1 and R2 together with the carbon atoms to which they are attached form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring;

R8为氢、氘、氰基、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

L1为被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a methylene group substituted by one or more L 1-1 or an ethylene group substituted by one or more L 1-2 ;

每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

或者，相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环或3-5元杂环；Alternatively, L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring;

L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-1和L2-2各自独立地为氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基、被一个或多个L2-1-2取代的C3-6环烃基或或被一个或多个L2-1-3取代的C1-6烷氧基；Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , C 3-6 cycloalkyl substituted by one or more L 2-1-2 , or C 1-6 alkoxy substituted by one or more L 2-1-3 ;

每个L2-1-1独立地为氘、C3-6环烃基或3-6元杂环烃基；Each L 2-1-1 is independently deuterium, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl;

每个L2-1-3独立地为C3-6环烃基或3-6元杂环烃基；Each L 2-1-3 is independently a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl;

每个L2-3独立地为氢、氘、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

或者，两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环；Alternatively, two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring;

以上情形1或情形2中， In the above situation 1 or situation 2,

每一“杂环烃基”中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In each "heterocyclic hydrocarbon group", the type of heteroatoms is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;

以上每一3-5元杂环中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In each of the above 3-5 membered heterocycles, the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;

以上每一5-6元杂环中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In each of the above 5-6-membered heterocycles, the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2;

以上3-12元含氮杂环中，杂原子为N或者N和O，杂原子的个数独立地为1个或2个。In the above 3-12 membered nitrogen-containing heterocyclic ring, the heteroatom is N or N and O, and the number of the heteroatoms is independently 1 or 2.

在本发明某些优选实施方案中，所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)。在本发明某一方案中，所述的情形1中，R1中，所述的卤素为F、Cl、Br或I。In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention"). In a certain embodiment of the present invention, in the situation 1, in R1 , the halogen is F, Cl, Br or I.

在本发明某一方案中，所述的情形1中，每个L2-1和L2-2各自独立地为氢、氘、卤素、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；In a certain embodiment of the present invention, in the above-mentioned situation 1, each L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

所述的情形2中，R1为-S(＝O)2(C1-6烷基)、氰基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基。In the scenario 2, R 1 is -S(=O) 2 (C 1-6 alkyl), cyano, C 1-6 alkoxy, or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 .

在本发明某一方案中，所述的情形1或情形2中，R1中，每一“C1-6烷基”独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, in R1 , each " C1-6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

在本发明某一方案中，所述的情形1或情形2中，R1中，每一“C1-6烷氧基”独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, in R1 , each " C1-6 alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

在本发明某一方案中，所述的情形1中，R1中，所述的C3-12环烃基为C3-6单环环烃基或C6-12多环环烃基；所述的C3-6单环环烃基可为C3-6单环环烷基或C3-6单环环烯基；所述的C6-12多环环烃基可为C6-12螺环环烃基、C6-12并环环烃基或C6-12桥环环烃基，所述的C6-12螺环环烃基可为C6-12螺环环烷基或C6-12螺环环烯基，所述的C6-12并环环烃基可为C6-12并环环烷基或C6-12并环环烯基，所述的C6-12桥环环烃基可为C6-12桥环环烷基或C6-12桥环环烯基。In a certain embodiment of the present invention, in the situation 1, in R1 , the C3-12 cycloalkyl is a C3-6 monocyclic cycloalkyl or a C6-12 polycyclic cycloalkyl; the C3-6 monocyclic cycloalkyl may be a C3-6 monocyclic cycloalkyl or a C3-6 monocyclic cycloalkenyl; the C6-12 polycyclic cycloalkyl may be a C6-12 spirocyclic cycloalkyl, a C6-12 paracyclic cycloalkyl or a C6-12 bridged cycloalkyl; the C6-12 spirocyclic cycloalkyl may be a C6-12 spirocyclic cycloalkyl or a C6-12 spirocyclic cycloalkenyl; the C6-12 paracyclic cycloalkyl may be a C6-12 paracyclic cycloalkyl or a C6-12 paracyclic cycloalkenyl; the C6-12 bridged cycloalkyl may be a C6-12 bridged cycloalkyl or a C6-12 bridged cycloalkenyl.

在本发明某一方案中，所述的情形1中，R1中，所述的3-12元杂环烃基为3-7元单环杂环烃基或6-12元多环杂环烃基；所述的3-7元单环杂环烃基可为3-7元单环杂环烷基或3-7元单环杂环烯基；所述的6-12元多环杂环烃基可为6-12元螺环杂环烃基、6-12元并环杂环烃基或6-12元桥环杂环烃基，所述的6-12元螺环杂环烃基可为6-12元螺环杂环烷基或6-12元螺环杂环烯基，所述的6-12元并环杂环烃基可为6-12元并环杂环烷基或6-12元并环杂环烯基，所述的6-12元桥环杂环烃基可为6-12元桥环杂环烷基或6-12元桥环杂环烯基。In a certain embodiment of the present invention, in the situation 1, in R1 , the 3-12 membered heterocyclic hydrocarbon group is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group; the 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group; the 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 6-12 membered bridged heterocyclic hydrocarbon group; the 6-12 membered spirocyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkenyl group; the 6-12 membered paracyclic heterocyclic hydrocarbon group may be a 6-12 membered paracyclic heterocyclic alkyl group or a 6-12 membered paracyclic heterocyclic alkenyl group; the 6-12 membered bridged heterocyclic hydrocarbon group may be a 6-12 membered bridged heterocyclic alkyl group or a 6-12 membered bridged heterocyclic alkenyl group.

在本发明某一方案中，所述的情形1中，R1-1和R1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F。In one embodiment of the present invention, in the situation 1, in R 1-1 and R 1-2 , the halogen is independently F, Cl, Br or I, for example, F.

在本发明某一方案中，所述的情形2中，R1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F。 In a certain embodiment of the present invention, in the scenario 2, in R 1-2 , the halogen is independently F, Cl, Br or I, such as F.

在本发明某一方案中，所述的情形1或情形2中，R8中，所述的卤素为F、Cl、Br或I。In a certain embodiment of the present invention, in the situation 1 or situation 2, in R8 , the halogen is F, Cl, Br or I.

在本发明某一方案中，所述的情形1或情形2中，R8中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In a certain embodiment of the present invention, in the scenario 1 or scenario 2, in R8 , the C1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

在本发明某一方案中，所述的情形1或情形2中，R8中，所述的C3-6环烃基为C3-6环烷基或C3-6环烯基，例如C3-6环烷基，进一步例如环丙基、环丁基、环戊基或环己基。In a certain embodiment of the present invention, in the scenario 1 or scenario 2, in R8 , the C3-6 cycloalkyl is a C3-6 cycloalkyl or a C3-6 cycloalkenyl, such as a C3-6 cycloalkyl, further such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

在本发明某一方案中，所述的情形1或情形2中，R8中，所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，例如4-6元杂环烷基或4-6元杂环烯基，进一步例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基、哌嗪基、二氢呋喃基、二氢吡咯基、四氢吡啶基、二氢吡啶基或二氢吡喃基。In a certain embodiment of the present invention, in the described situation 1 or situation 2, in R8 , the described 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, such as a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, further such as an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a dihydrofuranyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydropyridinyl group or a dihydropyranyl group.

在本发明某一方案中，所述的情形1或情形2中，L1-1和L1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, in L 1-1 and L 1-2 , the above-mentioned halogen is independently F, Cl, Br or I, for example, F.

在本发明某一方案中，所述的情形1或情形2中，L1-1和L1-2中，所述的C1-6烷基各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。In one embodiment of the present invention, in the scenario 1 or scenario 2, in L 1-1 and L 1-2 , the C 1-6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

在本发明某一方案中，所述的情形2中，当R1和R2与它们各自连接的碳原子共同形成C5-6碳环时，或RX与其相邻的R1和它们各自连接的碳原子共同形成C5-6碳环时，所述的C5-6碳环为C5-6饱和碳环或C5-6碳烯环。In a certain embodiment of the present invention, in the scenario 2, when R1 and R2 and the carbon atom to which they are respectively attached form a C5-6 carbocyclic ring, or when RX and its adjacent R1 and the carbon atom to which they are respectively attached form a C5-6 carbocyclic ring, the C5-6 carbocyclic ring is a C5-6 saturated carbocyclic ring or a C5-6 carbene ring.

在本发明某一方案中，所述的情形2中，当R1和R2与它们各自连接的碳原子共同形成C5-6碳环时，或RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环时，所述的5-6元杂环为5-6元饱和杂环或5-6元杂环烯，例如二氢呋喃或1,3-二氧杂环戊烯。In a certain embodiment of the present invention, in the scenario 2, when R1 and R2 and the carbon atom to which they are respectively attached form a C5-6 carbocyclic ring, or when RX and its adjacent R1 and the carbon atom to which they are respectively attached form a 5-6-membered heterocyclic ring, the 5-6-membered heterocyclic ring is a 5-6-membered saturated heterocyclic ring or a 5-6-membered heterocyclic alkene, such as dihydrofuran or 1,3-dioxole.

在本发明某一方案中，所述的情形1或情形2中，当同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一步例如环丙烷、环丁烷或环戊烷，优选环丙烷。In a certain embodiment of the present invention, in the situation 1 or situation 2, when two L 1-1 on the same carbon atom and the carbon atom to which they are commonly connected form a C 3-5 carbocycle, the C 3-5 carbocycle is a C 3-5 saturated carbocycle or a C 3-5 carbene ring, such as a C 3-5 saturated carbocycle, further such as cyclopropane, cyclobutane or cyclopentane, preferably cyclopropane.

在本发明某一方案中，所述的情形1或情形2中，当同一个碳原子上的两个L1-1与它们共同连接的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环。In a certain embodiment of the present invention, in the above situation 1 or situation 2, when two L 1-1 on the same carbon atom and the carbon atom to which they are commonly connected together form a 3-5 membered heterocyclic ring, the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.

在本发明某一方案中，所述的情形1或情形2中，当同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一步例如环丙烷、环丁烷或环戊烷，优选环丙烷或环丁烷。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, when two L 1-2 on the same carbon atom and the carbon atom to which they are commonly connected form a C 3-5 carbocycle, the C 3-5 carbocycle is a C 3-5 saturated carbocycle or a C 3-5 carbene ring, such as a C 3-5 saturated carbocycle, further such as cyclopropane, cyclobutane or cyclopentane, preferably cyclopropane or cyclobutane.

在本发明某一方案中，所述的情形1或情形2中，当同一个碳原子上的两个L1-2与它们共同连接的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, when two L 1-2 on the same carbon atom and the carbon atom to which they are commonly connected together form a 3-5 membered heterocyclic ring, the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.

在本发明某一方案中，所述的情形1或情形2中，当相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一 步例如环丙烷、环丁烷或环戊烷。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, when L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are connected form a C 3-5 carbocyclic ring, the C 3-5 carbocyclic ring is a C 3-5 saturated carbocyclic ring or a C 3-5 carbene ring, for example, a C 3-5 saturated carbocyclic ring, further The steps are for example cyclopropane, cyclobutane or cyclopentane.

在本发明某一方案中，所述的情形1或情形2中，当相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, when L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are respectively connected form a 3-5 membered heterocyclic ring, the above-mentioned 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring.

在本发明某一方案中，所述的情形1或情形2中，L2中，所述的“C3-12环烃基”为C3-6单环环烃基或C6-12多环环烃基；In one embodiment of the present invention, in the above scenario 1 or scenario 2, in L 2 , the "C 3-12 cycloalkyl" is a C 3-6 monocyclic cycloalkyl or a C 6-12 polycyclic cycloalkyl;

所述的C3-6单环环烃基可为C3-6单环环烷基或C3-6单环环烯基，例如C3-6单环环烷基，进一步例如环丙基、环丁基、环戊基或环己基，例如环戊基或环己基；The C 3-6 monocyclic cycloalkyl group may be a C 3-6 monocyclic cycloalkyl group or a C 3-6 monocyclic cycloalkenyl group, such as a C 3-6 monocyclic cycloalkyl group, further such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, such as a cyclopentyl group or a cyclohexyl group;

所述的C6-12多环环烃基可为C6-12螺环环烃基、C6-12并环环烃基或C6-12桥环环烃基；The C 6-12 polycyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group, a C 6-12 paracyclic cycloalkyl group or a C 6-12 bridged cycloalkyl group;

所述的C6-12螺环环烃基可为C6-12螺环环烷基或C6-12螺环环烯基，例如C6-12螺环环烷基，进一步例如螺[3.3]庚烷基、螺[3.4]辛烷基、螺[3.5]壬烷基、螺[4.5]癸烷基或螺[5.5]十一烷基；The C 6-12 spirocyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group or a C 6-12 spirocyclic cycloalkenyl group, such as a C 6-12 spirocyclic cycloalkyl group, further such as a spiro[3.3]heptyl group, a spiro[3.4]octyl group, a spiro[3.5]nonyl group, a spiro[4.5]decyl group or a spiro[5.5]undecyl group;

所述的C6-12并环环烃基可为C6-12并环环烷基或C6-12并环环烯基，例如C6-12并环环烷基，进一步例如双环[3.1.0]己烷基或双环[3.3.0]辛烷基，例如 The C 6-12 cycloalkyl group may be a C 6-12 cycloalkyl group or a C 6-12 cycloalkenyl group, such as a C 6-12 cycloalkyl group, further such as a bicyclo[3.1.0]hexyl group or a bicyclo[3.3.0]octyl group, for example

所述的C6-12桥环环烃基可为C6-12桥环环烷基或C6-12桥环环烯基，例如C6-12桥环环烷基，进一步例如双环[2.2.2]辛烷基。The C 6-12 bridged ring cycloalkyl group may be a C 6-12 bridged ring cycloalkyl group or a C 6-12 bridged ring cycloalkenyl group, for example a C 6-12 bridged ring cycloalkyl group, further for example a bicyclo[2.2.2]octanyl group.

在本发明某一方案中，所述的情形1或情形2中，L2中，所述的“3-12元杂环烃基”为3-7元单环杂环烃基或6-12元多环杂环烃基；In one embodiment of the present invention, in the above scenario 1 or scenario 2, in L 2 , the "3-12 membered heterocyclic hydrocarbon group" is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group;

所述的3-7元单环杂环烃基可为3-7元单环杂环烷基或3-7元单环杂环烯基；所述的3-7元单环杂环烷基可为4-7元单环杂环烷基，例如氮杂环丁烷基、氧杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基、哌嗪基或1,4-氧杂氮杂环庚基，例如 所述的3-7元单环杂环烯基可为4-7元单环杂环烯基，例如二氢吡咯基，优选 The 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group; the 3-7 membered monocyclic heterocyclic alkyl group may be a 4-7 membered monocyclic heterocyclic alkyl group, such as azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl or 1,4-oxaazepanyl, such as The 3-7 membered monocyclic heterocycloalkenyl group may be a 4-7 membered monocyclic heterocycloalkenyl group, such as dihydropyrrolyl, preferably

所述的6-12元多环杂环烃基可为6-12元螺环杂环烃基、6-12元并环杂环烃基或7-12元桥环杂环烃基；The 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 7-12 membered bridged heterocyclic hydrocarbon group;

所述的6-12元螺环杂环烃基可为6-12元螺环杂环烷基或6-12元螺环杂环烯基，所述的6-12元 螺环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-11元螺环杂环烷基，例如为以下情况的中任一种：The 6-12 membered spirocyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkenyl group. The spirocyclic heterocycloalkyl group may be a 6-11-membered spirocyclic heterocycloalkyl group in which the heteroatom is N and the number of heteroatoms is 1 or 2, for example, any one of the following:

情况1：4-氮杂螺[2.4]庚烷基、4-氮杂螺[2.5]辛烷、2-氮杂螺[3.3]庚烷基或2-氮杂螺[3.5]壬烷基，进一步例如 Case 1: 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane or 2-azaspiro[3.5]nonane, further such as

情况2：4-氮杂螺[2.4]庚烷基、4-氮杂螺[2.5]辛烷、2-氮杂螺[3.3]庚烷基、2-氮杂螺[3.5]壬烷基、9-氮杂-3-氧杂螺[5.5]十一烷基、1-氮杂-8-氧杂螺[4.5]癸烷基、7-氮杂-2-氧杂螺[4.5]癸烷基、7-氮杂-2-氧杂螺[3.5]壬烷基、6-氮杂螺[2.5]辛烷基、8-氮杂-2-氧杂螺[4.5]癸烷基、2-氮杂-6-氧杂螺[3.4]辛烷基、6-氮杂-2-氧杂螺[3.3]庚烷基或5-氮杂螺[2.3]己烷，优选 Case 2: 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 9-aza-3-oxaspiro[5.5]undecane, 1-aza-8-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[3.5]nonane, 6-azaspiro[2.5]octane, 8-aza-2-oxaspiro[4.5]decane, 2-aza-6-oxaspiro[3.4]octane, 6-aza-2-oxaspiro[3.3]heptane or 5-azaspiro[2.3]hexane, preferably

所述的6-12元并环杂环烃基可为6-12元并环杂环烷基或6-12元并环杂环烯基，所述的6-12元并环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-10元并环杂环烷基，例如 优选为以下情况中任一种：The 6-12 membered heterocyclic hydrocarbon group may be a 6-12 membered heterocyclic alkyl group or a 6-12 membered heterocyclic alkenyl group, and the 6-12 membered heterocyclic alkyl group may be a 6-10 membered heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example Preferably, any of the following situations:

情况1： Case 1:

情况2： Case 2:

所述的6-12元桥环杂环烃基可为6-12元桥环杂环烷基或6-12元桥环杂环烯基；所述的6-12元桥环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-12元桥环杂环烷基，例如为以下情况中的任一种：The 6-12 membered bridged heterocyclic hydrocarbon group may be a 6-12 membered bridged heterocyclic alkyl group or a 6-12 membered bridged heterocyclic alkenyl group; the 6-12 membered bridged heterocyclic alkyl group may be a 6-12 membered bridged heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example, any one of the following:

情况1：2-氮杂双环[2.2.2]辛烷基，进一步例如 Case 1: 2-azabicyclo[2.2.2]octanyl, further such as

情况2：2-氮杂双环[2.2.2]辛烷基或6-氮杂-3-氧杂双环[2.2.1]庚烷基，进一步例如 Case 2: 2-azabicyclo[2.2.2]octanyl or 6-aza-3-oxabicyclo[2.2.1]heptyl, further such as

在本发明某一方案中，所述的情形1中，L2-0中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。In one embodiment of the present invention, in the scenario 1, in L 2-0 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

在本发明某一方案中，所述的情形1或情形2中，L2-1和L2-2中，所述的卤素各自独立地为F、Cl、Br或I。In one embodiment of the present invention, in the scenario 1 or scenario 2, in L 2-1 and L 2-2 , the halogen is independently F, Cl, Br or I.

在本发明某一方案中，所述的情形1或情形2中，L2-1和L2-2中，每一“C1-6烷基”各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, in L 2-1 and L 2-2 , each "C 1-6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

在本发明某一方案中，所述的情形1或情形2中，L2-1和L2-2中，每一“C1-6烷氧基”各自独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。In a certain embodiment of the present invention, in the situation 1 or situation 2, in L 2-1 and L 2-2 , each "C 1-6 alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

在本发明某一方案中，所述的情形1或情形2中，L2-1和L2-2中，每一“C3-6环烃基”各自独立地为C3-6环烷基或C3-6环烯基，例如环丙基、环丁基、环戊基或环己基，优选为环丙基。In a certain embodiment of the present invention, in the situation 1 or situation 2, in L 2-1 and L 2-2 , each "C 3-6 cycloalkyl group" is independently a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

在本发明某一方案中，所述的情形1或情形2中，L2-1和L2-2中，所述的3-6元杂环烃基各自独立地为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基或哌嗪基。In a certain embodiment of the present invention, in the situation 1 or situation 2, in L 2-1 and L 2-2 , the 3-6 membered heterocyclic hydrocarbon group is each independently a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms as N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.

在本发明某一方案中，所述的情形1或情形2中，L2-1-2中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。 In one embodiment of the present invention, in the scenario 1 or scenario 2, in L 2-1-2 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

在本发明某一方案中，所述的情形1或情形2中，L2-3中，所述的卤素为F、Cl、Br或I。In a certain embodiment of the present invention, in the situation 1 or situation 2, in L 2-3 , the halogen is F, Cl, Br or I.

在本发明某一方案中，所述的情形1或情形2中，L2-3中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。In one embodiment of the present invention, in the scenario 1 or scenario 2, in L 2-3 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

在本发明某一方案中，所述的情形1或情形2中，L2-3中，所述的C3-6环烃基为C3-6环烷基或C3- 6环烯基，所述的C3-6环烷基可为环丙基、环丁基、环戊基或环己基。In a certain embodiment of the present invention, in the scenario 1 or scenario 2, in L 2-3 , the C 3-6 cycloalkyl group is a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, and the C 3-6 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

在本发明某一方案中，所述的情形2中，L2-1-1或L2-1-3中，所述的C3-6环烃基各自独立地为C3-6环烷基或C3-6环烯基，所述的C3-6环烷基可为环丙基、环丁基、环戊基或环己基，例如环丙基In one embodiment of the present invention, in the scenario 2, in L 2-1-1 or L 2-1-3 , the C 3-6 cycloalkyl groups are each independently C 3-6 cycloalkyl or C 3-6 cycloalkenyl, and the C 3-6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl

在本发明某一方案中，所述的情形2中，L2-1-1或L2-1-3中，所述的所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基或哌嗪基。In a certain embodiment of the present invention, in the situation 2, in L 2-1-1 or L 2-1-3 , the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms as N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.

在本发明某一方案中，所述的情形1或情形2中，L2-3中，所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基或哌嗪基。In a certain embodiment of the present invention, in the scenario 1 or scenario 2, in L 2-3 , the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group whose heteroatoms are N and/or O and the number of heteroatoms is 1 or 2, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl.

在本发明某一方案中，所述的情形1或情形2中，当两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环时，所述的3-12元含氮杂环可独立地为3-7元含氮单环杂环或6-12元含氮多环杂环；In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, when two L 2-3 and the nitrogen atom to which they are commonly connected form a 3-12-membered nitrogen-containing heterocyclic ring, the 3-12-membered nitrogen-containing heterocyclic ring may independently be a 3-7-membered nitrogen-containing monocyclic heterocyclic ring or a 6-12-membered nitrogen-containing polycyclic heterocyclic ring;

所述的3-7元含氮单环杂环可为3-7元饱和含氮单环杂环或3-7元含氮单环杂环烯，所述的3-7元含氮单环杂环可为杂原子为N或者N和O，杂原子的个数为1个或2个的4-6元饱和含氮单环杂环，例如氮杂环丁烷、四氢吡咯环、哌啶环、吗啉环或哌嗪环；The 3-7 membered nitrogen-containing monocyclic heterocycle may be a 3-7 membered saturated nitrogen-containing monocyclic heterocycle or a 3-7 membered nitrogen-containing monocyclic heterocycle alkene, and the 3-7 membered nitrogen-containing monocyclic heterocycle may be a 4-6 membered saturated nitrogen-containing monocyclic heterocycle in which the heteroatom is N or N and O and the number of heteroatoms is 1 or 2, such as azetidine, tetrahydropyrrole ring, piperidine ring, morpholine ring or piperazine ring;

所述的6-12元含氮多环杂环可为6-12元含氮螺环杂环、6-12元含氮并环杂环或6-12元含氮桥环杂环；The 6-12 membered nitrogen-containing polycyclic heterocycle may be a 6-12 membered nitrogen-containing spirocyclic heterocycle, a 6-12 membered nitrogen-containing cyclic heterocycle or a 6-12 membered nitrogen-containing bridged heterocycle;

所述的6-12元含氮螺环杂环可为6-12元饱和含氮螺环杂环或6-12元含氮螺环杂环烯，所述的6-12元饱和含氮螺环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮螺环杂环，例如氮杂螺[2.4]庚烷、氮杂螺[2.5]辛烷、氮杂螺[3,3]庚烷或氮杂螺[3,5]壬烷，优选 The 6-12 membered nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle or a 6-12 membered nitrogen-containing spiro heterocycle alkene. The 6-12 membered saturated nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azaspiro[2.4]heptane, azaspiro[2.5]octane, azaspiro[3,3]heptane or azaspiro[3,5]nonane, preferably

所述的6-12元含氮并环杂环可为6-12元饱和含氮并环杂环或6-12元含氮并环杂环烯，所述的6-12元饱和含氮并环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮并环杂环，进一步例如氮杂双环[3.1.0]己烷或八氢环戊烷并吡咯；The 6-12 membered nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle or a 6-12 membered nitrogen-containing paracyclic heterocycle alkene, and the 6-12 membered saturated nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle wherein the heteroatom is N and the number of heteroatoms is 1 or 2, further for example, azabicyclo[3.1.0]hexane or octahydrocyclopentapyrrole;

所述的6-12元含氮桥环杂环可为6-12元饱和含氮桥环杂环或6-12元含氮桥环杂环烯，所述的6-12元饱和含氮桥环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮桥环杂环，例如氮杂双环[2.2.2]辛烷。The 6-12 membered nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle or a 6-12 membered nitrogen-containing bridged ring heterocycle alkene. The 6-12 membered saturated nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azabicyclo[2.2.2]octane.

在本发明某一方案中，所述的情形1或情形2中，X为CH。 In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, X is CH.

在本发明某一方案中，所述的情形1或情形2中，X为N。In a certain embodiment of the present invention, in the scenario 1 or scenario 2, X is N.

在本发明某一方案中，所述的情形2中，RX为卤素，例如F。In one embodiment of the present invention, in the situation 2, RX is a halogen, such as F.

在本发明某一方案中，所述的情形1中，R1为C1-6烷基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基，例如C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基。In one embodiment of the present invention, in the situation 1, R 1 is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 , for example, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 .

在本发明某一方案中，所述的情形2中，R1为羟基或C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环。In one embodiment of the present invention, in the scenario 2, R1 is hydroxyl or C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are respectively attached form a 5-6 membered heterocyclic ring, or RX together with its adjacent R1 and the carbon atom to which they are respectively attached form a 5-6 membered heterocyclic ring.

在本发明某一方案中，所述的情形2中，R1为C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环。In one embodiment of the present invention, in the scenario 2, R1 is a C1-6 alkoxy group, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX together with its adjacent R1 and the carbon atom to which they are attached form a 5-6 membered heterocyclic ring.

在本发明某一方案中，所述的情形1或情形2中，R1-2独立地为氘或卤素；例如氘。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, R 1-2 is independently deuterium or halogen; for example, deuterium.

在本发明某一方案中，所述的情形2中，R2为氢、C1-6烷氧基或卤素，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环。In one embodiment of the present invention, in the scenario 2, R 2 is hydrogen, C 1-6 alkoxy or halogen, or R 1 and R 2 together with the carbon atoms to which they are respectively attached form a 5-6 membered heterocyclic ring.

在本发明某一方案中，所述的情形2中，R3为氢或卤素；例如氢。In one embodiment of the present invention, in the situation 2, R 3 is hydrogen or halogen; for example, hydrogen.

在本发明某一方案中，所述的情形1或情形2中，R8为氢、氘或氰基，例如氢或氰基；再例如氢。In one embodiment of the present invention, in the above-mentioned situation 1 or situation 2, R 8 is hydrogen, deuterium or cyano, for example, hydrogen or cyano; for example, hydrogen.

在本发明某一方案中，所述的情形1或情形2中，同一个碳原子上的两个L1-1与共同连接的碳原子形成C3-5碳环。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, two L 1-1 on the same carbon atom and the carbon atom to which they are connected form a C 3-5 carbocyclic ring.

在本发明某一方案中，所述的情形1或情形2中，同一碳原子上的两个L1-2与共同连接的碳原子形成C3-5碳环。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, two L 1-2 on the same carbon atom and the carbon atom to which they are connected form a C 3-5 carbocyclic ring.

在本发明某一方案中，所述的情形1中，L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；In one embodiment of the present invention, in the scenario 1, L 1 is a connecting bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;

每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环。Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring.

在本发明某一方案中，所述的情形1中，L1为连接键或被一个或多个L1-1取代的亚甲基；In one embodiment of the present invention, in the scenario 1, L 1 is a connecting bond or a methylene group substituted by one or more L 1-1 ;

每个L1-1各自独立地为氢、氘或C1-6烷基；较佳地，每个L1-1各自独立地为氢或氘。Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl; preferably, each L 1-1 is independently hydrogen or deuterium.

在本发明某一方案中，所述的情形2中，L1为亚甲基。In one embodiment of the present invention, in the situation 2, L1 is a methylene group.

在本发明某一方案中，所述的情形1中，每个L2-0独立地C1-6烷基。In one embodiment of the present invention, in the above-mentioned situation 1, each L 2-0 is independently C 1-6 alkyl.

在本发明某一方案中，所述的情形1中或情形2，每个L2-1独立地为-N(L2-3)2。In a certain embodiment of the present invention, in the above-mentioned scenario 1 or scenario 2, each L 2-1 is independently -N(L 2-3 ) 2 .

在本发明某一方案中，所述的情形1或情形2中，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基。In a certain embodiment of the present invention, in the situation 1 or situation 2, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 .

在本发明某一方案中，所述的情形1或情形2中，每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基，优选为C1-6烷基。 In a certain embodiment of the present invention, in the situation 1 or situation 2, each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 or C 3-6 cycloalkyl substituted by one or more L 2-1-2 , preferably C 1-6 alkyl.

在本发明某一方案中，所述的情形1或情形2中，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；较佳地，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；更佳地，为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；最佳地，为C1-6烷基或C1-6烷氧基。In a certain embodiment of the present invention, in the described situation 1 or situation 2, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 or C 1-6 alkyl substituted by one or more L 2-1-1 ; preferably, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; more preferably, it is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; most preferably, it is C 1-6 alkyl or C 1-6 alkoxy.

在本发明某一方案中，所述的情形2中，每个L2-1-1独立地为氘或C3-6环烃基，例如氘。In one embodiment of the present invention, in the scenario 2, each L 2-1-1 is independently deuterium or a C 3-6 cycloalkyl group, such as deuterium.

在本发明某一方案中，所述的情形1中，每个L2-1-1为氘。In one embodiment of the present invention, in the scenario 1, each L 2-1-1 is deuterium.

在本发明某一方案中，所述的情形1或情形2中，每个L2-3独立地为C1-6烷基，或者两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环；较佳地，每个L2-3独立地为C1-6烷基。In a certain embodiment of the present invention, in the above-mentioned situation 1 or situation 2, each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are commonly connected form a 3-12 membered nitrogen-containing heterocyclic ring; preferably, each L 2-3 is independently a C 1-6 alkyl group.

在本发明某一方案中，所述的情形1中，L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；In one embodiment of the present invention, in the above-described situation 1, L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium;

每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl;

每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环。Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.

在本发明某一方案中，所述的情形1中，L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；In one embodiment of the present invention, in the above-described situation 1, L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2- 3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2- 3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium;

每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl;

每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环。Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.

在本发明某一方案中，所述的情形1中，L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；In one embodiment of the present invention, in the above-described situation 1, L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ;

每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium;

每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环。Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 together with the nitrogen atom to which they are attached form a 3-12 membered nitrogen-containing heterocyclic ring.

在本发明某一方案中，所述的情形1或情形2中，L2为被1个、2个或3个L2-2取代的3-12元杂 环烷基；In one embodiment of the present invention, in the above-mentioned scenario 1 or scenario 2, L2 is a 3-12 membered heteroaryl substituted by 1, 2 or 3 L2-2. Cycloalkyl;

每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ;

每个L2-1-1独立地为氘。Each L 2-1-1 is independently deuterium.

在本发明某一方案中，所述的情形2中，所述的L2为被1个、2个或3个L2-2取代的3-12元杂环烃基，L2-2为C1-6烷基；较佳地，所述的L2为被1个、2个或3个L2-2取代的氮杂环丁烷基，L2-2为C1-6烷基；更佳地，所述的L2为L2-2为C1-6烷基。In a certain embodiment of the present invention, in the scenario 2, L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , and L 2-2 is a C 1-6 alkyl group; preferably, L 2 is an azetidinyl group substituted by 1, 2 or 3 L 2-2 , and L 2-2 is a C 1-6 alkyl group; more preferably, L 2 is L 2-2 is a C 1-6 alkyl group.

在本发明某一方案中，所述的情形1中，In a certain embodiment of the present invention, in the situation 1,

X为CH或N；X is CH or N;

R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

R1-2独立地为氘或卤素；R 1-2 are independently deuterium or halogen;

R8为氢或氰基；R 8 is hydrogen or cyano;

L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;

每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2- 3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2- 3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

L2-1-1独立地为氘；L 2-1-1 is independently deuterium;

L2-1-2独立地为C1-6烷基；L 2-1-2 is independently C 1-6 alkyl;

L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;

其中，如式(I)所示的化合物满足以下条件的一种、两种、三种或四种：Wherein, the compound as shown in formula (I) satisfies one, two, three or four of the following conditions:

I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: for L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;

II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基； II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;

III：为L1为被一个或多个L1-2取代的亚乙基，每个L1-2独立地为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；III: for L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基。IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .

在本发明某一方案中，所述的情形1中，In a certain embodiment of the present invention, in the situation 1,

X为CH或N；X is CH or N;

R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

R1-2独立地为氘；R 1-2 are independently deuterium;

R8为氢； R8 is hydrogen;

L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;

每个L1-1各自独立地为氢、氘或C1-6烷基；Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl;

L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ;

L2-1-1独立地为氘；L 2-1-1 is independently deuterium;

L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;

其中，如式(I)所示的化合物满足以下条件的一种、两种或三种：Wherein, the compound as shown in formula (I) satisfies one, two or three of the following conditions:

I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: for L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl;

II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基； II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;

IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基。IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .

在本发明某一方案中，所述的情形1中，In a certain embodiment of the present invention, in the situation 1,

为 for

X为CH或N；X is CH or N;

R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

R1-2独立地为氘；R 1-2 are independently deuterium;

R8为氢； R8 is hydrogen;

L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;

每个L1-1各自独立地为氢、氘或C1-6烷基；Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl;

L2为被1个、2个或3个L2-2取代的3-12元杂环烷基；所述的“3-12元杂环烃基”为3-12元单环杂环烃基；L 2 is a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; the "3-12 membered heterocycloalkyl" is a 3-12 membered monocyclic heterocycloalkyl;

每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ;

L2-1-1独立地为氘。L 2-1-1 is independently deuterium.

在本发明某一方案中，所述的情形1中，In a certain embodiment of the present invention, in the situation 1,

为 for

X为CH或N；X is CH or N;

R1为C1-6烷氧基； R1 is C1-6 alkoxy;

R8为氢； R8 is hydrogen;

L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a connecting bond or a methylene group substituted by one or more L 1-1 ;

每个L1-1各自独立地为氢或氘；Each L 1-1 is independently hydrogen or deuterium;

L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基或被1个、2个或3个L2-2取代的3-7元单环杂环烯基；每个L2-2独立地为C1-6烷基或C1-6烷氧基；所述3-7元单环杂环烷基或3-7元单环杂环烯基中的杂原子为N，杂原子个数为1个或2个。L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1 or 2.

在本发明某一方案中，所述的情形1中， In a certain embodiment of the present invention, in the situation 1,

为 for

X为CH；X is CH;

R1为C1-6烷氧基； R1 is C1-6 alkoxy;

R8为氢； R8 is hydrogen;

L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ;

每个L1-1各自独立地为氢或氘；Each L 1-1 is independently hydrogen or deuterium;

L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基或被1个、2个或3个L2-2取代的3-7元单环杂环烯基；每个L2-2独立地为C1-6烷基或C1-6烷氧基；所述3-7元单环杂环烷基或3-7元单环杂环烯基中的杂原子为N，杂原子个数为1个。L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1.

在本发明某一方案中，所述的情形1中，In a certain embodiment of the present invention, in the situation 1,

X为CH或N；X is CH or N;

R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ;

R1-2独立地为氘或卤素；R 1-2 are independently deuterium or halogen;

R8为氢或氰基；R 8 is hydrogen or cyano;

L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ;

每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ;

L2-1-1独立地为氘；L 2-1-1 is independently deuterium;

L2-1-2独立地为C1-6烷基；L 2-1-2 is independently C 1-6 alkyl;

L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring;

其中，如式(I)所示的化合物满足以下条件的一种、两种、三种或四种：Wherein, the compound as shown in formula (I) satisfies one, two, three or four of the following conditions:

I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的 “3-12元杂环烃基”为3-12元单环杂环烃基；I: for L2 is a C3-12 cycloalkyl substituted by 1, 2 or 3 L2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L2-2 , wherein the " C3-12 cycloalkyl" is a C3-12 monocyclic cycloalkyl. "3-12 membered heterocyclic hydrocarbon group" is a 3-12 membered monocyclic heterocyclic hydrocarbon group;

II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基；II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl;

III：为L1为被一个或多个L1-2取代的亚乙基，每个L1-2独立地为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；III: for L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring;

IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基。IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 .

在本发明某一方案中，所述的情形1中，R1为C1-6烷氧基。In one embodiment of the present invention, in the situation 1, R 1 is a C 1-6 alkoxy group.

在本发明某一方案中，所述的情形1中，R8为氢。In one embodiment of the present invention, in the situation 1, R 8 is hydrogen.

在本发明某一方案中，所述的情形1中，L1为连接键或被一个或多个L1-2取代的亚乙基。In one embodiment of the present invention, in the above-mentioned situation 1, L 1 is a connecting bond or an ethylene group substituted by one or more L 1-2 .

在本发明某一方案中，所述的情形1中，每个L1-2独立地为氢。In one embodiment of the present invention, in the above-mentioned situation 1, each L 1-2 is independently hydrogen.

在本发明某一方案中，所述的情形1中，L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基。In one embodiment of the present invention, in the above-described situation 1, L 2 is a C 3-12 cyclic hydrocarbon group substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 .

在本发明某一方案中，所述的情形1中，每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基或C3-6环烃基。In a certain embodiment of the present invention, in the above-mentioned situation 1, each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.

在本发明某一方案中，所述的情形1中，L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；In one embodiment of the present invention, in the above-described situation 1, L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ;

每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ;

每个L2-3独立地为C1-6烷基；Each L 2-3 is independently C 1-6 alkyl;

每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基或C3-6环烃基。Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.

在本发明某一方案中，所述的情形2中，In a certain embodiment of the present invention, in the situation 2,

X为CH或CRX；RX为卤素或C1-6烷基；X is CH or CR X ; RX is halogen or C 1-6 alkyl;

R1为羟基、C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring;

R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen;

R3为氢或卤素； R3 is hydrogen or halogen;

L1为亚甲基；L 1 is a methylene group;

L2为被1个、2个或3个L2-2取代的3-12元杂环烃基，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基，每个L2-1-1独立地为C3-6环烃基或氘。L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 , each L 2-1-1 is independently C 3-6 cycloalkyl or deuterium.

在本发明某一方案中，所述的情形2中， In a certain embodiment of the present invention, in the situation 2,

X为CH或CRX；RX为卤素；X is CH or CR X ; RX is halogen;

R1为羟基、C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring;

R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen;

R3为氢或卤素； R3 is hydrogen or halogen;

L1为亚甲基；L 1 is a methylene group;

L2为被1个、2个或3个L2-2取代的3-12元杂环烃基，每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；每个L2-1-1为氘。L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 alkyl group substituted by one or more L 2-1-1 ; each L 2-1-1 is deuterium.

在本发明某一方案中，所述的情形2中，In a certain embodiment of the present invention, in the situation 2,

X为CH或CRX；RX为卤素；X is CH or CR X ; RX is halogen;

R1为C1-6烷氧基，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is a C1-6 alkoxy group, or RX , its adjacent R1 and the carbon atom to which they are attached together form a 5-6 membered heterocyclic ring;

R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen;

R3为氢； R3 is hydrogen;

L1为亚甲基；L 1 is a methylene group;

L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基；每个L2-2独立地为C1-6烷基或C1-6烷氧；所述3-7元单环杂环烷基中的杂原子为N，杂原子个数为1个或2个；L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl is N, and the number of heteroatoms is 1 or 2;

较佳地，R2为氢，R3为氢，所述3-7元单环杂环烷基的杂原子个数为1个。Preferably, R2 is hydrogen, R3 is hydrogen, and the number of heteroatoms in the 3-7 membered monocyclic heterocycloalkyl group is 1.

在本发明某一方案中，所述的情形2中，X为CH、CF或C-CH3，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；较佳地，X为CH，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子。In one embodiment of the present invention, in the above situation 2, X is CH, CF or C-CH 3 , or RX and its adjacent R 1 and the carbon atom to which they are connected together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; preferably, X is CH, or RX and its adjacent R1 and the carbon atom to which they are connected together form The carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.

在本发明某一方案中，所述的情形2中，X为CH或CF，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子。In one embodiment of the present invention, in the above situation 2, X is CH or CF, or RX and its adjacent R1 and the carbon atom to which they are connected together form The carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.

在本发明某一方案中，所述的情形1中，R1-1为氘或F。In one embodiment of the present invention, in the situation 1, R 1-1 is deuterium or F.

在本发明某一方案中，所述的情形1中，R1为甲氧基、 In one embodiment of the present invention, in the situation 1, R 1 is methoxy,

在本发明某一方案中，所述的情形1中，R1为甲氧基或 In one embodiment of the present invention, in the situation 1, R 1 is methoxy or

在本发明某一方案中，所述的情形1中，R1为 In one embodiment of the present invention, in the situation 1, R 1 is

在本发明某一方案中，所述的情形1中，R1为甲氧基。In a certain embodiment of the present invention, in the situation 1, R 1 is methoxy.

在本发明某一方案中，所述的情形2中，R1为羟基、甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成 或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；In one embodiment of the present invention, in the situation 2, R1 is hydroxyl, methoxy, -S(=O) 2 CH 3 , -OCH(CH 3 ) 2 or CN, or R 1 and R 2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X;

较佳地，R1为羟基、甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；Preferably, R 1 is hydroxy, methoxy, -S(=O) 2 CH 3 , -OCH(CH 3 ) 2 or CN, or R 1 and R 2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X;

更佳地，R1为羟基或甲氧基，或者R1和R2与它们各自连接的碳原子共同形成 或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子。More preferably, R1 is hydroxyl or methoxy, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.

在本发明某一方案中，所述的情形2中，R1为甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示 其为X对应的碳原子。In one embodiment of the present invention, in the situation 2, R 1 is methoxy, -S(=O) 2 CH 3 , -OCH(CH 3 ) 2 or CN, or R 1 and R 2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" represents It is the carbon atom corresponding to X.

在本发明某一方案中，R1为甲氧基，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子。In one embodiment of the present invention, R1 is a methoxy group, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom labeled "a" indicates that it is the carbon atom corresponding to X.

在本发明某一方案中，所述的情形1中，R8为氢或氰基。In one embodiment of the present invention, in the situation 1, R 8 is hydrogen or cyano.

在本发明某一方案中，所述的情形2中，R8为氢。In one embodiment of the present invention, in the situation 2, R 8 is hydrogen.

在本发明某一方案中，所述的情形2中，R2为氢、甲氧基或F，或者，R1和R2与它们各自连接的碳原子共同形成较佳地，R2为氢、甲氧基或F，者，R1和R2与它们各自连接的碳原子共同形成 In one embodiment of the present invention, in the scenario 2, R2 is hydrogen, methoxy or F, or R1 and R2 together with the carbon atoms to which they are connected form Preferably, R2 is hydrogen, methoxy or F, or, R1 and R2 together with the carbon atoms to which they are attached form

在本发明某一方案中，所述的情形2中，R3为氢或F。In one embodiment of the present invention, in the situation 2, R 3 is hydrogen or F.

在本发明某一方案中，所述的情形1中，为例如进一步例如 In a certain embodiment of the present invention, in the situation 1, for For example Further example

在本发明某一方案中，所述的情形2中，为 优选为 In a certain embodiment of the present invention, in the situation 2, for Preferably

在本发明某一方案中，所述的情形2中，为 优选为 In a certain embodiment of the present invention, in the situation 2, for Preferably

在本发明某一方案中，所述的情形1中，每个L1-1和L1-2各自独立地为氢、氘、F或甲基；In one embodiment of the present invention, in the scenario 1, each L 1-1 and L 1-2 are independently hydrogen, deuterium, F or methyl;

或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成环丙烷或环丁烷；Alternatively, two L 1-1 groups on the same carbon atom and the carbon atom to which they are commonly attached form a cyclopropane or cyclobutane;

或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成环丙烷或环丁烷。Alternatively, two L 1-2 on the same carbon atom form cyclopropane or cyclobutane with the carbon atom to which they are commonly attached.

在本发明某一方案中，所述的情形1中，L1为连接键、亚甲基、亚乙基、 优选为连接键、亚甲基、亚乙基、 其中#侧与L2相连。In one embodiment of the present invention, in the above-mentioned situation 1, L1 is a connecting bond, a methylene group, an ethylene group, Preferably, it is a linker, a methylene group, an ethylene group, The # side is connected to L2 .

在本发明某一方案中，所述的情形1中，L1为连接键、亚甲基、亚乙基、 优选为连接键、亚甲基、亚乙基、 其中#侧与L2相连；更佳地，为连接键、亚甲基、亚乙基、最佳地，为连接键、亚甲基、 In one embodiment of the present invention, in the above-mentioned situation 1, L1 is a connecting bond, a methylene group, an ethylene group, Preferably, it is a linker, a methylene group, an ethylene group, Wherein the # side is connected to L2 ; more preferably, it is a connecting bond, methylene, ethylene, Most preferably, a linker, a methylene group,

在本发明某一方案中，所述的情形1中，L1为 优选为 其中#侧与L2相连。In a certain embodiment of the present invention, in the situation 1, L1 is Preferably The # side is connected to L2 .

在本发明某一方案中，所述的情形2中，L1为亚甲基、优选为亚甲基。In one embodiment of the present invention, in the situation 2, L1 is methylene, Preferred is methylene.

在本发明某一方案中，所述的情形1中，每个L2-0独立地为甲基。In one embodiment of the present invention, in the above-mentioned situation 1, each L 2-0 is independently a methyl group.

在本发明某一方案中，所述的情形1中，每个L2-1为-N(CH3)2或 In one embodiment of the present invention, in the above-mentioned situation 1, each L 2-1 is -N(CH 3 ) 2 or

在本发明某一方案中，所述的情形1中，每个L2-2独立地为甲基、环丙基、甲氧基、-N(CH3)2、 In one embodiment of the present invention, in the above situation 1, each L 2-2 is independently methyl, cyclopropyl, methoxy, -N(CH 3 ) 2 ,

在本发明某一方案中，所述的情形1中，L2为-N(CH3)2、 n为1、2或3，优选为1；L2优选为 例如 In one embodiment of the present invention, in the above-mentioned situation 1, L 2 is -N(CH 3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably For example

在本发明某一方案中，所述的情形1中，L2为-N(CH3)2、 n为1、2或3，优选为1；L2优选为 例如 In one embodiment of the present invention, in the above-mentioned situation 1, L 2 is -N(CH 3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably For example

在本发明某一方案中，所述L2中，为或由组成的混合物。In a certain embodiment of the present invention, in said L2 , for or by A mixture of components.

在本发明某一方案中，所述的情形1中，L2为 n为1、2、或3，优选为1；L2优选为 例如 进一步例如 In a certain embodiment of the present invention, in the situation 1, L2 is n is 1, 2, or 3, preferably 1; L2 is preferably For example Further example

在本发明某一方案中，所述的情形2中，L2为 n为1、2或3；L2优选为 n为1、2或3； In a certain embodiment of the present invention, in the situation 2, L2 is n is 1, 2 or 3; L 2 is preferably n is 1, 2 or 3;

较佳地，L2为 Preferably, L2 is

L2例如 优选为 L2 For example Preferably

在本发明某一方案中，所述的情形1中，所述的如式(I)所示的化合物为如式(I-1)、(I-2)、(I-3)、(I-4)、(I-5)或(I-6)所示的化合物：

In one embodiment of the present invention, in the scenario 1, the compound represented by formula (I) is a compound represented by formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6):

其中，如式(I-1)、(I-2)、(I-3)、(I-4)、(I-5)或(I-6)所示的化合物中，R1、R8、L2、L1-1和L1-2的定义如前任一方案所述。In the compounds represented by formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6), R 1 , R 8 , L 2 , L 1-1 and L 1-2 are as defined in any of the preceding embodiments.

在本发明某一方案中，如式(I-1)或(I-4)所示的化合物中，L2为 n为1、2或3，优选为1；L2优选为 In one embodiment of the present invention, in the compound represented by formula (I-1) or (I-4), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably

在本发明某一方案中，如式(I-2)或(I-5)所示的化合物中，L2为 n为1、2或3，优选为1；L2优选为 In one embodiment of the present invention, in the compound represented by formula (I-2) or (I-5), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably

在本发明某一方案中，如式(I-2)或(I-5)所示的化合物中，L2为 n为1、2或3，优选为1；L2优选为 In one embodiment of the present invention, in the compound represented by formula (I-2) or (I-5), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably

在本发明某一方案中，如式(I-3)或(I-6)所示的化合物中，L2为 n为1、2或3，优选为1；L2优选为 In one embodiment of the present invention, in the compound represented by formula (I-3) or (I-6), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably

在本发明某一方案中，如式(I-3)或(I-6)所示的化合物中，L2为-N(CH3)2，至少一个L1-2为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环。In one embodiment of the present invention, in the compound represented by formula (I-3) or (I-6), L 2 is -N(CH 3 ) 2 , at least one L 1-2 is deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom form a C 3-5 carbocycle with the carbon atom to which they are connected.

本发明某一方案中，所述的情形1和2中，所述的如式(I)所示的化合物中：In one embodiment of the present invention, in the above-mentioned situations 1 and 2, the compound represented by formula (I):

L1为亚甲基，L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；当L2中的碳原子与L1连接时，所述L2中与L1连接的碳原子为手性碳原子，所述手性碳原子为R构型、S构型或由R构型和S构型组成的混合物。 L1 is a methylene group, L2 is a C3-12 cycloalkyl group substituted by 1, 2 or 3 L2-1 groups , or a 3-12 membered heterocycloalkyl group substituted by 1, 2 or 3 L2-2 groups ; when the carbon atom in L2 is connected to L1 , the carbon atom in L2 connected to L1 is a chiral carbon atom, and the chiral carbon atom is in R configuration, S configuration or a mixture of R configuration and S configuration.

本发明某一方案中，所述的情形2中，所述的如式(I)所示的化合物为如式(I-A)、(I-B)或(I-C)所示的化合物：
In one embodiment of the present invention, in the scenario 2, the compound represented by formula (I) is a compound represented by formula (IA), (IB) or (IC):

其中，R1、R2、R3、X、L2-2和R8的定义如前任一方案所述。wherein R 1 , R 2 , R 3 , X, L 2-2 and R 8 are as defined in any of the preceding embodiments.

较佳地，所述如式(I-A)、(I-B)和(I-C)所示的化合物中，R3为H，X为CH。Preferably, in the compounds represented by formula (IA), (IB) and (IC), R 3 is H and X is CH.

在本发明某一方案中，所述的情形2中，所述的如式(I)所示的化合物为如式(I-7)所示的化合物：
In one embodiment of the present invention, in the scenario 2, the compound represented by formula (I) is a compound represented by formula (I-7):

其中，R1、R2、R3、X和R8的定义如前任一方案所述；较佳地，R3为H，X为CH。Wherein, R 1 , R 2 , R 3 , X and R 8 are defined as described in any of the previous schemes; preferably, R 3 is H, and X is CH.

本发明还提供一种如下所示化合物、它们药学上可接受的盐、它们的溶剂合物或它们药学上可 接受的盐的溶剂合物：





The present invention also provides a compound as shown below, their pharmaceutically acceptable salts, their solvates or their pharmaceutically acceptable Acceptable salt solvates:





它们药学上可接受的盐例如为以下化合物中的任一种：Their pharmaceutically acceptable salts are, for example, any of the following compounds:

的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、 的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐或的一甲酸盐。 Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, monoformate or The monoformate.

在本发明某一方案中，所述的如式(I)所示的化合物为以下任一化合物：In one embodiment of the present invention, the compound represented by formula (I) is any of the following compounds:

中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L甲酸水溶液，流动相中A的体积百分比为2-32％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-Xbridge-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为9min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-Xbridge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes first is 9min;

中在下述高效液相色谱条件下后出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L甲酸水溶液，流动相中A的体积百分比为2-32％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-Xbridge-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为9.2min； The compound that elutes later under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-Xbridge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes later is 9.2min;

中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为0.1％(v/v)甲酸水溶液，流动相中A的体积百分比为10-20％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-SunFire-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为7.3min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 0.1% (v/v) formic acid aqueous solution, the volume percentage of A in the mobile phase is 10-20%, gradient elution, flow rate 20 mL/min, and elution time is 17 min; preferably, the model of the chromatographic column is: Waters-SunFire-C18-10 μm-19*250 mm, and more preferably, the retention time of the compound that elutes first is 7.3 min;

中在下述高效液相色谱条件下后出峰的化合物： 色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为0.1％(v/v)甲酸水溶液，流动相中A的体积百分比为10-20％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-SunFire-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为7.7min； The compounds that elute later under the following HPLC conditions: The stationary phase of the chromatographic column is C18, and the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is 0.1% (v/v) formic acid aqueous solution, the volume percentage of A in the mobile phase is 10-20%, gradient elution, flow rate 20mL/min, elution time is 17min; preferably, the model of the chromatographic column is: Waters-SunFire-C18-10μm-19*250mm, more preferably, the retention time of the late peak compound is 7.7min;

中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L三氟乙酸水溶液，流动相中A的体积百分比为15-25％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-XBndge-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为5.7min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-XBndge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes first is 5.7min;

中在下述高效液相色谱条件下后出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L三氟乙酸水溶液，流动相中A的体积百分比为15-25％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-XBndge-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为7.5min。 The compound that elutes later under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10 mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20 mL/min, and elution time is 17 min; preferably, the model of the chromatographic column is: Waters-XBndge-C18-10 μm-19*250 mm, and more preferably, the retention time of the compound that elutes later is 7.5 min.

本发明还提供一种药物组合物，其包含物质X和药学上可接受的载体，所述的物质X为上述任一方案所述的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。The present invention also provides a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable carrier, wherein the substance X is the compound described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

本发明还提供一种药物组合物，其包含物质X和药学上可接受的载体，所述的物质X为上述如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。The present invention also provides a pharmaceutical composition, which comprises a substance X and a pharmaceutically acceptable carrier, wherein the substance X is the compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

本发明还提供一种上述任一方案所述的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或上述药物组合物在制备调控神经元可塑性的药物中的应用。The present invention also provides use of the compound described in any of the above schemes, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a drug for regulating neuronal plasticity.

本发明还提供一种上述任一项所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或上述药物组合物在制备调控神经元可塑性的药物中的应用。The present invention also provides a use of any of the above compounds as shown in formula (I), their pharmaceutically acceptable salts, their solvates, their pharmaceutically acceptable salt solvates or the above pharmaceutical compositions in the preparation of drugs for regulating neuronal plasticity.

本发明还提供一种上述任一方案所述的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或上述药物组合物在制备预防和/或治疗抑郁症、精神分裂症、焦虑或创伤后应激障碍的药物中的应用。The present invention also provides a use of the compound described in any of the above schemes, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a drug for preventing and/or treating depression, schizophrenia, anxiety or post-traumatic stress disorder.

本发明还提供一种上述任一项所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或上述药物组合物在制备预防和/或治疗抑郁症、精神分裂症、焦虑或创伤后应激障碍的药物中的应用。The present invention also provides a use of any of the above compounds as shown in formula (I), their pharmaceutically acceptable salts, their solvates, their pharmaceutically acceptable salt solvates or the above pharmaceutical compositions in the preparation of drugs for preventing and/or treating depression, schizophrenia, anxiety or post-traumatic stress disorder.

除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义： In addition to the foregoing, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the following meanings:

术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述药学上可接受的盐的例如为甲酸盐、戊二酸盐、辛酸盐、棕榈酸盐、月桂酸盐。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable salts are formate, glutarate, caprylate, palmitate, and laurate.

术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。The term "solvate" refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质。其中，溶剂的数量可以是化学计量的，也可以是非化学计量的。The term "pharmaceutically acceptable salt solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the amount of the solvent may be stoichiometric or non-stoichiometric.

术语“卤素”是指F、Cl、Br、I。The term "halogen" refers to F, Cl, Br, I.

术语“烷基”是指具有指定碳原子数(例如，C1-6)的、直链或支链的、饱和的一价烃基。烷基包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1-6 ). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的烷基。The term "alkoxy" refers to a group -ORX , wherein RX is alkyl as defined above.

术语“环烃基”是指具有指定数目环碳原子数(例如，C3-12或C3-6)的非芳香族的饱和或部分不饱和的环烃基，包括环烷基和环烯基，环烃基可以为单环或多环，可以为并环、螺环和桥环结构。环烃基包括但不限于：环丙基、环丁基、环戊基、环己基、双环[3.1.0]己烷基或双环[3.3.0]辛烷基。The term "cycloalkyl" refers to a non-aromatic saturated or partially unsaturated cycloalkyl having a specified number of ring carbon atoms (e.g., C 3-12 or C 3-6 ), including cycloalkyl and cycloalkenyl. The cycloalkyl may be monocyclic or polycyclic, and may be a cyclocyclic, spirocyclic, or bridged ring structure. The cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, or bicyclo[3.3.0]octyl.

术语“环烷基”是指具有指定的环碳原子数(例如，C3-12或C3-6)、环原子仅由碳原子组成的饱和单环、螺环、桥环或并环环状基团。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。The term "cycloalkyl" refers to a saturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of ring carbon atoms (e.g., C 3-12 or C 3-6 ), wherein the ring atoms consist only of carbon atoms. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

术语“环烯基”是指具有指定碳原子数(例如，C3-8)的、环原子仅由碳原子组成的不饱和单环、螺环、桥环或并环环状基团，其不具有芳香性。The term "cycloalkenyl" refers to an unsaturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of carbon atoms (eg, C 3-8 ) and the ring atoms consisting only of carbon atoms, which is not aromatic.

术语“杂环烃基”是指具有指定环原子数(例如，3-12元、3-6元或3-5元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的1种、2种或3种)的非芳香族的饱和或部分不饱和的环状基团，包括杂环烷基或杂环烯基，杂环烃基可以为单环或多环，可以为并环、螺环和桥环结构。杂环烃基包括但不限于：氮杂环丁烷基、氧杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基、哌嗪基、1,4-氧杂氮杂环庚基、二氢吡咯基、4-氮杂螺[2.4]庚烷基、2-氮杂螺[3.3]庚烷基、2-氮杂螺[3.5]壬烷基、或2-氮杂双环[2.2.2]辛烷基。The term "heterocyclic hydrocarbon group" refers to a non-aromatic saturated or partially unsaturated cyclic group having a specified number of ring atoms (e.g., 3-12 members, 3-6 members, or 3-5 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), including heterocyclic alkyl or heterocyclic alkenyl. The heterocyclic hydrocarbon group may be a monocyclic or polycyclic ring, and may be a cyclic, spirocyclic, or bridged ring structure. Heterocyclic hydrocarbon groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, 1,4-oxazaazacycloheptyl, dihydropyrrolyl, 4-azaspiro[2.4]heptyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, or 2-azabicyclo[2.2.2]octanyl.

术语“杂环烷基”是指具有指定环原子数(例如3-12元、3-6元或3-5元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的1种、2种或3种)的饱和单环、螺环、 桥环或并环环状基团，当为多环时，每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、氧杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基、哌嗪基、1,4-氧杂氮杂环庚基、2-氮杂螺[3,3]庚烷基、2-氮杂螺[3,5]壬烷基、 或2-氮杂双环[2.2.2]辛烷基。The term "heterocycloalkyl" refers to a saturated monocyclic, spirocyclic, or heterocyclic ring having a specified number of ring atoms (e.g., 3-12, 3-6, or 3-5 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S). The bridged or cyclic ring group, when it is polycyclic, each ring is saturated. Heterocycloalkyl includes but is not limited to azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, 1,4-oxazacycloheptyl, 2-azaspiro [3,3] heptyl, 2-azaspiro [3,5] nonyl, or 2-azabicyclo[2.2.2]octanyl.

术语“杂环烯基”是指具有指定环原子数(例如，3-12元、3-6元或3-5元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、不饱和的单环、螺环、桥环或并环烃基环状基团，其不具有芳香性。杂环烯基的例子包括但不限于二氢吡咯基。The term "heterocycloalkenyl" refers to an unsaturated monocyclic, spirocyclic, bridged or cyclic hydrocarbon ring group having a specified number of ring atoms (e.g., 3-12, 3-6 or 3-5), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), and having no aromaticity. Examples of heterocycloalkenyl include, but are not limited to, dihydropyrrolyl.

术语“杂环”满足下述任一条件，其余定义同术语“杂环烃基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "heterocycle" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocyclic hydrocarbon group": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

术语“杂环烯”满足下述任一条件，其余定义同术语“杂环烯基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "heterocycloalkene" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkenyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

术语“碳环”满足下述任一条件，其余定义同术语“环烃基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "carbocycle" satisfies any of the following conditions, and the rest of the definition is the same as the term "cycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

术语“碳烯环”满足下述任一条件，其余定义同术语“环烯基”：1、通过两个以上的单键与分子其余部分相连；2、与分子其余部分共用两个原子和一根键。The term "carbene ring" satisfies any of the following conditions, and the rest of the definition is the same as the term "cycloalkenyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团；即烷基中的一个氢被取代，烷基的定义如上所述，例如C1-6亚烷基。The term "alkylene" means a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon group by removing two hydrogen atoms; that is, one hydrogen in an alkyl group is replaced, and the definition of alkyl is as described above, for example, C1-6 alkylene.

术语“一个或多个”是指1、2、3、4或更多。The term "one or more" means 1, 2, 3, 4 or more.

本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的是指，相应的基团R通过该位点与化合物中的其它片段、基团进行连接。It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

术语“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2020年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

除非另有规定，在本发明中，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。Unless otherwise specified, in the present invention, the wedge-shaped solid line key and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter.

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.

本发明的积极进步效果在于：本发明化合物较容易合成，具有改进的物理化学性质、药代动力学性质或显著的抗抑郁效果。 The positive and progressive effects of the present invention are that the compounds of the present invention are easier to synthesize, have improved physicochemical properties, pharmacokinetic properties or significant antidepressant effects.

附图说明：Description of the drawings:

图1：化合物在促进大鼠原代皮层神经元突触增长方面的测试结果。Figure 1: Results of testing of compounds in promoting synaptic growth in rat primary cortical neurons.

图2：化合物在增加小鼠头部摆动次数方面的测试结果。Figure 2: Test results of compounds in increasing the number of head movements in mice.

图3：化合物在减少强迫游泳小鼠的不动时间方面的测试结果。Figure 3: Results of testing of compounds in reducing immobility time in forced swimming mice.

具体实施方式DETAILED DESCRIPTION

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

实施例1Example 1

合成路线：
Synthesis route:

第一步first step

将化合物1-1(1.00g,6.79mmol)溶解在甲醇(20mL)中，依次加入氢氧化钾(460mg,8.15mmol)和1-2(1.40g,8.15mmol)，在50℃下反应16小时。反应结束后，将反应液冷却至室温，用90mL冰水淬灭，乙酸乙酯萃取(100mL x 2)，机相减压浓缩，剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)分离得到化合物1-3。1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.38(d,J＝8.62Hz,1H),7.22(d,J＝2.32Hz,1H),6.87(d,J＝2.32Hz,1H),6.66(dd,J＝8.62,2.26Hz,1H),6.02(s,1H),4.19-4.17(m,2H),4.06-4.02(m,2H),3.76(s,3H),1.40(s,9H)。ESI-MS理论计算值:[M+H-56]+＝263.16,实测值263.0。Compound 1-1 (1.00 g, 6.79 mmol) was dissolved in methanol (20 mL), potassium hydroxide (460 mg, 8.15 mmol) and 1-2 (1.40 g, 8.15 mmol) were added in sequence, and the mixture was reacted at 50°C for 16 hours. After the reaction, the reaction solution was cooled to room temperature, quenched with 90 mL of ice water, extracted with ethyl acetate (100 mL x 2), and the organic phase was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 1-3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 7.38 (d, J = 8.62 Hz, 1H), 7.22 (d, J = 2.32 Hz, 1H), 6.87 (d, J = 2.32 Hz, 1H), 6.66 (dd, J = 8.62, 2.26 Hz, 1H), 6.02 (s, 1H), 4.19-4.17 (m, 2H), 4.06-4.02 (m, 2H), 3.76 (s, 3H), 1.40 (s, 9H). ESI-MS theoretical calculated value: [M+H-56] + = 263.16, found 263.0.

第二步Step 2

将化合物1-3(300mg,940mmol)溶解在THF(10mL)中,冰浴下加入四氢锂铝(214mg,5.65mmol),升温至70℃下反应18小时。反应结束后,将反应液冷却至室温,反应完成后,向反应液中加入水(0.7mL),15％氢氧化钠水溶液(0.7mL),再加入水(2.1mL),搅拌0.5小时,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-SunFire-C18,10μm,19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:2-32％,保留时间:9min)纯化得到化合物1的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.29(s,1H),7.44(d,J＝8.62Hz,1H),7.14(d,J＝2.32Hz,1H),6.84(d,J＝2.26Hz,1H),6.64(dd,J＝8.62,2.26Hz,1H),3.93-3.84(m,3H),3.74(s,3H),3.45-3.43(m,2H),2.47(s,3H).ESI-MS理论计算值:[M+H]+＝217.13,实测值217.2。Compound 1-3 (300 mg, 940 mmol) was dissolved in THF (10 mL), lithium aluminum tetrahydride (214 mg, 5.65 mmol) was added under ice bath, and the temperature was raised to 70°C for reaction for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (0.7 mL), 15% sodium hydroxide aqueous solution (0.7 mL), and then water (2.1 mL) were added to the reaction solution, stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-SunFire-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 2-32%, retention time: 9 min) to obtain the monoformate of compound 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 8.29 (s, 1H), 7.44 (d, J = 8.62 Hz, 1H), 7.14 (d, J = 2.32 Hz, 1H), 6.84 (d, J = 2.26 Hz, 1H), 6.64 (dd, J = 8.62, 2.26 Hz, 1H), 3.93-3.84 (m, 3H), 3.74 (s, 3H), 3.45-3.43 (m, 2H), 2.47 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 217.13, found 217.2.

实施例2Example 2

合成路线：
Synthesis route:

第一步first step

将化合物1-1(2.00g,13.6mmol)溶解在四氢呋喃(20mL)中，加入草酰氯(1.76g,13.9mmol)，在0℃下反应3小时。反应结束后，反应液减压浓缩得到粗品2-2。1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.28(d,J＝3.24Hz,1H),8.01(d,J＝8.82Hz,1H),7.03(d,J＝2.24Hz,1H),6.89(dd,J＝2.32,8.74Hz,1H),3.79(s,3H).Compound 1-1 (2.00 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL), oxalyl chloride (1.76 g, 13.9 mmol) was added, and the mixture was reacted at 0°C for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product 2-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.20 (s, 1H), 8.28 (d, J = 3.24 Hz, 1H), 8.01 (d, J = 8.82 Hz, 1H), 7.03 (d, J = 2.24 Hz, 1H), 6.89 (dd, J = 2.32, 8.74 Hz, 1H), 3.79 (s, 3H).

第二步Step 2

将三乙胺(5.45g,53.9mmol)和化合物2-3的盐酸盐(3.98g,26.9mmol)溶解在二氯甲烷(20mL)中,冰浴下加入化合物2-2(3.20g,13.5mmol),室温反应18小时。反应结束后,用50mL冰水淬灭,乙酸乙酯萃取(30mL x 3),有机相减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)分离得到化合物2-4。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.03(s,1H),7.96(d,J＝8.68Hz,1H),7.01(d,J＝2.28Hz,1H),6.89(dd,J＝8.68,2.28Hz,1H),3.80(s,3H),3.69-3.53(m,2H),3.37-3.30(m,1H),3.15-3.11(m,1H),2.70-2.59(m,2H),1.92-1.59(m,3H),1.59-1.22(m,3H).ESI-MS理论计算值:[M+H]+＝313.15,实测值313.1。Dissolve triethylamine (5.45 g, 53.9 mmol) and the hydrochloride of compound 2-3 (3.98 g, 26.9 mmol) in dichloromethane (20 mL), add compound 2-2 (3.20 g, 13.5 mmol) under ice bath, and react at room temperature for 18 hours. After the reaction is completed, quench with 50 mL of ice water, extract with ethyl acetate (30 mL x 3), concentrate the organic phase under reduced pressure, and separate the residue by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 2-4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 8.03 (s, 1H), 7.96 (d, J=8.68 Hz, 1H), 7.01 (d, J=2.28 Hz, 1H), 6.89 (dd, J=8.68, 2.28 Hz, 1H), 3.80 (s, 3H), 3.69-3.53 (m, 2H), 3.37-3.30 (m, 1H), 3.15-3.11 (m, 1H), 2.70-2.59 (m, 2H), 1.92-1.59 (m, 3H), 1.59-1.22 (m, 3H). ESI-MS calculated value: [M+H] + ＝313.15, found 313.1.

第三步Step 3

将化合物2-4(500mg,1.60mmol)溶解在THF(10mL)中,冰浴下加入四氢锂铝(364mg,9.60mmol),反应升温至70℃下反应18小时。反应结束后,将反应液冷却至室温,向反应液中加入水(0.7mL),15％氢氧化钠水溶液(0.7mL),再加入水(2.1mL),搅拌0.5小时,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-SunFire-C18,10μm,19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:6-36％,保留时间:9min)纯化得到化合物2的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.62(m,1H),8.31(s,1H),7.39(d,J＝8.62Hz,1H),7.01(d,J＝2.24Hz,1H),6.84(d,J＝2.24Hz,1H),6.64(dd,J＝8.62,2.24Hz,1H),3.75(s,3H),3.06-2.93(m,2H),2.92-2.78(m,4H),2.65-2.54(m,2H),2.42-2.39(m,2H),1.65-1.52(m,3H),1.54-1.34(m,3H).ESI-MS理论计算值:[M+H]+＝285.19,实测值285.2。Compound 2-4 (500 mg, 1.60 mmol) was dissolved in THF (10 mL), and lithium aluminum tetrahydride (364 mg, 9.60 mmol) was added under ice bath, and the reaction temperature was raised to 70°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (0.7 mL), 15% sodium hydroxide aqueous solution (0.7 mL), and then water (2.1 mL) were added to the reaction solution, stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-SunFire-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 6-36%, retention time: 9 min) to obtain the monoformate of compound 2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (m, 1H), 8.31 (s, 1H), 7.39 (d, J = 8.62 Hz, 1H), 7.01 (d, J = 2.24 Hz, 1H), 6.84 (d, J = 2.24 Hz, 1H), 6.64 (dd, J = 8.62, 2.24 Hz, 1H), 3.75 (s, 3H), 3.06-2.93 (m, 2H), 2.92-2.78 (m, 4H), 2.65-2.54 (m, 2H), 2.42-2.39 (m, 2H), 1.65-1.52 (m, 3H), 1.54-1.34 (m, 3H). ESI-MS theoretical value: [M+H] + =285.19, measured value 285.2.

实施例3 Example 3

合成路线：
Synthesis route:

第一步first step

将化合物3-1(755mg,6.79mmol),氯化锌的四氢呋喃溶液(0.68mL,0.68mmol,1mol/L),6-甲氧基吲哚(1.00g,6.79mmol)溶于1,2-二氯乙烷(15mL)中,氮气氛围下,反应液升至70℃搅拌18小时。反应液冷却至室温,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物3-2。ESI-MS理论计算值:[M+H]+＝259.10,实测值259.1。Compound 3-1 (755 mg, 6.79 mmol), tetrahydrofuran solution of zinc chloride (0.68 mL, 0.68 mmol, 1 mol/L), and 6-methoxyindole (1.00 g, 6.79 mmol) were dissolved in 1,2-dichloroethane (15 mL). Under a nitrogen atmosphere, the reaction solution was heated to 70 ° C and stirred for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 3-2. ESI-MS theoretical calculated value: [M+H] + = 259.10, measured value 259.1.

第二步Step 2

将化合物3-2(200mg,770mmol)溶于四氢呋喃(10mL)中,分批加入四氢铝锂(117mg,3.08mmol),反应液在80℃搅拌4小时。反应液冷却至室温,加入四氢呋喃(10mL)稀释,滴加水(1mL)淬灭反应,过滤,滤液减压浓缩,剩余物经高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:40-55％,保留时间:8.5min)纯化得到化合物3。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.44(d,J＝8.62Hz,1H),6.98(d,J＝2.22Hz,1H),6.83(d,J＝2.22Hz,1H),6.62(dd,J＝8.62,2.32Hz,1H),3.75(s,3H),3.52-3.44(m,1H),2.93(t,J＝8.28Hz,1H),2.72-2.66(m,1H),2.55-2.53(m,1H),2.42(t,J＝8.28Hz,1H),2.30(s,3H),2.27-2.18(m,1H),1.90-1.82(m,1H)。ESI-MS理论计算值:[M+H]+＝231.14,实测值231.1。Compound 3-2 (200 mg, 770 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (117 mg, 3.08 mmol) was added in batches, and the reaction solution was stirred at 80°C for 4 hours. The reaction solution was cooled to room temperature, diluted with tetrahydrofuran (10 mL), and water (1 mL) was added dropwise to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 40-55%, retention time: 8.5 min) to obtain compound 3. 1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),7.44(d,J＝8.62Hz,1H),6.98(d,J＝2.22Hz,1H),6.83(d,J＝2.22Hz,1H),6.62(dd,J＝8.62,2.32Hz,1H),3.75(s,3H),3.52-3.44(m,1H),2.93(t,J＝8.28Hz,1H),2.72-2.66(m,1H),2.55-2.53(m,1H),2.42(t,J＝8.28Hz,1H),2.30(s,3H),2.27-2.18(m,1H),1.90-1.82(m,1H)。 ESI-MS theoretical calculated value: [M+H] + = 231.14, found value 231.1.

实施例4Example 4

合成路线：
Synthesis route:

第一步first step

将化合物4-1(500mg,3.40mmol)溶解在六氟异丙醇(5mL),依次加入2-氯环戊酮(403mg,3.40mmol)和碳酸钠(396mg,3.74mmol),室温搅拌12小时。反应液减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物4-2。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),7.31(d,J＝8.62Hz,1H),7.00(d,J＝2.32Hz,1H),6.83(d,J＝2.28Hz,1H),6.61(dd,J＝8.62,2.28Hz,1H),3.74(s,3H),3.58-3.52(m,1H),2.44-2.26(m,3H),2.20-1.79(m,3H)。ESI-MS理论计算值:[M+H]+＝230.11,实测值230.2。Compound 4-1 (500 mg, 3.40 mmol) was dissolved in hexafluoroisopropanol (5 mL), 2-chlorocyclopentanone (403 mg, 3.40 mmol) and sodium carbonate (396 mg, 3.74 mmol) were added in sequence, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 4-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 7.31 (d, J = 8.62 Hz, 1H), 7.00 (d, J = 2.32 Hz, 1H), 6.83 (d, J = 2.28 Hz, 1H), 6.61 (dd, J = 8.62, 2.28 Hz, 1H), 3.74 (s, 3H), 3.58-3.52 (m, 1H), 2.44-2.26 (m, 3H), 2.20-1.79 (m, 3H). ESI-MS theoretical calculated value: [M+H] + = 230.11, found 230.2.

第二步Step 2

将化合物4-2(510mg,2.22mmol)和二甲胺盐酸盐(182mg,2.22mmol)溶解在二氯甲烷(20mL), 在20℃下加入三乙胺(225mg,2.22mmol)和醋酸(134mg,2.22mmol),搅拌0.5小时,加入醋酸硼氢化钠(938mg,4.45mmol),20℃下搅拌12小时。反应结束后,加水20mL,乙酸乙酯萃取(20mL x 3),有机相减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-SunFire-C18,10μm,19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:6-36％,保留时间:9min)纯化得到化合物4的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.28(s,1H),7.44-7.37(m,1H),7.17-7.06(m,1H),6.84(d,J＝2.36Hz,1H),6.64-6.61(m,1H),3.75(s,3H),3.51-3.29(m,1H),2.73-2.68(m,1H),2.30(s,3H),2.15(s,3H),1.94-1.54(m,6H)。ESI-MS理论计算值:[M+H]+＝259.17,实测值259.2。Compound 4-2 (510 mg, 2.22 mmol) and dimethylamine hydrochloride (182 mg, 2.22 mmol) were dissolved in dichloromethane (20 mL). Triethylamine (225 mg, 2.22 mmol) and acetic acid (134 mg, 2.22 mmol) were added at 20°C, stirred for 0.5 hours, sodium acetate borohydride (938 mg, 4.45 mmol) was added, and stirred at 20°C for 12 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL x 3), the organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Waters-SunFire-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 6-36%, retention time: 9 min) to obtain the monoformate of compound 4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.28 (s, 1H), 7.44-7.37 (m, 1H), 7.17-7.06 (m, 1H), 6.84 (d, J=2.36 Hz, 1H), 6.64-6.61 (m, 1H), 3.75 (s, 3H), 3.51-3.29 (m, 1H), 2.73-2.68 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 1.94-1.54 (m, 6H). ESI-MS theoretical calculated value: [M+H] + ＝259.17, found 259.2.

实施例5Example 5

合成路线：
Synthesis route:

第一步first step

将化合物5-1(3.00g,14.9mmol)溶解在二氯甲烷(20mL)中,0℃下滴加草酰氯(1.53mL,17.9mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.12mL,1.49mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将6-甲氧基吲哚(2.40g,16.3mmol)溶于在二氯甲烷(20mL),0℃下滴加乙基溴化镁的乙醚溶液(19.6mL,19.6mmol,1mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(20mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应结束,反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(20mL x 2)萃取,有机相用(30mL)洗涤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物5-2。ESI-MS理论计算值:[M+H-100]+＝231.16,实测值231.0。Compound 5-1 (3.00 g, 14.9 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (1.53 mL, 17.9 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (0.12 mL, 1.49 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 6-Methoxyindole (2.40 g, 16.3 mmol) was dissolved in dichloromethane (20 mL), ethyl magnesium bromide in ether solution (19.6 mL, 19.6 mmol, 1 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (20 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was washed with (30 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 5-2. ESI-MS theoretical calculated value: [M+H-100] + = 231.16, measured value 231.0.

第二步Step 2

将化合物5-2(950mg,2.88mmol)溶于四氢呋喃(30mL),0℃下缓慢加入四氢锂铝(545mg,14.4mmol),反应液60℃搅拌16小时。反应液冷却至室温,加入十水硫酸钠,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:2-22％,保留时间:9min)纯化得到化合物5的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.32(s,1H),7.41(d,J＝8.62Hz,1H),7.00(d,J＝2.20Hz,1H),6.84(d,J＝2.24Hz,1H),6.64(dd,J＝8.62,2.24Hz,1H),3.75(s,3H),3.62-3.43(m,2H),3.04-2.96(m,2H),2.88-2.82(m,1H),2.26(s,3H),2.08-2.03(m,1H),2.00-1.86(m,1H)。ESI-MS理论计算[M+H]+＝231.14,实测值231.2。Compound 5-2 (950 mg, 2.88 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum tetrahydride (545 mg, 14.4 mmol) was slowly added at 0°C, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 2-22%, retention time: 9 min) to obtain the monoformate of compound 5. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.64 (s, 1H), 8.32 (s, 1H), 7.41 (d, J = 8.62 Hz, 1H), 7.00 (d, J = 2.20 Hz, 1H), 6.84 (d, J = 2.24 Hz, 1H), 6.64 (dd, J = 8.62, 2.24 Hz, 1H), 3.75 (s, 3H), 3.62-3.43 (m, 2H), 3.04-2.96 (m, 2H), 2.88-2.82 (m, 1H), 2.26 (s, 3H), 2.08-2.03 (m, 1H), 2.00-1.86 (m, 1H). ESI-MS theoretical calculation [M+H] + = 231.14, found 231.2.

实施例6Example 6

合成路线：
Synthesis route:

第一步first step

将2-氮杂螺[3.3]庚烷半草酸盐(200mg,0.70mmol)溶解在四氢呋喃溶液(3mL)中,0℃下滴加溶解在四氢呋喃(2mL)中的化合物2-2(337mg,1.42mmol),反应液在0℃下搅拌2小时。反应结束,反应液加入水(20mL),乙酸乙酯(10mL x 2)萃取,有机相用(10mL)洗涤,减压浓缩,剩余物经硅胶柱层析法(二氯甲烷/甲醇,20/1,v/v)得到化合物6-1。ESI-MS理论计算值:[M+H]+＝299.13,实测值299.0。2-Azaspiro[3.3]heptane hemioxalate (200 mg, 0.70 mmol) was dissolved in tetrahydrofuran solution (3 mL), and compound 2-2 (337 mg, 1.42 mmol) dissolved in tetrahydrofuran (2 mL) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and ethyl acetate (10 mL x 2) was used to extract, and the organic phase was washed with (10 mL), concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol, 20/1, v/v) to obtain compound 6-1. ESI-MS theoretical calculated value: [M+H] + = 299.13, measured value 299.0.

第二步Step 2

将化合物6-1(170mg,0.57mmol)溶于四氢呋喃(10mL),0℃下缓慢加入四氢锂铝(108mg,2.85mmol),60℃搅拌5小时。反应结束后,加入十水硫酸钠,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:2-22％,保留时间:9min)纯化得到化合物6的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.29(s,1H),7.37(d,J＝8.60Hz,1H),6.98(d,J＝2.20Hz,1H),6.83(d,J＝2.24Hz,1H),6.64(dd,J＝8.60,2.24Hz,1H),3.75(s,3H),3.44-3.34(m,4H),2.82-2.76(m,2H),2.71-2.63(m,2H),2.10-2.04(m,4H),1.79-1.71(m,2H)。ESI-MS理论计算值:[M+H]+＝271.17,实测值271.2。Compound 6-1 (170 mg, 0.57 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (108 mg, 2.85 mmol) was slowly added at 0°C, and stirred at 60°C for 5 hours. After the reaction was completed, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 2-22%, retention time: 9 min) to obtain the monoformate of compound 6. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 8.29 (s, 1H), 7.37 (d, J = 8.60 Hz, 1H), 6.98 (d, J = 2.20 Hz, 1H), 6.83 (d, J = 2.24 Hz, 1H), 6.64 (dd, J = 8.60, 2.24 Hz, 1H), 3.75 (s, 3H), 3.44-3.34 (m, 4H), 2.82-2.76 (m, 2H), 2.71-2.63 (m, 2H), 2.10-2.04 (m, 4H), 1.79-1.71 (m, 2H). ESI-MS theoretical calculated value: [M+H] + = 271.17, found 271.2.

实施例7Example 7

合成路线：
Synthesis route:

第一步first step

将2-氮杂螺[3.4]壬烷盐酸盐(100mg,0.62mmol)溶于在四氢呋喃(3mL)中,0℃下滴加溶解于四氢呋喃(2mL)中的化合物2-2(294mg,1.24mmol),反应液在0℃下搅拌2小时。反应结束,反应液加入水溶液(20mL),乙酸乙酯(20mL x 3)萃取,有机相用(10mL)洗涤,减压浓缩,剩余物经硅胶柱层析法(二氯甲烷/甲醇,20/1,v/v)纯化得到化合物7-1。ESI-MS理论计算值:[M+H]+＝327.16,实测值327.2。2-Azaspiro[3.4]nonane hydrochloride (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (3 mL), and compound 2-2 (294 mg, 1.24 mmol) dissolved in tetrahydrofuran (2 mL) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was added with aqueous solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with (10 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 20/1, v/v) to obtain compound 7-1. ESI-MS theoretical calculated value: [M+H] + = 327.16, measured value 327.2.

第二步 Step 2

将化合物7-1(150mg,0.46mmol)溶于四氢呋喃(10mL),0℃下缓慢加入四氢锂铝(87.2mg,2.30mmol),60℃搅拌5小时。反应结束,加入十水硫酸钠,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:10-40％,保留时间:9min)纯化得到化合物7的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.29(s,1H),7.38(d,J＝8.60Hz,1H),6.98(d,J＝2.24Hz,1H),6.83(d,J＝2.32Hz,1H),6.63(dd,J＝8.60,2.32Hz,1H),3.74(s,3H),3.16(s,4H),2.86(dd,J＝8.98,6.66Hz,2H),2.68(dd,J＝8.98,6.66Hz,2H),1.60-1.57(m,4H),1.39-1.29(m,6H)。ESI-MS理论计算值:[M+H]+＝299.20,实测值299.2Compound 7-1 (150 mg, 0.46 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum tetrahydride (87.2 mg, 2.30 mmol) was slowly added at 0°C, and stirred at 60°C for 5 hours. After the reaction was completed, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 10-40%, retention time: 9 min) to obtain the monoformate of compound 7. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.29 (s, 1H), 7.38 (d, J = 8.60 Hz, 1H), 6.98 (d, J = 2.24 Hz, 1H), 6.83 (d, J = 2.32 Hz, 1H), 6.63 (dd, J = 8.60, 2.32 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 4H), 2.86 (dd, J = 8.98, 6.66 Hz, 2H), 2.68 (dd, J = 8.98, 6.66 Hz, 2H), 1.60-1.57 (m, 4H), 1.39-1.29 (m, 6H). ESI-MS theoretical calculated value: [M+H] + = 299.20, found 299.2

实施例8Example 8

合成路线：
Synthesis route:

第一步first step

将2-氮杂双环[2.2.2]辛烷盐酸盐(100mg,0.68mmol)溶于在四氢呋喃(3mL)中,0℃下滴加溶解于四氢呋喃(2mL)中的化合物2-2(320mg,1.35mmol),反应液在60℃反应5小时,反应结束,反应液加入水(20mL),乙酸乙酯(10mL x 3)萃取,有机相用(10mL)洗涤,减压浓缩,剩余物经硅胶柱层析法(二氯甲烷/甲醇,20/1,v/v)纯化得到化合物8-1。ESI-MS理论计算值:[M+H]+＝313.15,实测值313.0。2-Azabicyclo[2.2.2]octane hydrochloride (100 mg, 0.68 mmol) was dissolved in tetrahydrofuran (3 mL), and compound 2-2 (320 mg, 1.35 mmol) dissolved in tetrahydrofuran (2 mL) was added dropwise at 0°C. The reaction solution was reacted at 60°C for 5 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phase was washed with (10 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 20/1, v/v) to obtain compound 8-1. ESI-MS theoretical calculated value: [M+H] + = 313.15, measured value 313.0.

第二步Step 2

将化合物8-1(180mg,0.58mmol)溶于四氢呋喃(10mL),0℃下缓慢加入四氢锂铝(109mg,2.88mmol),60℃搅拌5小时。反应冷却至室温,加入十水硫酸钠,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:7-37％,保留时间:9min)纯化得到化合物8的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.43(s,1H),7.44(d,J＝8.60Hz,1H),7.04(d,J＝2.24Hz,1H),6.84(d,J＝2.24Hz,1H),6.64(dd,J＝8.60,2.32Hz,1H),3.75(s,3H),3.10-3.03(m,5H),2.94-2.90(m,2H),2.07-1.92(m,2H),1.81-1.75(m,1H),1.68-1.53(m,6H)。ESI-MS理论计算值:[M+H]+＝285.19,实测值285.2。Compound 8-1 (180 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum tetrahydride (109 mg, 2.88 mmol) was slowly added at 0°C, and stirred at 60°C for 5 hours. The reaction was cooled to room temperature, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 7-37%, retention time: 9 min) to obtain the monoformate of compound 8. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 8.43 (s, 1H), 7.44 (d, J = 8.60 Hz, 1H), 7.04 (d, J = 2.24 Hz, 1H), 6.84 (d, J = 2.24 Hz, 1H), 6.64 (dd, J = 8.60, 2.32 Hz, 1H), 3.75 (s, 3H), 3.10-3.03 (m, 5H), 2.94-2.90 (m, 2H), 2.07-1.92 (m, 2H), 1.81-1.75 (m, 1H), 1.68-1.53 (m, 6H). ESI-MS theoretical calculated value: [M+H] + = 285.19, found 285.2.

实施例9Example 9

合成路线：
Synthesis route:

第一步first step

将化合物9-1(350mg,2.36mmol),氢氧化钾(331mg,5.91mmol)溶解于N,N-二甲基甲酰胺(10mL)中,加入碘(660mg,2.60mmol),反应液25℃搅拌18小时。反应液倒入水(50mL)中,乙酸乙酯(50mL x 3)萃取,有机相用20％的亚硫酸钠水溶液(50mL)洗涤,无水硫酸钠干燥,过滤，滤液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物9-2。ESI-MS理论计算值:[M+H]+＝274.96,实测值274.9。Compound 9-1 (350 mg, 2.36 mmol) and potassium hydroxide (331 mg, 5.91 mmol) were dissolved in N,N-dimethylformamide (10 mL), iodine (660 mg, 2.60 mmol) was added, and the reaction solution was stirred at 25°C for 18 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was washed with 20% sodium sulfite aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 9-2. ESI-MS theoretical calculated value: [M+H] + = 274.96, measured value 274.9.

第二步Step 2

将化合物9-2(170mg,0.62mmol),碳酸钾(257mg,1.86mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(201mg,0.68mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(50.7mg,0.06mmol)溶于1,4-二氧六环(2mL)和水(1mL)中,氮气氛围下,反应液升至95℃搅拌10小时。反应液冷却至室温,倒入水(10mL)中,乙酸乙酯(20mL x 3)萃取,有机相用饱和食盐水(10mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物9-3。ESI-MS理论计算值:[M+H]+＝316.16,实测值316.1。Compound 9-2 (170 mg, 0.62 mmol), potassium carbonate (257 mg, 1.86 mmol), 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (201 mg, 0.68 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (50.7 mg, 0.06 mmol) were dissolved in 1,4-dioxane (2 mL) and water (1 mL). Under a nitrogen atmosphere, the reaction solution was heated to 95 ° C and stirred for 10 hours. The reaction solution was cooled to room temperature, poured into water (10 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 9-3. ESI-MS theoretical calculated value: [M+H] + =316.16, found value 316.1.

第三步Step 3

将化合物9-3(100mg,0.32mmol)溶于四氢呋喃(3mL)中,加入四氢铝锂(48.1mg,1.27mmol),反应液在80℃搅拌3小时。反应液冷却至室温,滴加水(1mL)淬灭反应,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:45-55％,保留时间:10.7min)纯化得到化合物9。1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.12(d,J＝8.52Hz,1H),7.19(s,1H),6.57(d,J＝8.52Hz,1H),6.07(t,J＝2.12Hz,1H),3.87(s,3H),3.73-3.68(m,2H),3.55-3.53(m,2H),2.44(s,3H)。ESI-MS理论计算值:[M+H]+＝230.12,实测值230.1。Compound 9-3 (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum tetrahydride (48.1 mg, 1.27 mmol) was added, and the reaction solution was stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, and water (1 mL) was added dropwise to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 45-55%, retention time: 10.7 min) to obtain compound 9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.57 (s, 1H), 8.12 (d, J = 8.52 Hz, 1H), 7.19 (s, 1H), 6.57 (d, J = 8.52 Hz, 1H), 6.07 (t, J = 2.12 Hz, 1H), 3.87 (s, 3H), 3.73-3.68 (m, 2H), 3.55-3.53 (m, 2H), 2.44 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 230.12, found 230.1.

实施例10Example 10

合成路线：
Synthesis route:

第一步first step

将化合物9(100mg,0.44mmol)溶于甲醇(5mL)中,加入钯碳(10％,4.64mg)和氢氧化钯碳(10％,6.12mg)后,反应液在氢气氛围下25℃搅拌18小时。反应液过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:40-55％,保留时间:8.5min)纯化得到化合物10。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.91(d,J＝8.40Hz,1H),6.97(s,1H),6.48(d,J＝8.40Hz,1H),3.85(s,3H),3.50-3.42(m,1H),2.92-2.89(m,1H),2.70-2.62(m,1H),2.59-2.53(m,1H),2.46-2.42(m,1H),2.30(s,3H),2.25-2.18(m,1H),1.88-1.80(m,1H)。ESI-MS理论计算值:[M+H]+＝232.14,实测值232.1。Compound 9 (100 mg, 0.44 mmol) was dissolved in methanol (5 mL), palladium carbon (10%, 4.64 mg) and palladium hydroxide carbon (10%, 6.12 mg) were added, and the reaction solution was stirred at 25°C for 18 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 40-55%, retention time: 8.5 min) to obtain compound 10. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.13 (s, 1H), 7.91 (d, J = 8.40 Hz, 1H), 6.97 (s, 1H), 6.48 (d, J = 8.40 Hz, 1H), 3.85 (s, 3H), 3.50-3.42 (m, 1H), 2.92-2.89 (m, 1H), 2.70-2.62 (m, 1H), 2.59-2.53 (m, 1H), 2.46-2.42 (m, 1H), 2.30 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.80 (m, 1H). ESI-MS theoretical calculated value: [M+H] + = 232.14, found 232.1.

实施例11Embodiment 11

合成路线：
Synthesis route:

第一步first step

将化合物11-1(3.82g,20.4mmol),氯化锌的四氢呋喃溶液(2.04mL,2.04mmol,1mol/L),6-甲氧基吲哚(3.00g,20.4mmol)溶于1,2-二氯乙烷(60mL)中,氮气氛围下,反应液80℃搅拌18小时。反应液冷却至室温,倒入水(50mL)中,乙酸乙酯(50mL x 3)萃取,有机相用饱和食盐水(50mL x 2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物11-2。ESI-MS理论计算值:[M+H]+＝335.13,实测值335.1。Compound 11-1 (3.82 g, 20.4 mmol), tetrahydrofuran solution of zinc chloride (2.04 mL, 2.04 mmol, 1 mol/L), and 6-methoxyindole (3.00 g, 20.4 mmol) were dissolved in 1,2-dichloroethane (60 mL), and the reaction solution was stirred at 80°C for 18 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 11-2. ESI-MS theoretical calculated value: [M+H] + = 335.13, measured value 335.1.

第二步Step 2

将化合物11-2(900mg,2.69mmol)溶于四氢呋喃(20mL)中,分批加入四氢铝锂(408mg,10.8mmol),反应液在70℃搅拌3小时。反应液冷却至室温,滴加水(1mL)淬灭反应,过滤,滤液减压浓缩,得到化合物11-3。ESI-MS理论计算值:[M+H]+＝307.17,实测值307.1。Compound 11-2 (900 mg, 2.69 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum tetrahydride (408 mg, 10.8 mmol) was added in batches, and the reaction solution was stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, and water (1 mL) was added dropwise to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-3. ESI-MS theoretical calculated value: [M+H] + = 307.17, measured value 307.1.

第三步 Step 3

将化合物11-3(300mg,0.98mmol)溶于乙醇(15mL)中,加入钯碳(10％,30.0mg)和氢氧化钯(10％,30.0mg),反应液在氢气氛围下,25℃搅拌18小时。反应液过滤,滤液减压浓缩,得到化合物11-4。ESI-MS理论计算值:[M+H]+＝217.13,实测值217.1。Compound 11-3 (300 mg, 0.98 mmol) was dissolved in ethanol (15 mL), palladium carbon (10%, 30.0 mg) and palladium hydroxide (10%, 30.0 mg) were added, and the reaction solution was stirred at 25°C for 18 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-4. ESI-MS theoretical calculated value: [M+H] + = 217.13, measured value 217.1.

第四步Step 4

将化合物11-4(150mg,0.69mmol),1-乙氧基-1-三甲基硅氧基环丙烷(1.21g,6.94mmol),三乙酰氧基硼氢化钠(585mg,2.77mmol)溶于1,2-二氯乙烷(10mL)中,氮气氛围下,反应液40℃搅拌6小时。反应液冷却至室温,倒入水(10mL)中,二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL x2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经过高效液相色谱(色谱柱:Waters-XBndge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:9.5min)纯化得到化合物11。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.42(d,J＝8.62Hz,1H),6.98(s,1H),6.82(d,J＝2.32Hz,1H),6.61(dd,J＝8.62,2.32Hz,1H),3.75(s,3H),3.47-3.43(m,1H),3.14-3.11(m,1H),2.87-2.83(m,1H),2.76-2.72(m,1H),2.65-2.61(m,1H),2.25-2.20(m,1H),1.91-1.84(m,1H),1.73-1.69(m,1H),0.43-0.31(m,4H)。ESI-MS理论计算值:[M+H]+＝257.16,实测值257.1。Compound 11-4 (150 mg, 0.69 mmol), 1-ethoxy-1-trimethylsilyloxycyclopropane (1.21 g, 6.94 mmol), sodium triacetoxyborohydride (585 mg, 2.77 mmol) were dissolved in 1,2-dichloroethane (10 mL), and the reaction solution was stirred at 40°C for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water (10 mL), extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (chromatographic column: Waters-XBndge-C18, 10 μm, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9.5 min) to obtain compound 11. 1 H NMR (400MHz, DMSO-d 6 ) δ10.56 (s, 1H), 7.42 (d, J = 8.62Hz, 1H), 6.98 (s, 1H), 6.82 (d, J = 2.32Hz, 1H), 6.61 (dd, J = 8.62, 2.32Hz, 1H), 3.75 (s, 3H), 3.47-3.4 0 .43-0.31(m,4H). ESI-MS theoretical calculated value: [M+H] + = 257.16, found value 257.1.

实施例12Example 12

合成路线：
Synthesis route:

第一步first step

将化合物12-1(2.00g,8.02mmol)溶解在二氯甲烷(20mL)中,0℃下滴加草酰氯(0.76mL,8.83mmol)搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.12mL,1.60mmol),0℃搅拌1.2小时,反应液减压浓缩,得到中间体的反应液。将6-甲氧基吲哚(1.30g,8.83mmol)溶于在二氯甲烷(20mL)中,0℃下加入乙基溴化镁的乙醚溶液(3.12mL,10.6mmol,3.4mol/L),0℃搅拌0.5小时。将中间体反应液缓慢滴入反应液,0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(30mL x 2)萃取,有机相用饱和氯化钠水溶液(30mL)洗涤,减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物12-2。ESI-MS理论计算值:[M+H]+＝379.16,实测值379.1。Dissolve compound 12-1 (2.00 g, 8.02 mmol) in dichloromethane (20 mL), add oxalyl chloride (0.76 mL, 8.83 mmol) dropwise at 0°C, stir for 10 minutes, slowly add N,N-dimethylformamide (0.12 mL, 1.60 mmol), stir at 0°C for 1.2 hours, and concentrate the reaction solution under reduced pressure to obtain the reaction solution of the intermediate. Dissolve 6-methoxyindole (1.30 g, 8.83 mmol) in dichloromethane (20 mL), add ethyl magnesium bromide in ether solution (3.12 mL, 10.6 mmol, 3.4 mol/L) at 0°C, and stir at 0°C for 0.5 hours. Slowly drop the intermediate reaction solution into the reaction solution, and stir at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (30 mL x 2), the organic phase was washed with saturated sodium chloride aqueous solution (30 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 12-2. ESI-MS theoretical calculated value: [M+H] + = 379.16, found value 379.1.

第二步Step 2

将化合物12-2(400mg,1.06mmol)溶于四氢呋喃(10mL),20℃下缓慢加入氢化铝锂(201mg,5.28mmol),60℃搅拌16小时。反应结束,加入十水硫酸钠,过滤,滤液减压浓缩,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:2-22％,保留时间:9min)得到化合物12的一甲酸盐。1H NMR(400MHz,CD3OD)δ8.53(s,1H),7.44(d,J＝8.64Hz,1H),7.06(d,J＝1.22Hz,1H),6.89(d,J＝2.24Hz,1H),6.72(dd,J＝8.64,2.24Hz,1H),3.80(s,3H),3.66-3.56(m,2H),3.27-3.25(m,1H),3.14-3.04(m,1H),3.01-2.97(m,1H),2.82(s,3H),2.25-2.14(m,1H),2.09-1.95 (m,2H),1.92-1.81(m,1H)。ESI-MS理论计算:[M+H]+＝245.16,实测值245.0。Compound 12-2 (400 mg, 1.06 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (201 mg, 5.28 mmol) was slowly added at 20°C, and stirred at 60°C for 16 hours. After the reaction was completed, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 2-22%, retention time: 9 min) to obtain the monoformate of compound 12. 1 H NMR (400MHz, CD 3 OD) δ 8.53 (s, 1H), 7.44 (d, J = 8.64Hz, 1H), 7.06 (d, J = 1.22Hz, 1H), 6.89 (d, J = 2.24Hz, 1H), 6.72 (dd, J = 8.64, 2.24Hz, 1H), 3.80 (s, 3H), 3.66-3.56(m,2H),3.27-3.25(m,1H),3.14-3.04(m,1H),3.01-2.97(m,1H),2.82(s,3H),2.25-2.14(m,1H),2.09-1.95 (m, 2H), 1.92-1.81 (m, 1H). ESI-MS theoretical calculation: [M+H] + = 245.16, found 245.0.

实施例13Embodiment 13

合成路线：
Synthesis route:

第一步first step

将化合1-1(1.00g,6.79mmol)溶解在六氟异丙醇(20mL),依次加入2-氯环己酮(0.78mL,6.79mmol)和碳酸钠(790mg,7.47mmol),20℃下搅拌4小时。反应液加入水(50mL),乙酸乙酯(50mL x2)萃取,有机相用饱和氯化钠水溶液(50mL)洗涤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物13-2。1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.20(d,J＝8.64Hz,1H),7.01(d,J＝2.26Hz,1H),6.83(d,J＝2.26Hz,1H),6.58(dd,J＝8.64,2.26Hz,1H),3.89-3.85(m,1H),3.74(s,3H),2.38-2.15(m,2H),2.10-1.98(m,2H),1.95-1.67(m,4H)。ESI-MS理论计算值:[M+H]+＝244.13,实测值244.2。Compound 1-1 (1.00 g, 6.79 mmol) was dissolved in hexafluoroisopropanol (20 mL), and 2-chlorocyclohexanone (0.78 mL, 6.79 mmol) and sodium carbonate (790 mg, 7.47 mmol) were added in sequence, and stirred at 20°C for 4 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 2) was used for extraction, and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 13-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 7.20 (d, J = 8.64 Hz, 1H), 7.01 (d, J = 2.26 Hz, 1H), 6.83 (d, J = 2.26 Hz, 1H), 6.58 (dd, J = 8.64, 2.26 Hz, 1H), 3.89-3.85 (m, 1H), 3.74 (s, 3H), 2.38-2.15 (m, 2H), 2.10-1.98 (m, 2H), 1.95-1.67 (m, 4H). ESI-MS theoretical calculated value: [M+H] + = 244.13, found 244.2.

第二步Step 2

将化合物13-2(400mg,1.64mmol)和二甲胺盐酸盐(134mg,1.64mmol)溶解在二氯甲烷(20mL),在25℃下加入三乙胺(166mg,1.64mmol)和醋酸(98.7mg,1.64mmol),20℃搅拌0.5小时,将醋酸硼氢化钠(694mg,3.29mmol)加入反应液中,20℃搅拌1小时。反应液减压浓缩,剩余物经过高效液相色谱(Waters-SunFire-C18-10μm-19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:6-35％,保留时间:9min)纯化得到化合物13的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.29(s,1H),7.42(d,J＝8.64Hz,1H),7.24(d,J＝2.26Hz,1H),6.85(d,J＝2.26Hz,1H),6.64(dd,J＝8.64,2.26Hz,1H),3.75(s,3H),3.70-3.67(m,1H),2.67-2.62(m,1H),2.23(s,6H),2.01-1.74(m,4H),1.70-1.62(m,1H),1.36-1.26(m,3H)。ESI-MS理论计算值:[M+H]+＝273.19,实测值273.2。Compound 13-2 (400 mg, 1.64 mmol) and dimethylamine hydrochloride (134 mg, 1.64 mmol) were dissolved in dichloromethane (20 mL), triethylamine (166 mg, 1.64 mmol) and acetic acid (98.7 mg, 1.64 mmol) were added at 25°C, stirred at 20°C for 0.5 hours, sodium acetate borohydride (694 mg, 3.29 mmol) was added to the reaction solution, and stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10μm-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 6-35%, retention time: 9 min) to obtain the monoformate of compound 13. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.29 (s, 1H), 7.42 (d, J = 8.64 Hz, 1H), 7.24 (d, J = 2.26 Hz, 1H), 6.85 (d, J = 2.26 Hz, 1H), 6.64 (dd, J = 8.64, 2.26 Hz, 1H), 3.75 (s, 3H), 3.70-3.67 (m, 1H), 2.67-2.62 (m, 1H), 2.23 (s, 6H), 2.01-1.74 (m, 4H), 1.70-1.62 (m, 1H), 1.36-1.26 (m, 3H). ESI-MS theoretical calculated value: [M+H] + = 273.19, found 273.2.

实施例14Embodiment 14

合成路线：
Synthesis route:

第一步first step

将化合物14-1(1.00g,4.32mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.49mmol),缓慢加入N,N-二甲基甲酰胺(31.6mg,0.43mmol),20℃搅拌3小时,反应液减压浓缩,得到中间体的反应液。将6-甲氧基吲哚(589mg,4.00mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(3.53mL,12.0mmol,3.4mol/L),0℃搅拌1小时。将中间体反应液溶解于二氯甲烷(10mL)缓慢滴入反应液,25℃搅拌18小时。反应液加入饱和氯化铵水溶液(30mL)淬灭,二氯甲烷(30mL x 3)萃取,有机相用饱和氯化钠水溶液(30mL x 2)洗涤,减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物14-2。ESI-MS理论计算值:[M+H]+＝261.12,实测值261.1。Dissolve compound 14-1 (1.00 g, 4.32 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.49 mmol) dropwise at 0°C, slowly add N,N-dimethylformamide (31.6 mg, 0.43 mmol), stir at 20°C for 3 hours, and concentrate the reaction solution under reduced pressure to obtain the reaction solution of the intermediate. Dissolve 6-methoxyindole (589 mg, 4.00 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (3.53 mL, 12.0 mmol, 3.4 mol/L) at 0°C, and stir at 0°C for 1 hour. Dissolve the intermediate reaction solution in dichloromethane (10 mL) and slowly dropwise add to the reaction solution, and stir at 25°C for 18 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (30 mL), extracted with dichloromethane (30 mL x 3), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 14-2. ESI-MS theoretical calculated value: [M+H] + = 261.12, found value 261.1.

第二步Step 2

将化合物14-2(250mg,0.96mmol)溶于四氢呋喃(10mL),0℃下缓慢加入氢化铝锂(182mg,4.80mmol),70℃搅拌3小时。反应结束后,反应液加入四氢呋喃(20mL)稀释,缓慢加入水(1mL)淬灭,无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物14-3。ESI-MS理论计算值:[M+H]+＝247.14,实测值247.1。Compound 14-2 (250 mg, 0.96 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (182 mg, 4.80 mmol) was slowly added at 0°C, and stirred at 70°C for 3 hours. After the reaction was completed, tetrahydrofuran (20 mL) was added to dilute the reaction solution, and water (1 mL) was slowly added to quench, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-3. ESI-MS theoretical calculated value: [M+H] + = 247.14, measured value 247.1.

第三步Step 3

将化合物14-3(200mg,0.81mmol),多聚甲醛(146mg,1.62mmol)溶于1,2-二氯乙烷(10mL),25℃下加入三乙酰氧基硼氢化钠(685mg,3.25mmol),25℃搅拌12小时。反应液过滤,滤液减压浓缩,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢氨水溶液,梯度:40-55％,保留时间:8min)纯化得到化合物14。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),7.36(d,J＝8.62Hz,1H),7.00(d,J＝2.22Hz,1H),6.84(d,J＝2.30Hz,1H),6.65(dd,J＝8.62,2.30Hz,1H),3.76(s,3H),3.68-3.61(m,1H),3.51-3.42(m,2H),3.17-3.12(m,1H),3.07-3.03(m,1H),2.68-2.65(m,1H),2.47-2.41(m,1H),2.37(s,3H),2.29-2.24(m,1H),2.23-2.15(m,1H)。ESI-MS理论计算值:[M+H]+＝261.15,实测值261.1。Compound 14-3 (200 mg, 0.81 mmol) and paraformaldehyde (146 mg, 1.62 mmol) were dissolved in 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (685 mg, 3.25 mmol) was added at 25°C, and stirred at 25°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L aqueous ammonium bicarbonate solution, gradient: 40-55%, retention time: 8min) to obtain compound 14. 1 H NMR (400MHz, DMSO-d 6 )δ10.61(s,1H),7.36(d,J＝8.62Hz,1H),7.00(d,J＝2.22Hz,1H),6.84(d,J＝2.30Hz,1H),6.65(dd,J＝8.62,2.30Hz,1H),3.76(s,3H),3.68-3.61(m,1H),3 .51-3.42(m,2H),3.17-3.12(m,1H),3.07-3.03(m,1H),2.68-2.65(m,1H),2.47-2.41(m,1H),2.37(s,3H),2.29-2.24(m,1H),2.23-2.15(m,1H). ESI-MS theoretical calculated value: [M+H] + = 261.15, found value 261.1.

实施例15Embodiment 15

合成路线：
Synthesis route:

第一步first step

氮气保护下,将化合物1-1(2.20g,15.0mmol)溶解在四氢呋喃(30mL)中,加入甲基溴化镁(5.48mL,16.4mmol,3.0M),25℃搅拌45分钟。反应液中滴加3,4-环氧四氢呋喃(1.42g,16.4mmol)溶解在四氢呋喃(30mL)的溶液,25℃搅拌16小时。反应液加入饱和碳酸氢钠水溶液(50mL)淬灭,乙酸乙酯(20mL x 4)萃取,有机相用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,4/1,v/v)纯化得到化合物15-2。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),7.46(d,J＝8.62Hz,1H),6.99(d,J＝2.32Hz,1H),6.83(d,J＝2.32Hz,1H),6.64(dd,J＝8.62,2.32Hz,1H),5.19-5.17(m,1H),4.31-4.25(m,1H),4.20-4.15(m,1H),3.92-3.86(m,1H),3.82-3.77(m,1H),3.75(s,3H),3.60-3.55(m,1H),3.37-3.33(m,1H)。ESI-MS理论计算值:[M+H]+＝234.11,实测值234.0。Under nitrogen protection, compound 1-1 (2.20 g, 15.0 mmol) was dissolved in tetrahydrofuran (30 mL), methylmagnesium bromide (5.48 mL, 16.4 mmol, 3.0 M) was added, and the mixture was stirred at 25°C for 45 minutes. A solution of 3,4-epoxytetrahydrofuran (1.42 g, 16.4 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 16 hours. The reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 4), and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain compound 15-2. 1 H NMR (400MHz, DMSO-d 6 ) δ10.67 (s, 1H), 7.46 (d, J = 8.62Hz, 1H), 6.99 (d, J = 2.32Hz, 1H), 6.83 (d, J = 2.32Hz, 1H), 6.64 (dd, J = 8.62, 2.32Hz, 1H), 5.19-5.17 (m ,1H),4.31-4.25(m,1H),4.20-4.15(m,1H),3.92-3.86(m,1H),3.82-3.77(m,1H),3.75(s,3H),3.60-3.55(m,1H),3.37-3.33(m,1H). ESI-MS theoretical calculated value: [M+H] + = 234.11, found value 234.0.

第二步Step 2

将化合物15-2(1.60g,6.86mmol)溶解在乙酸乙酯(30mL)中,加入2-碘酰基苯甲酸(5.76g,20.6mmol),80℃搅拌2.5小时。反应液冷却至室温,将反应液过滤,滤液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,4/1,v/v)纯化得到化合物15-3。ESI-MS理论计算值C13H14NO3[M+H]+＝232.09,实测值232.0。Compound 15-2 (1.60 g, 6.86 mmol) was dissolved in ethyl acetate (30 mL), 2-iodoacylbenzoic acid (5.76 g, 20.6 mmol) was added, and the mixture was stirred at 80°C for 2.5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain compound 15-3. ESI-MS theoretical calculated value C 13 H 14 NO 3 [M+H] + = 232.09, and the measured value was 232.0.

第三步Step 3

将化合物15-3(300mg,1.30mmol)溶解在二氯甲烷(5mL)中，加入盐酸二甲胺(106mg,1.30mmol),三乙胺(131mg,1.30mmol),氰基硼氢化钠(62.8mg,3.89mmol)和乙酸(7.79mg,0.13mmol),25℃搅拌16小时。反应液中加入水(30mL),乙酸乙酯(20mL x 3)萃取,合并有机相,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩。得到有目标化合物的粗品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢氨水溶液,梯度:20-50％,保留时间:8.0min)纯化得到化合物15。1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),7.43(d,J＝8.62Hz,1H),7.13(d,J＝2.32Hz,1H),6.84(d,J＝2.32Hz,1H),6.62(dd,J＝8.62,2.32Hz,1H),4.10-4.06(m,1H),3.96-3.91(m,1H),3.83-3.76(m,2H),3.75(s,3H),3.63-3.59(m,1H),2.95-2.89(m,1H),2.02(s,6H)。ESI-MS理论计算值:[M+H]+＝261.15,实测值261.1。 Compound 15-3 (300 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), and dimethylamine hydrochloride (106 mg, 1.30 mmol), triethylamine (131 mg, 1.30 mmol), sodium cyanoborohydride (62.8 mg, 3.89 mmol) and acetic acid (7.79 mg, 0.13 mmol) were added, and stirred at 25°C for 16 hours. Water (30 mL) and ethyl acetate (20 mL x 3) were added to the reaction solution for extraction, and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product of the target compound was obtained, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L aqueous ammonium bicarbonate solution, gradient: 20-50%, retention time: 8.0 min) to obtain compound 15. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 7.43 (d, J = 8.62 Hz, 1H), 7.13 (d, J = 2.32 Hz, 1H), 6.84 (d, J = 2.32 Hz, 1H), 6.62 (dd, J = 8.62, 2.32 Hz, 1H), 4.10-4.06 (m, 1H), 3.96-3.91 (m, 1H), 3.83-3.76 (m, 2H), 3.75 (s, 3H), 3.63-3.59 (m, 1H), 2.95-2.89 (m, 1H), 2.02 (s, 6H). ESI-MS theoretical calculated value: [M+H] + = 261.15, found 261.1.

实施例16Example 16

合成路线：
Synthesis route:

第一步first step

将化合物1-1(2.00g,13.6mmol)溶解在2-吡啶甲醇(2.62mL,27.2mmol)中,加入碳酸钾(1.88g,13.6mmol)和钯碳(1.45g,1.36mmol,10％纯度),80℃搅拌18小时。反应液冷却至室温,反应液中加入二氯甲烷(50mL),过滤,滤液减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(二氯甲烷/甲醇,10/1,v/v)得到化合物16-1。1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.74-7.66(m,3H),7.66-7.59(m,1H),7.35(d,J＝8.40Hz,1H),7.05-7.01(m,1H),6.86(d,J＝2.20Hz,1H),6.76-6.71(m,1H),4.33(s,2H),3.83(s,3H)。ESI-MS理论计算值:[M+H]+＝239.11,实测值239.2。Compound 1-1 (2.00 g, 13.6 mmol) was dissolved in 2-pyridinemethanol (2.62 mL, 27.2 mmol), potassium carbonate (1.88 g, 13.6 mmol) and palladium carbon (1.45 g, 1.36 mmol, 10% purity) were added, and stirred at 80°C for 18 hours. The reaction solution was cooled to room temperature, dichloromethane (50 mL) was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 16-1. 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (s, 1H), 7.74-7.66 (m, 3H), 7.66-7.59 (m, 1H), 7.35 (d, J=8.40 Hz, 1H), 7.05-7.01 (m, 1H), 6.86 (d, J=2.20 Hz, 1H), 6.76-6.71 (m, 1H), 4.33 (s, 2H), 3.83 (s, 3H). ESI-MS theoretical calculated value: [M+H] + =239.11, found value 239.2.

第二步Step 2

将化合物16-1(3.40g,14.3mmol)溶解在乙腈(30mL)中,加入溴化苄(3.41mL,28.5mmol),80℃搅拌5小时。反应液冷却至室温,减压浓缩,剩余物中加入乙酸乙酯(30mL),20℃搅拌0.5小时。过滤,固体减压浓缩,剩余物为化合物16-2。ESI-MS理论计算值:[M+H]+＝329.16,实测值329.2。Compound 16-1 (3.40 g, 14.3 mmol) was dissolved in acetonitrile (30 mL), benzyl bromide (3.41 mL, 28.5 mmol) was added, and the mixture was stirred at 80°C for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and ethyl acetate (30 mL) was added to the residue, and stirred at 20°C for 0.5 hours. The mixture was filtered, and the solid was concentrated under reduced pressure to obtain compound 16-2. ESI-MS theoretical calculated value: [M+H] + = 329.16, measured value 329.2.

第三步Step 3

将化合物16-2(4.70g,14.3mmol)溶于乙醇(50mL),20℃下缓慢加入硼氢化钠(2.16g,57.1mmol),20℃搅拌2小时。反应液中加入水(50mL)淬灭,二氯甲烷(25mL×2)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物溶于四氢呋喃(80mL),加入钯碳(2.88g,2.70mmol,10％纯度),氢气(15psi)氛围下20℃搅拌16小时。反应液过滤,滤液减压浓缩,得到含有目标化合物的粗品,经硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物16-3。ESI-MS理论计算值:[M+H]+＝335.20,实测值335.2。Compound 16-2 (4.70 g, 14.3 mmol) was dissolved in ethanol (50 mL), sodium borohydride (2.16 g, 57.1 mmol) was slowly added at 20°C, and stirred at 20°C for 2 hours. Water (50 mL) was added to the reaction solution to quench, and dichloromethane (25 mL × 2) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (80 mL), palladium carbon (2.88 g, 2.70 mmol, 10% purity) was added, and stirred at 20°C for 16 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 16-3. ESI-MS theoretical calculated value: [M+H] + = 335.20, measured value 335.2.

第四步Step 4

将化合物16-3(1.20g,3.59mmol)溶于四氢呋喃(20mL),加入钯碳(764mg,0.72mmol,10％纯度)和氢氧化钯(1.01g,0.72mmol,10％纯度),氢气(15psi)氛围下20℃搅拌16小时。反应液过滤,滤液 减压浓缩,得到含有目标化合物的粗品,经硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物16-4。ESI-MS理论计算值:[M+H]+＝245.16,实测值245.2。Compound 16-3 (1.20 g, 3.59 mmol) was dissolved in tetrahydrofuran (20 mL), palladium carbon (764 mg, 0.72 mmol, 10% purity) and palladium hydroxide (1.01 g, 0.72 mmol, 10% purity) were added, and stirred at 20°C for 16 hours under a hydrogen (15 psi) atmosphere. The reaction solution was filtered and the filtrate was The residue was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 16-4. ESI-MS theoretical calculated value: [M+H] + = 245.16, found value 245.2.

第五步Step 5

将化合物16-4(300mg,1.23mmol)溶于二氯甲烷(3mL),加入二碳酸二叔丁酯(0.26mL,1.23mmol)和三乙胺(0.51mL,3.68mmol),20℃搅拌2小时。反应液减压浓缩,得到含有目标化合物的粗品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢氨水溶液,梯度:60-80％,保留时间:9min)纯化得到化合物16-5。ESI-MS理论计算值:[M+H-56]+＝289.21,实测值289.2。Compound 16-4 (300 mg, 1.23 mmol) was dissolved in dichloromethane (3 mL), di-tert-butyl dicarbonate (0.26 mL, 1.23 mmol) and triethylamine (0.51 mL, 3.68 mmol) were added, and stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L aqueous ammonium bicarbonate solution, gradient: 60-80%, retention time: 9 min) to obtain compound 16-5. ESI-MS theoretical calculated value: [M+H-56] + = 289.21, measured value 289.2.

第六步Step 6

将化合物16-5(100mg,0.29mmol)溶于四氢呋喃(10mL),室温下缓慢加入氢化铝锂(66.1mg,1.74mmol),60℃搅拌16小时。反应液冷却至室温,向反应液中加入水(0.7mL),15％氢氧化钠水溶液(0.7mL),再加入水(2.1mL),室温搅拌半小时,过滤,滤液减压浓缩,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相：乙腈-10mmol/L甲酸水溶液,梯度：5-35％,保留时间：10min)纯化得到化合物16的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.28(s,1H),7.36(d,J＝8.00Hz,1H),6.99(d,J＝2.20Hz,1H),6.82(d,J＝2.00Hz,1H),6.66-6.59(m,1H),3.74(s,3H),3.46-3.43(m,1H),3.15-3.07(m,1H),2.93-2.82(m,1H),2.45(s,3H),2.35-2.30(m,1H),2.26-2.15(m,1H),1.60-1.41(m,4H),1.22-1.02(m,2H)。ESI-MS理论计算值:[M+H]+＝259.17,实测值259.1。Compound 16-5 (100 mg, 0.29 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (66.1 mg, 1.74 mmol) was slowly added at room temperature, and stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, and water (0.7 mL), 15% sodium hydroxide aqueous solution (0.7 mL), and then water (2.1 mL) were added to the reaction solution, and stirred at room temperature for half an hour, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-35%, retention time: 10min) to obtain the monoformate of compound 16. 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.28 (s, 1H), 7.36 (d, J = 8.00Hz, 1H), 6.99 (d, J = 2.20Hz, 1H), 6.82 (d, J = 2.00Hz, 1H), 6.66-6.59 (m, 1H), 3.74 (s, 3 H),3.46-3.43(m,1H),3.15-3.07(m,1H),2.93-2.82(m,1H),2.45(s,3H),2.35-2.30(m,1H),2.26-2.15(m,1H),1.60-1.41(m,4H),1.22-1.02(m,2 H). ESI-MS theoretical calculated value: [M+H] + = 259.17, found value 259.1.

实施例17Embodiment 17

合成路线：
Synthesis route:

第一步first step

将化合物17-1(6.80g,24.0mmol)溶解在四氢呋喃(10mL)中,在氮气保护下加入锌粉(5.24g,80.2mmol)和三甲基氯硅烷(0.20mL,1.6mmol),20℃搅拌1小时。将化合物17-1a(3.00g,8.01mmol)溶解在四氢呋喃(10mL)中,在氮气保护下加入三(二亚苄基丙酮)钯(0.73g,0.80mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.76g,1.60mmol),50℃搅拌16小时。反应液中加入饱和氯化铵水溶液(50mL),二氯甲烷(30mL×3)萃取,合并有机相,用饱和食盐水(40mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,5/1,v/v)得到化合物17-2。ESI-MS理论计算值:[M+H]+＝404.23,实测值404.2。Compound 17-1 (6.80 g, 24.0 mmol) was dissolved in tetrahydrofuran (10 mL), and zinc powder (5.24 g, 80.2 mmol) and trimethylsilyl chloride (0.20 mL, 1.6 mmol) were added under nitrogen protection, and stirred at 20°C for 1 hour. Compound 17-1a (3.00 g, 8.01 mmol) was dissolved in tetrahydrofuran (10 mL), and tris(dibenzylideneacetone)palladium (0.73 g, 0.80 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.76 g, 1.60 mmol) were added under nitrogen protection, and stirred at 50°C for 16 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 17-2. ESI-MS theoretical calculated value: [M+H] + = 404.23, found value 404.2.

第二步Step 2

将化合物17-2(50.0mg,0.12mmol)溶于四氢呋喃(2mL)中,加入四氢铝锂(18.8mg,0.50mmol), 反应液70℃搅拌3小时。反应液冷却至室温,加入四氢呋喃(10mL)稀释反应液,滴加水(1mL)淬灭反应,过滤,滤液减压浓缩,得到化合物17-3。ESI-MS理论计算值:[M+H]+＝318.19,实测值318.2。Compound 17-2 (50.0 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (18.8 mg, 0.50 mmol) was added. The reaction solution was stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, tetrahydrofuran (10 mL) was added to dilute the reaction solution, water (1 mL) was added dropwise to quench the reaction, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-3. ESI-MS theoretical calculated value: [M+H] + = 318.19, measured value 318.2.

第三步Step 3

将化合物17-3(40.0mg,0.13mmol)溶于四氢呋喃(2mL)中,加入三乙胺(25.5mg,0.25mmol)和四丁基氟化铵(65.9mg,0.25mmol),70℃搅拌3小时。反应液冷却至室温,过滤,滤液减压浓缩,剩余物经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相：乙腈-10mmol/L碳酸氢氨水溶液,梯度：50-65％,保留时间：8.5min)纯化得到化合物17。1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.18(d,J＝4.62Hz,1H),8.08(d,J＝7.90,1H),7.33(s,1H),7.03(t,J＝7.90Hz,1H),3.76-3.69(m,1H),3.68-3.61(m,2H),3.16-3.11(m,2H),2.29(s,3H)。ESI-MS理论计算值:[M+H]+＝188.11,实测值188.1。Compound 17-3 (40.0 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2 mL), triethylamine (25.5 mg, 0.25 mmol) and tetrabutylammonium fluoride (65.9 mg, 0.25 mmol) were added, and stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L aqueous ammonium bicarbonate solution, gradient: 50-65%, retention time: 8.5min) to obtain compound 17. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.41 (s, 1H), 8.18 (d, J = 4.62 Hz, 1H), 8.08 (d, J = 7.90, 1H), 7.33 (s, 1H), 7.03 (t, J = 7.90 Hz, 1H), 3.76-3.69 (m, 1H), 3.68-3.61 (m, 2H), 3.16-3.11 (m, 2H), 2.29 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 188.11, found 188.1.

实施例18Embodiment 18

合成路线：
Synthesis route:

第一步first step

将化合物18-1(10.0g,70.9mmol),(2S)-1,1,1-三氟丙烷-2-醇(8.08g,70.9mmol)和碳酸铯(69.3g,213mmol)溶解在N,N-二甲基甲酰胺(100mL)中,80℃搅拌16小时。反应液冷却至室温,反应液中加入水(300mL),乙酸乙酯(100mL×2)萃取,合并有机相,用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,20/1,v/v)得到化合物18-2。1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.30,1H),7.80(s,1H),7.50(dd,J＝8.30,2.24Hz,1H),7.29(d,J＝2.24,1H),4.81-4.70(m,1H),1.56(d,J＝6.48Hz,3H)。Compound 18-1 (10.0 g, 70.9 mmol), (2S)-1,1,1-trifluoropropane-2-ol (8.08 g, 70.9 mmol) and cesium carbonate (69.3 g, 213 mmol) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, water (300 mL) was added to the reaction solution, and ethyl acetate (100 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1, v/v) to obtain compound 18-2. 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝8.30,1H),7.80(s,1H),7.50(dd,J＝8.30,2.24Hz,1H),7.29(d,J＝2.24,1H),4.81-4.70(m,1H),1.56(d,J＝6.48Hz,3H)。

第二步Step 2

将化合物18-2(10.0g,42.5mmol),氯化铵(22.7g,425mmol)和铁粉(14.3g,255mmol)溶解在乙醇(100mL)和水(50mL)中,80℃搅拌2小时。反应冷却至室温,过滤,滤液加水(100mL),乙酸乙酯(100mL x 2)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,5/1,v/v)得到化合物18-3。1H NMR(400MHz,DMSO-d6)δ6.91-6.84(m,1H),6.23-6.12(m,3H),5.13(s,2H),5.04-4.94(m,1H),1.37(d,J＝6.48Hz,3H)。ESI-MS理论计算值:[M+H]+＝206.07,实测值206.0。Compound 18-2 (10.0 g, 42.5 mmol), ammonium chloride (22.7 g, 425 mmol) and iron powder (14.3 g, 255 mmol) were dissolved in ethanol (100 mL) and water (50 mL) and stirred at 80°C for 2 hours. The reaction was cooled to room temperature and filtered, and the filtrate was extracted with water (100 mL) and ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 18-3. 1 H NMR (400 MHz, DMSO-d 6 )δ6.91-6.84 (m, 1H), 6.23-6.12 (m, 3H), 5.13 (s, 2H), 5.04-4.94 (m, 1H), 1.37 (d, J＝6.48 Hz, 3H).ESI-MS theoretical calculated value: [M+H] + ＝206.07, found value 206.0.

第三步Step 3

将化合物18-3(3.00g,14.6mmol)溶解在浓盐酸(30mL)和水(30mL)中,0℃加入亚硝酸钠(1.51 g,21.9mmol),0℃搅拌0.5小时。加入氯化亚锡二水合物(8.80g,39.0mmol)溶解在盐酸(20mL)和水(20mL)的溶液,0℃搅拌0.5小时。0℃滴加30％的氢氧化钠水溶液至PH＝6,过滤,滤液减压浓缩得得到含有目标化合物的粗品18-4的盐酸盐直接用于下一步。ESI-MS理论计算值:[M+H]+＝221.08,实测值221.0。Compound 18-3 (3.00 g, 14.6 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (30 mL), and sodium nitrite (1.51 g, 21.9mmol), stirred at 0℃ for 0.5 hours. Add stannous chloride dihydrate (8.80g, 39.0mmol) dissolved in hydrochloric acid (20mL) and water (20mL), and stir at 0℃ for 0.5 hours. Add 30% sodium hydroxide aqueous solution dropwise at 0℃ until pH=6, filter, and concentrate the filtrate under reduced pressure to obtain the hydrochloride salt of crude product 18-4 containing the target compound, which is directly used in the next step. ESI-MS theoretical calculated value: [M+H] + = 221.08, found value 221.0.

第四步Step 4

将化合物的粗品18-4的盐酸盐(1.00g,3.67mmol)溶解在水(10mL)中,80℃加入4-二甲胺基丁醛缩二乙醇(0.99mL,4.40mmol),95℃搅拌16小时。反应液冷却至室温,0℃滴加30％的氢氧化钠水溶液至PH＝9,过滤,滤液加水(50mL),二氯甲烷(50mL x 2)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:8-38％,保留时间:9min)纯化得到化合物18的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.26(s,1H),7.44(d,J＝8.58Hz,1H),7.08(d,J＝2.24Hz,1H),7.00(d,J＝2.24Hz,1H),6.77-6.72(m,1H),5.12-5.05(m,1H),2.91-2.78(m,2H),2.75-2.62(m,2H),2.37(s,6H),1.41(d,J＝6.48Hz,3H)。ESI-MS理论计算值:[M+H]+＝301.14,实测值301.0。The hydrochloride of the crude compound 18-4 (1.00 g, 3.67 mmol) was dissolved in water (10 mL), 4-dimethylaminobutyraldehyde diethyl acetal (0.99 mL, 4.40 mmol) was added at 80°C, and stirred at 95°C for 16 hours. The reaction solution was cooled to room temperature, 30% sodium hydroxide aqueous solution was added dropwise at 0°C until pH = 9, filtered, the filtrate was added with water (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 8-38%, retention time: 9min) to obtain the monoformate of compound 18. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.26 (s, 1H), 7.44 (d, J = 8.58 Hz, 1H), 7.08 (d, J = 2.24 Hz, 1H), 7.00 (d, J = 2.24 Hz, 1H), 6.77-6.72 (m, 1H), 5.12-5.05 (m, 1H), 2.91-2.78 (m, 2H), 2.75-2.62 (m, 2H), 2.37 (s, 6H), 1.41 (d, J = 6.48 Hz, 3H). ESI-MS theoretical calculated value: [M+H] + = 301.14, found 301.0.

实施例19Embodiment 19

合成路线：
Synthesis route:

第一步first step

将化合物19-1(1.50g,5.05mmol)溶解在二氧六环(18mL)和水(2.5mL)中,加入化合物19-1a(1.00g,5.10mmol),碳酸钾(2.09g,15.1mmol),1,1-双(二苯基膦)二荗铁二氯化钯(0.74g,1.01mmol),氮气保护下80℃搅拌3小时。反应液冷却至室温,过滤,滤液加水(100mL),乙酸乙酯(50mL x 3)萃取,合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/1,v/v)得到化合物19-2。1H NMR(400MHz,CDCl3)δ8.68(dd,J＝4.98,1.52Hz,1H),8.20(dd,J＝7.96,1.52Hz,1H),7.49(s,1H),7.35(dd,J＝7.96,4.98Hz,1H),6.37-6.31(m,1H),5.04-4.99(m,2H),4.93-4.89(m,2H),1.70(s,9H)。ESI-MS理论计算值:[M+H-100]+＝187.13,实测值187.0。Compound 19-1 (1.50 g, 5.05 mmol) was dissolved in dioxane (18 mL) and water (2.5 mL), and compound 19-1a (1.00 g, 5.10 mmol), potassium carbonate (2.09 g, 15.1 mmol), 1,1-bis(diphenylphosphino)diferronichloridopalladium (0.74 g, 1.01 mmol) were added, and stirred at 80°C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 19-2. 1 H NMR (400 MHz, CDCl 3 ) δ8.68 (dd, J=4.98, 1.52 Hz, 1H), 8.20 (dd, J=7.96, 1.52 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J=7.96, 4.98 Hz, 1H), 6.37-6.31 (m, 1H), 5.04-4.99 (m, 2H), 4.93-4.89 (m, 2H), 1.70 (s, 9H). ESI-MS theoretical calculated value: [M+H-100] + =187.13, found 187.0.

第二步 Step 2

将化合物19-2(100mg,0.35mmol)溶解在四氢呋喃(5mL)中,0℃下缓慢滴加硼烷二甲硫醚溶液(0.17mL,0.52mmol,10mol/L),20℃反应3小时。反应液冷却至0℃,滴加3mol/L氢氧化钠溶液(0.35mL,1.05mmol),30％双氧水溶液(119mg,1.05mmol),0℃搅拌0.5小时。乙酸乙酯(30mL x 3)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/1,v/v)得到化合物19-3。1H NMR(400MHz,DMSO-d6)δ8.40(dd,J＝4.86,1.72Hz,1H),8.13(dd,J＝7.96,1.72Hz,1H),7.30(dd,J＝7.96,4.72Hz,1H),6.92(s,1H),5.36(d,J＝4.42Hz,1H),4.36-4.31(m,1H),4.22-4.18(m,1H),3.99-3.94(m,2H),3.87-3.83(m,1H),3.60-3.56(m,1H),1.61(s,9H)。ESI-MS理论计算值C16H21N2O4[M+H]+＝305.14,实测值305.2。Compound 19-2 (100 mg, 0.35 mmol) was dissolved in tetrahydrofuran (5 mL), and borane dimethyl sulfide solution (0.17 mL, 0.52 mmol, 10 mol/L) was slowly added dropwise at 0°C, and the mixture was reacted at 20°C for 3 hours. The reaction solution was cooled to 0°C, and 3 mol/L sodium hydroxide solution (0.35 mL, 1.05 mmol) and 30% hydrogen peroxide solution (119 mg, 1.05 mmol) were added dropwise, and the mixture was stirred at 0°C for 0.5 hours. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 19-3. 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (dd, J＝4.86, 1.72Hz, 1H), 8.13 (dd, J＝7.96, 1.72Hz, 1H), 7.30 (dd, J＝7.96, 4.72Hz, 1H), 6.92 (s, 1H), 5.36 (d, J＝4.42Hz, 1H), 4.36-4.31(m,1H),4.22-4.18(m,1H),3.99-3.94(m,2H),3.87-3.83(m,1H),3.60-3.56(m,1H),1.61(s,9H). ESI-MS theoretical calculated value for C 16 H 21 N 2 O 4 [M+H] + =305.14, found value 305.2.

第三步Step 3

将化合物19-3(200mg,0.66mmol)溶解在二氯甲烷(2mL)中,0℃下分批加入戴斯-马丁试剂(836mg,1.97mmol),20℃搅拌2小时。反应液加入饱和碳酸氢钠水溶液(20mL),乙酸乙酯(20mL x 3)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/1,v/v)得到化合物19-4。ESI-MS理论计算值:[M+H]+＝303.13,实测值303.0。Compound 19-3 (200 mg, 0.66 mmol) was dissolved in dichloromethane (2 mL), and Dess-Martin reagent (836 mg, 1.97 mmol) was added in batches at 0°C, and stirred at 20°C for 2 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 19-4. ESI-MS theoretical calculated value: [M+H] + = 303.13, measured value 303.0.

第四步Step 4

将化合物19-4(60.0mg,0.20mmol)溶解在二氯甲烷(20mL)中,加入二甲胺盐酸盐(19.4mg,0.24mmol),三乙胺(24.1mg,0.24mmol),醋酸(17.9mg,0.30mmol),三乙酰基醋酸硼氢化钠(126mg,0.60mmol),20℃搅拌18小时。反应液加入水(20mL),乙酸乙酯(20mL x 3)萃取,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(二氯甲烷/甲醇,10/1,v/v)得到化合物19-5。ESI-MS理论计算值:[M+H]+＝332.19,实测值332.2。Compound 19-4 (60.0 mg, 0.20 mmol) was dissolved in dichloromethane (20 mL), and dimethylamine hydrochloride (19.4 mg, 0.24 mmol), triethylamine (24.1 mg, 0.24 mmol), acetic acid (17.9 mg, 0.30 mmol), sodium triacetyl acetate borohydride (126 mg, 0.60 mmol) were added, and stirred at 20°C for 18 hours. Water (20 mL) and ethyl acetate (20 mL x 3) were added to the reaction solution for extraction, and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 19-5. ESI-MS theoretical calculated value: [M+H] + = 332.19, measured value 332.2.

第五步Step 5

将化合物19-5(30.0mg,0.09mmol)溶解在二氯甲烷(1.5mL)中,加入三氟乙酸(0.10mL,0.90mmol),20℃搅拌1.5小时。反应液减压浓缩得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢氨水溶液,梯度:58-88％,保留时间:11min)纯化得到化合物19。1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.19-8.14(m,1H),8.00(dd,J＝7.96,1.64Hz,1H),7.37(s,1H),7.02(dd,J＝7.96,4.62Hz,1H),4.13-4.09(m,1H),3.98-3.94(m,1H),3.86-3.74(m,2H),3.71-3.65(m,1H),2.97-2.93(m,1H),2.03(s,6H)。ESI-MS理论计算值:[M+H]+＝232.14,实测值232.1。Compound 19-5 (30.0 mg, 0.09 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.10 mL, 0.90 mmol) was added, and stirred at 20°C for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, and the residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L aqueous ammonium bicarbonate solution, gradient: 58-88%, retention time: 11 min) to obtain compound 19. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.37 (s, 1H), 8.19-8.14 (m, 1H), 8.00 (dd, J=7.96, 1.64 Hz, 1H), 7.37 (s, 1H), 7.02 (dd, J=7.96, 4.62 Hz, 1H), 4.13-4.09 (m, 1H), 3.98-3.94 (m, 1H), 3.86-3.74 (m, 2H), 3.71-3.65 (m, 1H), 2.97-2.93 (m, 1H), 2.03 (s, 6H). ESI-MS theoretical calculated value: [M+H] + = 232.14, found 232.1.

实施例20和21Examples 20 and 21

合成路线：
Synthesis route:

第一步first step

将化合物20-1(3.00g,20.4mmol),碳酸钾(5.63g,40.8mmol)和Pd/C(1.08g,10.2mmol,10％纯度)加入到(4-甲氧基吡啶-2-基)甲醇(8.51g,61.2mmol)中,80℃搅拌16小时。反应液冷却至室温,加入二氯甲烷(50mL),过滤,滤液减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(二氯甲烷/甲醇,10/1,v/v)得到化合物20-2。1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.30-8.25(m,1H),7.32(d,J＝8.64Hz,1H),7.04(d,J＝2.28Hz,1H),6.83(d,J＝2.28Hz,1H),6.78-6.74(m,2H),6.61-6.58(m,1H),4.05(s,2H),3.73(s,6H)。ESI-MS理论计算值:[M+H]+＝269.12,实测值269.2。Compound 20-1 (3.00 g, 20.4 mmol), potassium carbonate (5.63 g, 40.8 mmol) and Pd/C (1.08 g, 10.2 mmol, 10% purity) were added to (4-methoxypyridin-2-yl)methanol (8.51 g, 61.2 mmol) and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, dichloromethane (50 mL) was added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 20-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.30-8.25 (m, 1H), 7.32 (d, J = 8.64 Hz, 1H), 7.04 (d, J = 2.28 Hz, 1H), 6.83 (d, J = 2.28 Hz, 1H), 6.78-6.74 (m, 2H), 6.61-6.58 (m, 1H), 4.05 (s, 2H), 3.73 (s, 6H). ESI-MS theoretical calculated value: [M+H] + = 269.12, found 269.2.

第二步Step 2

将化合物20-2(600mg,2.24mmol),碘甲烷(0.14mL,2.24mmol)溶解在丙酮(10mL)中,60℃搅拌21.5小时,反应液冷却至室温,减压浓缩,得到含有目标化合物的粗品,加入乙酸乙酯(10mL),20℃搅拌1小时。过滤,固体减压浓缩得到粗品化合物20-3。ESI-MS理论计算值:[M+H]+＝283.14,实测值283.2。Compound 20-2 (600 mg, 2.24 mmol) and iodomethane (0.14 mL, 2.24 mmol) were dissolved in acetone (10 mL), stirred at 60 ° C for 21.5 hours, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain a crude product containing the target compound, ethyl acetate (10 mL) was added, and stirred at 20 ° C for 1 hour. Filtered, the solid was concentrated under reduced pressure to obtain a crude compound 20-3. ESI-MS theoretical calculated value: [M+H] + = 283.14, measured value 283.2.

第三步Step 3

将化合物20-3(600mg,2.12mmol)溶于乙醇(10mL),缓慢加入硼氢化钠(401mg,10.6mmol),25℃搅拌1.5小时。反应液加入水溶液(50mL),二氯甲烷(20mL x 2)萃取,合并有机相,用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。将剩余物溶于四氢呋喃(10mL),加入二氧化铂(31.8mg,0.14mmol),氢气(15psi)氛围下25℃搅拌16小时。反应液过滤,滤液减压浓缩得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:2-32％,流速20mL/min洗脱时间17min)纯化得到化合物20的一甲酸盐(保留时间:9min)。1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.24(s,1H),7.37(dd,J＝8.64,2.24Hz,1H),7.00(d,J＝2.32Hz,1H),6.83(d,J＝2.24Hz,1H),6.71-6.56(m,1H),3.74(s,3H),3.43-3.39(m,2H),3.08-3.03(m,4H),2.73-2.63(m,2H),2.55-2.51(m,1H),2.46(s,3H),1.66-1.45(m,3H),1.42-1.35(m,1H)。ESI-MS理论计算值:[M+H]+＝289.18,实测值289.2。和化合物21的一甲酸盐(保留时间:9.2min)。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.21(s,1H),7.35(d,J＝8.56Hz,1H),7.01(d,J＝2.24Hz,1H),6.83(d,J＝2.24Hz,1H),6.70-6.51(m,1H),3.75(s,3H),3.12-3.09(m,4H),3.03-2.87(m,2H),2.51-2.47(m, 1H),2.41(s,3H),2.18-2.14(m,2H),1.94-1.86(m,1H),1.81-1.71(m,1H),1.34-1.20(m,1H),1.10-0.95(m,1H)。ESI-MS理论计算值:[M+H]+＝289.18,实测值289.2。Compound 20-3 (600 mg, 2.12 mmol) was dissolved in ethanol (10 mL), sodium borohydride (401 mg, 10.6 mmol) was slowly added, and the mixture was stirred at 25 °C for 1.5 hours. The reaction solution was added with aqueous solution (50 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), platinum dioxide (31.8 mg, 0.14 mmol) was added, and stirred at 25 °C for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. The residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol/L formic acid aqueous solution, gradient: 2-32%, flow rate 20 mL/min, elution time 17 min) to obtain the monoformate of compound 20 (retention time: 9 min). 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.24 (s, 1H), 7.37 (dd, J = 8.64, 2.24Hz, 1H), 7.00 (d, J = 2.32Hz, 1H), 6.83 (d, J = 2.24Hz, 1H), 6.71-6.56 (m, 1H), 3.7 4(s,3H),3.43-3.39(m,2H),3.08-3.03(m,4H),2.73-2.63(m,2H),2.55-2.51(m,1H),2.46(s,3H),1.66-1.45(m,3H),1.42-1.35(m,1H). ESI-MS theoretical calculated value: [M+H] + = 289.18, found 289.2. and the monoformate of compound 21 (retention time: 9.2 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.64 (s, 1H), 8.21 (s, 1H), 7.35 (d, J = 8.56 Hz, 1H), 7.01 (d, J = 2.24 Hz, 1H), 6.83 (d, J = 2.24 Hz, 1H), 6.70-6.51 (m, 1H), 3.75 (s, 3H), 3.12-3.09 (m, 4H), 3.03-2.87 (m, 2H), 2.51-2.47 (m, 1H), 2.41 (s, 3H), 2.18-2.14 (m, 2H), 1.94-1.86 (m, 1H), 1.81-1.71 (m, 1H), 1.34-1.20 (m, 1H), 1.10-0.95 (m, 1H). ESI-MS theoretical calculated value: [M+H] + = 289.18, found 289.2.

实施例22Embodiment 22

合成路线：
Synthesis route:

第一步first step

将化合物16-5(1.00g,2.90mmol)溶于四氢呋喃(10mL),20℃下缓慢加入氘代氢化铝锂(0.61g,14.52mmol),60℃搅拌18小时。反应液冷却至室温,加入十水硫酸钠,过滤,滤液减压浓缩,得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:5-35％,保留时间:10min)纯化得到化合物22的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.26(s,1H),7.36(d,J＝8.62Hz,1H),6.99(d,J＝2.24Hz,1H),6.83(d,J＝2.24Hz,1H),6.67-6.60(m,1H),3.74(s,3H),3.16-3.07(m,1H),2.90-2.87(m,1H),2.49-2.47(m,1H),2.32-2.27(m,1H),2.24-2.21(m,1H),1.63-1.40(m,4H),1.26-1.03(m,2H)。ESI-MS理论计算值:[M+H]+＝262.19,实测值262.2。Compound 16-5 (1.00 g, 2.90 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (0.61 g, 14.52 mmol) was slowly added at 20°C, and stirred at 60°C for 18 hours. The reaction solution was cooled to room temperature, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. The residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-35%, retention time: 10min) to obtain the monoformate of compound 22. 1 H NMR (400MHz, DMSO-d 6 ) δ10.62 (s, 1H), 8.26 (s, 1H), 7.36 (d, J = 8.62Hz, 1H), 6.99 (d, J = 2.24Hz, 1H), 6.83 (d, J = 2.24Hz, 1H), 6.67-6.60 (m, 1H), 3.74 (s, 3 H),3.16-3.07(m,1H),2.90-2.87(m,1H),2.49-2.47(m,1H),2.32-2.27(m,1H),2.24-2.21(m,1H),1.63-1.40(m,4H),1.26-1.03(m,2H). ESI-MS theoretical calculated value: [M+H] + = 262.19, found value 262.2.

实施例23Embodiment 23

合成路线：
Synthesis route:

第一步first step

将化合物23-1(200mg,0.63mmol)溶解在二氯甲烷(5mL)中,0℃下滴加草酰氯(95.4mg,0.75mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(9.15mg,0.13mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将6-甲氧基吲哚(100mg,0.68mmol)溶于在二氯甲烷(10mL),0℃下滴加乙基溴化镁的乙醚溶液(0.41mL,0.82mmol,2mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应结束,反应液加入饱和碳酸氢钠水溶液(10mL),二氯甲烷(10mL x 2)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物23-2。ESI-MS理论计算值:[M+H]+＝449.20,实测值449.2。Compound 23-1 (200 mg, 0.63 mmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (95.4 mg, 0.75 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (9.15 mg, 0.13 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 6-Methoxyindole (100 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide in ether solution (0.41 mL, 0.82 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (10 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction solution was added with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (10 mL x 2), the organic phase was washed with saturated brine (10 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 23-2. ESI-MS theoretical calculated value: [M+H] + = 449.20, measured value 449.2.

第二步Step 2

将化合物23-2(100mg,0.22mmol)溶解在四氢呋喃(10mL)中，冰浴下加入四氢铝锂(50.8mg, 1.34mmol),反应液在70℃下搅拌18小时。反应冷却至室温,加入冰水(0.7mL)淬灭,加入15％氢氧化钠水溶液(0.7mL)和水(2.1mL),过滤,滤饼用乙酸乙酯(30mL x 3)洗涤,有机相用无水硫酸钠干燥,减压浓缩,得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-CORTECS-C18-2.7μm-4.6*30mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:5-35％,保留时间:9min)纯化得到化合物23的一甲酸盐。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.21(s,1H),7.36(d,J＝8.62Hz,1H),6.98(d,J＝2.26Hz,1H),6.82(d,J＝2.26Hz,1H),6.62(dd,J＝8.62,2.26Hz,1H),3.82-3.78(m,2H),3.74(s,3H),3.36-3.27(m,2H),3.02-2.97(m,1H),2.94-2.83(m,1H),2.42-2.38(m,1H),2.33(s,3H),1.90-1.78(m,2H),1.70-1.59(m,2H),1.48-1.33(m,2H),1.20-1.03(m,2H)。ESI-MS理论计算值:[M+H]+＝315.20,实测值315.2。Compound 23-2 (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (50.8 mg, 1.34mmol), the reaction solution was stirred at 70℃ for 18 hours. The reaction was cooled to room temperature, quenched by adding ice water (0.7mL), 15% sodium hydroxide aqueous solution (0.7mL) and water (2.1mL) were added, filtered, the filter cake was washed with ethyl acetate (30mL x 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound. The residue was purified by high performance liquid chromatography (Waters-CORTECS-C18-2.7μm-4.6*30mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-35%, retention time: 9min) to obtain the monoformate of compound 23. 1 H NMR (400MHz, DMSO-d 6 )δ10.61(s,1H),8.21(s,1H),7.36(d,J＝8.62Hz,1H),6.98(d,J＝2.26Hz,1H),6.82(d,J＝2.26Hz,1H),6.62(dd,J＝8.62,2.26Hz,1H),3.82-3.78(m,2H),3 .74(s,3H), 3.36-3.27 (m, 2H), 3.02-2.97 (m, 1H), 2.94-2.83 (m, 1H), 2.42-2.38 (m, 1H), 2.33 (s, 3H), 1.90-1.78 (m, 2H), 1.70-1.59 (m, 2H), 1.48-1.33 (m, 2H), 1.20-1.03 (m, 2H). ESI-MS theoretical calculated value: [M+H] + = 315.20, found 315.2.

实施例24Embodiment 24

合成路线：
Synthesis route:

第一步first step

将化合物24-1(5.00g,29.9mmol)溶解在四氢呋喃(50mL)中,-40℃下滴加乙烯基溴化镁(89.7mL,89.7mmol,1mol/L),-40℃搅拌30分钟。向反应液加入饱和氯化铵水溶液(50mL),水(100mL),乙酸乙酯(70mL x 2)萃取,有机相用饱和食盐水(80mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物24-2。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.30(d,J＝8.56Hz,1H),7.22-7.18(m,1H),6.77(d,J＝8.56Hz,1H),6.35-6.31(m,1H),3.78(s,3H),2.30(s,3H)。ESI-MS理论计算值:[M+H]+＝162.08,实测值162.0。Compound 24-1 (5.00 g, 29.9 mmol) was dissolved in tetrahydrofuran (50 mL), and vinylmagnesium bromide (89.7 mL, 89.7 mmol, 1 mol/L) was added dropwise at -40°C, and stirred at -40°C for 30 minutes. Saturated aqueous ammonium chloride solution (50 mL), water (100 mL), and ethyl acetate (70 mL x 2) were added to the reaction solution for extraction, and the organic phase was washed with saturated brine (80 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 24-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 7.30 (d, J = 8.56 Hz, 1H), 7.22-7.18 (m, 1H), 6.77 (d, J = 8.56 Hz, 1H), 6.35-6.31 (m, 1H), 3.78 (s, 3H), 2.30 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 162.08, found 162.0.

第二步Step 2

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(550mg,2.73mmol)溶解在二氯甲烷(5mL)中,0℃下滴加草酰氯(0.28mL,3.28mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(20.0mg,0.27mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物24-2(440mg,2.73mmol)溶于在二氯甲烷(2mL)中,0℃下加入乙基溴化镁(1.77mL,3.55mmol,2.0mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 2)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物24-3。ESI-MS理论计算值:[M+H-100]+＝245.17,实测值245.2。 Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (550 mg, 2.73 mmol) in dichloromethane (5 mL), add oxalyl chloride (0.28 mL, 3.28 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (20.0 mg, 0.27 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 24-2 (440 mg, 2.73 mmol) in dichloromethane (2 mL), add ethylmagnesium bromide (1.77 mL, 3.55 mmol, 2.0 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL x 2), the organic phase was washed with saturated brine (10 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 24-3. ESI-MS theoretical calculated value: [M+H-100] + = 245.17, found value 245.2.

第三步Step 3

将化合物24-3(220mg,0.64mmol)溶于四氢呋喃(5mL),0℃下缓慢加入氢化铝锂(242mg,6.39mmol),60℃搅拌2小时。反应冷却至室温,加入十水硫酸钠,过滤,滤液减压浓缩,得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:35-45％,保留时间:9min)纯化得到化合物24的一甲酸盐。1H NMR(400MHz,CD3OD)δ8.54(s,1H),7.38(d,J＝8.64Hz,1H),7.12(s,1H),6.84(d,J＝8.64Hz,1H),4.62-4.53(m,1H),4.05-3.97(m,1H),3.84(s,3H),3.82-3.79(m,1H),3.29-3.23(m,2H),2.55(s,3H),2.51-2.44(m,1H),2.43-2.35(m,1H),2.31(s,3H)。ESI-MS理论计算值:[M+H]+＝245.16,实测值245.2。Compound 24-3 (220 mg, 0.64 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (242 mg, 6.39 mmol) was slowly added at 0°C, and stirred at 60°C for 2 hours. The reaction was cooled to room temperature, sodium sulfate decahydrate was added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. The residue was purified by high performance liquid chromatography (Waters-Xbridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-45%, retention time: 9min) to obtain the monoformate of compound 24. 1 H NMR (400 MHz, CD 3 OD) δ8.54 (s, 1H), 7.38 (d, J = 8.64 Hz, 1H), 7.12 (s, 1H), 6.84 (d, J = 8.64 Hz, 1H), 4.62-4.53 (m, 1H), 4.05-3.97 (m, 1H), 3.84 (s, 3H), 3.82-3.79 (m, 1H), 3.29-3.23 (m, 2H), 2.55 (s, 3H), 2.51-2.44 (m, 1H), 2.43-2.35 (m, 1H), 2.31 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 245.16, found 245.2.

实施例25Embodiment 25

合成路线：
Synthesis route:

第一步first step

将化合物5-2(4.30g,13.0mmol)溶于二氯甲烷(40mL)中,0℃下滴加三氟乙酸(13mL)。反应液20℃搅拌2小时。反应液直接减压浓缩,剩余物中加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 2)萃取,有机相用饱和食盐水(30mL)洗涤,减压浓缩,剩余物为化合物25-1。ESI-MS理论计算值:[M+H]+＝231.11,实测值231.0。Compound 5-2 (4.30 g, 13.0 mmol) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (13 mL) was added dropwise at 0°C. The reaction solution was stirred at 20°C for 2 hours. The reaction solution was directly concentrated under reduced pressure, and a saturated sodium bicarbonate aqueous solution (50 mL) was added to the residue, and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (30 mL) and concentrated under reduced pressure. The residue was compound 25-1. ESI-MS theoretical calculated value: [M+H] + = 231.11, measured value 231.0.

第二步Step 2

将化合物25-1(2.20g,9.55mmol)溶于四氢呋喃(30mL)中,0℃下缓慢加入氢化铝锂(1.09g,28.7mmol),反应液在60℃搅拌12小时。反应液冷却至室温,0℃下缓慢加入5mL水,加入5mL 15％的氢氧化钠水溶液和15mL水,过滤,滤液减压浓缩得到有目标化合物的粗品,得到含有目标化合物的粗产品,剩余物经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:8.5min)纯化得到化合物25-2。ESI-MS理论计算值:[M+H]+＝217.13,实测值217.0。Compound 25-1 (2.20 g, 9.55 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (1.09 g, 28.7 mmol) was slowly added at 0°C, and the reaction solution was stirred at 60°C for 12 hours. The reaction solution was cooled to room temperature, 5 mL of water was slowly added at 0°C, 5 mL of 15% sodium hydroxide aqueous solution and 15 mL of water were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound, and the residue was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 8.5min) to obtain compound 25-2. ESI-MS theoretical calculated value: [M+H] + = 217.13, measured value 217.0.

第三步Step 3

将化合物25-2(120mg,0.55mmol),三乙酰氧基硼氢化钠(351mg,1.66mmol),乙醛(0.17mL,0.83mmol),醋酸(0.01mL,0.17mmol)溶于1,2-二氯乙烷(5mL)中,氮气氛围下,反应液在20℃搅拌12小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm, 流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:9min)纯化得到化合物25。1HNMR(400MHz,CD3OD)δ7.39(d,J＝8.64Hz,1H),6.92(s,1H),6.86(d,J＝2.26Hz,1H),6.67(dd,J＝8.64,2.26Hz,1H),3.80(s,3H),3.52-3.41(m,2H),3.08-3.02(m,1H),2.93-2.79(m,2H),2.59-2.54(m,1H),2.37-2.32(m,1H),2.10-2.06(m,1H),2.02-1.93(m,1H),0.96(t,J＝7.32Hz,3H)。ESI-MS理论计算值:[M+H]+＝245.16,实测值245.2。Compound 25-2 (120 mg, 0.55 mmol), sodium triacetoxyborohydride (351 mg, 1.66 mmol), acetaldehyde (0.17 mL, 0.83 mmol), acetic acid (0.01 mL, 0.17 mmol) were dissolved in 1,2-dichloroethane (5 mL), and the reaction solution was stirred at 20 ° C for 12 hours under a nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and dichloromethane (20 mL x 3) was used for extraction. The organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound. After high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, The mobile phase was acetonitrile-10 mmol/L aqueous ammonium bicarbonate solution, gradient: 35-45%, retention time: 9 min) to obtain compound 25. 1 HNMR (400MHz, CD 3 OD) δ7.39(d,J＝8.64Hz,1H),6.92(s,1H),6.86(d,J＝2.26Hz,1H),6.67(dd,J＝8.64,2.26Hz,1H),3.80(s,3H),3.52-3.41(m,2H),3.08 -3.02(m,1H),2.93-2.79(m,2H),2.59-2.54(m,1H),2.37-2.32(m,1H),2.10-2.06(m,1H),2.02-1.93(m,1H),0.96(t,J＝7.32Hz,3H). ESI-MS theoretical calculated value: [M+H] + = 245.16, found value 245.2.

实施例26Embodiment 26

合成路线：
Synthesis route:

第一步first step

将化合物25-2(158mg,0.73mmol),三乙酰氧基硼氢化钠(462mg,2.19mmol),丙酮(0.11mL,1.46mmol),醋酸(0.01mL,0.15mmol)溶于1,2-二氯乙烷(4mL)中,氮气氛围下,反应液在20℃搅拌12小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:9min)纯化得到化合物26。1H NMR(400MHz,CD3OD)δ7.36(d,J＝8.64Hz,1H),6.90(s,1H),6.86(d,J＝2.28Hz,1H),6.68(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.56-3.54(m,1H),3.44-3.40(m,1H),3.16-3.10(m,1H),2.94-2.87(m,2H),2.60-2.54(m,1H),2.00-1.96(m,1H),1.89-1.85(m,1H),1.11(d,J＝6.32Hz,3H),0.98(d,J＝6.32Hz,3H)。ESI-MS理论计算值:[M+H]+＝259.17,实测值259.2。Compound 25-2 (158 mg, 0.73 mmol), sodium triacetoxyborohydride (462 mg, 2.19 mmol), acetone (0.11 mL, 1.46 mmol), acetic acid (0.01 mL, 0.15 mmol) were dissolved in 1,2-dichloroethane (4 mL), and the reaction solution was stirred at 20 ° C for 12 hours under a nitrogen atmosphere. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min) to obtain compound 26. 1 H NMR (400MHz, CD 3 OD) δ7.36(d,J＝8.64Hz,1H),6.90(s,1H),6.86(d,J＝2.28Hz,1H),6.68(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.56-3.54(m,1H),3.44- 3.40(m,1H),3.16-3.10(m,1H),2.94-2.87(m,2H),2.60-2.54(m,1H),2.00 -1.96(m,1H),1.89-1.85(m,1H),1.11(d,J＝6.32Hz,3H),0.98(d,J＝6.32Hz ,3H). ESI-MS theoretical calculated value: [M+H] + = 259.17, found value 259.2.

实施例27Embodiment 27

合成路线：
Synthesis route:

将化合物25-2(156mg,0.72mmol),三乙酰氧基硼氢化钠(456mg,2.16mmol),丙醛(0.10mL,1.44mmol),醋酸(0.01mL,0.14mmol)溶于1,2-二氯乙烷(4mL)中,氮气氛围下,反应液在20℃搅拌12小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:9min)纯化得到化合物27。1HNMR(400MHz,CD3OD)δ7.38(d,J＝8.64Hz,1H),6.91(s,1H),6.86(d,J＝2.28Hz,1H),6.67(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.54-3.37(m,2H),3.06-3.02(m,1H),2.91-2.82(m,2H),2.52-2.48(m,1H), 2.27-2.23(m,1H),2.09-2.03(m,1H),2.01-1.94(m,1H),1.43-1.37(m,2H),0.86(t,J＝7.44Hz,3H)。ESI-MS理论计算值:[M+H]+＝259.17,实测值259.0。Compound 25-2 (156 mg, 0.72 mmol), sodium triacetoxyborohydride (456 mg, 2.16 mmol), propionaldehyde (0.10 mL, 1.44 mmol), acetic acid (0.01 mL, 0.14 mmol) were dissolved in 1,2-dichloroethane (4 mL), and the reaction solution was stirred at 20 ° C for 12 hours under a nitrogen atmosphere. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9min) to obtain compound 27. 1 HNMR (400MHz, CD 3 OD) δ7.38(d,J＝8.64Hz,1H),6.91(s,1H),6.86(d,J＝2.28Hz,1H),6.67(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.54-3.37(m,2H),3.06 -3.02(m,1H),2.91-2.82(m,2H),2.52-2.48(m,1H), 2.27-2.23 (m, 1H), 2.09-2.03 (m, 1H), 2.01-1.94 (m, 1H), 1.43-1.37 (m, 2H), 0.86 (t, J = 7.44 Hz, 3H). ESI-MS theoretical calculated value: [M+H] + = 259.17, found 259.0.

实施例28Embodiment 28

合成路线：
Synthesis route:

第一步first step

将化合物25-2(150mg,0.69mmol),三乙酰氧基硼氢化钠(439mg,2.08mmol),环丙甲醛(0.10mL,1.39mmol),醋酸(0.01mL,0.14mmol)溶于1,2-二氯乙烷(4mL)中,氮气氛围下,反应液在20℃搅拌12小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保留时间:9min)纯化得到化合物28。1H NMR(400MHz,CD3OD)δ7.40(d,J＝8.64Hz,1H),6.94(s,1H),6.86(d,J＝2.28Hz,1H),6.68(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.67-3.63(m,1H),3.58-3.54(m,1H),3.18-3.13(m,1H),3.06-3.01(m,1H),2.97-2.93(m,1H),2.43-2.37(m,1H),2.30-2.65(m,1H),2.13-1.99(m,2H),0.86-0.77(m,1H),0.51-0.44(m,2H),0.14-0.09(m,2H)。ESI-MS理论计算值:[M+H]+＝271.17,实测值271.2。Compound 25-2 (150 mg, 0.69 mmol), sodium triacetoxyborohydride (439 mg, 2.08 mmol), cyclopropanecarboxaldehyde (0.10 mL, 1.39 mmol), acetic acid (0.01 mL, 0.14 mmol) were dissolved in 1,2-dichloroethane (4 mL), and the reaction solution was stirred at 20 ° C for 12 hours under nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and dichloromethane (20 mL x 3) was used for extraction. The organic phase was washed with saturated brine (10 mL) and concentrated under reduced pressure to obtain a crude product of the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 9 min) to obtain compound 28. 1 H NMR (400 MHz, CD 3 OD)δ7.40(d,J＝8.64Hz,1H),6.94(s,1H),6.86(d,J＝2.28Hz,1H),6.68(dd,J＝8.64,2.28Hz,1H),3.80(s,3H),3.67-3.63(m,1H),3.58-3.54(m,1H),3. 18-3.13( m, 1H), 3.06-3.01 (m, 1H), 2.97-2.93 (m, 1H), 2.43-2.37 (m, 1H), 2.30-2.65 (m, 1H), 2.13-1.99 (m, 2H), 0.86-0.77 (m, 1H), 0.51-0.44 (m, 2H), 0.14-0.09 (m, 2H). ESI-MS theoretical calculated value: [M+H] + = 271.17, found 271.2.

实施例29Embodiment 29

合成路线：
Synthesis route:

第一步first step

将化合物25-2(120mg,0.55mmol),二碳酸二叔丁酯(133mg,0.61mmol),三乙胺(0.23mL,1.66mmol)溶于二氯甲烷(5mL)中,反应液在20℃搅拌5小时。反应液减压浓缩,剩余物经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物29-1。ESI-MS理论计算值:[M+H-56]+＝261.18,实测值261.0。Compound 25-2 (120 mg, 0.55 mmol), di-tert-butyl dicarbonate (133 mg, 0.61 mmol), and triethylamine (0.23 mL, 1.66 mmol) were dissolved in dichloromethane (5 mL), and the reaction solution was stirred at 20 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 29-1. ESI-MS theoretical calculated value: [M+H-56] + = 261.18, measured value 261.0.

第二步Step 2

将化合物29-1(108mg,0.34mmol)溶于四氢呋喃(4mL)中,0℃下加入氘代氢化锂铝(143mg,3.41mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,0℃下加入1mL水,加入1mL 15％的氢氧化钠水溶液和3mL水,过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-45％,保 留时间:8.4min)纯化得到化合物29。1H NMR(400MHz,CD3OD)δ7.40(d,J＝8.64Hz,1H),6.93(s,1H),6.86(d,J＝2.28Hz,1H),6.67(d,J＝8.64,2.28Hz,1H),3.80(s,3H),3.45-3.36(m,2H),3.01-2.96(m,1H),2.91-2.83(m,2H),2.13-2.08(m,1H),2.01-1.93(m,1H)。ESI-MS理论计算值:[M+H]+＝234.16,实测值234.0。Compound 29-1 (108 mg, 0.34 mmol) was dissolved in tetrahydrofuran (4 mL), and lithium aluminum deuteride (143 mg, 3.41 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, 1 mL of water was added at 0°C, 1 mL of 15% sodium hydroxide aqueous solution and 3 mL of water were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound. After high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 35-45%, retention time: 2 hours). The residue was purified by HPLC (retention time: 8.4 min) to give compound 29. 1 H NMR (400 MHz, CD 3 OD) δ7.40 (d, J=8.64 Hz, 1H), 6.93 (s, 1H), 6.86 (d, J=2.28 Hz, 1H), 6.67 (d, J=8.64, 2.28 Hz, 1H), 3.80 (s, 3H), 3.45-3.36 (m, 2H), 3.01-2.96 (m, 1H), 2.91-2.83 (m, 2H), 2.13-2.08 (m, 1H), 2.01-1.93 (m, 1H). ESI-MS theoretical calculated value: [M+H] + =234.16, found value 234.0.

实施例30Embodiment 30

合成路线：
Synthesis route:

第一步first step

将化合物30-1(500mg,2.44mmol),N-羧酸叔丁酯-3-氮杂环丁酮(543mg,3.17mmol),四氢吡咯(0.1mL,1.22mmol)和一水合醋酸铜(974mg,4.88mmol)溶于N,N-二甲基甲酰胺(5mL)中,氮气氛围下,反应液在100℃搅拌18小时。反应液冷却至室温,加入水(20mL),乙酸乙酯(20mL x 3)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物30-2。ESI-MS理论计算值:[M+H-56]+＝275.16,实测值275.0。Compound 30-1 (500 mg, 2.44 mmol), N-tert-butyl carboxylate-3-azetidinone (543 mg, 3.17 mmol), tetrahydropyrrole (0.1 mL, 1.22 mmol) and copper acetate monohydrate (974 mg, 4.88 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 100 ° C for 18 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 30-2. ESI-MS theoretical calculated value: [M+H-56] + = 275.16, measured value 275.0.

第二步Step 2

将化合物30-2(120mg,0.36mmol)溶于四氢呋喃(5mL)中,0℃下缓慢加入四氢铝锂(41.4mg,1.09mmol),氮气氛围下,反应液在70℃搅拌3小时。反应液冷却至室温,滴加水(1mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:40-55％,保留时间:8.0min)纯化得到化合物30。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.38(d,J＝8.62Hz,1H),7.01(s,1H),6.83(s,1H),6.63(d,J＝8.62Hz,1H),3.82-3.78(m,1H),3.75(s,3H),3.52-3.49(m,1H),2.92-2.90(m,1H),2.83-2.79(m,2H),2.42(t,J＝6.62Hz,1H),2.09(s,3H)。ESI-MS理论计算值:[M+H]+＝247.14,实测值247.1。Compound 30-2 (120 mg, 0.36 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (41.4 mg, 1.09 mmol) was slowly added at 0°C. The reaction solution was stirred at 70°C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (1 mL) was added dropwise, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 40-55%, retention time: 8.0min) to obtain compound 30. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 7.38 (d, J = 8.62 Hz, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 6.63 (d, J = 8.62 Hz, 1H), 3.82-3.78 (m, 1H), 3.75 (s, 3H), 3.52-3.49 (m, 1H), 2.92-2.90 (m, 1H), 2.83-2.79 (m, 2H), 2.42 (t, J = 6.62 Hz, 1H), 2.09 (s, 3H). ESI-MS theoretical calculated value: [M+H] + = 247.14, found 247.1.

实施例31Embodiment 31

合成路线：
Synthesis route:

第一步first step

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.00g,4.97mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.50mL,5.96mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.04mL,0.50mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物31-1(1.00g,4.55 mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(2.5mL,5.05mmol，2.0mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(10mL),二氯甲烷(20mL x 3)萃取,有机相用无水硫酸钠干燥后,过滤,有机相减压浓缩,粗产物用硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物31-2。ESI-MS理论计算值:[M+H]+＝349.15,实测值349.1。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.00 g, 4.97 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.50 mL, 5.96 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (0.04 mL, 0.50 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Compound 31-1 (1.00 g, 4.55 mmol) was dissolved in dichloromethane (10 mL), and ethylmagnesium bromide (2.5 mL, 5.05 mmol, 2.0 mol/L) was added at 0°C. Stir at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (10 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 31-2. ESI-MS theoretical calculated value: [M+H] + = 349.15, measured value 349.1.

第二步Step 2

将化合物31-2(100mg,0.29mmol),氢化锂铝(110mg,2.9mmol)溶于四氢呋喃(5mL)中,氮气氛围下,反应液在60℃搅拌6小时。反应冷却至室温，加入冰水(0.11mL)淬灭,加入15％氢氧化钠水溶液(0.33mL)和水(0.33mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-7.5mmol/L碳酸氢铵水溶液,梯度:25-35％,保留时间:17min)纯化得到化合物31。1H NMR(400MHz,DMSO-d6):δ10.67(s,1H),7.28(d,J＝12.06Hz,1H),7.01-6.97(m,2H),3.82(s,3H),3.27-3.12(m,1H),3.12-3.01(m,1H),2.87-2.80(m,1H),2.72-2.68(m,1H),2.61-2.55(m,1H),2.09(s,3H),1.95-1.89(m,1H),1.82-1.75(m,1H)。ESI-MS理论计算值:[M+H]+＝249.13,实测值249.2。Compound 31-2 (100 mg, 0.29 mmol) and lithium aluminum hydride (110 mg, 2.9 mmol) were dissolved in tetrahydrofuran (5 mL), and the reaction solution was stirred at 60°C for 6 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% sodium hydroxide aqueous solution (0.33 mL) and water (0.33 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-7.5mmol/L ammonium bicarbonate aqueous solution, gradient: 25-35%, retention time: 17min) to obtain compound 31. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.67 (s, 1H), 7.28 (d, J=12.06 Hz, 1H), 7.01-6.97 (m, 2H), 3.82 (s, 3H), 3.27-3.12 (m, 1H), 3.12-3.01 (m, 1H), 2.87-2.80 (m, 1H), 2.72-2.68 (m, 1H), 2.61-2.55 (m, 1H), 2.09 (s, 3H), 1.95-1.89 (m, 1H), 1.82-1.75 (m, 1H). ESI-MS theoretical calculated value: [M+H] + =249.13, found 249.2.

实施例32Embodiment 32

合成路线：
Synthesis route:

第一步first step

将化合物32-1(500mg,3.70mmol)和硫酸羟胺(3.04g,18.5mmol)溶于水(6mL)中,依次加入浓盐酸(0.17mL),化合物32-2(670mg,4.07mmol)和无水硫酸钠(3.68g,25.9mmol),反应液在60℃下搅拌0.5小时,再冷却至室温继续搅拌反应16小时。反应液过滤，收集滤饼得到化合物32-3。ESI-MS理论计算值:[M-H]+＝205.07,实测值205.2。Compound 32-1 (500 mg, 3.70 mmol) and hydroxylamine sulfate (3.04 g, 18.5 mmol) were dissolved in water (6 mL), and concentrated hydrochloric acid (0.17 mL), compound 32-2 (670 mg, 4.07 mmol) and anhydrous sodium sulfate (3.68 g, 25.9 mmol) were added in sequence. The reaction solution was stirred at 60 ° C for 0.5 hours, then cooled to room temperature and continued to stir and react for 16 hours. The reaction solution was filtered and the filter cake was collected to obtain compound 32-3. ESI-MS theoretical calculated value: [MH] + = 205.07, measured value 205.2.

第二步Step 2

将化合物32-3(700mg,3.39mmol)和甲烷磺酸(1.63g,17.0mmol)混合后,反应液在45℃下搅拌1小时。反应液冷却至室温,加入水(20mL),乙酸乙酯(30mL x 2)萃取,有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化 得到化合物32-4。1H NMR(400MHz,DMSO-d6):δ11.19(s,1H),7.38(d,J＝8.40Hz,1H),6.46(d,J＝8.04Hz,1H),4.72(t,J＝8.84Hz,2H),3.09(t,J＝8.40Hz,2H)。ESI-MS理论计算值:[M+H]+＝190.04,实测值190.1。After compound 32-3 (700 mg, 3.39 mmol) and methanesulfonic acid (1.63 g, 17.0 mmol) were mixed, the reaction solution was stirred at 45 °C for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) was added, and ethyl acetate (30 mL x 2) was used for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v). Compound 32-4 was obtained. 1 H NMR (400 MHz, DMSO-d 6 ): δ11.19 (s, 1H), 7.38 (d, J=8.40 Hz, 1H), 6.46 (d, J=8.04 Hz, 1H), 4.72 (t, J=8.84 Hz, 2H), 3.09 (t, J=8.40 Hz, 2H). ESI-MS theoretical calculated value: [M+H] + =190.04, found value 190.1.

第三步Step 3

将化合物32-4(1.00g,5.29mmol)溶于四氢呋喃(8mL)中,0℃下向溶液中依次加入三氟化硼乙醚(1.50g,10.6mmol)和硼氢化钠(0.40g,10.6mmol),氮气氛围下,反应液在25℃下搅拌2小时。反应结束后加入饱和氯化铵水溶液(30mL)淬灭,乙酸乙酯(20mL x 2)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经硅胶柱层析法(石油醚/乙酸乙酯,2/1,v/v)纯化得到化合物32-5。1H NMR(400MHz,DMSO-d6):δ10.86(s,1H),7.25(d,J＝8.40Hz,1H),7.17(t,J＝2.82Hz,1H),6.54(d,J＝8.40Hz,1H),6.35(dd,J＝3.26,2.06Hz,1H),4.55(t,J＝8.84Hz,2H),3.28(t,J＝8.84Hz,2H)。Compound 32-4 (1.00 g, 5.29 mmol) was dissolved in tetrahydrofuran (8 mL), and trifluoroboron ether (1.50 g, 10.6 mmol) and sodium borohydride (0.40 g, 10.6 mmol) were added to the solution at 0 ° C. The reaction solution was stirred at 25 ° C for 2 hours under a nitrogen atmosphere. After the reaction was completed, saturated ammonium chloride aqueous solution (30 mL) was added to quench, and ethyl acetate (20 mL x 2) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/1, v/v) to obtain compound 32-5. 1 H NMR (400MHz, DMSO-d 6 ): δ10.86 (s, 1H), 7.25 (d, J = 8.40Hz, 1H), 7.17 (t, J = 2.82Hz, 1H), 6.54 (d, J = 8.40Hz, 1H), 6.35 (dd, J = 3.26, 2.06Hz, 1H), 4.55 (t, J =8.84Hz,2H),3.28(t,J=8.84Hz,2H).

第四步Step 4

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(550mg,2.73mmol)溶解在二氯甲烷(5mL)中,0℃下滴加草酰氯(0.28mL,3.28mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(20.0mg,0.27mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物32-5(300mg,1.88mmol)溶于在二氯甲烷(5mL)中,0℃下加入乙基溴化镁(4.52mL,2.26mmol,2mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/9,v/v)纯化得到化合物32-6。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),8.25(d,J＝3.26Hz,1H),7.96(d,J＝8.40Hz,1H),6.74(d,J＝8.40Hz,1H),5.46-5.39(m,1H),4.61-4.55(m,2H),3.96-3.81(m,2H),3.32-3.26(m,2H),2.56-2.48(m,1H),2.07-1.93(m,1H),1.48-1.09(br,9H)。ESI-MS理论计算值:[M-H]+＝341.16,实测值341.3。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (550 mg, 2.73 mmol) in dichloromethane (5 mL), add oxalyl chloride (0.28 mL, 3.28 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (20.0 mg, 0.27 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 32-5 (300 mg, 1.88 mmol) in dichloromethane (5 mL), add ethylmagnesium bromide (4.52 mL, 2.26 mmol, 2 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated brine (10 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/9, v/v) to obtain compound 32-6. 1 H NMR (400 MHz, DMSO-d 6 ): δ11.89 (s, 1H), 8.25 (d, J=3.26 Hz, 1H), 7.96 (d, J=8.40 Hz, 1H), 6.74 (d, J=8.40 Hz, 1H), 5.46-5.39 (m, 1H), 4.61-4.55 (m, 2H), 3.96-3.81 (m, 2H), 3.32-3.26 (m, 2H), 2.56-2.48 (m, 1H), 2.07-1.93 (m, 1H), 1.48-1.09 (br, 9H). ESI-MS theoretical calculated value: [MH] + =341.16, found 341.3.

第五步Step 5

将化合物32-6(55.0mg,0.160mmol),氢化锂铝(60.7mg,1.60mmol)溶于四氢呋喃(5mL)中,氮气氛围下,反应液在60℃搅拌12小时。反应冷却至室温，加入冰水(0.06mL)淬灭,加入15％氢氧化钠水溶液(0.06mL)和水(0.18mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-SunFire-C18-10μm-19*250mm,流动相:乙腈-0.05％三氟乙酸水溶液,梯度:15-25％,保留时间:17min)纯化得到化合物32。1H NMR(400MHz,DMSO-d6):δ10.82(s,1H),9.92(s,1H),7.33(d,J＝8.40Hz,1H),7.10(s,1H),6.59(d,J＝8.40Hz,1H),4.56(t,J＝8.40Hz,2H),4.48-4.42(m,1H),4.04-3.94(m,1H),3.82-3.72(m,1H),3.33-3.23(m,3H),3.16-3.08(m,1H),2.61(s,3H),2.37-2.16(m,2H).ESI-MS理论计算值:[M+H]+＝243.14,实测值243.2。Compound 32-6 (55.0 mg, 0.160 mmol) and lithium aluminum hydride (60.7 mg, 1.60 mmol) were dissolved in tetrahydrofuran (5 mL), and the reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.06 mL), and 15% aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-SunFire-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution, gradient: 15-25%, retention time: 17 min) to obtain compound 32. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.82 (s, 1H), 9.92 (s, 1H), 7.33 (d, J=8.40 Hz, 1H), 7.10 (s, 1H), 6.59 (d, J=8.40 Hz, 1H), 4.56 (t, J=8.40 Hz, 2H), 4.48-4.42 (m, 1H), 4.04-3.94 (m, 1H), 3.82-3.72 (m, 1H), 3.33-3.23 (m, 3H), 3.16-3.08 (m, 1H), 2.61 (s, 3H), 2.37-2.16 (m, 2H). ESI-MS theoretical calculated value: [M+H] + ＝243.14, found 243.2.

实施例33和34Examples 33 and 34

合成路线：
Synthesis route:

第一步first step

将化合物30(400mg,1.20mmol)溶于二氯甲烷(10mL)中,室温下缓慢加入N,N,N',N'-四甲基-1,8-萘二胺(309mg,1.44mmol)和三甲基氧鎓四氟硼酸盐(213mg,1.44mmol),反应液在25℃搅拌16小时。反应结束后加入水(15mL),二氯甲烷(20mL x 3)萃取,有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物用硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物33-1。ESI-MS理论计算值:[M+Na]+＝369.19,实测值369.2。Compound 30 (400 mg, 1.20 mmol) was dissolved in dichloromethane (10 mL), and N,N,N',N'-tetramethyl-1,8-naphthalenediamine (309 mg, 1.44 mmol) and trimethyloxonium tetrafluoroborate (213 mg, 1.44 mmol) were slowly added at room temperature, and the reaction solution was stirred at 25 ° C for 16 hours. After the reaction, water (15 mL) was added, and dichloromethane (20 mL x 3) was used for extraction. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 33-1. ESI-MS theoretical calculated value: [M+Na] + = 369.19, measured value 369.2.

第二步Step 2

将化合物33-1(50.0mg,0.140mmol)溶于四氢呋喃(2mL)中,0℃下缓慢加入四氢铝锂(5.31mg,0.140mmol),氮气氛围下,反应液在60℃搅拌2小时。反应冷却至室温，加入冰水(0.14mL)淬灭,加入15％氢氧化钠水溶液(0.14mL)和水(0.42mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备硅胶板(二氯甲烷/甲醇,15/1,v/v，Rf＝05,0.4)纯化得到粗品33或34。Compound 33-1 (50.0 mg, 0.140 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum tetrahydride (5.31 mg, 0.140 mmol) was slowly added at 0°C. The reaction solution was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.14 mL), and 15% sodium hydroxide aqueous solution (0.14 mL) and water (0.42 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative silica gel plate (dichloromethane/methanol, 15/1, v/v, Rf=0.5, 0.4) to obtain a crude product 33 or 34.

进一步经过高效液相色谱(Waters-SunFire-C18-10μm-19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:10-20％，流速20mL/min洗脱时间17min，保留时间:7.7min)33的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.55(s,1H),8.19(s,1H),7.39(d,J＝8.84Hz,1H),6.93(d,J＝2.02Hz,1H),6.81(d,J＝2.42Hz,1H),6.62(dd,J＝8.40,2.02Hz,1H),3.97-3.95(m,1H),3.74(s,3H),3.36(m,2H),3.21(s,3H),2.98-2.92(m,1H),2.86-2.81(m,1H),2.81-2.74(m,1H),2.07(s,3H).ESI-MS理论计算值:[M+H]+＝261.15,实测值261.2。The monoformate of 33 was further purified by high performance liquid chromatography (Waters-SunFire-C18-10μm-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 10-20%, flow rate 20mL/min, elution time 17min, retention time: 7.7min). 1 H NMR (400 MHz, DMSO-d 6 ): δ10.55 (s, 1H), 8.19 (s, 1H), 7.39 (d, J=8.84 Hz, 1H), 6.93 (d, J=2.02 Hz, 1H), 6.81 (d, J=2.42 Hz, 1H), 6.62 (dd, J=8.40, 2.02 Hz, 1H), 3.97-3.95 (m, 1H), 3.74 (s, 3H), 3.36 (m, 2H), 3.21 (s, 3H), 2.98-2.92 (m, 1H), 2.86-2.81 (m, 1H), 2.81-2.74 (m, 1H), 2.07 (s, 3H). ESI-MS theoretical value: [M+H] + =261.15, measured value 261.2.

进一步经过高效液相色谱(Waters-SunFire-C18-10μm-19*250mm,流动相:乙腈-0.1％甲酸水溶液,梯度:10-20％,流速20mL/min洗脱时间17min，保留时间:7.3min)34的一甲酸盐。1H NMR(400MHz,CD3OD):δ7.45(d,J＝8.40Hz,1H),7.05(s,1H),6.88(s,1H),6.72(dd,J＝8.40,2.02Hz,1H),4.04-3.97(m,1H),3.88-3.83(m,1H),3.81(s,3H),3.75-3.72(m,1H),3.19-3.14(m,3H),3.02(s,3H),2.47(s,3H).ESI-MS理论计算值:[M+H]+＝261.15,实测值261.2。The monoformate of 34 was further purified by high performance liquid chromatography (Waters-SunFire-C18-10μm-19*250mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 10-20%, flow rate 20mL/min, elution time 17min, retention time: 7.3min). 1 H NMR (400 MHz, CD 3 OD): δ7.45 (d, J=8.40 Hz, 1H), 7.05 (s, 1H), 6.88 (s, 1H), 6.72 (dd, J=8.40, 2.02 Hz, 1H), 4.04-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.81 (s, 3H), 3.75-3.72 (m, 1H), 3.19-3.14 (m, 3H), 3.02 (s, 3H), 2.47 (s, 3H). ESI-MS calculated value: [M+H] + =261.15, found 261.2.

实施例35Embodiment 35

合成路线：
Synthesis route:

第一步first step

将化合物35-1(1.60g,7.95mmol)溶解在二氯甲烷(20mL)中,0℃下滴加草酰氯(0.87mL,10.3mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.06mL,0.80mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将1-1(1.00g,6.79mmol)溶于在二氯甲烷(10mL),0℃下滴加乙基溴化镁的乙醚溶液(3.22mL,6.45mmol,2mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应结束,反应液加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 3)萃取,有机相用(50mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/2,v/v)纯化得到化合物35-2。ESI-MS理论计算值:[M+H]+＝331.16,实测值331.0。Compound 35-1 (1.60 g, 7.95 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (0.87 mL, 10.3 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (0.06 mL, 0.80 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 1-1 (1.00 g, 6.79 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide in ether solution (3.22 mL, 6.45 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (10 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was washed with water (50 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/2, v/v) to obtain compound 35-2. ESI-MS theoretical calculated value: [M+H] + = 331.16, measured value 331.0.

第二步Step 2

将化合物35-2(250mg,0.76mmol),氢化锂铝(288mg,7.60mmol)溶于四氢呋喃(15mL)中,氮气氛围下,反应液在60℃搅拌12小时。反应冷却至室温，加入冰水(0.76mL)淬灭,加入15％氢氧化钠水溶液(0.76mL)和水(2.28mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备硅胶板(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物35。1H NMR(400MHz,DMSO-d6):δ10.68(s,1H),7.43(d,J＝8.84Hz,1H),7.04(d,J＝1.60Hz,1H),6.84(d,J＝2.42Hz,1H),6.65(dd,J＝8.84,2.42Hz,1H),4.00-3.76(m,1H),3.75(s,3H),3.68-3.56(m,1H),3.43-3.33(m,1H),3.15-3.05(m,1H),2.99-2.89(m,1H),2.38(s,3H),2.20-2.10(m,1H),2.09-1.95(m,1H).ESI-MS理论计算值:[M+H]+＝231.14,实测值231.1。Compound 35-2 (250 mg, 0.76 mmol) and lithium aluminum hydride (288 mg, 7.60 mmol) were dissolved in tetrahydrofuran (15 mL), and the reaction solution was stirred at 60 ° C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.76 mL), and 15% sodium hydroxide aqueous solution (0.76 mL) and water (2.28 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 35. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.68 (s, 1H), 7.43 (d, J = 8.84 Hz, 1H), 7.04 (d, J = 1.60 Hz, 1H), 6.84 (d, J = 2.42 Hz, 1H), 6.65 (dd, J = 8.84, 2.42 Hz, 1H), 4.00-3.76 (m, 1H), 3.75 (s, 3H), 3.68-3.56 (m, 1H), 3.43-3.33 (m, 1H), 3.15-3.05 (m, 1H), 2.99-2.89 (m, 1H), 2.38 (s, 3H), 2.20-2.10 (m, 1H), 2.09-1.95 (m, 1H). ESI-MS theoretical value: [M+H] + =231.14, measured value 231.1.

实施例36Embodiment 36

合成路线：
Synthesis route:

第一步first step

将化合物36-1(1.60g,7.95mmol)溶解在二氯甲烷(20mL)中,0℃下滴加草酰氯(0.87mL,10.3mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.06mL,0.80mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将1-1(1.00g,6.79mmol)溶于在二氯甲烷(10mL),0℃下滴加乙基溴化镁的乙醚溶液(3.40mL,6.79mmol,2mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应结束,反应液加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 3)萃取,有机相用(50mL)洗涤,减压浓缩,粗品经硅胶柱层析法 (石油醚/乙酸乙酯,1/2,v/v)纯化得到化合物36-2。ESI-MS理论计算值:[M+H]+＝331.16,实测值331.1。Compound 36-1 (1.60 g, 7.95 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (0.87 mL, 10.3 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (0.06 mL, 0.80 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 1-1 (1.00 g, 6.79 mmol) was dissolved in dichloromethane (10 mL), ethyl magnesium bromide in ether solution (3.40 mL, 6.79 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (10 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was added with saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (50 mL x 3), the organic phase was washed with water (50 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. (petroleum ether/ethyl acetate, 1/2, v/v) to obtain compound 36-2. ESI-MS theoretical calculated value: [M+H] + = 331.16, found value 331.1.

第二步Step 2

将化合物36-2(100mg,0.30mmol),氢化锂铝(114mg,3.00mmol)溶于四氢呋喃(10mL)中,氮气氛围下,反应液在60℃搅拌12小时。反应冷却至室温，加入冰水(1mL)淬灭,加入15％氢氧化钠水溶液(1mL)和水(3mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备硅胶板(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物36。1H NMR(400MHz,DMSO-d6):δ10.75(s,1H),7.46(d,J＝8.42Hz,1H),7.11(d,J＝2.08Hz,1H),6.85(d,J＝2.42Hz,1H),6.66(dd,J＝8.42,2.08Hz,1H),4.24-4.14(m,1H),3.85-3.76(m,1H),3.75(s,3H),3.64-3.47(m,1H),3.32(s,3H),3.28-3.18(m,1H),3.11-3.01(m,1H),2.28-2.21(m,1H),2.19-2.09(m,1H).ESI-MS理论计算值:[M+H]+＝231.14,实测值231.2。Compound 36-2 (100 mg, 0.30 mmol) and lithium aluminum hydride (114 mg, 3.00 mmol) were dissolved in tetrahydrofuran (10 mL), and the reaction solution was stirred at 60 ° C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (1 mL), and 15% sodium hydroxide aqueous solution (1 mL) and water (3 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 36. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.75 (s, 1H), 7.46 (d, J = 8.42 Hz, 1H), 7.11 (d, J = 2.08 Hz, 1H), 6.85 (d, J = 2.42 Hz, 1H), 6.66 (dd, J = 8.42, 2.08 Hz, 1H), 4.24-4.14 (m, 1H), 3.85-3.76 (m, 1H), 3.75 (s, 3H), 3.64-3.47 (m, 1H), 3.32 (s, 3H), 3.28-3.18 (m, 1H), 3.11-3.01 (m, 1H), 2.28-2.21 (m, 1H), 2.19-2.09 (m, 1H). ESI-MS calculated value: [M+H] + =231.14, measured value 231.2.

实施例37Embodiment 37

合成路线：
Synthesis route:

第一步first step

将化合物35-1(700mg,3.48mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.35mL,4.18mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.05mL,0.68mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将32-5(500mg,3.14mmol)溶于在二氯甲烷(5mL),0℃下滴加乙基溴化镁的乙醚溶液(1.49mL,2.98mmol,2mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应结束,反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(30mL x 3)萃取,有机相用(30mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物37-1。ESI-MS理论计算值:[M-H]+＝341.16,实测值341.0。Compound 35-1 (700 mg, 3.48 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (0.35 mL, 4.18 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (0.05 mL, 0.68 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 32-5 (500 mg, 3.14 mmol) was dissolved in dichloromethane (5 mL), ethyl magnesium bromide in ether solution (1.49 mL, 2.98 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (5 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with water (30 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 37-1. ESI-MS theoretical calculated value: [MH] + = 341.16, measured value 341.0.

第二步Step 2

将化合物37-1(200mg,0.58mmol)溶于四氢呋喃(5mL)中,0℃下滴加四氢锂铝的四氢呋喃溶液(2.32mL,5.80mmol,2.5mol/L),氮气氛围下,反应液在60℃搅拌12小时。反应冷却至室温，加入冰水(0.2mL)淬灭,加入15％氢氧化钠水溶液(0.2mL)和水(0.6mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备硅胶板(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物37。1H NMR(400MHz,DMSO-d6):δ10.56(s,1H),7.23(d,J＝8.02Hz,1H),6.92(d,J＝1.64Hz,1H),6.52(d,J＝8.02Hz,1H),4.54(t,J＝8.84Hz,2H),3.28-3.18(m,3H),3.14 -3.03(m,1H),2.91-2.81(m,1H),2.73-2.63(m,1H),2.63-2.53(m,1H),2.10(s,3H),1.96-1.85(m,1H),1.82-1.69(m,1H).ESI-MS理论计算值:[M+H]+＝243.14,实测值243.2。 Compound 37-1 (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium aluminum tetrahydride (2.32 mL, 5.80 mmol, 2.5 mol/L) was added dropwise at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.2 mL), and 15% sodium hydroxide aqueous solution (0.2 mL) and water (0.6 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 37. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.56 (s, 1H), 7.23 (d, J=8.02 Hz, 1H), 6.92 (d, J=1.64 Hz, 1H), 6.52 (d, J=8.02 Hz, 1H), 4.54 (t, J=8.84 Hz, 2H), 3.28-3.18 (m, 3H), 3.14 -3.03 (m, 1H), 2.91-2.81 (m, 1H), 2.73-2.63 (m, 1H), 2.63-2.53 (m, 1H), 2.10 (s, 3H), 1.96-1.85 (m, 1H), 1.82-1.69 (m, 1H). ESI-MS theoretical value: [M+H] + =243.14, measured value 243.2.

实施例38Embodiment 38

合成路线：
Synthesis route:

第一步first step

将化合物36-1(700mg,3.48mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.35mL,4.18mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(0.05mL,0.68mmol),反应液在0℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将32-5(500mg,3.14mmol)溶于在二氯甲烷(5mL),0℃下滴加乙基溴化镁的乙醚溶液(2.23mL,3.46mmol,2mol/L),0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应结束,反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(30mL x 3)萃取,有机相用(30mL)洗涤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/2,v/v)纯化得到化合物38-1。ESI-MS理论计算值:[M+H]+＝343.16,实测值343.2。Compound 36-1 (700 mg, 3.48 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (0.35 mL, 4.18 mmol) was added dropwise at 0°C, the reaction solution was stirred at 0°C for 10 minutes, N,N-dimethylformamide (0.05 mL, 0.68 mmol) was slowly added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. 32-5 (500 mg, 3.14 mmol) was dissolved in dichloromethane (5 mL), ethyl magnesium bromide in ether solution (2.23 mL, 3.46 mmol, 2 mol/L) was added dropwise at 0°C, and stirred at 0°C for 0.5 hours. The crude intermediate was dissolved in dichloromethane (5 mL), added dropwise to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with water (30 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/2, v/v) to obtain compound 38-1. ESI-MS theoretical calculated value: [M+H] + = 343.16, measured value 343.2.

第二步Step 2

将化合物38-1(100mg,0.29mmol)溶于四氢呋喃(5mL)中,0℃下滴加四氢锂铝的四氢呋喃溶液(1.45mL,2.90mmol,2mol/L),氮气氛围下,反应液在60℃搅拌12小时。反应冷却至室温，加入冰水(0.2mL)淬灭,加入15％氢氧化钠水溶液(0.2mL)和水(0.6mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过制备硅胶板(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物38。1H NMR(400MHz,DMSO-d6):δ10.78(s,1H),7.32(d,J＝8.42Hz,1H),7.11(s,1H),6.57(d,J＝8.42Hz,1H),4.55(t,J＝8.82Hz,2H),4.26-4.16(m,1H),3.85-3.75(m,1H),3.66-3.48(m,1H),3.32(s,3H),3.32-3.22(m,3H),3.12-3.02(m,1H),2.28-2.11(m,2H).ESI-MS理论计算值:[M+H]+＝243.14,实测值243.2。Compound 38-1 (100 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium aluminum tetrahydride (1.45 mL, 2.90 mmol, 2 mol/L) was added dropwise at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by adding ice water (0.2 mL), and 15% sodium hydroxide aqueous solution (0.2 mL) and water (0.6 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified on a preparative silica gel plate (dichloromethane/methanol, 10/1, v/v) to obtain compound 38. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.78 (s, 1H), 7.32 (d, J＝8.42 Hz, 1H), 7.11 (s, 1H), 6.57 (d, J＝8.42 Hz, 1H), 4.55 (t, J＝8.82 Hz, 2H), 4.26-4.16 (m, 1H), 3.85-3.75 (m, 1H), 3.66-3.48 (m, 1H), 3.32 (s, 3H), 3.32-3.22 (m, 3H), 3.12-3.02 (m, 1H), 2.28-2.11 (m, 2H). ESI-MS theoretical calculated value: [M+H] + ＝243.14, found 243.2.

实施例39Embodiment 39

合成路线：
Synthesis route:

第一步 first step

将化合物39-1(2.50g,10.7mmol),碳酸铯(6.99g,21.44mmol)和氘代碘甲烷(2.33g,16.08mmol)溶于乙腈(30mL)中,氮气氛围下,反应液在60℃搅拌1小时。反应冷却至室温,加入水(50mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物39-2。ESI-MS理论计算值:[M+H]+＝251.14,实测值251.2。Compound 39-1 (2.50 g, 10.7 mmol), cesium carbonate (6.99 g, 21.44 mmol) and deuterated iodomethane (2.33 g, 16.08 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 60 ° C for 1 hour under a nitrogen atmosphere. The reaction was cooled to room temperature, and water (50 mL) and ethyl acetate (50 mL x 3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39-2. ESI-MS theoretical calculated value: [M+H] + = 251.14, measured value 251.2.

第二步Step 2

将化合物39-2(2.60g,10.4mmol)溶于四氢呋喃(15mL),乙醇(15mL)和水(6mL)中,加入一水合氢氧化锂(2.18g,52.0mmol),反应液在60℃搅拌16小时。反应冷却至室温,加入水(50mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物39-3。ESI-MS理论计算值:[M+H]+＝151.09,实测值151.2。Compound 39-2 (2.60 g, 10.4 mmol) was dissolved in tetrahydrofuran (15 mL), ethanol (15 mL) and water (6 mL), and lithium hydroxide monohydrate (2.18 g, 52.0 mmol) was added, and the reaction solution was stirred at 60°C for 16 hours. The reaction was cooled to room temperature, and water (50 mL) was added, and ethyl acetate (100 mL x 3) was extracted, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 39-3. ESI-MS theoretical calculated value: [M+H] + = 151.09, measured value 151.2.

第三步Step 3

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物39-3(900mg,5.99mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(6.71mL,6.71mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(30mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物39-4。ESI-MS理论计算值:[M+H]+＝334.18,实测值334.4。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 39-3 (900 mg, 5.99 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.71 mL, 6.71 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 39-4. ESI-MS theoretical calculated value: [M+H] + = 334.18, found value 334.4.

第四步Step 4

将化合物39-4(190mg,0.57mmol)溶于四氢呋喃(15mL)中,0℃下加入四氢锂铝(216mg,5.70mmol),氮气氛围下,反应液在60℃搅拌6小时。反应液冷却至室温,加入冰水(0.22mL)淬灭,加入15％氢氧化钠水溶液(0.66mL)和水(0.22mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-SunFire-C18-10μm-19*250mm,流动相:乙腈-10mmol/L氨水溶液,梯度:25-35％,保留时间:17min)纯化得到化合物39。1H NMR(400MHz,DMSO-d6):δ10.55(s,1H),7.37(d,J＝8.82Hz,1H),6.93(s,1H),6.81(d,J＝2.04Hz,1H),6.61(dd,J＝8.82,2.04Hz,,1H),3.27-3.17(m,1H),3.10-3.05(m,1H),2.88-2.83(m,1H),2.72-2.68(m,1H),2.60-2.56(m,1H),2.10(s,3H),1.93-1.88(m,1H),1.78-1.70(m,1H)。ESI-MS理论计算值:[M+H]+＝234.16,实测值234.2。Compound 39-4 (190 mg, 0.57 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum tetrahydride (216 mg, 5.70 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.22 mL), and 15% sodium hydroxide aqueous solution (0.66 mL) and water (0.22 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-SunFire-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L ammonia aqueous solution, gradient: 25-35%, retention time: 17min) to obtain compound 39. 1 H NMR (400MHz, DMSO-d 6 ): δ10.55(s,1H),7.37(d,J＝8.82Hz,1H),6.93(s,1H),6.81(d,J＝2.04Hz,1H),6.61(dd,J＝8.82,2.04Hz,,1H),3.27-3.17(m,1H) ,3.10-3.05(m,1H),2.88-2.83(m,1H),2.72-2.68(m,1H),2.60-2.56(m,1H),2.10(s,3H),1.93-1.88(m,1H),1.78-1.70(m,1H). ESI-MS theoretical calculated value: [M+H] + = 234.16, found value 234.2.

实施例40Embodiment 40

合成路线：
Synthesis route:

第一步first step

将化合物30(150mg,0.45mmol)溶于二氯甲烷(2mL)中,氮气氛围下,0℃下缓慢加入二乙胺三氟化硫(72.5mg,0.45mmol),反应液在0℃搅拌1小时。反应完成后,向反应液加入饱和碳酸氢钠水溶液(50mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物40-1。ESI-MS理论计算值:[M+Na]+＝357.17,实测值357.2。Compound 30 (150 mg, 0.45 mmol) was dissolved in dichloromethane (2 mL), and diethylamine sulfur trifluoride (72.5 mg, 0.45 mmol) was slowly added at 0°C under a nitrogen atmosphere, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and ethyl acetate (100 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 40-1. ESI-MS theoretical calculated value: [M+Na] + = 357.17, measured value 357.2.

第二步Step 2

将化合物40-1(40.0mg,0.12mmol)溶于四氢呋喃(3mL)中,0℃下加入四氢锂铝(6.83mg,0.18mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.1mL)淬灭,加入15％氢氧化钠水溶液(0.3mL)和水(0.1mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:35-55％,保留时间:17.0min)纯化得到化合物40。1H NMR(400MHz,DMSO-d6):δ10.60(s,1H),7.39(d,J＝8.82Hz,1H),6.96(s,1H),6.82(d,J＝2.44Hz,1H),6.63(dd,J＝8.82,2.44Hz,1H),5.24-5.07(m,1H),3.74(s,3H),3.45-3.37(m,1H),3.30-3.22(m,1H),3.01-2.87(m,2H),2.85-2.75(m,1H),2.12(s,3H)。ESI-MS理论计算值:[M+H]+＝249.13,实测值249.1。Compound 40-1 (40.0 mg, 0.12 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum tetrahydride (6.83 mg, 0.18 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.1 mL), and 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.1 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 17.0 min) to obtain compound 40. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.60 (s, 1H), 7.39 (d, J=8.82 Hz, 1H), 6.96 (s, 1H), 6.82 (d, J=2.44 Hz, 1H), 6.63 (dd, J=8.82, 2.44 Hz, 1H), 5.24-5.07 (m, 1H), 3.74 (s, 3H), 3.45-3.37 (m, 1H), 3.30-3.22 (m, 1H), 3.01-2.87 (m, 2H), 2.85-2.75 (m, 1H), 2.12 (s, 3H). ESI-MS theoretical calculated value: [M+H] + =249.13, found 249.1.

实施例41Embodiment 41

合成路线：
Synthesis route:

第一步first step

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.65g,8.19mmol)溶解在二氯甲烷(15mL)中,0℃下滴加草酰氯(0.84mL,9.84mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(60.0mg,0.87mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物41-1(1.80g,8.19mmol)溶于在二氯甲烷(15mL)中,0℃下加入乙基溴化镁(8.2mL,8.2mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(60mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物41-2。ESI-MS理论计算值:[M+H]+＝345.14,实测值345.2。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.65 g, 8.19 mmol) in dichloromethane (15 mL), add oxalyl chloride (0.84 mL, 9.84 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (60.0 mg, 0.87 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 41-1 (1.80 g, 8.19 mmol) in dichloromethane (15 mL), add ethylmagnesium bromide (8.2 mL, 8.2 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour. The reaction solution was added with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (60 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 41-2. ESI-MS theoretical calculated value: [M+H] + = 345.14, found value 345.2.

第二步Step 2

将化合物41-2(200mg,0.58mmol)溶于四氢呋喃(5mL)中,0℃下加入四氢锂铝(220mg,5.80mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.22mL)淬灭,加入15％氢氧化钠水溶液(0.66mL)和水(0.22mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高 效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:35-55％,保留时间:17.0min)纯化得到化合物41的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.58(s,1H),8.25(s,1H),6.99(s,1H),6.94(s,1H),6.84(s,1H),5.90(s,2H),3.35-3.30(m,1H),2.91-2.67(m,4H),2.19(s,3H),1.98-1.94(m,1H),1.88-1.79(m,1H)。ESI-MS理论计算值:[M+H]+＝245.12,实测值245.2。Compound 41-2 (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (220 mg, 5.80 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.22 mL), and 15% sodium hydroxide aqueous solution (0.66 mL) and water (0.22 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound. After high temperature The monoformate of compound 41 was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 17.0min). 1H NMR (400MHz, DMSO- d6 ): δ10.58(s,1H),8.25(s,1H),6.99(s,1H),6.94(s,1H),6.84(s,1H),5.90(s,2H),3.35-3.30(m,1H),2.91-2.67(m,4H),2.19(s,3H),1.98-1.94(m,1H),1.88-1.79(m,1H). ESI-MS theoretical calculated value: [M+H] + = 245.12, found value 245.2.

实施例42Embodiment 42

合成路线：
Synthesis route:

第一步first step

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物42-1(1.00g,4.55mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(5.05mL,5.05mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(30mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物42-2。ESI-MS理论计算值:[M+H-100]+＝261.17,实测值261.2。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 42-1 (1.00 g, 4.55 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (5.05 mL, 5.05 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 42-2. ESI-MS theoretical calculated value: [M+H-100] + = 261.17, found value 261.2.

第二步Step 2

将化合物42-2(100mg,0.28mmol)溶于四氢呋喃(5mL)中,0℃下加入四氢锂铝(110mg,2.80mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.11mL)淬灭,加入15％氢氧化钠水溶液(0.33mL)和水(0.11mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:25-35％,保留时间:17.0min)纯化得到化合物42。1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),7.00(s,1H),6.90(s,1H),6.85(s,1H),3.75(s,6H),3.29-3.20(m,1H),3.16-3.07(m,1H),2.90-2.82(m,1H),2.73-2.65(m,1H),2.64-2.56(m,1H),2.12(s,3H),1.97-1.83(m,1H),1.84-1.76(m,1H)。ESI-MS理论计算值C15H20N2O2[M+H]+＝261.15,实测值261.2。Compound 42-2 (100 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (110 mg, 2.80 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% aqueous sodium hydroxide solution (0.33 mL) and water (0.11 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L aqueous ammonium bicarbonate solution, gradient: 25-35%, retention time: 17.0 min) to obtain compound 42. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.44 (s, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 3.75 (s, 6H), 3.29-3.20 (m, 1H), 3.16-3.07 (m, 1H), 2.90-2.82 (m, 1H), 2.73-2.65 (m, 1H), 2.64-2.56 (m, 1H), 2.12 (s, 3H), 1.97-1.83 (m, 1H), 1.84-1.76 (m, 1H). ESI-MS theoretical calculated value for C 15 H 20 N 2 O 2 [M+H] + = 261.15, found 261.2.

实施例43Embodiment 43

合成路线：
Synthesis route:

第一步first step

将化合物39-1(2.50g,10.7mmol),碳酸铯(6.99g,21.44mmol)和2-碘丙烷(2.73g,16.1mmol)溶于乙腈(30mL)中,氮气氛围下,反应液在60℃搅拌1小时。反应液冷却至室温,向反应液加入水(50mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到化合物43-1。1H NMR(400MHz,CDCl3):δ7.75(s,1H),7.47(d,J＝3.68Hz,1H),7.40(d,J＝8.42Hz,1H),6.85(dd,J＝8.42,2.44Hz,1H),6.48(d,J＝3.68Hz,1H),4.66-4.56(m,1H),1.67(s,9H),1.37(d,J＝6.46Hz,6H)。Compound 39-1 (2.50 g, 10.7 mmol), cesium carbonate (6.99 g, 21.44 mmol) and 2-iodopropane (2.73 g, 16.1 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 60 ° C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 43-1. 1 H NMR (400MHz, CDCl 3 ): δ7.75 (s, 1H), 7.47 (d, J = 3.68Hz, 1H), 7.40 (d, J = 8.42Hz, 1H), 6.85 (dd, J = 8.42, 2.44Hz, 1H), 6.48 (d, J = 3.68Hz, 1H), 4.66-4.56 (m ,1H),1.67(s,9H),1.37(d,J=6.46Hz,6H).

第二步Step 2

将化合物43-1(2.6g,9.44mmol)溶于乙醇(15mL),四氢呋喃(15mL)和水(5mL)的混合溶液中,加入一水合氢氧化锂(1.98g,47.2mmol),反应液在60℃搅拌16小时。反应液冷却至室温,向反应液加入水(50mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥后,过滤,减压浓缩得到粗产物,粗品经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物43-2。ESI-MS理论计算值:[M+H]+＝176.10,实测值176.2。Compound 43-1 (2.6 g, 9.44 mmol) was dissolved in a mixed solution of ethanol (15 mL), tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (1.98 g, 47.2 mmol) was added, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 43-2. ESI-MS theoretical calculated value: [M+H] + = 176.10, measured value 176.2.

第三步Step 3

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物43-2(1.00g,5.71mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(6.85mL,6.85mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌2小时。反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物43-3。ESI-MS理论计算值:[M+H]+＝359.19,实测值359.2。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 43-2 (1.00 g, 5.71 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.85 mL, 6.85 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 2 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 43-3. ESI-MS theoretical calculated value: [M+H] + = 359.19, found value 359.2.

第四步Step 4

将化合物43-3(260mg,0.73mmol)溶于四氢呋喃(10mL)中,0℃下加入四氢锂铝(277mg,7.30mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.27mL)淬灭,加入15％氢氧化钠水溶液(0.81mL)和水(0.27mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:25-40％,保留时间:17.0min)纯化得到化合物43的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.57(s,1H),8.30(s,1H),7.39(d,J＝8.42Hz,1H),6.99(s,1H),6.82(d,J＝2.04Hz,1H),6.61(dd,J＝8.42,2.04Hz, 1H),4.57-4.48(m,1H),3.52-3.44(m,2H),3.02-2.93(m,2H),2.86-2.81(m,1H),2.28(s,3H),2.04-1.99(m,1H),1.94-1.88(m,1H),1.26(d,J＝6.08Hz,6H)。ESI-MS理论计算值:[M+H]+＝259.17,实测值259.1。Compound 43-3 (260 mg, 0.73 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (277 mg, 7.30 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.27 mL), and 15% sodium hydroxide aqueous solution (0.81 mL) and water (0.27 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 25-40%, retention time: 17.0 min) to obtain the monoformate of compound 43. 1 H NMR (400MHz, DMSO-d 6 ): δ10.57 (s, 1H), 8.30 (s, 1H), 7.39 (d, J = 8.42Hz, 1H), 6.99 (s, 1H), 6.82 (d, J = 2.04Hz, 1H), 6.61 (dd, J = 8.42, 2.04Hz, 1H), 4.57-4.48 (m, 1H), 3.52-3.44 (m, 2H), 3.02-2.93 (m, 2H), 2.86-2.81 (m, 1H), 2.28 (s, 3H), 2.04-1.99 (m, 1H), 1.94-1.88 (m, 1H), 1.26 (d, J = 6.08 Hz, 6H). ESI-MS theoretical calculated value: [M+H] + = 259.17, found 259.1.

实施例44Embodiment 44

合成路线：
Synthesis route:

第一步first step

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(2.20g,10.9mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(1.12mL,13.1mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(80.0mg,1.16mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物44-1(2.00g,9.10mmol)溶于在二氯甲烷(20mL)中,0℃下加入乙基溴化镁(10.1mL,10.1mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(10mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(60mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物44-2。ESI-MS理论计算值:[M+H-100]+＝307.19,实测值307.1。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (2.20 g, 10.9 mmol) in dichloromethane (10 mL), add oxalyl chloride (1.12 mL, 13.1 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (80.0 mg, 1.16 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 44-1 (2.00 g, 9.10 mmol) in dichloromethane (20 mL), add ethylmagnesium bromide (10.1 mL, 10.1 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (10 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (60 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 44-2. ESI-MS theoretical calculated value: [M+H-100] + = 307.19, found value 307.1.

第二步Step 2

将化合物44-2(220mg,0.54mmol)溶于四氢呋喃(10mL)中,0℃下加入四氢锂铝(205mg,5.40mmol),氮气氛围下,反应液在60℃搅拌16小时。反应液冷却至室温,加入冰水(0.20mL)淬灭,加入15％氢氧化钠水溶液(0.60mL)和水(0.20mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:5-10％,保留时间:17.0min)纯化得到化合物44的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.28(s,1H),7.29(d,J＝8.42Hz,1H),6.89(s,1H),6.68(d,J＝2.04Hz,1H),6.51(dd,J＝8.42,2.04Hz,1H),3.46-3.42(m,2H),2.97-2.88(m,2H),2.84-2.76(m,1H),2.24(s,3H),2.04-1.97(m,1H),1.94-1.86(m,1H)。ESI-MS理论计算值:[M+H]+＝217.13,实测值217.2。Compound 44-2 (220 mg, 0.54 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (205 mg, 5.40 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.20 mL), and 15% sodium hydroxide aqueous solution (0.60 mL) and water (0.20 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 5-10%, retention time: 17.0 min) to obtain the monoformate of compound 44. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.41 (s, 1H), 8.28 (s, 1H), 7.29 (d, J=8.42 Hz, 1H), 6.89 (s, 1H), 6.68 (d, J=2.04 Hz, 1H), 6.51 (dd, J=8.42, 2.04 Hz, 1H), 3.46-3.42 (m, 2H), 2.97-2.88 (m, 2H), 2.84-2.76 (m, 1H), 2.24 (s, 3H), 2.04-1.97 (m, 1H), 1.94-1.86 (m, 1H). ESI-MS theoretical calculated value: [M+H] + =217.13, found 217.2.

实施例45Embodiment 45

合成路线：
Synthesis route:

第一步first step

将化合物45-1(10.0g,55.5mmol)溶于浓盐酸(50mL)中,0℃下缓慢加入亚硝酸钠(4.60g,66.6mmol)的水(20mL)溶液,0℃搅拌0.5小时。0℃下缓慢加入碘化钾(13.8g,83.3mmol)的水(20mL)溶液,0℃搅拌1小时。反应液加入水(100mL),乙酸乙酯(300mL x 2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物45-2。1H NMR(400MHz,DMSO-d6):δ7.75(s,1H),7.27(s,1H),4.69(t,J＝8.82Hz,2H),3.27(t,J＝8.82Hz,2H)。Compound 45-1 (10.0 g, 55.5 mmol) was dissolved in concentrated hydrochloric acid (50 mL), and a solution of sodium nitrite (4.60 g, 66.6 mmol) in water (20 mL) was slowly added at 0°C, and stirred at 0°C for 0.5 hours. A solution of potassium iodide (13.8 g, 83.3 mmol) in water (20 mL) was slowly added at 0°C, and stirred at 0°C for 1 hour. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (300 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 45-2. 1 H NMR (400MHz, DMSO-d 6 ): δ7.75 (s, 1H), 7.27 (s, 1H), 4.69 (t, J = 8.82 Hz, 2H), 3.27 (t, J = 8.82 Hz, 2H).

第二步Step 2

将化合物45-2(10.0g,34.4mmol)溶于乙醇(100mL)和水(50mL)中,依次加入铁粉(9.60g,172mmol)和氯化铵(9.19g,172mmol),氮气氛围下,80℃搅拌16小时。反应液冷却至室温,过滤,滤液中加入水(100mL),乙酸乙酯(150mL x 3)萃取,有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物45-3。ESI-MS理论计算值:[M+H]+＝261.97,实测值262.0。Compound 45-2 (10.0 g, 34.4 mmol) was dissolved in ethanol (100 mL) and water (50 mL), and iron powder (9.60 g, 172 mmol) and ammonium chloride (9.19 g, 172 mmol) were added in sequence. The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered. Water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 45-3. ESI-MS theoretical calculated value: [M+H] + = 261.97, measured value 262.0.

第三步Step 3

将化合物45-3(5.00g,19.2mmol),碘化亚铜(180mg,0.960mmol)和双三苯基磷二氯化钯(1.34g,1.92mmol)溶于三乙胺(50mL)中,加入三甲基硅基乙炔(2.82g,28.7mmol),氮气氛围下,25℃搅拌16小时。反应完成后,加入水(100mL),乙酸乙酯(150mL×3)萃取。有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到含有目标化合物的粗品,粗品经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物45-4。ESI-MS理论计算值:[M+H]+＝232.11,实测值232.2。Compound 45-3 (5.00 g, 19.2 mmol), cuprous iodide (180 mg, 0.960 mmol) and bistriphenylphosphine palladium dichloride (1.34 g, 1.92 mmol) were dissolved in triethylamine (50 mL), trimethylsilyl acetylene (2.82 g, 28.7 mmol) was added, and the mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (150 mL × 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 45-4. ESI-MS theoretical calculated value: [M+H] + = 232.11, measured value 232.2.

第四步Step 4

将化合物45-4(4.30g,18.6mmol),叔丁醇钾(6.25g,55.7mmol)溶于N-甲基吡咯烷酮(50mL)中,氮气氛围下,80℃搅拌15小时。反应液冷却至室温,加入水(100mL),乙酸乙酯(100mL×3)萃取。有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到含有目标化合物的粗品,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物45-5。1H NMR(400MHz,DMSO-d6):δ10.71(s,1H),7.30(s,1H),7.09(d,J＝1.62Hz,1H),6.69(s,1H),6.26(d,J＝1.62Hz,1H),4.48(t,J＝8.82Hz,2H),3.17(t,J＝8.82Hz,2H)。ESI-MS理论计算值:[M+H]+＝160.07,实测值160.0。 Compound 45-4 (4.30 g, 18.6 mmol) and potassium tert-butoxide (6.25 g, 55.7 mmol) were dissolved in N-methylpyrrolidone (50 mL) and stirred at 80 °C for 15 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (100 mL) was added and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 45-5. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.71 (s, 1H), 7.30 (s, 1H), 7.09 (d, J=1.62 Hz, 1H), 6.69 (s, 1H), 6.26 (d, J=1.62 Hz, 1H), 4.48 (t, J=8.82 Hz, 2H), 3.17 (t, J=8.82 Hz, 2H). ESI-MS theoretical calculated value: [M+H] + =160.07, found 160.0.

第五步Step 5

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物45-5(450mg,2.83mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(3.11mL,3.11mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌0.5小时。反应液加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(40mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物45-6。ESI-MS理论计算值:[M+H-100]+＝243.16,实测值243.2。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 45-5 (450 mg, 2.83 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (3.11 mL, 3.11 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 0.5 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (40 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 45-6. ESI-MS theoretical calculated value: [M+H-100] + = 243.16, found value 243.2.

第六步Step 6

将化合物45-6(50.0mg,0.15mmol)溶于四氢呋喃(5mL)中,0℃下加入四氢锂铝(57.0mg,1.50mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.05mL)淬灭,加入15％氢氧化钠水溶液(0.15mL)和水(0.05mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:40-55％,保留时间:8.0min)纯化得到化合物45的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),8.29(s,1H),7.31(s,1H),6.89(s,1H),6.63(s,1H),4.48(t,J＝8.42Hz,2H),3.39-3.35(m,1H),3.19(t,J＝8.42Hz,2H),2.95-2.89(m,1H),2.86-2.80(m,2H),2.78-2.74(m,1H),2.20(s,3H),2.02-1.98(m,1H),1.87-1.83(m,1H)。ESI-MS理论计算值:[M+H]+＝243.14,实测值243.2。Compound 45-6 (50.0 mg, 0.15 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (57.0 mg, 1.50 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.05 mL), and 15% sodium hydroxide aqueous solution (0.15 mL) and water (0.05 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min) to obtain the monoformate of compound 45. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.45 (s, 1H), 8.29 (s, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.48 (t, J=8.42 Hz, 2H), 3.39-3.35 (m, 1H), 3.19 (t, J=8.42 Hz, 2H), 2.95-2.89 (m, 1H), 2.86-2.80 (m, 2H), 2.78-2.74 (m, 1H), 2.20 (s, 3H), 2.02-1.98 (m, 1H), 1.87-1.83 (m, 1H). ESI-MS theoretical calculated value: [M+H] + =243.14, found 243.2.

实施例46Embodiment 46

合成路线：
Synthesis route:

第一步first step

将化合物46-1(4.00g,18.7mmol)和对甲苯磺酰氯(5.34g,28.0mmol)溶于四氢呋喃(40mL)中, 0℃下缓慢加入氢化钠(900mg,22.4mmol,60％纯度)。氮气氛围下,反应液在25℃搅拌2小时。反应完成后,加入水(100mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,4/1,v/v)纯化得到化合物46-2。1H NMR(400MHz,DMSO-d6):δ7.95-7.91(m,4H),7.45-7.40(m,3H),6.94(d,J＝3.62Hz,1H),2.35(s,3H)。Compound 46-1 (4.00 g, 18.7 mmol) and p-toluenesulfonyl chloride (5.34 g, 28.0 mmol) were dissolved in tetrahydrofuran (40 mL). Sodium hydride (900 mg, 22.4 mmol, 60% purity) was slowly added at 0°C. The reaction solution was stirred at 25°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain compound 46-2. 1 H NMR (400 MHz, DMSO-d 6 ): δ7.95-7.91 (m, 4H), 7.45-7.40 (m, 3H), 6.94 (d, J＝3.62 Hz, 1H), 2.35 (s, 3H).

第二步Step 2

将化合物46-2(2.00g,5.43mmol),双联频哪醇硼酸酯(2.07g,8.14mmol)溶于1,4-二氧六环(20mL)中,加入乙酸钾(1.07g,10.9mmol)和1,1'-双二苯基膦二茂铁二氯化钯(400mg,0.543mmol)。氮气氛围下,反应液在100℃搅拌12小时。反应冷却至室温,加入水(100mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,4/1,v/v)纯化得到化合物46-3。ESI-MS理论计算值:[M+Na]+＝438.14,实测值438.2。Compound 46-2 (2.00 g, 5.43 mmol) and bis-pinacol borate (2.07 g, 8.14 mmol) were dissolved in 1,4-dioxane (20 mL), and potassium acetate (1.07 g, 10.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (400 mg, 0.543 mmol) were added. The reaction solution was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, and water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4/1, v/v) to obtain compound 46-3. ESI-MS theoretical calculated value: [M+Na] + = 438.14, measured value 438.2.

第三步Step 3

将化合物46-3(1.00g,2.41mmol)溶于四氢呋喃(50mL)中,氮气氛围下,缓慢加入30％的过氧化氢溶液(410mg,12.1mmol)。反应液在25℃搅拌2小时。反应完成后,加入饱和亚硫酸钠水溶液(100mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物46-4。ESI-MS理论计算值:[M+H]+＝306.05,实测值306.0。Compound 46-3 (1.00 g, 2.41 mmol) was dissolved in tetrahydrofuran (50 mL), and 30% hydrogen peroxide solution (410 mg, 12.1 mmol) was slowly added under nitrogen atmosphere. The reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, saturated sodium sulfite aqueous solution (100 mL) was added, and ethyl acetate (100 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 46-4. ESI-MS theoretical calculated value: [M+H] + = 306.05, measured value 306.0.

第四步Step 4

将化合物46-4(8.00g,26.2mmol)溶于乙腈(50mL)中,加入碘甲烷(18.6g,131mmol)和碳酸铯(17.1g,52.4mmol)。反应液在80℃搅拌12小时。反应冷却至室温,加入水(50mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物46-5。ESI-MS理论计算值:[M+H]+＝320.07,实测值320.0。Compound 46-4 (8.00 g, 26.2 mmol) was dissolved in acetonitrile (50 mL), and iodomethane (18.6 g, 131 mmol) and cesium carbonate (17.1 g, 52.4 mmol) were added. The reaction solution was stirred at 80 ° C for 12 hours. The reaction was cooled to room temperature, and water (50 mL) was added, and ethyl acetate (100 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 46-5. ESI-MS theoretical calculated value: [M+H] + = 320.07, measured value 320.0.

第五步Step 5

将化合物46-5(4.10g,12.8mmol)溶于乙醇(20mL),四氢呋喃(20mL)和水(10mL)中,加入氢氧化钾(3.60g,64.2mmol),反应液在60℃搅拌1小时。反应冷却至室温,加入水(50mL),乙酸乙酯(100mL x 2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物46-6。ESI-MS理论计算值:[M+H]+＝166.06,实测值166.0。Compound 46-5 (4.10 g, 12.8 mmol) was dissolved in ethanol (20 mL), tetrahydrofuran (20 mL) and water (10 mL), potassium hydroxide (3.60 g, 64.2 mmol) was added, and the reaction solution was stirred at 60°C for 1 hour. The reaction was cooled to room temperature, water (50 mL) was added, and ethyl acetate (100 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 46-6. ESI-MS theoretical calculated value: [M+H] + = 166.06, measured value 166.0.

第六步Step 6

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物46-6(1.00g,6.05mmol)溶于在二氯甲烷(20mL)中,0℃下加入乙基溴化镁(7.26mL,7.26mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应液加入饱和碳酸氢钠水溶液(100mL),二氯甲烷(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物46-7。ESI-MS理论计算值:[M+H]+＝349.15,实测值349.3。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 46-6 (1.00 g, 6.05 mmol) in dichloromethane (20 mL), add ethylmagnesium bromide (7.26 mL, 7.26 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour. The reaction solution was added with saturated sodium bicarbonate aqueous solution (100 mL), extracted with dichloromethane (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 46-7. ESI-MS theoretical calculated value: [M+H] + = 349.15, found value 349.3.

第七步 Step 7

将化合物46-7(150mg,0.43mmol)溶于四氢呋喃(10mL)中,0℃下加入四氢锂铝(163mg,4.30mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.15mL)淬灭,加入15％氢氧化钠水溶液(0.45mL)和水(0.15mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:10-20％,保留时间:17.0min)纯化得到化合物46的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ10.88(s,1H),8.23(s,1H),6.98(d,J＝2.02Hz,1H),6.66(d,J＝2.02Hz,1H),6.41(dd,J＝12.84,2.02Hz,1H),3.75(s,3H),3.38-3.33(m,2H),3.05-2.95(m,1H),2.86-2.77(m,2H),2.18(s,3H),2.02-1.93(m,1H),1.90-1.78(m,1H)。ESI-MS理论计算值:[M+H]+＝249.13,实测值249.2。Compound 46-7 (150 mg, 0.43 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (163 mg, 4.30 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.15 mL), and 15% sodium hydroxide aqueous solution (0.45 mL) and water (0.15 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 10-20%, retention time: 17.0 min) to obtain the monoformate of compound 46. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.88 (s, 1H), 8.23 (s, 1H), 6.98 (d, J=2.02 Hz, 1H), 6.66 (d, J=2.02 Hz, 1H), 6.41 (dd, J=12.84, 2.02 Hz, 1H), 3.75 (s, 3H), 3.38-3.33 (m, 2H), 3.05-2.95 (m, 1H), 2.86-2.77 (m, 2H), 2.18 (s, 3H), 2.02-1.93 (m, 1H), 1.90-1.78 (m, 1H). ESI-MS theoretical calculated value: [M+H] + =249.13, found 249.2.

实施例47Embodiment 47

合成路线：
Synthesis route:

第一步first step

将化合物47-1(6.60g,30.8mmol)溶于四氢呋喃(70mL)中,0℃下缓慢加入氢化钠(1.73g,43.2mmol,60％纯度),0℃搅拌0.5小时。氮气氛围下,加入对甲苯磺酰氯(6.47g,33.9mmol),反应液在25℃搅拌1小时。反应完成后,加入冰水(300mL),乙酸乙酯(200mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物47-2。1H NMR(400MHz,DMSO-d6):δ7.95(d,J＝3.62Hz,1H),7.83(d,J＝8.04Hz,2H),7.47(d,J＝6.04Hz,2H),7.45-7.41(m,2H),6.96-6.92(m,1H),2.36(s,3H)。Compound 47-1 (6.60 g, 30.8 mmol) was dissolved in tetrahydrofuran (70 mL), sodium hydride (1.73 g, 43.2 mmol, 60% purity) was slowly added at 0°C, and stirred at 0°C for 0.5 hours. p-Toluenesulfonyl chloride (6.47 g, 33.9 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, ice water (300 mL) was added, and ethyl acetate (200 mL x 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 47-2. 1 H NMR (400MHz, DMSO-d 6 ): δ7.95 (d, J = 3.62 Hz, 1H), 7.83 (d, J = 8.04 Hz, 2H), 7.47 (d, J = 6.04 Hz, 2H), 7.45-7.41 (m, 2H), 6.96-6.92 (m, 1H), 2.36 (s, 3H).

第二步Step 2

将化合物47-2(9.30g,25.3mmol),双联频哪醇硼酸酯(9.62g,37.9mmol)溶于1,4-二氧六环(90mL)中,加入乙酸钾(4.96g,50.5mmol)和1,1'-双二苯基膦二茂铁二氯化钯(1.85g,2.53mmol)。氮气氛围下,反应液在100℃搅拌12小时。反应冷却至室温,加入水(50mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物47-3。1H NMR(400MHz,DMSO-d6):δ8.00(d,J＝3.62Hz,1H),7.81(d,J＝8.04Hz,2H),7.48-7.43(m,4H),6.94(dd,J＝3.62,2.42Hz,1H),2.36(s,3H),1.29(s,12H)。ESI-MS理论计算值:[M+H]+＝ 416.14,实测值416.2。Compound 47-2 (9.30 g, 25.3 mmol) and bis-pinacol borate (9.62 g, 37.9 mmol) were dissolved in 1,4-dioxane (90 mL), and potassium acetate (4.96 g, 50.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.85 g, 2.53 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, and water (50 mL) was added and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 47-3. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.00 (d, J=3.62 Hz, 1H), 7.81 (d, J=8.04 Hz, 2H), 7.48-7.43 (m, 4H), 6.94 (dd, J=3.62, 2.42 Hz, 1H), 2.36 (s, 3H), 1.29 (s, 12H). ESI-MS theoretical calculated value: [M+H] + = 416.14, measured value 416.2.

第三步Step 3

将化合物47-3(1.60g,3.85mmol)溶于四氢呋喃(15mL)中,氮气氛围下,缓慢加入30％的过氧化氢溶液(2.18g,19.3mmol)。反应液在25℃搅拌1小时。反应完成后,加入饱和亚硫酸钠水溶液(50mL),乙酸乙酯(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物47-4。ESI-MS理论计算值:[M+H]+＝306.05,实测值306.0。Compound 47-3 (1.60 g, 3.85 mmol) was dissolved in tetrahydrofuran (15 mL), and 30% hydrogen peroxide solution (2.18 g, 19.3 mmol) was slowly added under nitrogen atmosphere. The reaction solution was stirred at 25 ° C for 1 hour. After the reaction was completed, saturated sodium sulfite aqueous solution (50 mL) was added, and ethyl acetate (100 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 47-4. ESI-MS theoretical calculated value: [M+H] + = 306.05, measured value 306.0.

第四步Step 4

将化合物47-4(9.00g,29.5mmol)溶于乙腈(90mL)中,加入碘甲烷(41.8g,295mmol)和碳酸铯(19.2g,59.0mmol)。反应液在80℃搅拌12小时。反应冷却至室温,加入水(100mL),乙酸乙酯(150mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,10/1,v/v)纯化得到化合物47-5。1H NMR(400MHz,DMSO-d6):δ7.82-7.72(m,3H),7.42(d,J＝8.04Hz,2H),7.35(d,J＝8.42Hz,1H),7.16-7.10(m,1H),6.83-6.79(m,1H),3.82(s,3H),2.34(s,3H)。Compound 47-4 (9.00 g, 29.5 mmol) was dissolved in acetonitrile (90 mL), and iodomethane (41.8 g, 295 mmol) and cesium carbonate (19.2 g, 59.0 mmol) were added. The reaction solution was stirred at 80 ° C for 12 hours. The reaction was cooled to room temperature, water (100 mL) was added, and ethyl acetate (150 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain compound 47-5. 1 H NMR (400MHz, DMSO-d 6 ): δ7.82-7.72(m,3H),7.42(d,J＝8.04Hz,2H),7.35(d,J＝8.42Hz,1H),7.16-7.10(m,1H),6.83-6.79(m,1H),3.82(s,3H),2.34(s ,3H).

第五步Step 5

将化合物47-5(5.00g,15.7mmol)溶于乙醇(25mL),四氢呋喃(25mL)和水(10mL)中,加入氢氧化钾(4.39g,78.3mmol),反应液在60℃搅拌1小时。反应冷却至室温,加入水(100mL),乙酸乙酯(150mL x 2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物47-6。1H NMR(400MHz,DMSO-d6):δ11.34(s,1H),7.30-7.22(m,2H),6.91-6.87(m,1H),6.42-6.40(s,1H),3.85(s,3H)。ESI-MS理论计算值:[M+H]+＝166.06,实测值166.0。Compound 47-5 (5.00 g, 15.7 mmol) was dissolved in ethanol (25 mL), tetrahydrofuran (25 mL) and water (10 mL), potassium hydroxide (4.39 g, 78.3 mmol) was added, and the reaction solution was stirred at 60°C for 1 hour. The reaction was cooled to room temperature, water (100 mL) was added, and ethyl acetate (150 mL x 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 47-6. 1 H NMR (400 MHz, DMSO-d 6 ): δ11.34 (s, 1H), 7.30-7.22 (m, 2H), 6.91-6.87 (m, 1H), 6.42-6.40 (s, 1H), 3.85 (s, 3H). ESI-MS theoretical calculated value: [M+H] + =166.06, found value 166.0.

第六步Step 6

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(1.10g,5.46mmol)溶解在二氯甲烷(10mL)中,0℃下滴加草酰氯(0.56mL,6.56mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(40.0mg,0.58mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物47-6(1.00g,6.05mmol)溶于在二氯甲烷(10mL)中,0℃下加入乙基溴化镁(6.66mL,6.66mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(5mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应液加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/3,v/v)纯化得到化合物47-7。ESI-MS理论计算值:[M+H]+＝349.15,实测值349.1。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (1.10 g, 5.46 mmol) in dichloromethane (10 mL), add oxalyl chloride (0.56 mL, 6.56 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (40.0 mg, 0.58 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 47-6 (1.00 g, 6.05 mmol) in dichloromethane (10 mL), add ethylmagnesium bromide (6.66 mL, 6.66 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (5 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour. The reaction solution was added with saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/3, v/v) to obtain compound 47-7. ESI-MS theoretical calculated value: [M+H] + = 349.15, found value 349.1.

第七步Step 7

将化合物47-7(85.0mg,0.24mmol)溶于四氢呋喃(10mL)中,0℃下加入四氢锂铝(91.1mg,2.40mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.1mL)淬灭,加入15％氢氧化钠水溶液(0.3mL)和水(0.1mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:40-55％,保留时间:8.0min)纯化得到化合物47的一甲酸盐。1H NMR(400MHz,DMSO-d6):δ11.11(s,1H),8.28(s,1H),7.27(d,J＝8.42Hz,1H),7.09(s,1H),6.89(t,J＝8.02Hz,1H),3.84(s,3H),3.52-3.43(m,2H),3.02-2.91(m,2H),2.89-2.80(m,1H),2.23(s,3H),2.06-1.98(m,1H),1.94-1.88(m,1H)。ESI-MS理论计算值: [M+H]+＝249.13,实测值249.2。Compound 47-7 (85.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (91.1 mg, 2.40 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.1 mL), and 15% sodium hydroxide aqueous solution (0.3 mL) and water (0.1 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 40-55%, retention time: 8.0 min) to obtain the monoformate of compound 47. 1 H NMR (400 MHz, DMSO-d 6 ): δ11.11 (s, 1H), 8.28 (s, 1H), 7.27 (d, J=8.42 Hz, 1H), 7.09 (s, 1H), 6.89 (t, J=8.02 Hz, 1H), 3.84 (s, 3H), 3.52-3.43 (m, 2H), 3.02-2.91 (m, 2H), 2.89-2.80 (m, 1H), 2.23 (s, 3H), 2.06-1.98 (m, 1H), 1.94-1.88 (m, 1H). ESI-MS theoretical calculated value: [M+H] + = 249.13, found 249.2.

实施例48和49Examples 48 and 49

合成路线：
Synthesis route:

第一步first step

将化合物5-2(600mg,1.82mmol)溶于四氢呋喃(10mL)中,0℃下缓慢加入氢化钠(102mg,2.55mmol,60％纯度),0℃搅拌0.5小时。氮气氛围下,加入对甲苯磺酰氯(380mg,2.00mmol),反应液在25℃搅拌2小时。反应完成后,加入冰水(30mL),乙酸乙酯(20mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物48-1。ESI-MS理论计算值:[M+H-100]+＝485.17,实测值385.2。Compound 5-2 (600 mg, 1.82 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (102 mg, 2.55 mmol, 60% purity) was slowly added at 0°C, and stirred at 0°C for 0.5 hours. p-Toluenesulfonyl chloride (380 mg, 2.00 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, ice water (30 mL) was added, and ethyl acetate (20 mL x 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 48-1. ESI-MS theoretical calculated value: [M+H-100] + = 485.17, measured value 385.2.

第二步Step 2

将化合物48-1(910mg,1.88mmol)溶于四氢呋喃(15mL)中,0℃下缓慢滴加甲基溴化镁(9.4mL,9.4mmol,1.0mol/L)。氮气氛围下,反应液在50℃搅拌16小时。反应液冷却至室温,加入饱和氯化铵水溶液(20mL),乙酸乙酯(30mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,2/1,v/v)纯化得到化合物48-2。ESI-MS理论计算值:[M+Na]+＝523.20,实测值523.2。Compound 48-1 (910 mg, 1.88 mmol) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (9.4 mL, 9.4 mmol, 1.0 mol/L) was slowly added dropwise at 0°C. The reaction solution was stirred at 50°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution (20 mL) was added, and ethyl acetate (30 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/1, v/v) to obtain compound 48-2. ESI-MS theoretical calculated value: [M+Na] + = 523.20, measured value 523.2.

第三步Step 3

将化合物48-2(80.0mg,0.16mmol)溶于乙醇(3mL),四氢呋喃(3mL)和水(3mL)中,加入氢氧化钾(44.9mg,0.80mmol),反应液在60℃搅拌16小时。反应冷却至室温,加入水(20mL),乙酸乙酯(20mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/10,v/v)纯化得到化合物48-3。ESI-MS理论计算值:[M+H]+＝369.19,实测值369.1。Compound 48-2 (80.0 mg, 0.16 mmol) was dissolved in ethanol (3 mL), tetrahydrofuran (3 mL) and water (3 mL), potassium hydroxide (44.9 mg, 0.80 mmol) was added, and the reaction solution was stirred at 60 ° C for 16 hours. The reaction was cooled to room temperature, water (20 mL) was added, and ethyl acetate (20 mL x 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/10, v/v) to obtain compound 48-3. ESI-MS theoretical calculated value: [M+H] + = 369.19, measured value 369.1.

第四步Step 4

将化合物48-3(100mg,0.29mmol)溶于四氢呋喃(5mL)中,0℃下加入四氢锂铝(110mg,2.90mmol),氮气氛围下,反应液在60℃搅拌16小时。反应液冷却至室温,加入冰水(0.11mL)淬灭,加入15％氢氧化钠水溶液(0.33mL)和水(0.11mL),过滤,滤液减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L三氟乙酸水溶液,梯度:15-25％，流速20mL/min洗脱时间17min)纯化得到化合物48(保留时间:5.7min)或49(保留时间:7.5min)。1H NMR(400MHz,CD3OD):δ7.49(d,J＝8.42Hz,1H),7.05(s,1H),6.90(d,J＝2.04Hz, 1H),6.72(dd,J＝8.82,2.42Hz,1H),4.57-4.51(m,1H),4.10-4.03(m,1H),3.85-3.81(m,1H),3.80(s,3H),3.58-3.52(m,1H),2.91(s,3H),2.36-2.25(m,2H),1.47(d,J＝7.26Hz,3H)。ESI-MS理论计算值:[M+H]+＝245.16,实测值245.1。和化合物48或49。1H NMR(400MHz,CD3OD):δ7.55(d,J＝8.82Hz,1H),7.12(s,1H),6.92(d,J＝2.04Hz,1H),6.74(dd,J＝8.82,2.04Hz,1H),4.69-4.62(m,1H),4.03-3.97(m,1H),3.87-3.83(m,1H),3.81(s,3H),3.40-3.33(m,1H),2.68-2.61(m,1H),2.48-2.41(m,1H),2.23(s,3H),1.37(d,J＝7.26Hz,3H)。ESI-MS理论计算值C15H20N2O[M+H]+＝245.16,实测值245.2。Compound 48-3 (100 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (110 mg, 2.90 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% sodium hydroxide aqueous solution (0.33 mL) and water (0.11 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L trifluoroacetic acid aqueous solution, gradient: 15-25%, flow rate 20mL/min, elution time 17min) to obtain compound 48 (retention time: 5.7min) or 49 (retention time: 7.5min). 1 H NMR (400MHz, CD 3 OD): δ7.49 (d, J = 8.42Hz, 1H), 7.05 (s, 1H), 6.90 (d, J = 2.04Hz, 1H), 6.72 (dd, J = 8.82, 2.42 Hz, 1H), 4.57-4.51 (m, 1H), 4.10-4.03 (m, 1H), 3.85-3.81 (m, 1H), 3.80 (s, 3H), 3.58-3.52 (m, 1H), 2.91 (s, 3H), 2.36-2.25 (m, 2H), 1.47 (d, J = 7.26 Hz, 3H). ESI-MS theoretical calculated value: [M+H] + = 245.16, found 245.1. and compound 48 or 49. 1 H NMR (400MHz, CD 3 OD): δ7.55(d,J＝8.82Hz,1H),7.12(s,1H),6.92(d,J＝2.04Hz,1H),6.74(dd,J＝8.82,2.04Hz,1H),4.69-4.62(m,1H),4.03-3.97(m,1 H),3.87-3.83(m,1H),3.81(s,3H),3.40-3.33(m,1H),2.68-2.61(m,1H),2.48-2.41(m,1H),2.23(s,3H),1.37(d,J＝7.26Hz,3H). ESI-MS theoretical calculated value for C 15 H 20 N 2 O [M+H] + = 245.16, found value 245.2.

实施例50Embodiment 50

合成路线：
Synthesis route:

第一步first step

将化合物30-2(2.00g,6.05mmol)溶于二氯甲烷(20mL)中,氮气氛围下,0℃下加入三乙胺(735mg,7.26mmol),滴加化合物二碳酸二叔丁酯(1.59g,7.26mmol),反应液在25℃搅拌16小时。反应液中加入水(50mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,5/1,v/v)纯化得到化合物50-1。ESI-MS理论计算值:[M+H]+＝431.21,实测值431.2。Compound 30-2 (2.00 g, 6.05 mmol) was dissolved in dichloromethane (20 mL), triethylamine (735 mg, 7.26 mmol) was added under nitrogen atmosphere at 0°C, and di-tert-butyl dicarbonate (1.59 g, 7.26 mmol) was added dropwise, and the reaction solution was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to obtain compound 50-1. ESI-MS theoretical calculated value: [M+H] + = 431.21, measured value 431.2.

第二步Step 2

将化合物甲基三苯基碘化磷(2.34g,5.80mmol)溶于四氢呋喃(20mL)中,氮气氛围下,0℃下加入叔丁醇钾(650mg,5.80mmol),滴加化合物50-1(1.00g,2.32mmol)溶于四氢呋喃(5mL)的溶液,反应液在25℃搅拌16小时。反应液中加入水(50mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物50-2。ESI-MS理论计算值:[M+H]+＝429.23,实测值429.2。Compound methyl triphenylphosphonium iodide (2.34 g, 5.80 mmol) was dissolved in tetrahydrofuran (20 mL), potassium tert-butoxide (650 mg, 5.80 mmol) was added at 0°C under nitrogen atmosphere, and a solution of compound 50-1 (1.00 g, 2.32 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise, and the reaction solution was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 50-2. ESI-MS theoretical calculated value: [M+H] + = 429.23, measured value 429.2.

第三步Step 3

将化合物50-2(460mg,10.7mmol)溶于四氢呋喃(10mL)中,氮气氛围下,加入10％的湿钯碳(50mg),反应液置换3次氢气,氢气氛围下,反应液在25℃搅拌2小时。反应完成后,过滤,有机相减压浓缩,粗产物用硅胶柱层析法(石油醚/乙酸乙酯,3/1,v/v)纯化得到化合物50-3。ESI-MS理论计算值:[M+H]+＝431.25,实测值431.2。 Compound 50-2 (460 mg, 10.7 mmol) was dissolved in tetrahydrofuran (10 mL), and 10% wet palladium carbon (50 mg) was added under nitrogen atmosphere. The reaction solution was replaced with hydrogen three times. The reaction solution was stirred at 25°C for 2 hours under hydrogen atmosphere. After the reaction was completed, the reaction was filtered, the organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1, v/v) to obtain compound 50-3. ESI-MS theoretical calculated value: [M+H] + = 431.25, measured value 431.2.

第四步Step 4

将化合物50-3(400mg,0.93mmol)溶于乙醇(5mL),四氢呋喃(5mL)和水(5mL)的混合溶液中,加入一水合氢氧化锂(111mg,4.65mmol),反应液在60℃搅拌16小时。反应液冷却至室温,向反应液加入水(20mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥后,过滤,减压浓缩得到粗产物,粗品经硅胶柱层析法(石油醚/乙酸乙酯,2/1,v/v)纯化得到化合物50-4。ESI-MS理论计算值:[M+H]+＝331.19,实测值331.2。Compound 50-3 (400 mg, 0.93 mmol) was dissolved in a mixed solution of ethanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (111 mg, 4.65 mmol) was added. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/1, v/v) to obtain compound 50-4. ESI-MS theoretical calculated value: [M+H] + = 331.19, measured value 331.2.

第五步Step 5

将化合物50-4(100mg,0.30mmol)溶于四氢呋喃(5mL)中,0℃下加入四氢锂铝(114mg,3.00mmol),氮气氛围下,反应液在60℃搅拌12小时。反应液冷却至室温,加入冰水(0.11mL)淬灭,加入15％氢氧化钠水溶液(0.33mL)和水(0.11mL),过滤,滤液减压浓缩得到有目标化合物的粗品,粗品经硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物50。1H NMR(400MHz,DMSO-d6):δ10.77(s,1H),7.48(d,J＝8.80Hz,1H),7.14(s,1H),6.86(d,J＝2.40Hz,1H),6.67(dd,J＝8.80,2.40Hz,1H),4.57-4.29(m,1H),3.75(s,3H),3.50-3.40(m,1H),3.39-3.31(m,1H),3.25-3.15(m,1H),3.09-3.00(m,1H),2.75-2.65(m,1H),2.41(s,3H),1.27(d,J＝7.20Hz,2.72H),0.91(d,J＝6.40Hz,0.28H).ESI-MS理论计算值C15H20N2O[M+H]+＝245.17,实测值245.1。Compound 50-4 (100 mg, 0.30 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (114 mg, 3.00 mmol) was added at 0°C. The reaction solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched by adding ice water (0.11 mL), and 15% sodium hydroxide aqueous solution (0.33 mL) and water (0.11 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the target compound. The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 50. 1 H NMR (400 MHz, DMSO-d 6 ): δ10.77 (s, 1H), 7.48 (d, J = 8.80 Hz, 1H), 7.14 (s, 1H), 6.86 (d, J = 2.40 Hz, 1H), 6.67 (dd, J = 8.80, 2.40 Hz, 1H), 4.57-4.29 (m, 1H), 3.75 (s, 3H), 3.50-3.40 (m, 1H), 3.39-3.31 (m, 1H), 3.25-3.15 (m, 1H), 3.09-3.00 (m, 1H), 2.75-2.65 (m, 1H), 2.41 (s, 3H), 1.27 (d, J = 7.20 Hz, 2.72H), 0.91 (d, J = 6.40 Hz, 0.28H). ESI-MS theoretical calculated value C 15 H 20 N 2 O[M+H] + ＝245.17, found 245.1.

实施例51Embodiment 51

合成路线：
Synthesis route:

第一步first step

将N-羧酸叔丁酯-氮杂环丁烷-2-羧酸(5.50g,27.3mmol)溶解在二氯甲烷(50mL)中,0℃下滴加草酰氯(2.81mL,32.8mmol),反应液0℃下搅拌10分钟,缓慢加入N,N-二甲基甲酰胺(200mg,2.90mmol),反应液在25℃搅拌1小时。反应液减压浓缩,得到粗品中间态。将化合物51-1(3.00g,21.1mmol)溶于在二氯甲烷(50mL)中,0℃下加入乙基溴化镁(25.3mL,25.3mmol,1mol/L)。0℃搅拌0.5小时。将粗品中间态溶解在二氯甲烷(20mL)中,0℃滴加到反应液,反应液在0℃搅拌1小时。反应液加入饱和碳酸氢钠水溶液(100mL),二氯甲烷(100mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,1/1,v/v)纯化得到化合物51-2。ESI-MS理论计算值:[M+H]+＝326.14,实测值326.3。Dissolve N-tert-butyl carboxylate-azetidine-2-carboxylic acid (5.50 g, 27.3 mmol) in dichloromethane (50 mL), add oxalyl chloride (2.81 mL, 32.8 mmol) dropwise at 0°C, stir the reaction solution at 0°C for 10 minutes, slowly add N,N-dimethylformamide (200 mg, 2.90 mmol), and stir the reaction solution at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude intermediate. Dissolve compound 51-1 (3.00 g, 21.1 mmol) in dichloromethane (50 mL), add ethylmagnesium bromide (25.3 mL, 25.3 mmol, 1 mol/L) at 0°C. Stir at 0°C for 0.5 hours. Dissolve the crude intermediate in dichloromethane (20 mL), add dropwise to the reaction solution at 0°C, and stir the reaction solution at 0°C for 1 hour. The reaction solution was added with saturated sodium bicarbonate aqueous solution (100 mL), extracted with dichloromethane (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain compound 51-2. ESI-MS theoretical calculated value: [M+H] + = 326.14, found value 326.3.

第二步 Step 2

将化合物51-2(600g,1.84mmol)溶于乙醇(10mL)中,氮气氛围下,0℃下缓慢加入硼氢化钠(139mg,3.68mmol),反应液在25℃搅拌5小时。反应液加入水(50mL),乙酸乙酯(80mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯,2/1,v/v)纯化得到化合物51-3。ESI-MS理论计算值:[M+Na]+＝350.16,实测值350.1。Compound 51-2 (600 g, 1.84 mmol) was dissolved in ethanol (10 mL), and sodium borohydride (139 mg, 3.68 mmol) was slowly added at 0°C under a nitrogen atmosphere, and the reaction solution was stirred at 25°C for 5 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (80 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/1, v/v) to obtain compound 51-3. ESI-MS theoretical calculated value: [M+Na] + = 350.16, measured value 350.1.

第三步Step 3

将化合物51-3(150mg,0.46mmol)溶于二氯甲烷(10mL)中,缓慢滴入三氟乙酸(1.05g,9.20mmol),反应液在25℃搅拌1小时。反应液减压浓缩,剩余物中加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物51-4。ESI-MS理论计算值:[M+H]+＝228.11,实测值228.2。Compound 51-3 (150 mg, 0.46 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.05 g, 9.20 mmol) was slowly added dropwise, and the reaction solution was stirred at 25 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate aqueous solution (30 mL) was added to the residue, and extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 51-4. ESI-MS theoretical calculated value: [M+H] + = 228.11, measured value 228.2.

第四步Step 4

将粗品化合物51-4(100mg,0.44mmol)溶于二氯甲烷(10mL)中,缓慢滴加三氟乙酸(1.00g,8.80mmol)和三乙基硅烷(512mg,4.40mmol)。氮气氛围下,反应液在60℃搅拌4小时。反应液冷却至室温,加入饱和碳酸氢钠水溶液(30mL),二氯甲烷(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,粗产物用硅胶柱层析法(二氯甲烷/甲醇,10/1,v/v)纯化得到化合物51-5。ESI-MS理论计算值:[M+H]+＝212.11,实测值212.1。The crude compound 51-4 (100 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.00 g, 8.80 mmol) and triethylsilane (512 mg, 4.40 mmol) were slowly added dropwise. The reaction solution was stirred at 60 ° C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (30 mL) was added, and dichloromethane (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane/methanol, 10/1, v/v) to obtain compound 51-5. ESI-MS theoretical calculated value: [M+H] + = 212.11, measured value 212.1.

第五步Step 5

将化合物51-5(50.0mg,0.24mmol),多聚甲醛(10.8mg,0.36mmol)溶于1,2-二氯乙烷(10mL)中,加入乙酸(14.4mg,0.24mmol),和三乙酰氧基硼氢化钠(102mg,0.48mmol)。氮气氛围下,反应液在25℃搅拌12小时。反应液加入饱和碳酸氢钠水溶液(30mL),乙酸乙酯(50mL x 3)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到有目标化合物的粗品,经过高效液相色谱(Waters-XBndge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L甲酸水溶液,梯度:35-55％,保留时间:7.0min)纯化得到化合物51的一甲酸盐。1H NMR(400MHz,CD3OD):δ7.82-7.76(m,2H),7.52(s,1H),7.39-7.34(m,1H),4.68-4.58(m,1H),4.17-4.09(m,1H),3.90-3.84(m,1H),3.45-3.41(m,1H),3.36-3.31(m,1H),2.66(s,3H),2.54-2.41(m,2H)。ESI-MS理论计算值:[M+H]+＝226.13,实测值226.1。Compound 51-5 (50.0 mg, 0.24 mmol) and paraformaldehyde (10.8 mg, 0.36 mmol) were dissolved in 1,2-dichloroethane (10 mL), and acetic acid (14.4 mg, 0.24 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) were added. The reaction solution was stirred at 25 °C for 12 hours under a nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution (30 mL) and ethyl acetate (50 mL x 3) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of the target compound, which was purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol/L formic acid aqueous solution, gradient: 35-55%, retention time: 7.0 min) to obtain the monoformate of compound 51. 1 H NMR (400 MHz, CD 3 OD): δ7.82-7.76 (m, 2H), 7.52 (s, 1H), 7.39-7.34 (m, 1H), 4.68-4.58 (m, 1H), 4.17-4.09 (m, 1H), 3.90-3.84 (m, 1H), 3.45-3.41 (m, 1H), 3.36-3.31 (m, 1H), 2.66 (s, 3H), 2.54-2.41 (m, 2H). ESI-MS theoretical calculated value: [M+H] + = 226.13, found 226.1.

效果实施例1化合物对5-HT2A受体的钙流激动活性评价Effect Example 1 Evaluation of the calcium flux agonist activity of the compound on 5-HT 2A receptor

实验目的：Purpose:

利用表达人源5-HT2A受体的稳转系细胞(HEK293细胞)，测定化合物对5-HT2A受体的活性。The activity of the compounds on 5-HT 2A receptor was determined using a stably transfected cell line (HEK293 cells) expressing human 5-HT 2A receptor.

实验试剂和耗材：

Experimental reagents and consumables:

实验仪器:
Experimental equipment:

实验操作：Experimental operation:

第一天：细胞接种和化合物制备Day 1: Cell seeding and compound preparation

使用DMSO将测试化合物稀释成384孔LDV板上的400倍浓度的储备溶液。然后将化合物溶液转移到384孔板中。Test compounds were diluted to 400-fold concentration of stock solution on 384-well LDV plates using DMSO. The compound solution was then transferred to the 384-well plate.

使用DMEM培养基(10％ FBS)培养HEK-293/5-HT2A细胞，当细胞达到80％的密度时，使用0.25％ Trypsin-EDTA将细胞分离。HEK-293/5-HT 2A cells were cultured using DMEM medium (10% FBS), and when the cells reached 80% of the density, the cells were detached using 0.25% Trypsin-EDTA.

测量细胞密度，并使用DMEM(10％ FBS)将细胞进行稀释。Measure the cell density and dilute the cells using DMEM (10% FBS).

使用Multidrop在Matrigel涂层的384孔板的每个孔中加入30微升的细胞(每孔25000个细胞)，并在37℃，5％ CO2条件下培养20-24小时。Use Multidrop to add 30 μl of cells to each well of a Matrigel-coated 384-well plate (25,000 cells per well) and incubate at 37°C, 5% CO2 for 20-24 h.

第二天：细胞基础实验步骤Day 2: Cell-Based Experimental Procedures

从细胞板中移除培养基，向细胞板中的每个孔中加入40微升的荧光染料。在37℃，5％ CO2的黑暗条件下孵育0.5小时。Remove the culture medium from the cell plate and add 40 μl of fluorescent dye to each well of the cell plate. Incubate for 0.5 h in the dark at 37°C, 5% CO2.

向化合物板中的每个孔中加入20微升的实验缓冲液(1X HBSS+20mM HEPES+0.1％ BSA)，以准备5倍浓度的激动剂工作溶液，用于钙信号读数。编程将10微升的化合物加入细胞板(10微升+40微升)以收集激活数据。Add 20 μl of assay buffer (1X HBSS + 20 mM HEPES + 0.1% BSA) to each well in the compound plate to prepare a 5x concentration of agonist working solution for calcium signaling readings. Program 10 μl of compound to be added to the cell plate (10 μl + 40 μl) to collect activation data.

10.使用指定设置在室温下使用FLIPR读取并保存数据。10. Read and save the data using the FLIPR at room temperature using the specified settings.

数据分析：Data Analysis:

化合物稀释是从20mmol二甲基亚砜(DMSO)储备液中制备的。在荧光成像平板阅读器上进行了化合物的加入，并监测了反映钙离子释放的荧光变化，每隔1秒进行一次，共持续130秒(激发波长＝470-495纳米，发射波长＝515-575纳米)。数据以每个孔最大荧光和最小荧光之间的差异形式导出。使用非线性回归计算结果，确定激动剂EC50和Emax值(使用XL-fit和Graphpad Prism软件)。Compound dilutions were prepared from 20 mmol dimethyl sulfoxide (DMSO) stock solutions. Compound additions were performed on a fluorescence imaging plate reader and fluorescence changes reflecting calcium ion release were monitored every 1 second for 130 seconds (excitation wavelength = 470-495 nm, emission wavelength = 515-575 nm). Data were exported as the difference between maximum and minimum fluorescence for each well. Results were calculated using nonlinear regression to determine agonist EC 50 and Emax values (using XL-fit and Graphpad Prism software).

实验结果：

Experimental results:

实验结论:Experimental conclusion:

实验样品(化合物)由相应实施例制得，结果如上表所示，本申请化合物在该试验体系中，对5-HT2A受体显示出激动活性。The experimental samples (compounds) were prepared from the corresponding examples. The results are shown in the table above. The compounds of the present application showed agonist activity on 5-HT 2A receptors in this test system.

效果实施例2通过beta-arrestin 2募集作用评价化合物对5-HT2A受体的激动作用Effect Example 2 Evaluation of the Agonistic Effect of Compounds on 5-HT 2A Receptor by Recruiting Beta-arrestin 2

实验目的：Purpose:

利用表达人源5-HT2A受体的稳转系细胞(细胞系名称：5-HT2A&beta-arrestin 2OE HEK293T，载体：pLVX-Puro/pCDHBSD，培养基：DMEM+10％FBS+1％PS+2μg/mL puromycin+5μg/mL blasticidin)，通过beta-arrestin 2募集作用评价化合物对5-HT2A受体的激动作用。Using a stably transfected cell line expressing human 5-HT 2A receptor (cell line name: 5-HT 2A & beta-arrestin 2OE HEK293T, vector: pLVX-Puro/pCDHBSD, culture medium: DMEM+10% FBS+1% PS+2μg/mL puromycin+5μg/mL blasticidin), the agonist effect of the compound on the 5-HT 2A receptor was evaluated by the recruitment of beta-arrestin 2.

实验材料：
Experimental Materials:

实验仪器:

Experimental equipment:

细胞培养与细胞铺板：Cell culture and cell plating:

1)人5-HT-2A & beta-arrestin 2 OE HEK293T细胞培养在DMEM完全培养基中(DMEM+10％FBS+1％P/S+2μg/mL Puromycin Dihydrochloride+5μg/mL Blasticidin S HCl)，待细胞密度达到约80％后进行消化与铺板。1) Human 5-HT-2A & beta-arrestin 2 OE HEK293T cells were cultured in DMEM complete medium (DMEM + 10% FBS + 1% P/S + 2μg/mL Puromycin Dihydrochloride + 5μg/mL Blasticidin S HCl), and digested and plated after the cell density reached about 80%.

2)将消化后的细胞重悬于Assay medium(Opti-MEM+1％ P/S)中，计数后调整细胞浓度至0.75*106/mL，384孔板中每孔加入40μL的细胞悬液，使最终每孔的细胞量为3*104，并在37℃，5％CO2的培养箱中孵育过夜。2) Resuspend the digested cells in Assay medium (Opti-MEM + 1% P/S), adjust the cell concentration to 0.75*106/mL after counting, add 40μL of cell suspension to each well of the 384-well plate, so that the final cell amount in each well is 3*104, and incubate in an incubator at 37℃, 5% CO2 overnight.

化合物处理与稀释配制：Compound handling and dilution preparation:

1)化合物的配置和稀释：将测化合物和及阳性参考化合物的溶解。其中以1μM 5-羟色胺处理组作为高信号处理孔，以Vehicle(二甲基亚砜)处理组作为低信号处理孔。1) Compound preparation and dilution: Dissolve the test compound and the positive reference compound. The 1μM 5-HT treatment group is used as the high signal treatment well, and the Vehicle (dimethyl sulfoxide) treatment group is used as the low signal treatment well.

2)在LDV板中用Bravo按照4倍梯度稀释(5-羟色胺组按照3倍稀释)。2) Use Bravo to make 4-fold serial dilutions in LDV plates (5-HT group should make 3-fold dilutions).

3)用Opti-MEM培养基稀释荧光素酶底物，每孔转移5μL。3) Dilute luciferase substrate with Opti-MEM medium and transfer 5 μL to each well.

4)用Echo从LDV板中转移2000nL到化合物稀释板中，加入18μL Opti-MEM并利用Bravo转移5μL至细胞板中，阳参化合物5-羟色胺在细胞板中的起始浓度为1μM，待测化合物在细胞板中的起始浓度为100μM。在37℃，5％ CO2的培养箱中孵育约30分钟。4) Use Echo to transfer 2000nL from the LDV plate to the compound dilution plate, add 18μL Opti-MEM and use Bravo to transfer 5μL to the cell plate, the starting concentration of the Yangshen compound 5-hydroxytryptamine in the cell plate is 1μM, and the starting concentration of the test compound in the cell plate is 100μM. Incubate in a 37°C, 5% CO2 incubator for about 30 minutes.

5)在37℃，5％ CO2的培养箱中孵育约30～40分钟。5) Incubate in a 37°C, 5% CO 2 incubator for about 30 to 40 minutes.

6)利用Envision读取化学发光信号。6) Read the chemiluminescent signal using Envision.

数据分析：Data Analysis:

1)样品活性＝100％×(样品孔平均每孔信号值–阴性性对照孔平均每孔信号值)/(阳性对照孔平均每孔信号值–阴性对照孔平均每孔信号值))1) Sample activity = 100% × (average signal value per well of sample wells – average signal value per well of negative control wells) / (average signal value per well of positive control wells – average signal value per well of negative control wells)

2)使用GraphPad Prism按照剂量-反应(％活性)-激动-对数[激动剂]/反应-变斜率(四参数)模型，计算每个测试样品在每个板上的EC50和Emax值。2) Calculate the EC50 and Emax values for each test sample on each plate using GraphPad Prism according to the dose-response (% activity)-agonism-log [agonist]/response-variable slope (four-parameter) model.

实验结果：
Experimental results:

实验结论:Experimental conclusion:

实验样品(化合物)由相应实施例制得，结果如上表所示，本申请化合物在该试验体系中，对5-HT2A受体显示出激动活性。The experimental samples (compounds) were prepared from the corresponding examples. The results are shown in the table above. The compounds of the present application showed agonist activity on 5-HT 2A receptors in the test system.

效果实施例3化合物对大鼠原代皮层神经元突触作用的检测 Effect Example 3 Detection of the synaptic effects of the compound on primary cortical neurons of rats

实验目的：Purpose:

经体外实验检测化合物对体外培养的原代皮层神经元神经突触生长的影响。In vitro experiments were performed to detect the effects of the compounds on the synaptic growth of primary cortical neurons cultured in vitro.

实验材料：
Experimental Materials:

实验仪器：
Experimental instruments:

细胞处理：Cell treatment:

本研究采用了大鼠胚胎原代皮层神经元细胞。从孕18天的大鼠胚胎脑中分离皮层神经元。详细的神经元培养方法如下：This study used rat embryonic primary cortical neurons. Cortical neurons were isolated from the 18-day-old rat embryonic brain. The detailed neuron culture method is as follows:

孕鼠购自上海实验动物研究中心(证书号码：SCXK(沪)2018-0006，质量控制：20180006050501)。孕18天的大鼠用二氧化碳处死，将胚胎从子宫取出，随后取出大脑并置于冰上的DPBS中分离皮层组织。经1mL木瓜蛋白酶消化液在37℃孵育8～10min后，用2mL木瓜蛋白酶抑制剂溶液终止消化，并用移液器吹打皮层组织直至没有肉眼可见的组织块。然后，将其在70μm过滤器过滤并1000rpm离心5min，去其上清并加入培养基重悬。接着用台盼蓝计数，确定活细胞得 率。在有经过0.1mg/mL聚d-赖氨酸盐酸盐包被过的细胞爬片的35mm培养皿中接种2x 10^5个神经元细胞，每皿加入2mL培养基，最后放入37℃，5％ CO2/95％ O2培养箱培养。接种时间为第0天。Pregnant mice were purchased from Shanghai Experimental Animal Research Center (certificate number: SCXK (Shanghai) 2018-0006, quality control: 20180006050501). Rats at 18 days of gestation were killed with carbon dioxide, and the embryos were removed from the uterus. The brains were then removed and placed in DPBS on ice to separate the cortical tissue. After incubation with 1 mL of papain digestion solution at 37°C for 8 to 10 min, the digestion was terminated with 2 mL of papain inhibitor solution, and the cortical tissue was blown with a pipette until there were no visible tissue chunks. Then, it was filtered through a 70 μm filter and centrifuged at 1000 rpm for 5 min. The supernatant was removed and resuspended in culture medium. Trypan blue was then used to count the live cells to determine whether the cells were viable. Rate. 2 x 10^5 neuronal cells were inoculated in a 35 mm culture dish with a cell slide coated with 0.1 mg/mL poly-d-lysine hydrochloride, 2 mL of culture medium was added to each dish, and finally placed in a 37°C, 5% CO2/95% O2 incubator for culture. The inoculation time was day 0.

实验操作：Experimental operation:

第0天，原代皮层神经元贴壁2h后，加入对照或待测化合物并作用72h。然后，将原代皮层神经元固定染色。On day 0, after primary cortical neurons were attached for 2 hours, control or test compounds were added and allowed to act for 72 hours. Then, primary cortical neurons were fixed and stained.

1实验分组1 Experimental Grouping

1)对照组：用0.1％ DMSO处理；1) Control group: treated with 0.1% DMSO;

2)阳性对照组：用10μM S-氯胺酮处理；2) Positive control group: treated with 10 μM S-ketamine;

3)测试组：用待测化合物处理(溶媒为DMSO)。3) Test group: treated with the test compound (the solvent is DMSO).

2给药和处理2. Dosage and treatment

1)给药：在原代皮层神经元贴壁2h后，吸除培养皿中一半的培养基，再加入等体积含2倍体积化合物或阳性药的培养基，孵育72h。1) Drug administration: 2 hours after the primary cortical neurons adhered to the wall, half of the culture medium in the culture dish was removed, and an equal volume of culture medium containing 2 times the volume of the compound or positive drug was added and incubated for 72 hours.

2)免疫荧光实验：2) Immunofluorescence experiment:

a.药物处理72h后，去除培养基并用DPBS清洗2次，每次5min；a. After 72 h of drug treatment, the culture medium was removed and the cells were washed twice with DPBS, each time for 5 min;

b.去除DPBS，加入组织固定液固定15min；b. Remove DPBS and add tissue fixative for 15 minutes;

c.去除组织固定液，用DPBS清洗两次，每次5min；c. Remove the tissue fixative and wash twice with DPBS, 5 min each time;

d.用含有0.3％ Triton X-100的3％ BSA封闭1h；d. Block with 3% BSA containing 0.3% Triton X-100 for 1 hour;

e.用兔源的β3-微管蛋白单克隆抗体孵育过夜；e. Incubate overnight with rabbit β3-tubulin monoclonal antibody;

f.用DPBS清洗两次，每次5min；f. Wash twice with DPBS, 5 min each time;

g.加入兔源抗体的山羊抗兔IgG二抗和4,6-二氨基-2-苯基吡啶孵育1h；g. Add goat anti-rabbit IgG secondary antibody and 4,6-diamino-2-phenylpyridine to incubate for 1 hour;

h.用DPBS清洗两次，每次5min；h. Wash twice with DPBS, 5 min each time;

i.用抗荧光淬灭封片液封片。i. Seal the slides with anti-fluorescence quenching sealing solution.

3图像处理和分析3 Image processing and analysis

免疫荧光图片是由Nikon A1激光共聚焦显微镜拍摄；神经元neurites分析由FIJI(Image J)软件手动统计并分析突触长度；数据由Graphpad Prism 8.3和Excel处理。经One-way ANOVA分析，进行组与组之间的统计学差异分析，差异的显著性以p<0.05为差异显著，p<0.01，p<0.001，p<0.0001为差异非常显著。*代表为p<0.05，**代表为p<0.01，***代表为p<0.001，****代表为p<0.0001。Immunofluorescence images were taken by a Nikon A1 laser confocal microscope; neurites were manually counted and synaptic length was analyzed by FIJI (Image J) software; data were processed by Graphpad Prism 8.3 and Excel. One-way ANOVA analysis was performed to analyze the statistical differences between groups. The significance of the difference was p<0.05 for significant difference, p<0.01, p<0.001, and p<0.0001 for very significant difference. * represents p<0.05, ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001.

实验结果如图1所示。The experimental results are shown in Figure 1.

实验结论:供试品由相应实施例制得，结果显示，本申请化合物能够显著促进大鼠原代皮层神经元突触增长。Experimental conclusion: The test samples were prepared from the corresponding examples, and the results showed that the compounds of the present application can significantly promote the synaptic growth of primary cortical neurons in rats.

效果实施例4化合物在小鼠体内药代动力学性质评价Evaluation of the pharmacokinetic properties of the compound in mice

实验目的：Purpose:

评价本发明实施例在CD-1小鼠体内的药代动力学性质。The pharmacokinetic properties of the examples of the present invention were evaluated in CD-1 mice.

实验材料：

Experimental Materials:

实验操作：Experimental operation:

以标准方案测试化合物静脉注射、皮下注射和口服灌胃给药后啮齿类动物的药代动力学特征。实验中候选化合物用指定溶媒配置成澄清溶液或混悬液,分别给予三只小鼠单次静脉注射、皮下注射和口服灌胃给药。静脉注射、皮下注射和口服灌胃给药的溶媒均为10％磺丁基-β-环糊精水溶液。收集8小时内全血样品至商品化的EDTA2K抗凝管中,离心得到上层血浆样品,加入含内标的乙腈溶液沉淀蛋白，离心取上清液加入等体积的水,再离心后取上清液进样，以LCMS/MS分析方法定量分析血药浓度、计算药代动力学参数。The pharmacokinetic characteristics of the compounds in rodents after intravenous, subcutaneous and oral gavage administration were tested by standard protocols. In the experiment, the candidate compound was prepared into a clear solution or suspension with a specified solvent and given a single intravenous injection, subcutaneous injection and oral gavage to three mice. The solvents for intravenous, subcutaneous and oral gavage administration were all 10% sulfobutyl-β-cyclodextrin aqueous solution. Whole blood samples were collected within 8 hours into commercial EDTA2K anticoagulant tubes, centrifuged to obtain the upper plasma sample, and acetonitrile solution containing internal standard was added to precipitate the protein. The supernatant was centrifuged and added with an equal volume of water. After centrifugation, the supernatant was sampled and the blood drug concentration was quantitatively analyzed by LCMS/MS analysis method and the pharmacokinetic parameters were calculated.

给药方式：
Dosage:

实验结果：


Experimental results:


实验结论:Experimental conclusion:

供试品由相应实施例制得，结果显示，本发明实施例在小鼠体内具有良好的药代动力学性质。The test samples were prepared from the corresponding examples, and the results showed that the examples of the present invention had good pharmacokinetic properties in mice.

效果实施例5化合物在大鼠体内药代动力学性质评价Evaluation of the pharmacokinetic properties of the compound in rats

实验目的：Purpose:

评价本发明实施例所得化合物在SD大鼠体内的药代动力学性质。The pharmacokinetic properties of the compounds obtained in the examples of the present invention were evaluated in SD rats.

实验材料：
Experimental Materials:

实验操作：Experimental operation:

以标准方案测试化合物静脉注射和口服给药后啮齿类动物的药代动力学特征。实验中候选化合物用指定溶媒配置成澄清溶液或混悬液,分别给予三只大鼠单次静脉注射及口服给药。静脉注射的溶媒和口服给药的溶媒为10％磺丁基-β-环糊精水溶液。收集24小时内全血样品至商品化的EDTA2K抗凝管中,离心得到上层血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等体积的水,再离心后取上清液进样,以LCMS/MS分析方法定量分析血药浓度、计算药代动力学参数。 The pharmacokinetic characteristics of the compounds after intravenous and oral administration in rodents were tested by standard protocols. In the experiment, the candidate compounds were prepared into clear solutions or suspensions with the specified solvents and given a single intravenous injection and oral administration to three rats. The solvent for intravenous injection and the solvent for oral administration were 10% sulfobutyl-β-cyclodextrin aqueous solution. Whole blood samples within 24 hours were collected into commercial EDTA2K anticoagulant tubes, centrifuged to obtain the upper plasma sample, and acetonitrile solution containing internal standard was added to precipitate protein. The supernatant was centrifuged and added with an equal volume of water. After centrifugation, the supernatant was sampled and the blood drug concentration was quantitatively analyzed by LCMS/MS analysis method and the pharmacokinetic parameters were calculated.

实验方法：
Experimental methods:

实验结果：Experimental results:

供试品由相应实施例制得，结果显示，本申请化合物在大鼠体内具有良好的药代动力学性质。The test samples were prepared according to the corresponding examples, and the results showed that the compounds of the present application had good pharmacokinetic properties in rats.

效果实施例6化合物诱导的小鼠摆头反应模型Effect Example 6 Compound-induced head shaking reaction model in mice

实验目的：Purpose:

许多哺乳动物在耳廓受到机械或化学刺激时，会表现出阵发性的头部旋转晃动，小鼠在服用致幻剂后也表现出类似的行为。通过小鼠头部摆动模型(Head Twitch Response，HTR)评价本发明实施例化合物对C57BL6/J小鼠摆头次数的变化，评判本发明实施例化合物的致幻作用。Many mammals will show paroxysmal head rotation and shaking when the auricle is mechanically or chemically stimulated, and mice also show similar behavior after taking hallucinogens. The head twitch response (HTR) model of mice was used to evaluate the changes in the number of head shaking of C57BL6/J mice by the compounds of the embodiments of the present invention, and to judge the hallucinogenic effect of the compounds of the embodiments of the present invention.

实验材料：
Experimental Materials:

实验分组：Experimental groups:

每只动物均有唯一编号。实验开始前一天，根据动物的体重随机分组，分组情况如下表：
Each animal has a unique number. The day before the experiment, the animals were randomly divided into groups according to their weight. The grouping is as follows:

实验操作：Experimental operation:

实验当天，在T(时间)＝0min时间点进行灌胃给药组给药。给药实验员未被告知给药组成分。On the day of the experiment, the intragastric administration group was administered with medication at T (time) = 0 min. The dosing experimenter was not informed of the composition of the dosing group.

在T＝15min时间点，将小鼠放置于驯化笼内。驯化笼为边长15cm的白色方形盒子，底部铺有一层干净小鼠垫料。At T = 15 min, the mice were placed in an acclimation cage, which was a white square box with a side length of 15 cm and a layer of clean mouse bedding on the bottom.

在T＝30min时间点，将小鼠转移至测试用观察笼。观察笼和驯化笼外观上完全一致，底部铺有一层干净小鼠垫料。At T = 30 min, the mice were transferred to the test observation cage. The observation cage and the acclimation cage were completely identical in appearance, with a layer of clean mouse bedding on the bottom.

腹腔注射组在T＝15min时放入驯化笼，在T＝30min时给与注射液并转移至测试用观察笼。The mice in the intraperitoneal injection group were placed in the acclimation cage at T=15 min, and were given the injection solution at T=30 min and transferred to the test observation cage.

在T＝30～60min期间，使用高速摄像机(SANS精密行为分析系统)从观察笼正上方拍摄采集小 鼠活动视频，摄像频率100HZ。During T = 30-60 min, a high-speed camera (SANS Precision Behavior Analysis System) was used to capture the small Mouse activity video, recording frequency 100HZ.

在T＝60min时间点，实验结束，小鼠安乐死。At T=60 min, the experiment was terminated and the mice were euthanized.

数据分析：Data Analysis:

视频由小动物精密行为分析软件(SANS精密行为分析系统)进行分析。一次摆头被定义为清晰的、快速的、左右摇头甩毛行为。单次摆头行为时间为0.05～0.15s，包含3～5次摇头甩毛动作。测试时间内的摆头次数由软件计算并统计。实验数据以均值±标准误(AVE±SEM)表示。摆头数据采用GraphPad Prism 10进行统计学分析。实验结果如图2所示。The video was analyzed by the Small Animal Precision Behavior Analysis Software (SANS Precision Behavior Analysis System). A head shake was defined as a clear, rapid, left-right head shaking and hair shaking behavior. The duration of a single head shake behavior was 0.05-0.15 s, including 3-5 head shaking and hair shaking movements. The number of head shakes during the test time was calculated and counted by the software. The experimental data were expressed as mean ± standard error (AVE±SEM). The head shaking data were statistically analyzed using GraphPad Prism 10. The experimental results are shown in Figure 2.

实验结论:Experimental conclusion:

供试品由相应实施例制得，结果显示，赛洛西斌会显著增加小鼠头部摆动次数。本申请化合物不会增加小鼠头部摆动次数，不具有致幻性。The test samples were prepared from the corresponding examples, and the results showed that psilocybin significantly increased the number of head shaking in mice. The compound of the present application did not increase the number of head shaking in mice and was not hallucinogenic.

效果实施例7化合物在小鼠自发活动模型中的作用Effect Example 7 Effect of the Compound in the Mouse Spontaneous Activity Model

实验目的：Purpose:

研究本发明实施例化合物对雄性C57BL/6J小鼠自发活动的影响。The effects of the compounds of the present invention on the spontaneous activity of male C57BL/6J mice were studied.

实验材料：
Experimental Materials:

实验分组：Experimental groups:

实验动物提前5天进入动物房饲养，实验前产生随机分组序列，并在实验当天依据随机分组序列分配动物。分组情况如下表：
The experimental animals were kept in the animal room 5 days in advance. A random grouping sequence was generated before the experiment, and the animals were allocated according to the random grouping sequence on the day of the experiment. The grouping is as follows:

实验操作：Experimental operation:

实验前提前30分钟将实验动物转入操作间适应环境，随机描号称重并根据实验分组把动物分为溶媒组，不同剂量的受试物组，每组10只动物。The experimental animals were transferred to the operating room 30 minutes before the experiment to adapt to the environment, and were randomly numbered and weighed. According to the experimental groups, the animals were divided into a solvent group and different doses of the test substance groups, with 10 animals in each group.

动物称重完毕后，依次放入自发活动记录箱适应30分钟，并开启自发活动实验分析系统记录30分钟活动量。After the animals were weighed, they were placed in a spontaneous activity recording box to adapt for 30 minutes, and the spontaneous activity experimental analysis system was turned on to record the activity for 30 minutes.

30分钟后取出动物，根据实验分组给予溶媒(10％磺丁基-β-环糊精)或不同剂量的受试物，剂量组给予不同浓度受试物，溶媒组给予同体积溶媒，给药体积为10mL/kg，给药后立即把动物放回原自发活动行为记录箱中，继续记录动物自发活动60分钟。After 30 minutes, the animals were taken out and given solvent (10% sulfobutyl-β-cyclodextrin) or different doses of the test substance according to the experimental groups. The dose group was given different concentrations of the test substance, and the solvent group was given the same volume of solvent. The administration volume was 10 mL/kg. After administration, the animals were immediately put back into the original spontaneous activity behavior recording box, and the spontaneous activity of the animals continued to be recorded for 60 minutes.

测试结束后，取出动物，用75％酒精擦拭清理自发活动记录箱。After the test, remove the animal and clean the locomotor activity recording box with 75% alcohol wipes.

数据分析： Data Analysis:

自发活动实验分析系统统计一次动物每5min，在观察箱中活动的路程(cm)，记录给药后在0-60min内移动的总路程(cm)。所有计量资料均以均数±标准误(Mean±SEM)表示，采用Prism 8.3.0统计软件中作检验分析。The spontaneous activity analysis system counted the distance (cm) that the animals moved in the observation box every 5 minutes, and recorded the total distance (cm) moved within 0-60 minutes after drug administration. All quantitative data were expressed as mean ± standard error (Mean ± SEM) and analyzed using Prism 8.3.0 statistical software.

实验结论:Experimental conclusion:

供试品由相应实施例制得，结果显示，申请化合物与溶媒对照组的小鼠相比总运动路程无明显差异，对小鼠的自发活动无影响。The test samples were prepared according to the corresponding examples, and the results showed that there was no significant difference in the total movement distance of mice compared with the vehicle control group, and no effect on the spontaneous activity of mice.

效果实施例8化合物在小鼠强迫游泳模型中的抗抑郁药效评价Effect Example 8 Evaluation of the Antidepressant Efficacy of Compounds in the Mouse Forced Swim Model

实验目的：Purpose:

评价本发明实施例在C57BL/6J小鼠强迫游泳模型中的抗抑郁药效。The antidepressant efficacy of the examples of the present invention was evaluated in the C57BL/6J mouse forced swimming model.

实验材料：
Experimental Materials:

实验分组：Experimental groups:

动物适应实验环境7天；实验前记录动物体重并随机分组。分组情况如下表：
The animals were allowed to adapt to the experimental environment for 7 days; their weights were recorded and they were randomly divided into groups before the experiment. The groupings are as follows:

实验操作：Experimental operation:

在小鼠圆柱形游泳桶中加入已调好温度的水，水位高度在圆柱形桶的三分之二处；将小鼠放入圆柱形游泳桶中，使其预游泳10min；取出小鼠并烘干，放回笼中，隔天进行正式检测。Add water of adjusted temperature into a cylindrical swimming bucket for mice, with the water level at two-thirds of the bucket; place the mice into the cylindrical swimming bucket and allow them to pre-swim for 10 minutes; take out the mice, dry them, put them back into the cage, and conduct formal testing the next day.

第二天，在小鼠圆柱形游泳桶中加入已调好温度的水；调试小鼠强迫游泳装置与摄像机的位置，连接电脑录制实验视频；给药1h后将小鼠从饲养笼中轻轻取出，安抚1min后待动物不紧张时，将其放入水中，并立即离开视频拍摄范围。On the second day, add water with adjusted temperature to the cylindrical swimming bucket for mice; adjust the position of the mouse forced swimming device and the camera, and connect them to a computer to record the experimental video; 1 hour after drug administration, gently take the mouse out of the cage, soothe it for 1 minute, put it into the water when the animal is no longer nervous, and immediately leave the video shooting range.

通过软件记录小鼠6min内的游泳视频。测试结束，将小鼠取出彻底烘干并放回笼中，重复以上过程直至全部小鼠测试完毕。The software records the swimming video of the mice for 6 minutes. After the test, the mice are taken out, dried thoroughly and put back into the cage, and the above process is repeated until all mice are tested.

实验结束后，所有动物进行安乐死处理。After the experiment, all animals were euthanized.

数据分析人员通过视频评价小鼠的静止不动行为,分析小鼠在测试阶段第2-6min的不动时长，并记录小鼠在该时间段出现不动的潜伏期；小鼠不动时间越长表明抑郁程度越重。Data analysts evaluated the immobility behavior of mice through video, analyzed the immobility time of mice in the 2nd to 6th minute of the test phase, and recorded the latency of mice to become immobile during this time period; the longer the immobility time of mice, the more severe the depression.

数据分析： Data Analysis:

所有原始数据录入Excel，使用GraphPad Prism 9.0进行统计分析，以Mean±S.E.M.表示，经One-way ANOVA分析，进行组与组之间的统计学差异分析，差异的显著性以p<0.05为差异显著，p<0.01，p<0.001为差异非常显著。*代表为p<0.05，**代表为p<0.01，***代表为p<0.001。All raw data were entered into Excel and statistically analyzed using GraphPad Prism 9.0, expressed as Mean±S.E.M., and analyzed by One-way ANOVA for statistical differences between groups. The significance of the difference was considered significant at p<0.05, and very significant at p<0.01 and p<0.001. * represents p<0.05, ** represents p<0.01, and *** represents p<0.001.

实验结果如图3所示。The experimental results are shown in Figure 3.

实验结论:Experimental conclusion:

供试品由相应实施例制得，结果显示，本申请化合物能够显著减少强迫游泳小鼠的不动时间,在C57BL/6J小鼠强迫游泳模型中展现出良好的抗抑郁药效。The test samples were prepared according to the corresponding examples, and the results showed that the compounds of the present application could significantly reduce the immobility time of forced swimming mice and exhibited good antidepressant efficacy in the forced swimming model of C57BL/6J mice.

效果实施例9化合物在小鼠悬尾模型中的抗抑郁药效评价Effect Example 9 Evaluation of the Antidepressant Efficacy of Compounds in the Mouse Tail Suspension Model

实验目的：Purpose:

评价本发明实施例在C57BL/6J小鼠悬尾模型中的抗抑郁药效。The antidepressant efficacy of the embodiments of the present invention was evaluated in the C57BL/6J mouse tail suspension model.

实验材料：
Experimental Materials:

实验分组：Experimental groups:

动物适应实验环境7天；实验前记录动物体重并随机分组。分组情况如下表：
The animals were allowed to adapt to the experimental environment for 7 days; their weights were recorded and they were randomly divided into groups before the experiment. The groupings are as follows:

实验操作：Experimental operation:

调试悬尾装置与摄像机的位置，打开动物行为学分析软件(VisTrack XR-VT)，连接电脑录制视频；Adjust the position of the tail suspension device and the camera, open the animal behavior analysis software (VisTrack XR-VT), and connect the computer to record the video;

给药1h后，测试前将小鼠从饲养笼中轻轻取出，安抚1-3min后待动物不紧张的时候，用医用胶带缠绕小鼠尾尖部1/3处，使其悬于悬尾箱内，然后实验员迅速离开；One hour after administration and before testing, the mice were gently taken out of the cage, and after being comforted for 1-3 minutes until the animals were no longer nervous, medical tape was used to wrap around the 1/3 of the tip of the tail of the mice, so that they were suspended in the tail suspension box, and then the experimenter quickly left;

通过视频记录小鼠6min内活动轨迹；The activity trajectory of mice within 6 minutes was recorded by video;

测试结束，将小鼠取出，放回笼中，同时清理悬尾装置上面小鼠排泄物；After the test, take the mice out and put them back into the cage, and clean the mouse excrement on the tail suspension device;

重复以上过程直到全部小鼠测试完毕；Repeat the above process until all mice have been tested;

实验结束后，妥善收纳保管实验装置，小鼠进行安乐死处理。After the experiment, the experimental equipment was properly stored and the mice were euthanized.

软件记录视频中动物后2-6min累计不动时间。不动时间越长，抑郁越严重。不动状态是指动物放弃主动挣扎，躯体处于垂直不扭动状态。The software records the cumulative immobility time of the animal in the video for 2-6 minutes. The longer the immobility time, the more severe the depression. The immobility state means that the animal has given up active struggle and the body is in a vertical state without twisting.

数据分析：Data Analysis:

所有原始数据录入Excel，使用GraphPad Prism 9.0进行统计分析，以Mean±S.E.M.表示，经One-way ANOVA分析，进行组与组之间的统计学差异分析，差异的显著性以p<0.05为差异显著，p<0.01，p<0.001为差异非常显著。*代表为p<0.05，**代表为p<0.01，***代表为p<0.001。All raw data were entered into Excel and statistically analyzed using GraphPad Prism 9.0, expressed as Mean±S.E.M., and analyzed by One-way ANOVA for statistical differences between groups. The significance of the difference was considered significant at p<0.05, and very significant at p<0.01 and p<0.001. * represents p<0.05, ** represents p<0.01, and *** represents p<0.001.

实验结论:Experimental conclusion:

供试品由相应实施例制得，结果显示，本申请化合物能够显著减少悬尾小鼠的不动时间,在 C57BL/6J小鼠强迫游泳模型中展现出良好的抗抑郁药效。The test samples were prepared from the corresponding examples, and the results showed that the compounds of the present application could significantly reduce the immobility time of tail-suspended mice. It showed good antidepressant efficacy in the forced swimming model of C57BL/6J mice.

效果实施例10化合物在小鼠习得性无助抑郁模型中的药效评价Evaluation of the efficacy of the compound in the mouse model of learned helplessness and depression

实验目的：Purpose:

评价本发明实施例在C57BL/6J习得性无助抑郁模型中的药效。The efficacy of the embodiments of the present invention in the C57BL/6J learned helplessness depression model was evaluated.

实验材料：
Experimental Materials:

实验操作：Experimental operation:

1)造模阶段：1) Modeling stage:

动物适应实验环境7天；实验前记录动物体重并随机分组。The animals were acclimatized to the experimental environment for 7 days; their body weights were recorded and they were randomly divided into groups before the experiment.

调试电刺激箱与摄像机的位置，打开吉量行为学软件，连接电脑录制视频；Adjust the position of the electrical stimulation box and the camera, open the Jiliang Behavioral Software, and connect the computer to record the video;

将小鼠从饲养笼中取出，放入电刺激穿梭箱中，连续8天，每天1次，每次包含120次不可逃避的足底电击，电流强度0.3mA，单次电击持续时间随机1-3s，每两次电击随机间隔1-15s；阴性对照组与模型组操作相同，但不给予动物电击。The mice were removed from their cages and placed in an electrical stimulation shuttle box for 8 consecutive days, once a day, each time containing 120 inescapable foot shocks, with a current intensity of 0.3 mA, a single shock duration of 1-3 s, and a random interval of 1-15 s between each shock; the negative control group was operated in the same way as the model group, but the animals were not given electric shocks.

2)实验分组：2) Experimental groups:

阴性对照组和造模成功动物实验前记录动物体重并随机分组。分组情况如下表：
The weight of the animals in the negative control group and the successfully modeled animals was recorded before the experiment and they were randomly divided into groups. The grouping is as follows:

3)测试阶段：3) Testing phase:

在电击造模结束24小时后进行测试，按照实验分组动物给予溶媒或不同剂量的化合物，阴性对照组给予溶媒。The test was carried out 24 hours after the end of the electric shock modeling. The animals were given solvent or different doses of compounds according to the experimental groups, and the negative control group was given solvent.

给药后1h及24h后将小鼠放入电刺激穿梭箱中，让其在穿梭箱两侧自由探索3分钟；测试阶段包括30次的电击。每次以5秒长的光刺激开始，然后是10秒的电击(0.3mA)，间隔为30s；每次电击开始前，穿梭箱的隔板都会开启，当小鼠穿梭至另一侧时，则电击终止；阴性对照组与其他组操作相同，但不给予动物电击。One hour and 24 hours after administration, mice were placed in an electrical stimulation shuttle box and allowed to freely explore the two sides of the shuttle box for 3 minutes; the test phase included 30 electric shocks. Each time started with a 5-second light stimulation, followed by a 10-second electric shock (0.3mA), with an interval of 30s; before each electric shock, the partition of the shuttle box would open, and the electric shock would end when the mouse shuttled to the other side; the negative control group was operated the same as the other groups, but no electric shock was given to the animals.

在光刺激提示下进行逃离，记为主动逃避。电击期间逃离，记录逃脱潜伏期视为被动逃避。不逃脱时，记为逃逸失败。在30次测试中，超过15个失败被定义为习得性无助。If the animal escapes under the light stimulation prompt, it is recorded as active escape. If the animal escapes during the electric shock, the escape latency is recorded as passive escape. If the animal does not escape, it is recorded as escape failure. More than 15 failures in 30 tests are defined as learned helplessness.

4)测试结束：4) End of test:

每只小鼠测试结束后，放回笼中，同时清理电刺激箱上面小鼠排泄物；After each mouse test, it was put back into the cage and the mouse excrement on the electrical stimulation box was cleaned;

重复以上过程直到全部小鼠测试完毕；Repeat the above process until all mice have been tested;

实验结束后，妥善收纳保管实验装置，小鼠进行安乐死处理。After the experiment, the experimental equipment was properly stored and the mice were euthanized.

数据分析：Data Analysis:

所有原始数据录入Excel，使用GraphPad Prism 9.0进行统计分析，以Mean±S.E.M.表示，经 One-way ANOVA分析，进行组与组之间的统计学差异分析，差异的显著性以p<0.05为差异显著，p<0.01，p<0.001为差异非常显著。###代表为与阴性对照+溶媒组p<0.001，**代表为与模型+溶媒组p<0.01，***代表为与模型+溶媒组p<0.001。All raw data were entered into Excel and statistically analyzed using GraphPad Prism 9.0. The data were expressed as Mean ± SEM. One-way ANOVA analysis was performed to analyze the statistical differences between groups. The significance of the difference was considered significant at p<0.05, and very significant at p<0.01 and p<0.001. ### represents p<0.001 compared with the negative control + solvent group, ** represents p<0.01 compared with the model + solvent group, and *** represents p<0.001 compared with the model + solvent group.

实验结论:供试品由相应实施例制得，结果显示，本申请化合物能够明显降低了在习得性无助实验中动物的逃避失败次数，在C57BL/6J习得性无助抑郁模型中展现出良好的抗抑郁药效。 Experimental conclusion: The test samples were prepared from the corresponding examples. The results showed that the compounds of the present application could significantly reduce the number of escape failures of animals in the learned helplessness experiment and exhibited good antidepressant efficacy in the C57BL/6J learned helplessness depression model.

Claims (16)

一种如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物：
A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
所述的如式(I)所示的化合物为以下情形1或情形2：The compound as shown in formula (I) is the following situation 1 or situation 2: 情形1：q为1，Case 1: q is 1, 所述的如式(I)所示的化合物为如下所示的化合物：
The compound shown in formula (I) is the compound shown below:
其中，X为CH或N；Wherein, X is CH or N; R1为硝基、氰基、卤素、C1-6烷基、C1-6烷氧基、C3-12环烃基、3-12元杂环烃基、被1个、2个或3个R1-1取代的C1-6烷基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is nitro, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 1-6 alkyl substituted by 1, 2 or 3 R 1-1 , or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; 每个R1-1和R1-2各自独立地为氘或卤素；Each of R 1-1 and R 1-2 is independently deuterium or halogen; R8为氢、氘、氰基、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ; 每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; 或者，相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环或3-5元杂环；Alternatively, L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；L 2 is -N(L 2-0 ) 2 , a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地为氢或C1-6烷基；Each L 2-0 is independently hydrogen or C 1-6 alkyl; 每个L2-1和L2-2各自独立地为氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; 每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium; 每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl; 每个L2-3独立地为氢、氘、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 或者，两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环； Alternatively, two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring; 其中，如式(I)所示的化合物满足以下条件的一种、两种、三种或四种：Wherein, the compound as shown in formula (I) satisfies one, two, three or four of the following conditions: I：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl; II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基；II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl; III：L1为被一个或多个L1-2取代的亚乙基，每个L1- 2独立地为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；III: L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; IV：R1为被1个、2个或3个R1-2取代的C1-6烷氧基；IV: R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 ; 情形2：q为3，Case 2: q is 3, 所述的如式(I)所示的化合物为如下所示的化合物：
The compound shown in formula (I) is the compound shown below:
其中，X为CH或CRX；Wherein, X is CH or CR X ; RX为卤素或C1-6烷基； RX is halogen or C1-6 alkyl; R1为羟基、-S(＝O)2(C1-6烷基)、氰基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is hydroxy, -S(=O) 2 (C 1-6 alkyl), cyano, C 1-6 alkoxy, or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; R1-2独立地为氘或卤素；R 1-2 are independently deuterium or halogen; 或者，RX与其相邻的R1和它们各自连接的碳原子共同形成C5-6碳环或5-6元杂环；Alternatively, RX, its adjacent R1 and the carbon atom to which they are each attached together form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring; R2和R3各自独立地为氢、C1-6烷氧基或卤素； R2 and R3 are each independently hydrogen, C1-6 alkoxy or halogen; 或者，R1和R2与它们各自连接的碳原子共同形成C5-6碳环或5-6元杂环；Alternatively, R1 and R2 together with the carbon atoms to which they are attached form a C5-6 carbocyclic ring or a 5-6 membered heterocyclic ring; R8为氢、氘、氰基、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；R 8 is hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; L1为被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a methylene group substituted by one or more L 1-1 or an ethylene group substituted by one or more L 1-2 ; 每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基； Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环或3-5元杂环；Alternatively, two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; 或者，相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环或3-5元杂环；Alternatively, L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are attached together form a C 3-5 carbocyclic ring or a 3-5 membered heterocyclic ring; L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-1和L2-2各自独立地为氢、氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基、被一个或多个L2-1-2取代的C3-6环烃基或或被一个或多个L2-1-3取代的C1-6烷氧基；Each of L 2-1 and L 2-2 is independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , C 3-6 cycloalkyl substituted by one or more L 2-1-2 , or C 1-6 alkoxy substituted by one or more L 2-1-3 ; 每个L2-1-1独立地为氘、C3-6环烃基或3-6元杂环烃基；Each L 2-1-1 is independently deuterium, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl; 每个L2-1-3独立地为C3-6环烃基或3-6元杂环烃基；Each L 2-1-3 is independently a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl; 每个L2-3独立地为氢、氘、卤素、C1-6烷基、C3-6环烃基或3-6元杂环烃基；Each L 2-3 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 或者，两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环；Alternatively, two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring; 以上情形1或情形2中，以上每一“杂环烃基”中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In the above case 1 or case 2, in each of the above "heterocyclic hydrocarbon groups", the type of heteroatoms is independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2; 以上每一3-5元杂环中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In each of the above 3-5 membered heterocycles, the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2; 以上每一5-6元杂环中，杂原子的种类各自独立地选自N和O的一种或两种，杂原子的个数各自独立地为1个或2个；In each of the above 5-6-membered heterocycles, the type of heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently 1 or 2; 以上3-12元含氮杂环中，杂原子为N或者N和O，杂原子的个数独立地为1个或2个。In the above 3-12 membered nitrogen-containing heterocyclic ring, the heteroatom is N or N and O, and the number of the heteroatoms is independently 1 or 2. 如权利要求1所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的情形1中，每个L2-1和L2-2各自独立地为氢、氘、卤素、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that in the scenario 1, each L 2-1 and L 2-2 are independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; 所述的情形2中，R1为-S(＝O)2(C1-6烷基)、氰基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基。In the scenario 2, R 1 is -S(=O) 2 (C 1-6 alkyl), cyano, C 1-6 alkoxy, or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 . 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式(I)所示的化合物满足以下条件的一种或多种：The compound as shown in formula (I) according to claim 1 or 2, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that the compound as shown in formula (I) satisfies one or more of the following conditions: (1)所述的情形1中，R1中，所述的卤素为F、Cl、Br或I；(1) In the above scenario 1, in R 1 , the halogen is F, Cl, Br or I; (2)所述的情形1或情形2中，R1中，每一“C1-6烷基”独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(2) In the above-mentioned scenario 1 or scenario 2, in R 1 , each "C 1-6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3)所述的情形1或情形2中，R1中，每一“C1-6烷氧基”独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基；(3) In the above-mentioned situation 1 or situation 2, in R 1 , each "C 1-6 alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy; (4)所述的情形1中，R1中，所述的C3-12环烃基为C3-6单环环烃基或C6-12多环环烃基；所述 的C3-6单环环烃基可为C3-6单环环烷基或C3-6单环环烯基；(4) In the above situation 1, in R1 , the C3-12 cycloalkyl is a C3-6 monocyclic cycloalkyl or a C6-12 polycyclic cycloalkyl; The C 3-6 monocyclic cycloalkyl group may be a C 3-6 monocyclic cycloalkyl group or a C 3-6 monocyclic cycloalkenyl group; 所述的C6-12多环环烃基可为C6-12螺环环烃基、C6-12并环环烃基或C6-12桥环环烃基；The C 6-12 polycyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group, a C 6-12 paracyclic cycloalkyl group or a C 6-12 bridged cycloalkyl group; 所述的C6-12螺环环烃基可为C6-12螺环环烷基或C6-12螺环环烯基；The C 6-12 spirocyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group or a C 6-12 spirocyclic cycloalkenyl group; 所述的C6-12并环环烃基可为C6-12并环环烷基或C6-12并环环烯基；The C 6-12 cycloalkyl group may be a C 6-12 cycloalkyl group or a C 6-12 cycloalkenyl group; 所述的C6-12桥环环烃基可为C6-12桥环环烷基或C6-12桥环环烯基；The C 6-12 bridged ring cycloalkyl group may be a C 6-12 bridged ring cycloalkyl group or a C 6-12 bridged ring cycloalkenyl group; (5)所述的情形1中，R1中，所述的3-12元杂环烃基为3-7元单环杂环烃基或6-12元多环杂环烃基；(5) In the above situation 1, in R1 , the 3-12 membered heterocyclic hydrocarbon group is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group; 所述的3-7元单环杂环烃基可为3-7元单环杂环烷基或3-7元单环杂环烯基；The 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group; 所述的6-12元多环杂环烃基可为6-12元螺环杂环烃基、6-12元并环杂环烃基或6-12元桥环杂环烃基；The 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 6-12 membered bridged heterocyclic hydrocarbon group; 所述的6-12元螺环杂环烃基可为6-12元螺环杂环烷基或6-12元螺环杂环烯基；The 6-12 membered spirocyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkenyl group; 所述的6-12元并环杂环烃基可为6-12元并环杂环烷基或6-12元并环杂环烯基；The 6-12 membered cycloheterocyclic hydrocarbon group may be a 6-12 membered cycloheterocyclic alkyl group or a 6-12 membered cycloheterocyclic alkenyl group; 所述的6-12元桥环杂环烃基可为6-12元桥环杂环烷基或6-12元桥环杂环烯基；The 6-12 membered bridged heterocyclic hydrocarbon group may be a 6-12 membered bridged heterocyclic alkyl group or a 6-12 membered bridged heterocyclic alkenyl group; (6)所述的情形1中，R1-1和R1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F；(6) In the above situation 1, in R 1-1 and R 1-2 , the halogen is independently F, Cl, Br or I, such as F; (7)所述的情形1或情形2中，R8中，所述的卤素为F、Cl、Br或I；(7) In the above scenario 1 or 2, in R 8 , the halogen is F, Cl, Br or I; (8)所述的情形1或情形2中，R8中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(8) In the above scenario 1 or scenario 2, in R 8 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (9)所述的情形1或情形2中，R8中，所述的C3-6环烃基为C3-6环烷基或C3-6环烯基，例如C3- 6环烷基，进一步例如环丙基、环丁基、环戊基或环己基；(9) In the above scenario 1 or scenario 2, in R8 , the C3-6 cycloalkyl group is a C3-6 cycloalkyl group or a C3-6 cycloalkenyl group, such as a C3-6 cycloalkyl group, and further such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; (10)所述的情形1或情形2中，R8中，所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，例如4-6元杂环烷基或4-6元杂环烯基，进一步例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基、哌嗪基、二氢呋喃基、二氢吡咯基、四氢吡啶基、二氢吡啶基或二氢吡喃基；(10) In the above scenario 1 or scenario 2, in R8 , the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, such as a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, further such as an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a dihydrofuranyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydropyridinyl group or a dihydropyranyl group; (11)所述的情形1或情形2中，L1-1和L1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F；(11) In the case 1 or 2, in L 1-1 and L 1-2 , the halogen is independently F, Cl, Br or I, for example, F; (12)所述的情形1或情形2中，L1-1和L1-2中，所述的C1-6烷基各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；(12) In the above scenario 1 or scenario 2, in L 1-1 and L 1-2 , the C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (13)所述的情形1或情形2中，当同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一步例如环丙烷、环丁烷或环戊烷，优选环丙烷；(13) In the above situation 1 or situation 2, when two L 1-1 on the same carbon atom and the carbon atom to which they are commonly connected form a C 3-5 carbocyclic ring, the C 3-5 carbocyclic ring is a C 3-5 saturated carbocyclic ring or a C 3-5 carbene ring, such as a C 3-5 saturated carbocyclic ring, further such as cyclopropane, cyclobutane or cyclopentane, preferably cyclopropane; (14)所述的情形1或情形2中，当同一个碳原子上的两个L1-1与它们共同连接的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环；(14) In the above situation 1 or situation 2, when two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached together form a 3-5 membered heterocyclic ring, the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring; (15)所述的情形1或情形2中，当同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一步例如环丙烷、 环丁烷或环戊烷，优选环丙烷或环丁烷；(15) In the above-mentioned case 1 or case 2, when two L 1-2 on the same carbon atom form a C 3-5 carbocyclic ring with the carbon atom to which they are commonly connected, the C 3-5 carbocyclic ring is a C 3-5 saturated carbocyclic ring or a C 3-5 carbene ring, such as a C 3-5 saturated carbocyclic ring, further such as cyclopropane, Cyclobutane or cyclopentane, preferably cyclopropane or cyclobutane; (16)所述的情形1或情形2中，当同一个碳原子上的两个L1-2与它们共同连接的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环；(16) In the above situation 1 or situation 2, when two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached together form a 3-5 membered heterocyclic ring, the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring; (17)所述的情形1或情形2中，当相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成C3-5碳环，所述的C3-5碳环为C3-5饱和碳环或C3-5碳烯环，例如C3-5饱和碳环，进一步例如环丙烷、环丁烷或环戊烷；(17) In the above scenario 1 or scenario 2, when L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are connected together form a C 3-5 carbocyclic ring, the C 3-5 carbocyclic ring is a C 3-5 saturated carbocyclic ring or a C 3-5 carbene ring, such as a C 3-5 saturated carbocyclic ring, further such as cyclopropane, cyclobutane or cyclopentane; (18)所述的情形1或情形2中，当相邻两个碳原子上的L1-2与它们各自相连的碳原子共同形成3-5元杂环，所述的3-5元杂环为3-5元饱和杂环或3-5元杂环烯，例如4-5元饱和杂环或4-5元杂环烯，进一步例如氧杂环丁烷、氮杂环丁烷、四氢吡咯环、四氢呋喃环、二氢吡咯环或二氢呋喃环；(18) In the case 1 or 2, when L 1-2 on two adjacent carbon atoms and the carbon atoms to which they are connected together form a 3-5 membered heterocyclic ring, the 3-5 membered heterocyclic ring is a 3-5 membered saturated heterocyclic ring or a 3-5 membered heterocyclic alkene, such as a 4-5 membered saturated heterocyclic ring or a 4-5 membered heterocyclic alkene, further such as oxetane, azetidine, tetrahydropyrrole ring, tetrahydrofuran ring, dihydropyrrole ring or dihydrofuran ring; (19)所述的情形1或情形2中，L2中，所述的“C3-12环烃基”为C3-6单环环烃基或C6-12多环环烃基；(19) In the case 1 or 2, in L2 , the "C 3-12 cycloalkyl" is a C 3-6 monocyclic cycloalkyl or a C 6-12 polycyclic cycloalkyl; 所述的C3-6单环环烃基可为C3-6单环环烷基或C3-6单环环烯基，例如C3-6单环环烷基，进一步例如环丙基、环丁基、环戊基或环己基，例如环戊基或环己基；The C 3-6 monocyclic cycloalkyl group may be a C 3-6 monocyclic cycloalkyl group or a C 3-6 monocyclic cycloalkenyl group, such as a C 3-6 monocyclic cycloalkyl group, further such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, such as a cyclopentyl group or a cyclohexyl group; 所述的C6-12多环环烃基可为C6-12螺环环烃基、C6-12并环环烃基或C6-12桥环环烃基；The C 6-12 polycyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group, a C 6-12 paracyclic cycloalkyl group or a C 6-12 bridged cycloalkyl group; 所述的C6-12螺环环烃基可为C6-12螺环环烷基或C6-12螺环环烯基，例如C6-12螺环环烷基，进一步例如螺[3.3]庚烷基、螺[3.4]辛烷基、螺[3.5]壬烷基、螺[4.5]癸烷基或螺[5.5]十一烷基；The C 6-12 spirocyclic cycloalkyl group may be a C 6-12 spirocyclic cycloalkyl group or a C 6-12 spirocyclic cycloalkenyl group, such as a C 6-12 spirocyclic cycloalkyl group, further such as a spiro[3.3]heptyl group, a spiro[3.4]octyl group, a spiro[3.5]nonyl group, a spiro[4.5]decyl group or a spiro[5.5]undecyl group; 所述的C6-12并环环烃基可为C6-12并环环烷基或C6-12并环环烯基，例如C6-12并环环烷基，进一步例如双环[3.1.0]己烷基或双环[3.3.0]辛烷基，例如 The C 6-12 cycloalkyl group may be a C 6-12 cycloalkyl group or a C 6-12 cycloalkenyl group, such as a C 6-12 cycloalkyl group, further such as a bicyclo[3.1.0]hexyl group or a bicyclo[3.3.0]octyl group, for example 所述的C6-12桥环环烃基可为C6-12桥环环烷基或C6-12桥环环烯基，例如C6-12桥环环烷基，进一步例如双环[2.2.2]辛烷基；The C 6-12 bridged ring cycloalkyl group may be a C 6-12 bridged ring cycloalkyl group or a C 6-12 bridged ring cycloalkenyl group, such as a C 6-12 bridged ring cycloalkyl group, further such as a bicyclo[2.2.2]octanyl group; (20)所述的情形1或情形2中，L2中，所述的“3-12元杂环烃基”为3-7元单环杂环烃基或6-12元多环杂环烃基；(20) In the above scenario 1 or scenario 2, in L2 , the "3-12 membered heterocyclic hydrocarbon group" is a 3-7 membered monocyclic heterocyclic hydrocarbon group or a 6-12 membered polycyclic heterocyclic hydrocarbon group; 所述的3-7元单环杂环烃基可为3-7元单环杂环烷基或3-7元单环杂环烯基；所述的3-7元单环杂环烷基可为4-7元单环杂环烷基，例如氮杂环丁烷基、氧杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、4-甲氧基哌啶基、吗啉基、哌嗪基或1,4-氧杂氮杂环庚基，例如 所述的 3-7元单环杂环烯基可为4-7元单环杂环烯基，例如二氢吡咯基，优选 The 3-7 membered monocyclic heterocyclic hydrocarbon group may be a 3-7 membered monocyclic heterocyclic alkyl group or a 3-7 membered monocyclic heterocyclic alkenyl group; the 3-7 membered monocyclic heterocyclic alkyl group may be a 4-7 membered monocyclic heterocyclic alkyl group, such as azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, 4-methoxypiperidinyl, morpholinyl, piperazinyl or 1,4-oxaazepanyl, such as The The 3-7 membered monocyclic heterocycloalkenyl group may be a 4-7 membered monocyclic heterocycloalkenyl group, such as dihydropyrrolyl, preferably 所述的6-12元多环杂环烃基可为6-12元螺环杂环烃基、6-12元并环杂环烃基或6-12元桥环杂环烃基；The 6-12 membered polycyclic heterocyclic hydrocarbon group may be a 6-12 membered spirocyclic heterocyclic hydrocarbon group, a 6-12 membered paracyclic heterocyclic hydrocarbon group or a 6-12 membered bridged heterocyclic hydrocarbon group; 所述的6-12元螺环杂环烃基可为6-12元螺环杂环烷基或6-12元螺环杂环烯基，所述的6-12元螺环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-11元螺环杂环烷基，例如为以下情况的中任一种：The 6-12 membered spiro heterocyclic hydrocarbon group may be a 6-12 membered spiro heterocyclic alkyl group or a 6-12 membered spiro heterocyclic alkenyl group, and the 6-12 membered spiro heterocyclic alkyl group may be a 6-11 membered spiro heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example, any one of the following: 情况1：4-氮杂螺[2.4]庚烷基、4-氮杂螺[2.5]辛烷、2-氮杂螺[3.3]庚烷基或2-氮杂螺[3.5]壬烷基，进一步例如 Case 1: 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane or 2-azaspiro[3.5]nonane, further such as 情况2：4-氮杂螺[2.4]庚烷基、4-氮杂螺[2.5]辛烷、2-氮杂螺[3.3]庚烷基、2-氮杂螺[3.5]壬烷基、9-氮杂-3-氧杂螺[5.5]十一烷基、1-氮杂-8-氧杂螺[4.5]癸烷基、7-氮杂-2-氧杂螺[4.5]癸烷基、7-氮杂-2-氧杂螺[3.5]壬烷基、6-氮杂螺[2.5]辛烷基、8-氮杂-2-氧杂螺[4.5]癸烷基、2-氮杂-6-氧杂螺[3.4]辛烷基、6-氮杂-2-氧杂螺[3.3]庚烷基或5-氮杂螺[2.3]己烷，优选 Case 2: 4-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.5]nonane, 9-aza-3-oxaspiro[5.5]undecane, 1-aza-8-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[4.5]decane, 7-aza-2-oxaspiro[3.5]nonane, 6-azaspiro[2.5]octane, 8-aza-2-oxaspiro[4.5]decane, 2-aza-6-oxaspiro[3.4]octane, 6-aza-2-oxaspiro[3.3]heptane or 5-azaspiro[2.3]hexane, preferably 所述的6-12元并环杂环烃基可为6-12元并环杂环烷基或6-12元并环杂环烯基，所述的6-12元并环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-10元并环杂环烷基，例如 优选为以下情况中任一种：The 6-12 membered heterocyclic hydrocarbon group may be a 6-12 membered heterocyclic alkyl group or a 6-12 membered heterocyclic alkenyl group, and the 6-12 membered heterocyclic alkyl group may be a 6-10 membered heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example Preferably, any of the following situations: 情况1： Case 1: 情况2： Case 2: 所述的6-12元桥环杂环烃基可为6-12元桥环杂环烷基或6-12元桥环杂环烯基；所述的6-12元桥环杂环烷基可为杂原子为N，杂原子的个数为1个或2个的6-12元桥环杂环烷基，例如为以下情况中的任一种：The 6-12 membered bridged heterocyclic hydrocarbon group may be a 6-12 membered bridged heterocyclic alkyl group or a 6-12 membered bridged heterocyclic alkenyl group; the 6-12 membered bridged heterocyclic alkyl group may be a 6-12 membered bridged heterocyclic alkyl group in which the hetero atom is N and the number of hetero atoms is 1 or 2, for example, any one of the following: 情况1：2-氮杂双环[2.2.2]辛烷基，进一步例如 Case 1: 2-azabicyclo[2.2.2]octanyl, further such as 情况2：2-氮杂双环[2.2.2]辛烷基或6-氮杂-3-氧杂双环[2.2.1]庚烷基，进一步例如 Case 2: 2-azabicyclo[2.2.2]octanyl or 6-aza-3-oxabicyclo[2.2.1]heptyl, further such as (21)所述的情形1中，L2-0中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；(21) In the scenario 1, in L 2-0 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (22)所述的情形1或情形2中，L2-1和L2-2中，所述的卤素各自独立地为F、Cl、Br或I；(22) In the case 1 or 2, in L 2-1 and L 2-2 , the halogen is independently F, Cl, Br or I; (23)所述的情形1或情形2中，L2-1和L2-2中，每一“C1-6烷基”各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；(23) In case 1 or case 2, in L 2-1 and L 2-2 , each "C 1-6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (24)所述的情形1或情形2中，L2-1和L2-2中，每一“C3-6环烃基”各自独立地为C3-6环烷基或C3-6环烯基，例如环丙基、环丁基、环戊基或环己基，优选为环丙基；(24) In case 1 or case 2, in L 2-1 and L 2-2 , each "C 3-6 cycloalkyl group" is independently a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably a cyclopropyl group; (25)所述的情形1或情形2中，L2-1和L2-2中，所述的3-6元杂环烃基各自独立地为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基 或哌嗪基；(25) In the above scenario 1 or scenario 2, in L 2-1 and L 2-2 , the 3-6 membered heterocyclic hydrocarbon group is each independently a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms and being N and/or O, such as an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a piperidinyl group, a morpholinyl group, or a cyclopentyl group. or piperazinyl; (26)所述的情形1或情形2中，L2-1-2中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；(26) In the case 1 or 2, in L 2-1-2 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (27)所述的情形1或情形2中，L2-3中，所述的卤素为F、Cl、Br或I；(27) In the case 1 or 2, in L 2-3 , the halogen is F, Cl, Br or I; (28)所述的情形1或情形2中，L2-3中，所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；(28) In the case 1 or 2, in L 2-3 , the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (29)所述的情形1或情形2中，L2-3中，所述的C3-6环烃基为C3-6环烷基或C3-6环烯基，所述的C3-6环烷基可为环丙基、环丁基、环戊基或环己基；(29) In the above scenario 1 or scenario 2, in L 2-3 , the C 3-6 cycloalkyl group is a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, and the C 3-6 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; (30)所述的情形1或情形2中，L2-3中，所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基或哌嗪基；(30) In the above scenario 1 or scenario 2, in L 2-3 , the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms and being N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl; (31)所述的情形1或情形2中，当两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环时，所述的3-12元含氮杂环可独立地为3-7元含氮单环杂环或6-12元含氮多环杂环；(31) In case 1 or case 2, when two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12-membered nitrogen-containing heterocyclic ring, the 3-12-membered nitrogen-containing heterocyclic ring may independently be a 3-7-membered nitrogen-containing monocyclic heterocyclic ring or a 6-12-membered nitrogen-containing polycyclic heterocyclic ring; 所述的3-7元含氮单环杂环可为3-7元饱和含氮单环杂环或3-7元含氮单环杂环烯，所述的3-7元含氮单环杂环可为杂原子为N或者N和O，杂原子的个数为1个或2个的4-6元饱和含氮单环杂环，例如氮杂环丁烷、四氢吡咯环、哌啶环、吗啉环或哌嗪环；The 3-7 membered nitrogen-containing monocyclic heterocycle may be a 3-7 membered saturated nitrogen-containing monocyclic heterocycle or a 3-7 membered nitrogen-containing monocyclic heterocycle alkene, and the 3-7 membered nitrogen-containing monocyclic heterocycle may be a 4-6 membered saturated nitrogen-containing monocyclic heterocycle in which the heteroatom is N or N and O and the number of heteroatoms is 1 or 2, such as azetidine, tetrahydropyrrole ring, piperidine ring, morpholine ring or piperazine ring; 所述的6-12元含氮多环杂环可为6-12元含氮螺环杂环、6-12元含氮并环杂环或6-12元含氮桥环杂环；The 6-12 membered nitrogen-containing polycyclic heterocycle may be a 6-12 membered nitrogen-containing spirocyclic heterocycle, a 6-12 membered nitrogen-containing cyclic heterocycle or a 6-12 membered nitrogen-containing bridged heterocycle; 所述的6-12元含氮螺环杂环可为6-12元饱和含氮螺环杂环或6-12元含氮螺环杂环烯，所述的6-12元饱和含氮螺环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮螺环杂环，例如氮杂螺[2.4]庚烷、氮杂螺[2.5]辛烷、氮杂螺[3,3]庚烷或氮杂螺[3,5]壬烷，优选 The 6-12 membered nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle or a 6-12 membered nitrogen-containing spiro heterocycle alkene. The 6-12 membered saturated nitrogen-containing spiro heterocycle may be a 6-12 membered saturated nitrogen-containing spiro heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azaspiro[2.4]heptane, azaspiro[2.5]octane, azaspiro[3,3]heptane or azaspiro[3,5]nonane, preferably 所述的6-12元含氮并环杂环可为6-12元饱和含氮并环杂环或6-12元含氮并环杂环烯，所述的6-12元饱和含氮并环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮并环杂环，进一步例如氮杂双环[3.1.0]己烷或八氢环戊烷并吡咯；The 6-12 membered nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle or a 6-12 membered nitrogen-containing paracyclic heterocycle alkene, and the 6-12 membered saturated nitrogen-containing paracyclic heterocycle may be a 6-12 membered saturated nitrogen-containing paracyclic heterocycle wherein the heteroatom is N and the number of heteroatoms is 1 or 2, further for example, azabicyclo[3.1.0]hexane or octahydrocyclopentapyrrole; 所述的6-12元含氮桥环杂环可为6-12元饱和含氮桥环杂环或6-12元含氮桥环杂环烯，所述的6-12元饱和含氮桥环杂环可为杂原子为N，杂原子的个数为1个或2个的6-12元饱和含氮桥环杂环，例如氮杂双环[2.2.2]辛烷；The 6-12 membered nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle or a 6-12 membered nitrogen-containing bridged ring heterocycle alkene, and the 6-12 membered saturated nitrogen-containing bridged ring heterocycle may be a 6-12 membered saturated nitrogen-containing bridged ring heterocycle in which the heteroatom is N and the number of heteroatoms is 1 or 2, such as azabicyclo[2.2.2]octane; (32)所述的情形2中，R1-2中，所述的卤素各自独立地为F、Cl、Br或I，例如F；(32) In the scenario 2, in R 1-2 , the halogen is independently F, Cl, Br or I, such as F; (33)所述的情形2中，当R1和R2与它们各自连接的碳原子共同形成C5-6碳环时，或RX与其相邻的R1和它们各自连接的碳原子共同形成C5-6碳环时，所述的C5-6碳环为C5-6饱和碳环或C5-6碳烯环；(33) In the case 2, when R1 and R2 together with the carbon atom to which they are attached form a C5-6 carbocyclic ring, or when RX and its adjacent R1 and the carbon atom to which they are attached form a C5-6 carbocyclic ring, the C5-6 carbocyclic ring is a C5-6 saturated carbocyclic ring or a C5-6 carbene ring; (34)所述的情形2中，当R1和R2与它们各自连接的碳原子共同形成C5-6碳环时，或RX与其 相邻的R1和它们各自连接的碳原子共同形成5-6元杂环时，所述的5-6元杂环为5-6元饱和杂环或5-6元杂环烯，例如二氢呋喃或1,3-二氧杂环戊烯；(34) In situation 2, when R1 and R2 together with the carbon atoms to which they are attached form a C5-6 carbon ring, or R X together with When adjacent R 1 and the carbon atoms to which they are respectively connected form a 5-6-membered heterocyclic ring, the 5-6-membered heterocyclic ring is a 5-6-membered saturated heterocyclic ring or a 5-6-membered heterocyclic alkene, such as dihydrofuran or 1,3-dioxole; (35)所述的情形1或情形2中，L2-1和L2-2中，每一“C1-6烷氧基”各自独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基；(35) In case 1 or case 2, in L 2-1 and L 2-2 , each "C 1-6 alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy; (36)所述的情形2中，L2-1-1或L2-1-3中，所述的C3-6环烃基各自独立地为C3-6环烷基或C3-6环烯基，所述的C3-6环烷基可为环丙基、环丁基、环戊基或环己基，例如环丙基；(36) In the situation 2, in L 2-1-1 or L 2-1-3 , the C 3-6 cycloalkyl group is independently a C 3-6 cycloalkyl group or a C 3-6 cycloalkenyl group, and the C 3-6 cycloalkyl group can be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group; (37)所述的情形2中，L2-1-1或L2-1-3中，所述的所述的3-6元杂环烃基为3-6元杂环烷基或3-6元杂环烯基，所述的3-6元杂环烷基可为杂原子为N和/或O，杂原子的个数为1个或2个的4-6元杂环烷基，例如氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、四氢呋喃基、哌啶基、吗啉基或哌嗪基。(37) In the situation 2, in L 2-1-1 or L 2-1-3 , the 3-6 membered heterocyclic hydrocarbon group is a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, and the 3-6 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group having 1 or 2 heteroatoms as N and/or O, such as oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, morpholinyl or piperazinyl. 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：The compound of formula (I) as claimed in claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1或情形2中，X为CH；(1) In case 1 or case 2, X is CH; (2)所述的情形1中，R1为C1-6烷基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基，例如C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；(2) In the above situation 1, R 1 is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 , for example, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; (3)所述的情形1或情形2中，R1-2独立地为氘或卤素；例如氘；(3) In the above-mentioned case 1 or case 2, R 1-2 is independently deuterium or halogen; for example, deuterium; (4)所述的情形1或情形2中，R8为氢、氘或氰基，例如氢或氰基；再例如氢；(4) In the above-mentioned case 1 or case 2, R 8 is hydrogen, deuterium or cyano, for example hydrogen or cyano; for example hydrogen; (5)所述的情形1或情形2中，每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；(5) In the above scenario 1 or scenario 2, each L 1-1 and L 1-2 are independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; (6)所述的情形1中，每个L2-0独立地C1-6烷基；(6) In the case 1, each L 2-0 is independently C 1-6 alkyl; (7)所述的情形1或情形2中，每个L2-1独立地为-N(L2-3)2；(7) In the above case 1 or case 2, each L 2-1 is independently -N(L 2-3 ) 2 ; (8)所述的情形1或情形2中，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3- 6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；较佳地，每个L2-2独立地为方案1或方案2，方案1：每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基，优选为C1-6烷基；方案2：每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；较佳地，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；更佳地每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；最佳地，为C1-6烷基或C1-6烷氧基；(8) In the above-described scenario 1 or scenario 2, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; preferably, each L 2-2 is independently Scheme 1 or Scheme 2. Scheme 1: each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 , preferably C 1-6 alkyl; Scheme 2: each L L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 or C 1-6 alkyl substituted by one or more L 2-1-1 ; preferably, each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; more preferably, each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; most preferably, it is C 1-6 alkyl or C 1-6 alkoxy; (9)所述的情形1或情形2中，每个L2-3独立地为C1-6烷基，或者两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环；较佳地，每个L2-3独立地为C1-6烷基；(9) In the above scenario 1 or scenario 2, each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are commonly connected form a 3-12 membered nitrogen-containing heterocyclic ring; preferably, each L 2-3 is independently a C 1-6 alkyl group; (10)所述的情形2中，R1为羟基或C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环；较佳地，R1为C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1 和它们各自连接的碳原子共同形成5-6元杂环；(10) In the situation 2 described above, R1 is hydroxyl or C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 and the carbon atom to which they are attached form a 5-6 membered heterocyclic ring; preferably, R1 is C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic ring; (11)所述的情形2中，R2为氢、C1-6烷氧基或卤素，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环；(11) In situation 2, R 2 is hydrogen, C 1-6 alkoxy or halogen, or R 1 and R 2 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic ring; (12)所述的情形2中，R3为氢或卤素；例如氢；(12) In situation 2, R 3 is hydrogen or halogen; for example, hydrogen; (13)所述的情形2中，L1为亚甲基；(13) In situation 2, L 1 is a methylene group; (14)所述的情形2中，RX为卤素，例如F；(14) In situation 2, RX is a halogen, such as F; (15)所述的情形2中，每个L2-1-1独立地为氘或C3-6环烃基，例如氘；(15) In the case 2 described above, each L 2-1-1 is independently deuterium or a C 3-6 cycloalkyl group, such as deuterium; (16)所述的情形1中，每个L2-1-1为氘。(16) In case 1, each L 2-1-1 is deuterium. 如权利要求1或2所示的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：The compound of formula (I) as shown in claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1中，X为N；(1) In the case 1 described above, X is N; (2)所述的情形1中，R1为C1-6烷基、C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基，例如C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；(2) In the above situation 1, R 1 is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 , for example, C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; (3)所述的情形1中，R1-2独立地为氘或卤素；(3) In the above situation 1, R 1-2 is independently deuterium or halogen; (4)所述的情形1中，R8为氢、氘或氰基，例如氢或氰基；(4) In the above situation 1, R 8 is hydrogen, deuterium or cyano, for example hydrogen or cyano; (5)所述的情形1中，每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；(5) In the above situation 1, each L 1-1 and L 1-2 are independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; (6)所述的情形1中，每个L2-0独立地C1-6烷基；(6) In the case 1, each L 2-0 is independently C 1-6 alkyl; (7)所述的情形1中，每个L2-1独立地为-N(L2-3)2；(7) In the case 1, each L 2-1 is independently -N(L 2-3 ) 2 ; (8)所述的情形1中，每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；(8) In the above situation 1, each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; (9)所述的情形1中，每个L2-3独立地为C1-6烷基，或者两个L2-3与它们共同连接的氮原子形成3-12元含氮杂环。(9) In the above situation 1, each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are commonly attached form a 3-12 membered nitrogen-containing heterocyclic ring. 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：The compound of formula (I) as claimed in claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1中，R1为C1-6烷氧基；(1) In the case 1, R 1 is C 1-6 alkoxy; (2)所述的情形1中，R8为氢；(2) In the case 1, R 8 is hydrogen; (3)所述的情形1中，L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；(3) In the above situation 1, L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ; 每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; 较佳地，L1为连接键或被一个或多个L1-2取代的亚乙基；或者，L1为连接键或被一个或多个L1-1取代的亚甲基；每个L1-1各自独立地为氢、氘或C1-6烷基，较佳地，每个L1-1各自独立地为氢或氘； Preferably, L 1 is a linking bond or an ethylene group substituted by one or more L 1-2 ; or, L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ; each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl, preferably, each L 1-1 is independently hydrogen or deuterium; (4)所述的情形1中，每个L1-2独立地为氢、氘、F或甲基，例如氢；(4) In the case 1, each L 1-2 is independently hydrogen, deuterium, F or methyl, such as hydrogen; (5)所述的情形1中，所述的L2为以下任一方案：(5) In the above scenario 1, L2 is any of the following: 方案1：L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；Scheme 1: L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl; 每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ; 每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2-3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2-3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; 每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium; 每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl; 每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring; 方案2：L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；Scheme 2: L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl; 每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ; 每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; 每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium; 每个L2-1-2独立地为C1-6烷基；Each L 2-1-2 is independently C 1-6 alkyl; 每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring; 方案3：L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；Scheme 3: L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl; 每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ; 每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ; 每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium; 每个L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；Each L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring; 方案4：L2为被1个、2个或3个L2-2取代的3-12元杂环烷基；Scheme 4: L 2 is a 3-12 membered heterocycloalkyl group substituted by 1, 2 or 3 L 2-2 ; 每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ; 每个L2-1-1独立地为氘；Each L 2-1-1 is independently deuterium; 方案5：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；Scheme 5: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; (6)所述的情形1中，每个L2-2独立地为氢、C1-6烷基、C1-6烷氧基或C3-6环烃基；(6) In the above situation 1, each L 2-2 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; (7)所述的情形2中，L2为被1个、2个或3个L2-2取代的3-12元杂环烷基；每个L2-2独立地 为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；每个L2-1-1独立地为氘；较佳地，所述的L2为被1个、2个或3个L2-1取代的3-12元杂环烃基，L2-1为C1-6烷基；较佳地，所述的L2为被1个、2个或3个L2-1取代的旦杂环丁烷基，L2-1为C1-6烷基；更佳地，所述的L2为L2-1为C1-6烷基。(7) In the above situation 2, L 2 is a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently is C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 ; each L 2-1-1 is independently deuterium; preferably, the L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-1 , L 2-1 is C 1-6 alkyl; preferably, the L 2 is a cyclobutyl group substituted by 1, 2 or 3 L 2-1 , L 2-1 is C 1-6 alkyl; more preferably, the L 2 is L 2-1 is a C 1-6 alkyl group. 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：The compound of formula (I) as claimed in claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1中，R1-1为氘或F；(1) In the above situation 1, R 1-1 is deuterium or F; (2)所述的情形1中，为例如 (2) In the above situation 1, for For example (3)所述的情形1中，每个L1-1和L1-2各自独立地为氢、氘、F或甲基；(3) In the above situation 1, each L 1-1 and L 1-2 are independently hydrogen, deuterium, F or methyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成环丙烷或环丁烷；Alternatively, two L 1-1 groups on the same carbon atom and the carbon atom to which they are commonly attached form cyclopropane or cyclobutane; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成环丙烷或环丁烷；Alternatively, two L 1-2 on the same carbon atom form a cyclopropane or cyclobutane with the carbon atom to which they are commonly attached; (4)所述的情形1中，每个L2-0独立地为甲基；(4) In the case 1, each L 2-0 is independently methyl; (5)所述的情形1中，每个L2-1为-N(CH3)2或 (5) In the case 1, each L 2-1 is -N(CH 3 ) 2 or (6)所述的情形1中，每个L2-2独立地为甲基、环丙基、甲氧基、-N(CH3)2、 (6) In the case 1, each L 2-2 is independently methyl, cyclopropyl, methoxy, -N(CH 3 ) 2 , (7)所述的情形2中，X为CH、CF或C-CH3，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；较佳地，X为方案1或方案2，方案1：X为CH，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成 其中“a”标注的碳原子表示其为X对应的碳原子；方案2：X为CH或CF，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；(7) In the case 2, X is CH, CF or C-CH 3 , or RX and its adjacent R 1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; preferably, X is Scheme 1 or Scheme 2, Scheme 1: X is CH, or RX and its adjacent R1 and the carbon atom to which they are connected together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; Scheme 2: X is CH or CF, or RX and its adjacent R1 and the carbon atom to which they are connected together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; (8)所述的情形2中，R1为方案1或方案2，方案1：R1为甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成 或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；(8) In the case 2, R 1 is Scheme 1 or Scheme 2. Scheme 1: R 1 is methoxy, -S(=O) 2 CH 3 , -OCH(CH 3 ) 2 or CN, or R 1 and R 2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; 较佳地，R1为甲氧基，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；方案2：R1为羟基、甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；Preferably, R1 is a methoxy group, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; Scheme 2: R 1 is hydroxyl, methoxy, -S(=O) 2 CH 3 , -OCH(CH 3 ) 2 or CN, or R 1 and R 2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; 较佳地，R1为羟基、甲氧基、-S(＝O)2CH3、-OCH(CH3)2或CN，或者R1和R2与它们各自连接的碳原子共同形成或者RX与其相邻的R1和它们各自连接的碳原子共同形成 其中“a”标注的碳原子表示其为X对应的碳原子；Preferably, R1 is hydroxyl, methoxy, -S(=O) 2CH3 , -OCH( CH3 ) 2 or CN, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; 更佳地，R1为羟基或甲氧基，或者R1和R2与它们各自连接的碳原子共同形成 或者RX与其相邻的R1和它们各自连接的碳原子共同形成其中“a”标注的碳原子表示其为X对应的碳原子；More preferably, R1 is hydroxyl or methoxy, or R1 and R2 together with the carbon atoms to which they are attached form Or RX and its adjacent R1 and the carbon atom to which they are attached together form The carbon atom marked with "a" indicates that it is the carbon atom corresponding to X; (9)所述的情形2中，R8为氢；(9) In the case 2 described above, R 8 is hydrogen; (10)所述的情形2中，R2为氢、甲氧基或F，或者，R1和R2与它们各自连接的碳原子共同形成较佳地，R2为氢、甲氧基或F，者，R1和R2与它们各自连接的碳原子共同形成 (10) In the case 2, R2 is hydrogen, methoxy or F, or R1 and R2 together with the carbon atoms to which they are attached form Preferably, R2 is hydrogen, methoxy or F, or, R1 and R2 together with the carbon atoms to which they are attached form (11)所述的情形2中，R3为氢或F。In aspect 2 described in (11), R 3 is hydrogen or F. 如权利要求1所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1中，R1为甲氧基、例如R1为甲氧基或 (1) In the case 1, R1 is methoxy, For example, R1 is methoxy or 较佳地，为 Preferably, for (2)所述的情形1中，R8为氢或氰基；(2) In the above situation 1, R 8 is hydrogen or cyano; (3)所述的情形1中，L1为方案1或方案2，方案1：L1为连接键、亚甲基、亚乙基、 优选为连接键、亚甲基、亚乙基、 其中#侧与L2相连；(3) In the above-mentioned situation 1, L1 is Scheme 1 or Scheme 2. Scheme 1: L1 is a linking bond, methylene, ethylene, Preferably, it is a linker, a methylene group, an ethylene group, The # side is connected to L 2 ; 方案2：L1为连接键、亚甲基、亚乙基、 优选为连接键、亚甲基、亚乙基、 其中#侧与L2相连；更佳地，为连接键、亚甲基、亚乙基、最佳地，为连接键、亚甲基、 Scheme 2: L 1 is a connecting bond, methylene, ethylene, Preferably, it is a linker, a methylene group, an ethylene group, Wherein the # side is connected to L2 ; more preferably, it is a connecting bond, methylene, ethylene, Most preferably, a linker, a methylene group, (4)所述的情形1中，L2为方案1或方案2，方案1：(4) In the above-mentioned situation 1, L2 is solution 1 or solution 2, and solution 1: L2为-N(CH3)2、 n为1、2或3，优选为1；L2优选为 L2 is -N( CH3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably 例如 较佳地，为或由组成的混合物；For example Preferably, for or by mixture of components; 方案2：L2为-N(CH3)2、 n为1、2或3，优选为1；L2优选为 例如 Scheme 2: L 2 is -N(CH 3 ) 2 , n is 1, 2 or 3, preferably 1; L2 is preferably For example (5)所述的情形2中，为 较佳地，为方案1或方案2，方案1： 优选为 方案2： (5) In the case 2 described above, for Preferably, it is Scheme 1 or Scheme 2, Scheme 1: Preferably Scenario 2: (6)所述的情形2中，L1为亚甲基、优选为亚甲基；(6) In the case 2, L1 is a methylene group, Preferably it is methylene; (7)所述的情形2中，L2为 n为1、2或3；L2优选为 n为1、2或3；较佳地，L2为 (7) In case 2, L2 is n is 1, 2 or 3; L 2 is preferably n is 1, 2 or 3; preferably, L 2 is L2例如 优选为 L2 For example Preferably 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种： The compound of formula (I) as claimed in claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions: (1)所述的情形1中，R1为 In the case 1 described in (1), R1 is (2)所述的情形1中，L1为 优选为 其中#侧与L2相连；(2) In the case 1 described above, L1 is Preferably The # side is connected to L 2 ; (3)所述的情形1中，L2为 n为1、2、或3，优选为1；L2优选为 例如 进一步例如 (3) In the case 1 described above, L2 is n is 1, 2, or 3, preferably 1; L2 is preferably For example Further example 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的情形1中，R1为甲氧基。The compound of formula (I) as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that in the scenario 1, R 1 is methoxy. 如权利要求1-10中至少一项所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的情形1中，所述的如式(I)所示的化合物为如式(I-1)、(I-2)、(I-3)、(I-4)、(I-5)或(I-6)所示的化合物：
The compound of formula (I) according to at least one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that in the scenario 1, the compound of formula (I) is a compound of formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6):
其中，如式(I-1)、(I-2)、(I-3)、(I-4)、(I-5)或(I-6)所示的化合物中，R1、R8、L2、L1-1和L1-2的定义如权利要求1-10中至少一项所述； Wherein, in the compound represented by formula (I-1), (I-2), (I-3), (I-4), (I-5) or (I-6), R 1 , R 8 , L 2 , L 1-1 and L 1-2 are defined as at least one of claims 1 to 10; 较佳地，所述的如式(I-1)或(I-4)所示的化合物中，L2为 n为1、2或3，优选为1；L2优选为 Preferably, in the compound as shown in formula (I-1) or (I-4), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably 较佳地，如式(I-2)或(I-5)所示的化合物中，L2为方案1或方案2，方案1：Preferably, in the compound represented by formula (I-2) or (I-5), L2 is Scheme 1 or Scheme 2, Scheme 1: L2为 n为1、2或3，优选为1；L2优选为 L2 is n is 1, 2 or 3, preferably 1; L2 is preferably 方案2：L2为 n为1、2或3，优选为1；L2优选为 较佳地，如式(I-3)或(I-6)所示的化合物中，L2为n为1、2或3，优选为1；L2优选为或者，Scheme 2: L2 is n is 1, 2 or 3, preferably 1; L2 is preferably Preferably, in the compound represented by formula (I-3) or (I-6), L2 is n is 1, 2 or 3, preferably 1; L2 is preferably or, 如式(I-3)或(I-6)所示的化合物中，L2为-N(CH3)2，且至少一个L1-2为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；In the compound represented by formula (I-3) or (I-6), L 2 is -N(CH 3 ) 2 , and at least one L 1-2 is deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom form a C 3-5 carbocyclic ring with the carbon atom to which they are commonly attached; 和/或，所述的情形2中，所述的如式(I)所示的化合物为如式(I-7)所示的化合物：
And/or, in the scenario 2, the compound represented by formula (I) is a compound represented by formula (I-7):
其中，R1、R2、R3、X和R8的定义如权利要求1-10中至少一项所述；较佳地，R3为H，X为CH。 Wherein, R 1 , R 2 , R 3 , X and R 8 are defined as at least one of claims 1 to 10; preferably, R 3 is H, and X is CH. 如权利要求1或2所述的如式(I)所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式(I)所示的化合物为以下任一方案：The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (I) is any of the following: 方案1：Scenario 1: 所述的情形1中，In the above situation 1, X为CH或N；X is CH or N; R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; R1-1独立地为氘或卤素；R 1-1 is independently deuterium or halogen; R8为氢或氰基；R 8 is hydrogen or cyano; L1为连接键、被一个或多个L1-1取代的亚甲基或被一个或多个L1-2取代的亚乙基；L 1 is a linking bond, a methylene group substituted by one or more L 1-1 , or an ethylene group substituted by one or more L 1-2 ; 每个L1-1和L1-2各自独立地为氢、氘、卤素或C1-6烷基；Each L 1-1 and L 1-2 is independently hydrogen, deuterium, halogen or C 1-6 alkyl; 或者，同一个碳原子上的两个L1-1与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-1 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; 或者，同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环；Alternatively, two L 1-2 groups on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl; 每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ; 每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、3-6元杂环烃基、-N(L2- 3)2、被一个或多个L2-1-1取代的C1-6烷基或被一个或多个L2-1-2取代的C3-6环烃基；Each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -N(L 2- 3 ) 2 , C 1-6 alkyl substituted by one or more L 2-1-1 , or C 3-6 cycloalkyl substituted by one or more L 2-1-2 ; L2-1-1独立地为氘；L 2-1-1 is independently deuterium; L2-1-2独立地为C1-6烷基；L 2-1-2 is independently C 1-6 alkyl; L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring; 其中，如式(I)所示的化合物满足以下条件的一种、两种、三种或四种：Wherein, the compound as shown in formula (I) satisfies one, two, three or four of the following conditions: I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: for L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl; II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基；II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl; III：为L1为被一个或多个L1-2取代的亚乙基，每个L1-2独立地为氘、卤素或C1-6烷基，或者同一个碳原子上的两个L1-2与它们共同连接的碳原子形成C3-5碳环； III: for L 1 is ethylene substituted by one or more L 1-2 , each L 1-2 is independently deuterium, halogen or C 1-6 alkyl, or two L 1-2 on the same carbon atom and the carbon atom to which they are commonly attached form a C 3-5 carbocyclic ring; IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基；IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 ; 方案2：所述的情形1中，Solution 2: In the above scenario 1, X为CH或N；X is CH or N; R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; R1-2独立地为氘；R 1-2 are independently deuterium; R8为氢； R8 is hydrogen; L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ; 每个L1-1各自独立地为氢、氘或C1-6烷基；Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl; L2为-N(L2-0)2、被1个、2个或3个L2-1取代的C3-12环烷基或被1个、2个或3个L2-2取代的3-12元杂环烷基；L 2 is -N(L 2-0 ) 2 , C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 , or 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; 每个L2-0独立地C1-6烷基；Each L 2-0 is independently C 1-6 alkyl; 每个L2-1独立地为-N(L2-3)2；Each L 2-1 is independently -N(L 2-3 ) 2 ; 每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基、C3-6环烃基、-N(L2-3)2或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -N(L 2-3 ) 2 , or C 1-6 alkyl substituted by one or more L 2-1-1 ; L2-1-1独立地为氘；L 2-1-1 is independently deuterium; L2-3独立地为C1-6烷基，或者两个L2-3与它们相连的氮原子共同形成3-12元含氮杂环；L 2-3 is independently a C 1-6 alkyl group, or two L 2-3 and the nitrogen atom to which they are attached together form a 3-12 membered nitrogen-containing heterocyclic ring; 其中，如式(I)所示的化合物满足以下条件的一种、两种或三种：Wherein, the compound as shown in formula (I) satisfies one, two or three of the following conditions: I：为L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12单环环烃基，所述的“3-12元杂环烃基”为3-12元单环杂环烃基；I: for L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 monocyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered monocyclic heterocycloalkyl; II：L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基，所述的“C3-12环烃基”为C3-12多环环烃基，所述的“3-12元杂环烃基”为3-12元多环杂环烃基；II: L 2 is a C 3-12 cycloalkyl substituted by 1, 2 or 3 L 2-1 or a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 , wherein the “C 3-12 cycloalkyl” is a C 3-12 polycyclic cycloalkyl, and the “3-12 membered heterocycloalkyl” is a 3-12 membered polycyclic heterocycloalkyl; IV：为R1为被1个、2个或3个R1-2取代的C1-6烷氧基；IV: for R 1 is a C 1-6 alkoxy group substituted by 1, 2 or 3 R 1-2 ; 方案3：Solution 3: 所述的情形1中，
为 In the above situation 1,
for X为CH或N；X is CH or N; R1为C1-6烷氧基或被1个、2个或3个R1-2取代的C1-6烷氧基；R 1 is C 1-6 alkoxy or C 1-6 alkoxy substituted by 1, 2 or 3 R 1-2 ; R1-2独立地为氘；R 1-2 are independently deuterium; R8为氢； R8 is hydrogen; L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ; 每个L1-1各自独立地为氢、氘或C1-6烷基；Each L 1-1 is independently hydrogen, deuterium or C 1-6 alkyl; L2为被1个、2个或3个L2-2取代的3-12元杂环烷基；所述的“3-12元杂环烃基”为3-12元单环杂环烃基；L 2 is a 3-12 membered heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; the "3-12 membered heterocycloalkyl" is a 3-12 membered monocyclic heterocycloalkyl; 每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；Each L 2-2 is independently C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl substituted by one or more L 2-1-1 ; L2-1-1独立地为氘；L 2-1-1 is independently deuterium; 方案4：Solution 4: 所述的情形1中，
为 In the above situation 1,
for X为CH或N；X is CH or N; R1为C1-6烷氧基； R1 is C1-6 alkoxy; R8为氢； R8 is hydrogen; L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ; 每个L1-1各自独立地为氢或氘；Each L 1-1 is independently hydrogen or deuterium; L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基或被1个、2个或3个L2-2取代的3-7元单环杂环烯基；每个L2-2独立地为C1-6烷基或C1-6烷氧基；所述3-7元单环杂环烷基或3-7元单环杂环烯基中的杂原子为N，杂原子个数为1个或2个；L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1 or 2; 方案5：Solution 5: 所述的情形1中，
为 In the above situation 1,
for X为CH；X is CH; R1为C1-6烷氧基； R1 is C1-6 alkoxy; R8为氢； R8 is hydrogen; L1为连接键或被一个或多个L1-1取代的亚甲基；L 1 is a linking bond or a methylene group substituted by one or more L 1-1 ; 每个L1-1各自独立地为氢或氘；Each L 1-1 is independently hydrogen or deuterium; L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基或被1个、2个或3个L2-2取代的3-7元单环杂环烯基；每个L2-2独立地为C1-6烷基或C1-6烷氧基；所述3-7元单环杂环烷基或3-7元单环杂环烯基中的杂原子为N，杂原子个数为1个；L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 or a 3-7 membered monocyclic heterocycloalkenyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1; 方案6：Solution 6: 所述的情形2中，In the situation 2 described above, X为CH或CRX；RX为卤素或C1-6烷基；X is CH or CR X ; RX is halogen or C 1-6 alkyl; R1为羟基、C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring; R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen; R3为氢或卤素； R3 is hydrogen or halogen; L1为亚甲基；L 1 is a methylene group; L2为被1个、2个或3个L2-2取代的3-12元杂环烃基，每个L2-2独立地为氢、卤素、羟基、C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基，每个L2-1-1独立地为C3-6环烃基或氘；L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more L 2-1-1 , each L 2-1-1 is independently C 3-6 cycloalkyl or deuterium; 方案7：所述的情形2中，Solution 7: In the above scenario 2, X为CH或CRX；RX为卤素；X is CH or CR X ; RX is halogen; R1为羟基、C1-6烷氧基，或者R1和R2与它们各自连接的碳原子共同形成5-6元杂环，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is hydroxyl, C1-6 alkoxy, or R1 and R2 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring, or RX and its adjacent R1 together with the carbon atom to which they are attached form a 5-6 membered heterocyclic ring; R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen; R3为氢或卤素； R3 is hydrogen or halogen; L1为亚甲基；L 1 is a methylene group; L2为被1个、2个或3个L2-2取代的3-12元杂环烃基，每个L2-2独立地为C1-6烷基、C1-6烷氧基或被一个或多个L2-1-1取代的C1-6烷基；每个L2-1-1为氘；L 2 is a 3-12 membered heterocyclic hydrocarbon group substituted by 1, 2 or 3 L 2-2 , each L 2-2 is independently a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 alkyl group substituted by one or more L 2-1-1 ; each L 2-1-1 is deuterium; 方案8：Solution 8: 所述的情形2中，In the situation 2 described above, X为CH或CRX；RX为卤素；X is CH or CR X ; RX is halogen; R1为C1-6烷氧基，或者，RX与其相邻的R1和它们各自连接的碳原子共同形成5-6元杂环； R1 is a C1-6 alkoxy group, or RX , its adjacent R1 and the carbon atom to which they are attached together form a 5-6 membered heterocyclic ring; R2为氢、C1-6烷氧基或卤素； R2 is hydrogen, C1-6 alkoxy or halogen; R3为氢； R3 is hydrogen; L1为亚甲基；L 1 is a methylene group; L2为被1个、2个或3个L2-2取代的3-7元单环杂环烷基；每个L2-2独立地为C1-6烷基或C1-6烷氧；所述3-7元单环杂环烷基或3-7元单环杂环烯基中的杂原子为N，杂原子个数为1个或2个(例如1个)； L 2 is a 3-7 membered monocyclic heterocycloalkyl substituted by 1, 2 or 3 L 2-2 ; each L 2-2 is independently a C 1-6 alkyl or a C 1-6 alkoxy; the heteroatom in the 3-7 membered monocyclic heterocycloalkyl or 3-7 membered monocyclic heterocycloalkenyl is N, and the number of heteroatoms is 1 or 2 (e.g., 1); 方案9：所述的情形1和2中，所述的如式(I)所示的化合物中：Scheme 9: In the above-mentioned situations 1 and 2, in the above-mentioned compound represented by formula (I): L1为亚甲基，L2为被1个、2个或3个L2-1取代的C3-12环烃基或被1个、2个或3个L2-2取代的3-12元杂环烃基；当L2中的碳原子与L1连接时，所述L2中与L1连接的碳原子为手性碳原子，所述手性碳原子为R构型、S构型或由R构型和S构型组成的混合物； L1 is a methylene group, L2 is a C3-12 cycloalkyl group substituted by 1, 2 or 3 L2-1 groups , or a 3-12 membered heterocycloalkyl group substituted by 1, 2 or 3 L2-2 groups ; when the carbon atom in L2 is connected to L1 , the carbon atom in L2 connected to L1 is a chiral carbon atom, and the chiral carbon atom is in R configuration, S configuration or a mixture of R configuration and S configuration; 方案10：所述的情形2中，所述的如式(I)所示的化合物为如式(I-A)、(I-B)或(I-C)所示的化合物：
Scheme 10: In the scenario 2, the compound represented by formula (I) is a compound represented by formula (IA), (IB) or (IC):
其中，R1、R2、R3、X、L2-2和R8的定义如权利要求1-10中至少一项所述；wherein R 1 , R 2 , R 3 , X, L 2-2 and R 8 are defined as at least one of claims 1 to 10; 较佳地，所述如式(I-A)、(I-B)和(I-C)所示的化合物中，R3为H，X为CH。Preferably, in the compounds represented by formula (IA), (IB) and (IC), R 3 is H and X is CH. 一种如下所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，





A compound as shown below, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,





它们药学上可接受的盐例如为以下化合物中的任一种： Their pharmaceutically acceptable salts are, for example, any of the following compounds: 的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、 的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐、的一甲酸盐或的一甲酸盐； Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, Monoformate, monoformate or Monoformate of; 较佳地，所述的如式(I)所示的化合物为以下任一化合物：Preferably, the compound represented by formula (I) is any of the following compounds: 中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L甲酸水溶液，流动相中A的体积百分比为2-32％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-Xbridge-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为9min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-Xbridge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes first is 9min; 中在下述高效液相色谱条件下后出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L甲酸水溶液，流动相中A的体积百分比为2-32％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-Xbridge-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为9.2min； The compound that elutes later under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L formic acid aqueous solution, the volume percentage of A in the mobile phase is 2-32%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-Xbridge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes later is 9.2min; 中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为0.1％(v/v)甲酸水溶液，流动相中A的体积百分比为10-20％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-SunFire-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为7.3min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 0.1% (v/v) formic acid aqueous solution, the volume percentage of A in the mobile phase is 10-20%, gradient elution, flow rate 20 mL/min, and elution time is 17 min; preferably, the model of the chromatographic column is: Waters-SunFire-C18-10 μm-19*250 mm, and more preferably, the retention time of the compound that elutes first is 7.3 min; 中在下述高效液相色谱条件下后出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为0.1％(v/v)甲酸水溶液，流动相中A的体积百分比为10-20％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-SunFire-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为7.7min； The compound that elutes later under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is 0.1% (v/v) formic acid aqueous solution, the volume percentage of A in the mobile phase is 10-20%, gradient elution, flow rate 20 mL/min, and elution time is 17 min; preferably, the model of the chromatographic column is: Waters-SunFire-C18-10 μm-19*250 mm, and more preferably, the retention time of the compound that elutes later is 7.7 min; 中在下述高效液相色谱条件下先出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L三氟乙酸水溶液，流动相中A的体积百分比为15-25％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-XBndge-C18-10μm-19*250mm，更佳地，所述的先出峰的化合物的保留时间为5.7min； The compound that elutes first under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20mL/min, and elution time is 17min; preferably, the model of the chromatographic column is: Waters-XBndge-C18-10μm-19*250mm, and more preferably, the retention time of the compound that elutes first is 5.7min; 中在下述高效液相色谱条件下后出峰的化合物：色谱柱的固定相为C18，流动相为A和B的混合物，其中A为乙腈，B为10mmol/L三氟乙酸水溶液，流动相中A的体积百分比为15-25％，梯度洗脱，流速20mL/min，洗脱时间为17min；较佳地，所述色谱柱的型号：Waters-XBndge-C18-10μm-19*250mm，更佳地，所述的后出峰的化合物的保留时间为7.5min。 The compound that elutes later under the following high performance liquid chromatography conditions: the stationary phase of the chromatographic column is C18, the mobile phase is a mixture of A and B, wherein A is acetonitrile, B is a 10 mmol/L trifluoroacetic acid aqueous solution, the volume percentage of A in the mobile phase is 15-25%, gradient elution, flow rate 20 mL/min, and elution time is 17 min; preferably, the model of the chromatographic column is: Waters-XBndge-C18-10 μm-19*250 mm, and more preferably, the retention time of the compound that elutes later is 7.5 min. 一种药物组合物，其包含物质X和药学上可接受的载体，所述的物质X为如权利要求1-13中至少一项所述的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable carrier, wherein the substance X is a compound according to at least one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 一种如权利要求1-13中至少一项所述的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如权利要求14所述的药物组合物在制备调控神经元可塑性的药物中的应用。A use of at least one of the compounds according to claims 1 to 13, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a drug for regulating neuronal plasticity. 一种如权利要求1-13中至少一项所述的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物或如权利要求14所述的药物组合物在制备预防和/或治疗抑郁症、精神分裂症、焦虑或创伤后应激障碍的药物中的应用。 Use of at least one of the compounds according to claims 1 to 13, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and/or treating depression, schizophrenia, anxiety or post-traumatic stress disorder.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993764A (en) * 1974-12-09 1976-11-23 Roussel-Uclaf Treatment of depressive states and Parkinson's disease
WO2015082499A2 (en) * 2013-12-03 2015-06-11 Iomet Pharma Ltd Pharmaceutical compound
CN113840600A (en) * 2019-02-27 2021-12-24 加利福尼亚大学董事会 N-Substituted Indoles and Other Heterocyclic Compounds for the Treatment of Brain Diseases
WO2023108174A1 (en) * 2021-12-10 2023-06-15 Terran Biosciences, Inc. Analogs of 6-methoxy- n, n-dimethyltryptamine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993764A (en) * 1974-12-09 1976-11-23 Roussel-Uclaf Treatment of depressive states and Parkinson's disease
WO2015082499A2 (en) * 2013-12-03 2015-06-11 Iomet Pharma Ltd Pharmaceutical compound
CN113840600A (en) * 2019-02-27 2021-12-24 加利福尼亚大学董事会 N-Substituted Indoles and Other Heterocyclic Compounds for the Treatment of Brain Diseases
WO2023108174A1 (en) * 2021-12-10 2023-06-15 Terran Biosciences, Inc. Analogs of 6-methoxy- n, n-dimethyltryptamine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRANCISCO-JAVIER GAMO, LAURA M. SANZ, JAUME VIDAL, CRISTINA DE COZAR, EMILIO ALVAREZ, JOSE-LUIS LAVANDERA, DANA E. VANDERWALL, DAR: "Thousands of chemical starting points for antimalarial lead identification", NATURE, vol. 465, 20 May 2010 (2010-05-20), pages 305 - 310, XP002698188, DOI: 10.1038/NATURE09107 *
MATTSON RONALD J., CATT JOHN D., DENHART DEREK J., DESKUS JEFFREY A., DITTA JONATHAN L., HIGGINS MENDI A., MARCIN LAWRENCE R., SLO: "Conformationally Restricted Homotryptamines. 2. Indole Cyclopropylmethylamines as Selective Serotonin Reuptake Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 19, 1 September 2005 (2005-09-01), US , pages 6023 - 6034, XP093221529, ISSN: 0022-2623, DOI: 10.1021/jm0503291 *

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