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WO2025103493A1 - Cannabinoid receptor 1 antagonist and use thereof - Google Patents

Cannabinoid receptor 1 antagonist and use thereof Download PDF

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Publication number
WO2025103493A1
WO2025103493A1 PCT/CN2024/132475 CN2024132475W WO2025103493A1 WO 2025103493 A1 WO2025103493 A1 WO 2025103493A1 CN 2024132475 W CN2024132475 W CN 2024132475W WO 2025103493 A1 WO2025103493 A1 WO 2025103493A1
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Prior art keywords
alkyl
cycloalkyl
compound
alkoxy
deuterated
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PCT/CN2024/132475
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French (fr)
Chinese (zh)
Inventor
李瑶
任磊
张浩亮
石宗军
宋长伟
程凤凯
裴云鹏
王杰
付超
王景富
张晨
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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Publication of WO2025103493A1 publication Critical patent/WO2025103493A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a cannabinoid receptor 1 (CB1) antagonist, its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, cocrystal or deuterated substance, and use thereof in preparing a drug for treating CB1-mediated related diseases.
  • CBD1 cannabinoid receptor 1
  • CB1 is expressed not only in the brain, but also in peripheral cells and tissues, and is a component of the endocannabinoid system.
  • CB1 activates intracellular signals through stimulation or binding of cannabinoids and their derivatives, and exerts a wide range of biological effects. Activation of this system can increase appetite, promote the synthesis and storage of lipids, etc.
  • CB1 antagonists can reduce weight by inhibiting the endocannabinoid system, reducing appetite, and reducing food intake.
  • CB1 antagonists have been shown to have weight loss effects, such as rimonabant, and have the effects of sensitizing insulin and improving lipid metabolism disorders. However, it was withdrawn from the market because of its central side effects.
  • drugs that can be used for diseases such as metabolic syndrome, obesity, diabetic nephropathy, insulin-dependent diabetes or non-insulin-dependent diabetes.
  • the purpose of the present invention is to provide a CB1 antagonist with the advantages of novel structure, good efficacy, high bioavailability, small side effects, rapid onset and long-term effect.
  • the present invention relates to a compound represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), and a stereoisomer or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C
  • R 2 is selected from hydrogen
  • R 1 is selected from halogen;
  • R 3 is selected from C 1-4 haloalkyl; in certain embodiments, R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl; in certain embodiments, R 1 is selected from F, Cl, Br, methyl, ethyl, acetylene;
  • R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;
  • R 1 is selected from F, Cl, Br; R 3 is selected from -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F; In certain embodiments, R 1 is selected from F, Cl, Br, methyl; R 3 is selected from -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, vinyl, ethynyl, 1-fluorovinyl; In certain embodiments, R 1 is selected from Cl; R 3 is selected from -CF 3 ; In certain embodiments, R 1 is selected from halogen, C 1-3 alkyl; In certain embodiments, R 1 is selected from Cl; In certain embodiments, R 1 is selected from -CH 3 ; In certain embodiments, R 1 is selected from acetylene;
  • R 3 is selected from halogen, SF 5 , C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl; In certain embodiments, R 3 is selected from F, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, vinyl, ethynyl, 1-fluorovinyl, SF 5 ;
  • R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy;
  • L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L 1 is selected from a bond
  • L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L2 is selected from a bond, C1-2 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • R A1 is selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloal
  • R A1 is selected from cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • R A1 is selected from cyano, methyl, ethyl, propyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolyl, oxhexyl, thiazole, azetyl, azohexyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, Optionally further substituted with 1-5 Ra;
  • R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl, azopentyl, azohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, Optionally further substituted with 1-5 Ra;
  • R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, aziridine, azohexyl, phenyl, Optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-4 alkyl, halogen, cyano;
  • R W1 is selected from H, C 1-2 alkyl, halogen, cyano; In certain embodiments, R W1 is selected from H, C 1-2 alkyl, cyano; In certain embodiments, R W1 is selected from H, cyano;
  • Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl,
  • Ra is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substitute
  • R is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 halogen, oxo, C 1-4 alkyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or deuterated C
  • Ra is substituted with a C 1-4 alkoxy group; in some embodiments, Ra is selected from deuterium, halogen, oxo,
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;
  • two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; in certain embodiments, alternatively, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl; in certain embodiments, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl; in certain embodiments, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl;
  • RA is selected from
  • RA is selected from
  • RA is selected from:
  • R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;
  • R A2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;
  • RA2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl , ethyl, isopropyl, methoxy, ethoxy, F, Cl, oxo, methylidene, ethylidene, 1 - methylethyliden
  • R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-4 alkoxy;
  • R A2 is selected from C 3-6 cycloalkyl, which is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;
  • RA2 is selected from cyclopropyl, cyclobutyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxacyclohexyl, azohexyl, morpholinyl, piperazinyl, the ...
  • oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxhexyl, azohexyl, morpholinyl, piperazinyl are optionally further substituted with 1-3 groups selected from methyl, ethyl, F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene , -CH2D, -CHD2 , -CD3 , -CH2CH2D , -CH2CHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDC
  • X1 , X2 , X3 , X4 are selected from CH or N; in some embodiments, X1 , X2 , X3 , X4 are selected from CH or N, and at least one of X1 , X2 , X3 , X4 is selected from N; in certain embodiments, X1 , X2 are selected from CH, X3 , X4 are selected from N; in certain embodiments, X1 , X2 are selected from N, X3 , X4 are selected from CH; in certain embodiments, X1 is selected from N, X2 , X3 , X4 are selected from CH; in certain embodiments, X2 is selected from N, X1 , X3 , X4 are selected from CH; in certain embodiments, X3 is selected from N, X1 , X2 , X4 are selected from CH; in certain embodiments, X3 is selected from N, X1
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or a 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy;
  • two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;
  • n is selected from 0, 1, 2, 3, 4 or 5; in certain embodiments, n is selected from 0, 1, 2 or 3; in certain embodiments, n is selected from 0 or 1; in certain embodiments, n is selected from 0;
  • n is selected from 1, 2, 3, 4 or 5; in certain embodiments, m is selected from 1, 2 or 3; in certain embodiments, m is selected from 1 or 2; in certain embodiments, m is selected from 1;
  • k is selected from 1, 2, 3, 4 or 5; in certain embodiments, k is selected from 1, 2 or 3; in certain embodiments, k is selected from 1 or 2; in certain embodiments, k is selected from 1;
  • R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;
  • the compounds of the present invention are not selected from the following structures
  • one embodiment of the present invention relates to a compound represented by formula (I), formula (IV), formula (IV-a), formula (IV-b), and stereoisomers and pharmaceutically acceptable salts thereof.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;
  • L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;
  • R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-4 alkyl, halogen, cyano;
  • Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl,
  • R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;
  • X 1 , X 2 , X 3 , X 4 are selected from CH or N;
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2, 3, 4 or 5;
  • k is selected from 1, 2, 3, 4 or 5;
  • R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;
  • one embodiment of the present invention relates to a compound represented by formula (I) or formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;
  • R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-4 alkyl, halogen, cyano;
  • Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl,
  • R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;
  • X 1 , X 2 , X 3 , and X 4 are selected from CH or N, and at least one of X 1 , X 2 , X 3 , and X 4 is selected from N;
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2, 3, 4 or 5;
  • k is selected from 1, 2, 3, 4 or 5;
  • R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;
  • Another embodiment of the present invention relates to a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;
  • L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;
  • R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-4 alkyl, halogen, cyano;
  • Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, -C(O) C1-4 alkyl, -C(O) C1-4 deuterated alkyl, -NRW1C(O) C1-4 alkyl, -NRW1C(O) C1-4 deuterated alkyl, -S(O) 2NH2 , -S ( O) 2NHC1-4 alkyl , -C(O) C3-8 cycloalkyl , -C(O ) NRW1C1-4 alkyl , -NRW1C(O) C3-8 cycloalkyl , -S(O
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2, 3, 4 or 5;
  • k is selected from 1, 2, 3, 4 or 5;
  • the conditions are:
  • R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl.
  • Another embodiment of the present invention relates to a compound represented by formula (IV), its stereoisomers, and pharmaceutically acceptable salts.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl,
  • R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • X 1 , X 2 , X 3 , X 4 are selected from CH or N; in some embodiments, X 1 , X 2 , X 3 , X 4 are selected from CH or N, and at least one of X 1 , X 2 , X 3 , X 4 is selected from N;
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2, 3, 4 or 5;
  • k is selected from 1, 2, 3, 4 or 5.
  • the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -SF 5 , -SCF 3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra;
  • n is selected from 0, 1, 2 or 3;
  • n is selected from 1, 2 or 3;
  • k is selected from 1, 2 or 3.
  • the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • RA is selected from -W1 - L2 - W2 - RA1, -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;
  • L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ;
  • R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, halogen, cyano;
  • Ra is selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -
  • R A2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy.
  • the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • RA is selected from -W1 - W2 - RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 .
  • R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, cyano
  • Ra is selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl or -S(O) 2 C 1-4
  • R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-4 alkoxy;
  • two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy.
  • the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • RA is selected from -W1 - L2 - W2 - RA1, -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;
  • L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ;
  • R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, halogen, cyano;
  • Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 members selected from halogen, oxo,
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or C 2-6 alkynyl.
  • the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, cyano
  • Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl;
  • the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, cyano
  • Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl.
  • the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;
  • R2 is selected from hydrogen
  • two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;
  • X 1 , X 2 , X 3 , X 4 are selected from CH or N;
  • R A1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl
  • R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, and the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy.
  • R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;
  • R2 is selected from hydrogen
  • R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;
  • two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;
  • R A1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl
  • R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;
  • R2 is selected from hydrogen
  • R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;
  • two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;
  • X 1 , X 2 , X 3 , X 4 are selected from CH or N;
  • R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, and the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy.
  • the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts wherein
  • R A is selected from:
  • R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy , F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluor
  • R A is selected from:
  • R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy , F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluor
  • Another embodiment of the present invention is a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;
  • RA is selected from -L1-W1 - L2 - W2 - RA1 ;
  • L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ;
  • L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;
  • R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-4 alkyl, halogen, cyano;
  • R is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 1, 2, 3, 4 or 5;
  • k is selected from 1, 2, 3, 4 or 5;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -SF 5 , -SCF 3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra;
  • n is selected from 0, 1, 2 or 3;
  • n is selected from 1, 2 or 3;
  • k is selected from 1, 2 or 3;
  • the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts wherein:
  • RA is selected from -W1 - L2 - W2 - RA1 ;
  • L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ;
  • R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, halogen, cyano;
  • R is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy;
  • two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or C 2-6 alkynyl.
  • the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts wherein:
  • RA is selected from -W1 - W2 - RA1 ;
  • R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;
  • R W1 is selected from H, C 1-2 alkyl, cyano
  • Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl;
  • the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts wherein:
  • R A is selected from:
  • the present invention also relates to a pharmaceutical composition, which comprises: the above-mentioned compound, its stereoisomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also relates to the use of the compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or compositions containing the compound of the present invention in the preparation of drugs for treating diseases mediated by CB1 receptors.
  • the present invention relates to the use of a compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or a composition containing the compound of the present invention in the preparation of a CB1 antagonist.
  • the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.
  • the present invention also relates to a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the compounds of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1-1000 mg, the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.
  • the mammal in the present invention includes a human.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1-1000 mg, and the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia, or gout.
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof to a subject at a daily dose of 1-1000 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to: 1-1000 mg/day, 1-300 mg/day, 5-500 mg/day, 10-500 mg/day , 10-400 mg/day, 10-300 mg/day, 10-100 mg/day, 20-400 mg/day, 20-200 mg/day, 20-100 mg/day, 50-500 mg/day, 50-250 mg/day, 50-200 mg/day, 50-150 mg/day, 50-100 mg/day, 100-500 mg/day, 100-300 mg/day, 100-200 mg/day;
  • daily doses include but are not limited to: 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 12.5 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 120 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 1000 mg/day.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains the compound of the present invention or its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt, and the amount of the compound of the present invention or its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the present invention or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt in the present invention is in each case calculated based on the free base form.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • alkyl refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., " C1-20 alkyl”.
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C1-8 alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C1-3 alkyl).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • alkylene refers to divalent straight and branched chain saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the like.
  • alkynyl refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C ⁇ C), generally containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms, examples of which include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; alkynyl can be substituted or unsubstituted, and
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., a C3-20 cycloalkyl.
  • the cycloalkyl is preferably a cycloalkyl having 3 to 12 carbon atoms (i.e., a C3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., a C3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., a C3-6 cycloalkyl), and most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., a C3-5 cycloalkyl).
  • Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl, etc.
  • Non-limiting examples of the polycyclic cycloalkyl include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C5-20 spirocycloalkyl).
  • the spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., C6-14 spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., C7-10 spirocycloalkyl).
  • the spirocycloalkyl group is divided into monospirocycloalkyl group, bispirocycloalkyl group or polyspirocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospirocycloalkyl group or bispirocycloalkyl group, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 6-membered/3-member
  • fused cycloalkyl refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C5-20 fused cycloalkyl). It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the fused cycloalkyl preferably has a fused cycloalkyl having 6 to 14 ring atoms (i.e., C6-14 fused cycloalkyl), and more preferably has a fused cycloalkyl having 7 to 10 ring atoms (i.e., C7-10 fused cycloalkyl).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic condensed cycloalkyl groups or tricyclic condensed cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membere
  • bridged cycloalkyl refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 bridged cycloalkyl). It contains one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the bridged cycloalkyl preferably has a bridged cycloalkyl with 6 to 14 ring atoms (i.e., C 6-14 bridged cycloalkyl), and more preferably has a bridged cycloalkyl with 7 to 10 ring atoms (i.e., C 7-10 bridged cycloalkyl). According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl.
  • the cycloalkyl may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl.
  • the cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the cycloalkyl is substituted with a substituent, the substituent is no longer substituted further.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., a monocyclic heterocycloalkyl) or a polycyclic heterocyclic hydrocarbon substituent (i.e., a polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12-membered heterocycloalkyl), wherein 1-4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., 3-8-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., 3-6-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., 5-6-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms.
  • Non-limiting examples of the monocyclic heterocycloalkyl include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl, etc.
  • Non-limiting examples of the polycyclic heterocycloalkyl include: spiroheterocycloalkyl, fused heterocycloalkyl and bridged heterocycloalkyl.
  • spiroheterocycloalkyl refers to a polycyclic heterocycloalkyl group in which one atom (called spiro atom) is shared between monocyclic rings, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20 membered spiroheterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon.
  • the spiroheterocycloalkyl preferably has a spiroheterocycloalkyl having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), and more preferably has a spiroheterocycloalkyl having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl).
  • the spiro heterocycloalkyl group is divided into monospiro heterocycloalkyl group, bispiro heterocycloalkyl group or polyspiro heterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiro heterocycloalkyl group or bispiro heterocycloalkyl group, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 6-
  • fused heterocycloalkyl refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20-membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon.
  • the fused heterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6-14-membered fused heterocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7-10-membered fused heterocycloalkyl).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups preferably bicyclic fused heterocycloalkyl groups or tricyclic fused heterocycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic
  • bridged heterocycloalkyl refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20-membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon.
  • the heterocycloalkyl may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocycloalkyl.
  • the heterocycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment). When the heterocycloalkyl is substituted by a substituent, the substituent is no longer substituted further.
  • aryl refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated ⁇ electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 aryl).
  • the aryl preferably has an aryl having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., C 6-10 aryl), further preferably phenyl or naphthyl, most preferably phenyl.
  • the monocyclic aryl for example, phenyl.
  • Non-limiting examples of the polycyclic aryl include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the aryl group may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, preferably a benzo C 3-8 cycloalkyl, a benzo 3-8 membered heterocycloalkyl, a benzo 5-6 membered heteroaryl, more preferably a benzo C 4-6 cycloalkyl, a benzo 4-6 membered heterocycloalkyl, a benzo 5-6 membered heteroaryl, further preferably a benzocyclobutyl, a benzocyclopentyl, a benzocyclohexyl, a benzoazetidinyl, a benzoxe ...
  • the aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the aryl group is substituted with a substituent, the substituent may
  • heteroaryl refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl) having a conjugated ⁇ electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14-membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m , and S(O) n (wherein m and n are integers of 0-2), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • 5 to 14 e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14
  • ring atoms
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10-membered heteroaryl).
  • the monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, and the like.
  • the polycyclic heteroaryl group is preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-10-membered heteroaryl and a C 6-10 aryl, or a C 6-10 aryl and a 5-10-membered heteroaryl, and is further preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-6-membered heteroaryl and a phenyl group, or a phenyl and a 5-6-membered heteroaryl group.
  • Non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl, and the like.
  • the heteroaryl group may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, preferably a 5-6-membered heteroaryl and C 3-8 cycloalkyl, a 5-6-membered heteroaryl and 3-8-membered heterocycloalkyl, a 5-6-membered heteroaryl and phenyl, more preferably a 5-6-membered heteroaryl and C 4-6 cycloalkyl, a 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl, a 5-6-membered heteroaryl and phenyl.
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the heteroaryl group is substituted by a substituent, the substituent is no longer substituted further.
  • alkoxy refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 alkoxy).
  • the alkoxy preferably has an alkoxy with 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably an alkoxy with 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably an alkoxy with 1 to 3 carbon atoms (i.e., C 1-3 alkoxy).
  • Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the alkoxy is substituted by a substituent, the substituent is no longer further substituted.
  • alkylthio refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ) carbon atoms (i.e., C 1-10 alkylthio).
  • the alkylthio is preferably an alkylthio having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), and most preferably an alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 alkylthio).
  • Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • the alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the alkylthio group is substituted with a substituent, the substituent may not be further substituted.
  • halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluor
  • thiol refers to -SH.
  • hydroxy refers to -OH.
  • nitro refers to -NO2 .
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • aminoacyl refers to -C(O) NH2 .
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium, wherein alkoxy is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • alkylamino refers to an alkyl-NH- group, wherein alkyl is as defined above.
  • mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values.
  • C2 - C8 " or " C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2 - C5 , C3 - C4 , C2 - C6 , C3 - C6 , C4 - C6 , C4 - C7 , C4 - C8, etc., as well as C2 , C3 , C4 , C5 , C6 , C7 , C8, etc.
  • C3 - C10 or " C3-10” should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8-C9, etc. , as well as C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , etc.
  • C 1 -C 6 or "C 1-6” encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression "three yuan to ten yuan” should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc.
  • Other similar expressions in this document should also be understood in a similar manner.
  • cycloalkyl optionally substituted with alkyl means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.
  • substituted and “substituted” refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds. When describing that a substituent does not exist, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state.
  • substituents include, but are not limited to, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 heteroalkyl, C5-12 aryl, 5-12 membered heteroaryl, hydroxy, C1-6 alkoxy, C5-12 aryloxy, thiol, C1-6 alkylthio, cyano, halogen, C1-6 alkylthiocarbonyl, C1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, amino, phosphonic acid, -CO2( C1-6 alkyl), -OC
  • variable e.g., R
  • variables with labels e.g., R1 , R2 , R3 , R4 , R5 , R6 , R7 , etc.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity.
  • Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention.
  • the purification and separation of such substances can be achieved by standard techniques known in the art.
  • the compounds of the present invention also include their tautomers.
  • the tautomers of the compounds disclosed herein may be "NH 2 " tautomers, or "NH” tautomers, or a combination of the two. For example:
  • the hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • Compounds of the present invention include all suitable isotopic derivatives of their compounds.
  • the term "isotopic derivative” refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses.
  • isotopes that can be introduced into compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P , 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • the position when a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation).
  • the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • pharmaceutically acceptable refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.
  • composition refers to a composition containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.
  • pharmaceutically acceptable carrier refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.
  • administration refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.
  • the term "treat” includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention.
  • Treatment also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated.
  • a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed.
  • a prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition.
  • neuropsychiatric disease refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
  • the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • “individual” includes humans or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • room temperature refers to a temperature from 10°C to 40°C. In some embodiments, “room temperature” refers to a temperature from 15°C to 30°C; in other embodiments, “room temperature” refers to a temperature from 18°C to 25°C.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Step 2 Dissolve compound 1B (400 mg, 1.22 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 6 h. Concentrate the reaction solution under reduced pressure to obtain compound 1C (600 mg), which is directly used in the next step.
  • LC-MS (ESI): m/z 128.1 [M+H] + .
  • Step 4 Compound 1E was subjected to chiral separation to obtain compounds 1 (SFC analysis retention time: 0.942 min, 70 mg) and 1-2 (SFC analysis retention time: 1.635 min, 80 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 254 nm.
  • Step 1 Dissolve compound 3A (99.17 mg, 0.78 mmol, synthesized according to patent WO201711552) in isopropanol (6 mL), add N,N-diisopropylethylamine (201.61 mg, 1.56 mmol), and react at room temperature for 3 h. Then add a dichloromethane (10 mL) solution of compound 1D (207 mg, 0.39 mmol) at -25 ° C, and react overnight at room temperature after the addition is complete. After the reaction is complete, the reaction solution is concentrated, and the residue is purified by preparative HPLC to obtain compound 3 (210 mg, yield: 87%).
  • Step 1 Dissolve compound 4A (5.00 g, 39.65 mmol) in DMF (40 mL), add potassium carbonate (13.70 g, 99.12 mmol), replace nitrogen three times, and then slowly add deuterated iodomethane (5.75 g, 39.65 mmol) dropwise in an ice bath. After the addition is completed, the reaction is stirred at room temperature for 2 h. Add water (100 mL) to dilute the reaction, and extract it three times with dichloromethane (100 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Compound 4C (1.20 g, 9.29 mmol) was dissolved in DMF (40 mL), HATU (3.89 g, 10.22 mmol) and triethylamine (2.35 g, 23.23 mmol) were added, nitrogen was replaced and stirred at room temperature for 15 min, then 1,3-di(tert-butoxycarbonyl)guanidine (2.89 g, 11.15 mmol) was added. After the addition was completed, the reaction was stirred at room temperature for 16 h. Water (100 mL) was added to the reaction solution to dilute the reaction, and it was extracted three times with dichloromethane (100 mL).
  • Step 4 Dissolve compound 4D (1.50 g, 4.05 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 4 h. Concentrate the reaction solution under reduced pressure to obtain compound 4E (1.2 g crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 171.1 [M+H] + .
  • Step 5 Compound 4E (200 mg, 0.95 mmol) was synthesized by referring to the third step of Example 1 to obtain compound 4F (450 mg, yield: 71.77%).
  • LC-MS (ESI): m/z 660.2 [M+H] + .
  • Step 6 Compound 4F was subjected to chiral separation to obtain Compound 4 (SFC analysis retention time: 2.033 min, 169.8 mg) and Compound 5 (SFC analysis retention time: 2.235 min, 145.1 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 2.5 min; Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 3.0 mL each time.
  • Step 1 Dissolve compound 4H-1,2,4-triazole-3-carboxylic acid (1.13 g, 10 mmol) in N,N-dimethylformamide (20 mL), add HATU (5.7 g, 15 mmol), 1,3-di(tert-butoxycarbonyl)guanidine (2.59 g, 10 mmol) and N,N-diisopropylethylamine (3.9 g, 30 mmol) in sequence, and react at room temperature for 2 h.
  • HATU 5.7 g, 15 mmol
  • 1,3-di(tert-butoxycarbonyl)guanidine (2.59 g, 10 mmol
  • N,N-diisopropylethylamine 3.9 g, 30 mmol
  • Step 2 Dissolve compound 6A (443 mg, 1.25 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature overnight. Concentrate the reaction solution under reduced pressure to obtain compound 6B (371 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 155.5 [M+H] + .
  • Step 3 Compound 6B (371 mg crude product) was synthesized by referring to the third step of Example 1 to obtain compound 6C (224 mg, yield: 61%).
  • Step 4 Compound 6C was subjected to chiral separation to obtain compound 6 (SFC analysis retention time: 2.323 min, 58.3 mg) and compound 7 (SFC analysis retention time: 2.668 min, 56.5 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 3 mg/mL, Methanol solution injection: 5 mL each time.
  • Step 1 Dissolve compound 1A (2.2 g, 8.57 mmol) and 8A (0.8 g, 7.14 mmol) in N,N-dimethylformamide (20 mL), add diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol), stir at room temperature overnight after the addition is complete.
  • Step 2 Dissolve compound 8B (400 mg, 1.12 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (3 mL), and stir at room temperature overnight. Concentrate the reaction solution under reduced pressure to obtain compound 8C (600 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 154.0 [M+H] + .
  • Step 3 Compound 8C (600 mg, 1.12 mmol) was subjected to the third step of Example 1 (solvent: DMF) to obtain compound 8D (170 mg, yield: 63.0%).
  • Step 4 Compound 8D was subjected to chiral separation to obtain compound 8 (SFC analysis retention time: 2.118 min, 50 mg) and compound 9 (SFC analysis retention time: 2.498 min, 60 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 6.2 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 3.0 mL each time.
  • Step 1 Compound 1A (2.77 g, 10.7 mmol) and 10A (0.8 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol) were added. After the addition was completed, the mixture was stirred at room temperature overnight. Water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Dissolve compound 10B (600 mg, 1.70 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 10C (800 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 154.2 [M+H] + .
  • Step 3 Compound 1D (250 mg, 0.47 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain Compound 10D (180 mg, yield: 59.6%).
  • Step 4 Compound 10D was subjected to chiral separation to obtain compound 10 (SFC analysis retention time: 2.305 min, 70 mg) and compound 11 (SFC analysis retention time: 2.547 min, 80 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral Whelk Column; Mobile phase: A: CO 2 , B: Isopropanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.3 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.
  • Step 2 Compound 12B (450 mg, 1.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 12C (190 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 154.1 [M+H] + .
  • Step 3 Compound 12C (190 mg, 1.14 mmol) was subjected to the same operation as in the first step of Example 3 (solvent: DMF) to obtain compound 12D (120 mg, yield: 49.28%).
  • Step 4 Compound 12D was subjected to chiral separation to obtain compound 12 (SFC analysis retention time: 2.118 min, 50 mg) and compound 13 (SFC analysis retention time: 2.498 min, 60 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 5 mg/mL, acetonitrile ethanol mixed solution injection: 2.0 mL each time.
  • Step 1 Dissolve compound 1D (0.5 g, 0.95 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (0.96 g, 9.5 mmol), then add a tetrahydrofuran (5 mL) solution of compound 14A (0.5 g, 4.37 mmol, synthesized according to patent WO2020181952) at 0 ° C, and stir at room temperature for 1 h after the addition is complete.
  • Step 2 Compound 14B (0.52 g) was subjected to chiral separation to obtain compound 14 (SFC analysis retention time: 1.744 min, 220 mg) and compound 15 (SFC analysis retention time: 1.948 min, 206 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf; column: Chiral AS column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 5-40%; flow rate: 3 mL/min; back pressure: 100 bar; column temperature: 35°C; wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC; Column: Chiral AS column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: B for 35%; Elution flow rate: 120mL/min; Back pressure: 100bar; Column temperature: room temperature; Wavelength: 220nm; Cycle time: 6.0min; Sample preparation: Sample concentration is 15mg/mL, dissolved in acetonitrile and methanol. Injection: 3.0ml per injection.
  • Step 2 Dissolve compound 16B (620 mg, 0.94 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 16C (529 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 562.3 [M+H] + .
  • Step 3 Compound 16C (530 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL), triethylamine (333 mg, 3.29 mmol) was added, nitrogen was replaced three times, and acetyl chloride (111 mg, 1.41 mmol) was slowly added dropwise in an ice bath. After the addition was completed, the reaction was kept in an ice bath and stirred for 1 h. Water (30 mL) was added to quench the reaction, and dichloromethane (50 mL) was used to extract twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 16D (490 mg) was subjected to chiral separation to obtain compound 16 (SFC analysis retention time: 1.210 min, 153 mg) and compound 17 (SFC analysis retention time: 1.335 min, 151 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf; column: Chiral OJ column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 5-40%; flow rate: 3 mL/min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC; Column: Chiral OJ column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: B for 25%; Elution flow rate: 70mL/min; Back pressure: 100bar; Column temperature: room temperature; Wavelength: 220nm; Cycle time: 7.0min; Sample preparation: Sample concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 3.0ml per injection.
  • Step 1 Compound 1D (1.05 g, 1.99 mmol) was dissolved in DMF (15 mL), and N,N-diisopropylethylamine (0.90 g, 6.96 mmol) was added. Then, a DMF (5 mL) solution of compound 18A (0.25 g, 2.49 mmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (100 mL ⁇ 3).
  • Step 2 Compound 18B (985 mg) was subjected to chiral separation to obtain compound 18 (SFC analysis retention time: 2.420 min, 226 mg), compound 19 (SFC analysis retention time: 2.769 min, 170 mg), compound 20 (SFC analysis retention time: 3.279 min, 180 mg) and compound 21 (SFC analysis retention time: 3.537 min, 204 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf; column: Chiral OD column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 20-30%; flow rate: 1.5 mL/min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 254 nm.
  • SFC separation method First separation: Instrument: Waters 150Prep-SFC; Column: Chiral OD column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: B for 35%; Elution flow rate: 120mL/min; Back pressure: 100bar; Column temperature: Room temperature; Wavelength: 220nm; Cycle time: 5.0min; Sample preparation: Compound concentration is 20mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Component A and component B are separated.
  • the above component A was further subjected to SFC separation, purification method: instrument: Waters 150 Prep-SFC; column: Chiral AD column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile; gradient: B for 35%; elution flow rate: 100mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 4.0min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Compound 18 and compound 19 were separated.
  • the above component B was further subjected to SFC separation and purification method: instrument: Waters 150 Prep-SFC; column: Chiral WHEIK column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in methanol; gradient: B for 40%; elution flow rate: 120mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 3.0min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Compound 20 and compound 21 were separated.
  • Step 1 Add ammonia 1,4-dioxane solution (0.5M, 20mL) to compound 22A (0.8g, 2.64mmol, preparation reference: ChemMedChem, 2015, vol.10, #3, p.461-469), stir at room temperature for 16 hours, and directly concentrate under reduced pressure to obtain compound 22B (0.75g crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 282.0[MH] - .
  • LC-MS (ESI): m/z 368.0 [MH] - .
  • LC-MS (ESI): m/z 584.0 [M+H] + .
  • Step 5 Compound 22F (160 mg, 0.27 mmol) and taurine hydrochloride (87 mg, 0.54 mmol) were treated with the same method as in Example 1 to obtain compound 22G (150 mg, yield: 82%).
  • LC-MS (ESI): m/z 672.1 [M+H] + .
  • Step 6 Compound 22G was further subjected to chiral separation to obtain compound 22 (SFC analysis retention time: 0.732 min, 73 mg) and compound 23 (SFC analysis retention time: 1.339 min, 71 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in EtOH; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.0 min Sample preparation: Sample concentration 10 mg/mL, methanol solution injection: 1.5 mL each time.
  • Step 2 Compound 24B (700 mg, 1.54 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the reaction was stirred at room temperature for 10 h. The reaction solution was concentrated under vacuum to obtain compound 24C (500 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 154.1 [M+H] + .
  • Step 3 Compound 24C (870 mg, 3.26 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain compound 24D (200 mg).
  • Step 4 Compound 24D was subjected to chiral separation by SFC to obtain compounds 24 (SFC analysis retention time: 0.836 min, 70 mg) and 25 (SFC analysis retention time: 1.437 min, 70 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C, wavelength: 254 nm, cycle time: 4.5 min.
  • Sample preparation Sample concentration 10 mg/mL, ethanol solution injection: 2.0 mL each time.
  • Step 2 Compound 26B (1.20 g, 2.65 mmol) was dissolved in dichloromethane (24 mL), trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 26C (1.00 g crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 154.2 [M+H] + .
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 40% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.9 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 8.0 mL each time.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol and acetonitrile; Gradient: 35% B gradient elution flow rate: 100 mL/min, column temperature: 25°C wavelength: 254 nm cycle time: 10.0 min; Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 5 mL each time.
  • Step 2 Compound 32B (5.0 g, 15.16 mmol), acetamide (1.79 g, 30.32 mmol), palladium acetate (0.68 g, 3.03 mmol), Xant phos (3.51 g, 6.06 mmol) and potassium carbonate (4.19 g, 30.32 mmol) were added to 1,4-dioxane (80 mL) successively, and the mixture was heated to 100°C and stirred overnight under nitrogen protection. After cooling, the mixture was filtered, and the filtrate was diluted with water and extracted with EA.
  • Step 3 Compound 32C (1.0 g, 2.84 mmol) was added to dichloromethane (6 mL), and then 3 mL of trifluoroacetic acid was added, and stirred at room temperature for 10 hours. After concentration, saturated sodium bicarbonate solution was added to the residue, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32D (crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 153.1 [M+H] + .
  • Step 5 Compound 32E was further resolved by chiral SFC to obtain compounds 32 (SFC analysis retention time: 2.002 min, 120 mg) and 33 (SFC analysis retention time: 2.314 min, 120 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD sf, Column: Chiral AD column; Mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; Gradient: 5-40% B; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm.
  • Step 1 Compound 34A (60 mg, 0.40 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 34B (130 mg, yield: 53.37%).
  • LC-MS (ESI): m/z 641.1 [M+H] + .
  • Step 2 Compound 34B was subjected to chiral separation to obtain compound 34 (SFC analysis retention time: 2.392 min, 15.4 mg) and compound 35 (SFC analysis retention time: 2.847 min, 19.2 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 45% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.1 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.
  • Step 2 Compound 36A (1.00 g crude product) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 36B (350 mg, yield: 33.56%).
  • LC-MS (ESI): m/z 549.2 [M+H] + .
  • Step 3 Compound 36B (350 mg, 0.64 mmol) was dissolved in dichloromethane (50 mL), and compound 36C (100 mg, 0.75 mmol, synthesized according to patent CN107759587) and triethylamine (130 mg, 1.28 mmol) were added respectively, and the reaction solution was stirred at room temperature for 1.5 hours. Water (40 mL) was added to quench the reaction, and dichloromethane (50 mL) was used for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 4 Compound 36D was subjected to chiral separation to obtain compound 36 (SFC analysis retention time: 0.856 min, 56.4 mg) and compound 37 (SFC analysis retention time: 1.160 min, 94.8 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 50% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 55% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 7.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 6.5 min; sample preparation: sample concentration 3.3 mg/mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.
  • Step 1 Dissolve compound 40A (0.5 g, 4.46 mmol) and N-Boc-guanidine (1.06 g, 6.7 mmol) in N,N-dimethylformamide (10 mL), add diisopropylethylamine (1.72 g, 13.38 mmol) and HATU (2.0 g, 5.35 mmol), stir at room temperature overnight after the addition is complete.
  • LC-MS (ESI): m/z 254.2[M+H] + .
  • Step 2 Compound 40B (300 mg, 1.18 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 40C (500 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 154.1 [M+H] + .
  • Step 3 Compound 1D (200 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), and crude compound 40C (500 mg, 1.18 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added respectively, and stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 40D (230 mg, yield: 94.2%).
  • Step 4 Compound 40D was separated by chiral SFC to obtain compound 40 (SFC analysis retention time: 0.913 min, 90 mg) and compound 41 (SFC analysis retention time: 1.370 min, 39 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 30% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.0 min; Sample preparation: Sample concentration 7.0 mg/mL, acetonitrile ethanol mixed solution injection: 2.0 mL each time.
  • Step 2 Compound 42B (500 mg, 1.84 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added, and the mixture was stirred at room temperature for 10 h. The reaction solution was concentrated to obtain compound 42C (320 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 172.1 [M+H] + .
  • Step 3 Compound 42C (320 mg, 1.12 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain compound 42D (180 mg).
  • Step 4 Compound 42D was further separated by chiral SFC to obtain compound 42 (SFC analysis retention time: 0.736 min, 70 mg) and compound 43 (SFC analysis retention time: 1.429 min, 70 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral Cellulose-2 column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in isopropanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 254 nm Cycle time: 4.5 min Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 2.0 mL each time.
  • Example 44 Example 45, Example 46 and Example 47
  • Step 1 Add tert-butyl 2-methylmercaptoethylamine carbonate (3.00 g, 15.68 mmol) to ammonia methanol solution (7 mol/L, 50 mL), cool to 0-10°C in an ice bath, slowly add iodophenyl diacetic acid (12.63 g, 39.20 mmol), and then stir at room temperature for 4 hours.
  • Step 2 Compound 44B was added to a 4 mol/L hydrochloric acid 1,4-dioxane solution (30 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the filter cake was collected and washed with acetonitrile and dried to obtain compound 44C (1.6 g, yield: 89.69%).
  • LC-MS (ESI): m/z 123.1 [M+H] + .
  • Step 3 Compound 44C (0.14 g, 0.91 mmol) was treated with the same method as in Step 3 of Example 1 to obtain Compound 44D (331 mg, yield: 71.16%).
  • LC-MS (ESI): m/z 612.0 [M+H] + .
  • Step 4 Compound 44D (331 mg, 0.54 mmol) was subjected to chiral SFC separation to obtain compound 44 (SFC analysis retention time: 0.882 min, 63.8 mg), compound 45 (SFC analysis retention time: 1.082 min, 65.7 mg), compound 46 (SFC analysis retention time: 1.385 min, 76.4 mg) and compound 47 (SFC analysis retention time: 1.586 min, 77.6 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf; chromatographic column: Chiral OX column; mobile phase: A for CO 2 ; B for 0.05% DEA in ethanol; gradient: B 5-40%; flow rate: 3.0 mL/min; column pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm).
  • SFC chiral separation method Instrument: Waters 150 Prep-SFC; Chromatographic column: Chiral OX column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: B 40%; Flow rate: 120 mL/min; Column pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm) Cycle time: ⁇ 3.5 min. Sample preparation: Dissolve the compound in acetonitrile at a concentration of 3.0 mg/mL; Injection: 2 mL each time.
  • Step 2 Compound 48B (800 mg, 2.50 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 48C (600 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 220.1 [M+H] + .
  • Step 3 The crude product of compound 48C (150 mg, 0.68 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 48D (50 mg).
  • Step 4 Compound 48D was separated by chiral SFC to obtain compound 48 (SFC analysis retention time: 2.228 min, 11 mg) and compound 49 (SFC analysis retention time: 2.661 min, 15 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 254 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 7.5 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.
  • Step 2 Compound 50B (600 mg, 2.11 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 50C (600 mg crude product), which was directly used in the next step.
  • Step 3 The crude product of compound 50C (100 mg, 0.54 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 50D (80 mg).
  • Step 4 Compound 50D was separated by chiral SFC to obtain compound 50 (SFC analysis retention time: 0.855 min, 51 mg) and compound 51 (SFC analysis retention time: 1.642 min, 45 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 50% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 2.5 min; Sample preparation: Sample concentration 5 mg/mL, ethanol solution injection: 5 mL each time.
  • Step 1 Compound 52A (1.00 g, 7.19 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.86 g, 14.38 mmol) was added, and the reaction solution was replaced with nitrogen protection, and acetyl chloride (680 mg, 8.64 mmol) was slowly added dropwise under ice bath, and the reaction solution was stirred at room temperature for 2 hours after the addition was completed. Water (10 mL) was added to quench the reaction, and dichloromethane (15 mL) was used for extraction three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 52B (700 mg, yield: 53.76%).
  • Step 2 Compound 52B (700 mg, 3.86 mmol) was dissolved in methanol (20 mL), palladium carbon (690 mg, 0.58 mmol, 10% wt) was added, the reaction solution was replaced with hydrogen, and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 52C (400 mg crude product), which was directly used in the next step reaction.
  • Step 4 Compound 52D was subjected to chiral SFC separation to obtain compound 52 (SFC analysis retention time: 0.848 min, 24.3 mg) and compound 53 (SFC analysis retention time: 1.133 min, 24.0 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 45% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.
  • Step 2 Compound 54B (230 mg, 1.27 mmol) was dissolved in methanol (10 mL), palladium carbon (130 mg, 0.19 mmol, 10% wt) was added, and the reaction solution was replaced with hydrogen protection and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 54C (120 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 152.2 [M+H] + .
  • Step 3 Compound 54C (120 mg, 0.79 mmol) was processed according to the third step of Example 52 to obtain Compound 54D (300 mg, yield: 82.11%).
  • LC-MS (ESI): m/z 641.2 [M+H] + .
  • Step 4 Compound 54D was subjected to chiral SFC separation to obtain compound 54 (SFC analysis retention time: 1.951 min, 36.4 mg) and compound 55 (SFC analysis retention time: 2.193 min, 50.1 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral AD Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral AD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 7.5 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.
  • Step 1 Dissolve compound 56A (2.0 g, 19.59 mmol) and BOC-guanidine (3.43 g, 21.55 mmol) in N,N-dimethylformamide (50 mL), add triethylamine (3.96 g, 39.18 mmol) and HATU (8.94 g, 23.51 mmol), stir at room temperature overnight after the addition is complete.
  • LC-MS (ESI): m/z 244.1[M+H] + .
  • Step 2 Compound 56B (600 mg, 1.70 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 56C (800 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 144.1 [M+H] + .
  • Step 3 Compound 56C (480 mg, 1.87 mmol) was prepared by referring to the third step of Example 1 to obtain compound 56D (150 mg, yield: 46%).
  • Step 4 Compound 56D was subjected to chiral SFC separation to obtain compound 56 (SFC analysis retention time: 2.305 min, 50 mg) and compound 57 (SFC analysis retention time: 2.547 min, 45 mg).
  • SFC analysis method instrument: SHIMADZU LC-20AP, column: C18 column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral Whelk Column; Mobile phase: A: CO 2 , B: Isopropanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.3 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.
  • Example 58 and Example 59
  • Step 1 Dissolve compound 58A (2.0 g, 19.61 mmol) and BOC-guanidine (3.74 g, 23.53 mmol) in dichloromethane (50 mL), add triethylamine (5.94 g, 58.83 mmol), then add HATU (8.94 g, 23.53 mmol), protect with nitrogen, and stir at room temperature for 2 h.
  • LC-MS (ESI): m/z 244.2[M+H] + .
  • Step 3 Compound 58C (500 mg, 1.77 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 58D (200 mg).
  • Step 4 Compound 58D was further separated by chiral SFC to obtain compound 58 (SFC analysis retention time: 0.944 min, 73.7 mg) and compound 59 (SFC analysis retention time: 1.781 min, 78.6 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD sf, column: Chiral IK column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • Example 60 Example 61, Example 62 and Example 63
  • Step 2 Dissolve compound 60B (800 mg, 2.96 mmol) in dichloromethane (35 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 16 h. Concentrate the reaction solution to obtain compound 60C (1 g crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 171.2 [M+H] + .
  • Step 3 Compound 60C (1 g) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 60D (1 g, yield: 80%).
  • LC-MS (ESI): m/z 660.1 [M+H] + .
  • Step 4 Compound 60D was further separated by chiral SFC to obtain compound 60 (SFC analysis retention time: 0.795 min, 41.6 mg), compound 61 (SFC analysis retention time: 0.826 min, 27.9 mg), compound 62 (SFC analysis retention time: 1.265 min, 64.8 mg) and compound 63 (SFC analysis retention time: 1.312 min, 68.3 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral OX column; mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol and acetonitrile; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • Instrument Waters 150 Prep-SFC; Column: Chiral OX column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in methanol and acetonitrile; Gradient: B for 50%; Elution flow rate: 100mL/min; Back pressure: 100bar; Column temperature: Room temperature; Wavelength: 220nm; Cycle time: 5.0min; Sample preparation: Compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Component A and component B are separated.
  • the above component A was further subjected to SFC separation and purification method: instrument: SHIMADZU LC-20AP; column: Chiral IA column; mobile phase: A for n-Hexane; B for 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile; gradient: B for 17%; elution flow rate: 80mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 14min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0 ml each time. Compound 60 and compound 61 were separated.
  • the above component B was further subjected to SFC separation and purification method: instrument: Waters 150 Prep-SFC; column: Chiral IC column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile; gradient: B for 40%; elution flow rate: 120mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 7.5min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 4.0 ml each time. Compound 62 and compound 63 were separated.
  • Step 1 Compound 64A (1.4 g, 6.19 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.89 g, 18.77 mmol) was added, nitrogen was replaced three times, methyl chloroformate (664 mg, 7.06 mmol) was slowly added dropwise under ice bath conditions, and the mixture was slowly returned to room temperature and stirred for 1 h.
  • Step 3 Add toluene (20 mL) to a 100 mL single-mouth bottle, then add compound 64D (2.24 g, 4.41 mmol) and N,N-diisopropylethylamine (1.42 g, 11.03 mmol), then slowly dropwise add phosphorus oxychloride (1.01 g, 6.62 mmol), after the addition is complete, the system is protected by nitrogen, heated to 100 ° C and stirred for 1 h. After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure to obtain compound 64E (3 g crude product), which is directly used in the next step.
  • LCMS (ESI): m/z 527.2 [M+H] + .
  • Step 4 Compound 64E (350 mg, 0.66 mmol) was dissolved in dichloromethane (30 mL), and compound 1C (320 mg, 1.12 mmol) and triethylamine (200 mg, 1.98 mmol) were added respectively. After the addition was completed, the reaction was stirred at room temperature overnight, water (40 mL) was added to quench the reaction, and it was extracted three times with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 64F (180 mg).
  • Step 5 Compound 64F was subjected to chiral SFC separation to obtain compound 64 (SFC analysis retention time: 5.85 min, 50 mg) and compound 65 (SFC analysis retention time: 7.05 min, 40 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: SFC Prep 150AP; chromatographic column: AD (19 mm ⁇ 250 mm); the sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution.
  • Preparative chromatographic conditions a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 40%; c. Flow rate 40 mL/min.
  • Step 3 Compound 66B was separated by chiral SFC to obtain compound 66 (pre-SFC preparation peak, 30 mg) and compound 67 (post-SFC preparation peak, 35 mg).
  • SFC preparation method Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm ⁇ 250 mm); The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution.
  • Preparative chromatography conditions a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 50%; c. Flow rate 38 mL/min.
  • Step 2 Compound 68B (800 mg, 3.09 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 68D (800 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 160.1 [M+H] + .
  • Step 3 Compound 68D (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 68E (120 mg, yield: 65%).
  • Step 4 Compound 68E was separated by chiral SFC to obtain compound 68 (pre-SFC preparation peak, 35 mg) and compound 69 (post-SFC preparation peak, 40 mg).
  • SFC preparation method Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm ⁇ 250 mm); The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution.
  • Preparative chromatography conditions a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 50%; c. Flow rate 38 mL/min.
  • Step 2 Dissolve compound 70B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 70C (420 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 142.2 [M+H] + .
  • Step 3 Compound 70C (420 mg crude product, 2.07 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 70D (550 mg, yield: 91.75%).
  • LC-MS (ESI): m/z 631.2 [M+H] + .
  • Step 4 Compound 70D was separated by chiral SFC to obtain compound 70 (SFC analysis retention time: 2.217 min, 203.8 mg) and compound 71 (SFC analysis retention time: 2.485 min, 153.5 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 4.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.
  • Step 2 Dissolve compound 72B (500 mg, 1.87 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 72C (500 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 168.1 [M+H] + .
  • Step 3 Compound 72C (500 mg crude product, 1.87 mmol) was processed according to the third step of Example 1 to obtain compound 72D (600 mg, yield: 96.13%).
  • LC-MS (ESI): m/z 657.2 [M+H] + .
  • Step 4 Compound 72D was separated by chiral SFC to obtain compound 72 (SFC analysis retention time: 1.884 min, 265.0 mg) and compound 73 (SFC analysis retention time: 2.165 min, 262.2 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in ethanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 4.3 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.
  • Step 1 Dissolve compound 68C (200 mg, 0.77 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 74A (200 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 160.1 [M+H] + .
  • Step 2 Compound 74A (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 74B (120 mg, yield: 65%).
  • Step 3 Compound 74B was separated by chiral SFC to obtain compound 74 (pre-SFC preparation peak, 45 mg) and compound 75 (post-SFC preparation peak, 35 mg).
  • SFC preparation method Instrument: SFC Prep 150AP; Chromatographic column: IG (19 mm ⁇ 250 mm); The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution.
  • Preparative chromatography conditions a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 30%; c. Flow rate 40 mL/min.
  • Example 76 and Example 77
  • Step 1 Compound 76A (1.0 g, 4.42 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.34 g, 13.26 mmol) was added, and the atmosphere was replaced with nitrogen three times. Isopropyl chloroformate (810 mg, 6.63 mmol) was slowly added dropwise under ice bath conditions. After the addition was completed, the mixture was slowly returned to room temperature and stirred for 1 h. After TLC monitoring of the reaction was complete, water (10 mL) was added and stirred for 5 min. The organic phase was washed twice with dilute hydrochloric acid solution (1 mol/L), and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 76B (1.0 g, yield: 72%).
  • Step 4 Compound 76D (220 mg, 0.42 mmol) was dissolved in dichloromethane (20 mL), and compound 1C (200 mg, 0.84 mmol) and triethylamine (130 mg, 1.26 mmol) were added respectively. After the addition was completed, the reaction was stirred at room temperature overnight, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 76E (150 mg).
  • Step 5 Compound 76E obtained in the previous step was further resolved by chiral SFC to obtain compounds 76 (SFC pre-preparation peak, 55 mg) and 77 (SFC post-preparation peak, 50 mg).
  • SFC preparation method 1. Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm ⁇ 250 mm); The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 52%.
  • Example 78 and Example 79
  • Step 2 Dissolve compound 78B (500 mg, 1.70 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 4 hours. Concentrate the reaction solution under reduced pressure to obtain compound 78C (400 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 195.1 [M+H] + .
  • Step 3 Compound 78C (200 mg crude product, 0.85 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 78D (250 mg, yield: 96.18%).
  • LC-MS (ESI): m/z 684.2 [M+H] + .
  • Step 4 Compound 78D was separated by chiral SFC to obtain compound 78 (SFC analysis retention time: 2.135 min, 62.6 mg) and compound 79 (SFC analysis retention time: 2.366 min, 62.1 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in ethanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 3.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.
  • Step 2 Dissolve compound 80B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain compound 80C (500 mg crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 142.1 [M+H] + .
  • Step 3 Compound 80C (250 mg crude product, 1.03 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 80D (230 mg, yield: 95.92%).
  • LC-MS (ESI): m/z 631.2 [M+H] + .
  • Step 4 Compound 80D was separated by chiral SFC to obtain compound 80 (SFC analysis retention time: 0.525 min, 84.2 mg) and compound 81 (SFC analysis retention time: 0.797 min, 62.3 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 40% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 2.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.
  • Step 2 Compound 82B (500 mg, 1.88 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 82C (500 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 166.1 [M+H] + .
  • Step 3 The crude product of compound 82C (200 mg, 1.22 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 82D (80 mg).
  • Step 4 Compound 82D was separated by chiral SFC to obtain compound 82 (pre-SFC preparation peak, 20 mg) and compound 83 (post-SFC preparation peak, 25 mg).
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: 50% B gradient elution flow rate: 40 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 20 min; Sample preparation: Sample concentration 2 mg/mL, methanol solution injection: 2 mL each time.
  • Step 2 Compound 84B (0.48 g) was subjected to chiral SFC separation to obtain compound 84 (pre-SFC preparation peak, 160 mg) and compound 85 (post-SFC preparation peak, 156 mg).
  • SFC preparation method 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm ⁇ 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 45%; c. Flow rate 38 mL/min.
  • Step 2 Dissolve compound 86B (1.0 g, 4.36 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 86C (1.15 g, crude product), which is directly used in the next step.
  • Step 3 Compound 86C (1.15 g, 4.36 mmol) was processed by referring to the first step of Example 18 to obtain compound 86D (0.35 g, yield: 60%).
  • LC-MS (ESI): m/z 619.3 [M+H] + .
  • Step 4 Compound 86D (0.35 g) was subjected to chiral SFC separation to obtain compound 86 (SFC pre-preparation peak, 102 mg) and compound 87 (SFC post-preparation peak, 95 mg).
  • SFC preparation method 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm ⁇ 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 28%; c. Flow rate 42 mL/min.
  • Step 2 Dissolve compound 88B (665 mg, 2.61 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 88C (645 mg, crude product), which is directly used in the next step.
  • Step 3 Compound 88C (645 mg, 2.61 mmol) was processed by referring to the first step of Example 18 to obtain compound 88D (0.48 g, yield: 78%).
  • LC-MS (ESI): m/z 644.2 [M+H] + .
  • Step 4 Compound 88D (0.48 g) was separated by chiral SFC to obtain compound 88 (SFC preparative front peak, 204 mg) and compound 89 (SFC preparative rear peak, 195 mg).
  • SFC preparation method 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm ⁇ 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 20%; c. Flow rate 40 mL/min.
  • Step 2 Compound 90B (650 mg, 2.56 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 90C (660 mg, crude product), which was directly used in the next step.
  • Step 3 Compound 90C (660 mg, 2.56 mmol) was subjected to the same operation as in the first step of Example 18 to obtain compound 90D (0.41 g, yield: 67%).
  • LC-MS (ESI): m/z 644.2 [M+H] + .
  • Step 4 Compound 90D (0.41 g) was subjected to chiral SFC separation to obtain compound 90 (pre-SFC preparation peak, 135 mg) and compound 91 (post-SFC preparation peak, 128 mg).
  • SFC preparation method 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm ⁇ 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3.
  • Preparative chromatographic conditions a. Composition of mobile phase A, B: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 25%; c. Flow rate 40 mL/min.
  • Example 92 Example 92, Example 93, Example 94 and Example 95
  • Step 1 Dissolve the compound 1-methyl-2-oxopiperidine-4-carboxylic acid (314 mg, 2 mmol) in N,N-dimethylformamide (10 mL), add HATU (1.14 g, 3 mmol), tert-butyloxycarbonylguanidine (477 mg, 3 mmol) and N,N-diisopropylethylamine (1.3 g, 10 mmol) in sequence, and react at room temperature for 2 h.
  • Step 2 Compound 92A (368 mg, 1.23 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 92B (247 mg, crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 199.1 [M+H] + .
  • Step 3 Compound 1D (525 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL), and compound 92B (247 mg, crude product) and N,N-diisopropylethylamine (2 mL) were added respectively, and the mixture was reacted at 40° C. for 0.5 h. After the reaction was completed as monitored by LCMS, the residue was directly concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 92C (256 mg, yield: 37.2%).
  • Step 4 Compound 92C was separated by chiral SFC to obtain compound 92 (SFC analysis retention time: 2.907min, 28.6mg), compound 93 (SFC analysis retention time: 3.303min, 22.1mg), compound 94 (SFC analysis retention time: 4.183min, 29.9mg) and compound 95 (SFC analysis retention time: 4.955min, 29.7mg).
  • SFC analysis method instrument: SHIMADZU LC-20AD, column: Chiral IK Column; mobile phase: A: n-Hexane, B: 0.1% IPAmin isopropanol and acetonitrile; gradient: 35% B in A; flow rate: 1mL/min column temperature: 35°C wavelength: 220nm.
  • Compound 92 and compound 93 were prepared by SFC for the first time.
  • instrument Waters 150 Prep-SFC, column: Chiral WHELK column; mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile; gradient: 40% B in A; flow rate: 120 mL/min, column temperature: room temperature, wavelength: 220 nm, cycle time: 4.8 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and methanol solution injection: 3 mL each time.
  • Step 1 Dissolve compound 96A (3.1 g, 14 mmol) (synthesis reference: ACS Catalysis (2021), 11 (15), 9715-9721) in 140 mL of anhydrous ethanol, add excess hydrazine hydrate, and reflux for 6 h. After the reaction, directly concentrate to obtain compound 96B (3.3 g, crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 237.1 [M+H] + .
  • Step 4 Compound 1C (127 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL), and compound 96D (505 mg, 1 mmol) and N,N-diisopropylethylamine (2 mL) were added respectively, and the mixture was reacted at 40°C for 0.5 h. After the reaction was completed as monitored by LCMS, the mixture was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 96E (384 mg, yield: 64.4%).
  • Step 5 Compound 96E was separated by chiral SFC to obtain compound 96 (SFC analysis retention time: 1.747 min, 183.8 mg) and compound 97 (SFC analysis retention time: 2.147 min, 181.6 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 35% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 4.0 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile and ethanol solution injection: 5 mL each time.
  • Step 1 In a 100 mL eggplant-shaped bottle, compound 98A (530 mg, 2.37 mmol) (synthesized according to patent WO2023169481), benzyl mercaptan (440 mg, 3.5 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (87.7 mg, 0.12 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (138 mg, 0.24 mmol) and N,N-diisopropylethylamine (2 mL) were added in sequence, and then 20 mL of anhydrous toluene was added, and the reaction was carried out at 100 ° C for 4 hours after nitrogen replacement. After the reaction was completed, it was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 98B (472 mg, yield: 72.1%).
  • Step 2 In a 50 mL eggplant-shaped bottle, add 98B (472 mg, 1.71 mmol) and N-chlorosuccinimide (0.9 g, 6.84 mmol), then add 10 mL of anhydrous acetic acid and 2 mL of water. React at room temperature for 2 h. After the reaction, add 50 mL of water, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, concentrate, and purify the residue by silica gel column chromatography to obtain compound 98C (296 mg, yield: 69.1%).
  • Step 3 Compound 98C (296 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), and a 0.1 M amine solution in 1,4-dioxane (16 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction, the mixture was concentrated to obtain compound 98D (287 mg, crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 234.0 [M+H] + .
  • LC-MS (ESI): m/z 514.3 [MH] -
  • Step 8 Compound 98J was separated by chiral SFC to obtain compound 98 (SFC pre-preparation peak, 84.1 mg) and compound 99 (SFC post-preparation peak, 86.1 mg).
  • SFC preparation method instrument: SFC Prep 150AP, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in isopropanol; gradient: 50% B gradient elution flow rate: 40 mL/min, column temperature: room temperature wavelength: 220 nm cycle time: 4.0 min; sample preparation: sample concentration 5 mg/mL, DMF solution injection: 5 mL each time.
  • Step 7 Compound 100G was separated by chiral SFC to obtain compound 100 (SFC analysis retention time: 0.473 min, 12 mg) and compound 101 (SFC analysis retention time: 0.714 min, 11 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 6.2 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 3.0 mL each time.
  • Example 102 and Example 103
  • Step 2 Compound 102B (300 mg, 1.22 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 102C (500 mg crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 146.1 [M+H] + .
  • Step 3 Compound 1D (200 mg, 0.38 mmol) was dissolved in acetonitrile (10 mL), and compound 40C (500 mg, 1.22 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added respectively, and heated to 40°C for 2 hours. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain compound 102D (150 mg, yield: 62.2%).
  • Step 4 Compound 102D was separated by chiral SFC to obtain compound 102 (SFC analysis retention time: 1.903 min, 61 mg) and compound 103 (SFC analysis retention time: 2.181 min, 70 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral AD column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in isopropanol; Gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 6.0 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.
  • Example 104 and Example 105
  • Step 1 Compound 104A (6 g, 40.50 mmol) was dissolved in dichloromethane (50 mL) and oxalyl chloride (12.85 g, 101.25 mmol) was slowly added under an ice-water bath, reacted for 1 h, and directly concentrated to obtain a crude acyl chloride. Then N, O-dimethylhydroxylamine hydrochloride (7.11 g, 72.9 mmol) and triethylamine (12.29 g, 121.5 mmol) were dissolved in dichloromethane (50 mL), and the obtained acyl chloride was dissolved in dichloromethane and slowly added to the above reaction, and reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104B (5.5 g, yield: 71%).
  • Step 4 Compound 104D (3.6 g, 15.37 mmol) was dissolved in ethanol (35 mL), and then hydrazine hydrate (6.16 g, 122.96 mmol) was added and reacted at 80°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104E (2.8 g, yield: 73%).
  • LC-MS (ESI): m/z 249.2[M+H] + .
  • Step 8 Compound 104I (130 mg, 0.21 mmol) was subjected to chiral SFC separation to obtain compound 104 (SFC analysis retention time: 1.992 min, 58 mg) and compound 105 (SFC analysis retention time: 2.349 min, 56 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35° C. wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: for methanol; gradient: 40% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 3.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.
  • Example 106 Example 106
  • Step 1 Dissolve 3-N-tert-butyloxycarbonylaminocyclobutylamine (1g, 5.81mmol) and triethylamine (1.76g, 17.43mmol) in dichloromethane (10mL), then slowly add compound 106A (0.90g, 6.39mmol) dropwise, and react at room temperature for 2h. After the reaction is completed, concentrate, add 100mL of ethyl acetate to the system, wash with saturated brine (50mL ⁇ 4), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain compound 106B (1.2g, yield: 74.78%).
  • Step 2 Compound 106B (0.3 g, 1.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 106C (0.2 g crude product), which was directly used in the next step.
  • Step 3 Compound 106C (0.2 g crude product) was processed by referring to the first step of Example 18 to obtain Compound 106D (0.25 g, yield: 65.85%).
  • LC-MS (ESI): m/z 666.2 [M+H] + .
  • Step 4 Compound 106D was separated by chiral SFC to obtain compound 106 (SFC pre-preparation peak, 80 mg) and compound 107 (SFC post-preparation peak, 85 mg).
  • SFC preparation method instrument: SFC Prep 150AP, column: AS (19 mm*250 mm); mobile phase: A: CO 2 , B: 0.01% ammonia in isopropanol; gradient: isocratic, 50% B; flow rate: 38 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 5.0 min; sample preparation: sample concentration 3 mg/mL, methanol solution injection: 5 mL each time.
  • Example 108 and Example 109
  • Step 1 Dissolve 3-N-tert-butyloxycarbonylaminocyclobutylamine (1g, 5.81mmol) and triethylamine (1.76g, 17.43mmol) in dichloromethane (10mL), then slowly add compound 108A (1.01g, 5.81mmol) dropwise, and react at room temperature for 2h. After the reaction is completed, concentrate, add 100mL of ethyl acetate to the system, wash with saturated brine (50mL ⁇ 4), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate the residue to obtain compound 108B (1.1g, yield: 68.55%).
  • Step 2 Compound 108B (0.2 g, 0.80 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 108C (0.2 g crude product), which was directly used in the next step.
  • Step 3 Compound 108C (0.2 g) was treated with the same method as in the first step of Example 18 to obtain Compound 108D (0.27 g, yield: 74.01%).
  • LC-MS (ESI): m/z 640.2 [M+H] + .
  • Step 4 Compound 108D was separated by chiral SFC to obtain compound 108 (SFC pre-preparation peak, 85 mg) and compound 109 (SFC post-preparation peak, 87 mg).
  • SFC preparation method instrument: SFC Prep 150AP, column: AS (19 mm*250 mm); mobile phase: A: CO 2 , B: 0.01% ammonia in isopropanol; gradient: isocratic, 40% B; flow rate: 40 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 5.0 min; sample preparation: sample concentration 3 mg/mL, methanol solution injection: 5 mL each time.
  • Step 1 Add compound 110A (5.0 g, 26.45 mmol) to a reaction bottle, dissolve it with acetonitrile (100 mL), then add 1,2-dibromoethane-d4 (5.08 g, 26.45 mmol), and react at 85°C for 12 hours. After the reaction is completed by TLC monitoring, cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 110B (4.4 g, yield: 75.92%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 7.06-7.04 (m, 1H), 6.99-6.95 (m, 1H), 6.84-6.80 (m, 1H).
  • Step 2 Compound 110B (4.4 g, 20.08 mmol), benzyl mercaptan (4.99 g, 40.16 mmol), Pd(dppf)Cl 2 (1.46 g, 2.01 mmol), Xantphos (2.3 g, 4.02 mmol) and DIPEA (10.5 mL, 60.24 mmol) were added to a reaction bottle, dissolved with toluene (100 mL), replaced with nitrogen three times, and reacted at 100° C. for 16 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 110C (1.55 g, yield: 29.41%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 7.30-7.19 (m, 5H), 6.85-6.93 (m, 1H), 6.80-6.77 (m, 2H), 4.11 (s, 2H).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 14.61 (s, 1H), 7.08-7.02 (m, 2H), 6.79-6.76 (m, 1H).
  • Step 4 Compound 110D (0.80 g, 3.63 mmol) was added to a reaction flask, dissolved with NH 3 in 1,4-dioxane solution (25 mL), and then DIPEA (3 mL) was added and reacted at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 110E (0.75 g, yield: 94.17%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 7.30-7.26 (m, 2H), 7.19 (s, 2H), 7.02-6.99 (m, 1H).
  • Step 9 Compound 110I was subjected to chiral SFC separation to obtain compound 110 (SFC pre-preparation peak, 30 mg) and compound 111 (SFC post-preparation peak, 27 mg).
  • SFC preparation method 1. Instrument: SFC prep 150AP, chromatographic column: IK (19 mm*250 mm), 2. The sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: mobile phase A: CO 2 , mobile phase B: isopropanol, isocratic elution, mobile phase B content 60%, flow rate: 38 mL/min.
  • Step 1 Dissolve compound 112A (5 g, 28.54 mmol) and triethylamine (8.66 g, 85.62 mmol) in dichloromethane (60 mL), then add ethyl chloroformate (4.03 g, 37.10 mmol) under an ice-water bath, and react at room temperature overnight. After the reaction is completed, add saturated sodium bicarbonate solution to quench the reaction, then add dilute hydrochloric acid to adjust to acidity, extract with dichloromethane 3 times, combine the organic phases and concentrate to obtain compound 112B (7 g crude product), which is directly used in the next step.
  • LC-MS (ESI): m/z 248.2[M+H] + .
  • Step 2 Compound 112B (2 g, 8.09 mmol) and compound 22D (2.70 g, 10.52 mmol) were dissolved in toluene (25 mL) and then reacted at 120°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The residue was slurried to obtain compound 112C (3.6 g, yield: 97%).
  • LC-MS (ESI): m/z 458.2 [M+H] + .
  • Step 5 Compound 112E was separated by chiral SFC to obtain compound 112 (SFC analysis retention time: 2.100 min, 56 mg) and compound 113 (SFC analysis retention time: 2.418 min, 56 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 254 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in methanol; gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C; wavelength: 254 nm; cycle time: 6.5 min; sample preparation: sample concentration 5 mg/mL, methanol and acetonitrile solution injection: 3 mL each time.
  • Step 3 Compound 114C was subjected to chiral separation to obtain Compound 114 (SFC analysis retention time: 2.034 min, 5.6 mg) and Compound 115 (SFC analysis retention time: 2.266 min, 6.1 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in MeOH; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in MeOH; Gradient: 35% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 2 mg/mL, Methanol solution injection: 2 mL each time.
  • Example 116 Example 116, Example 117, Example 118 and Example 119
  • Step 1 Dissolve p-toluenesulfonamide (10 g, 58.4 mmol), ammonium persulfate (66.63 g, 292 mmol) and selective fluorine reagent (82.76 g, 233.6 mmol) in acetonitrile (100 mL) and water (100 mL), add silver nitrate (1.98 g, 11.68 mmol) at 0°C, then replace with nitrogen 3 times, and finally heat to 80°C for 5 hours. After the reaction is completed, slowly add saturated sodium bicarbonate solution to the system until no bubbles are generated.
  • Step 2 Dissolve the mixture of compound 116B and compound 118B (1.5 g) and triethylamine (0.63 g, 2.15 mmol) in dichloromethane (30 mL), then slowly add isopropyl chloroformate (0.98 g, 7.96 mmol) and react at room temperature for 2 h. After the reaction, add water (100 mL) to the system, adjust the pH to 3 with 1M HCl, and then extract with dichloromethane (50 mL) 3 times, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a mixture of compound 116C and 118C (1.6 g), which is directly used in the next step.
  • Step 3 Add a mixture of compound 116C and compound 118C (0.5 g) and compound 22D (0.63 g, 2.15 mmol) to toluene (30 mL), protect with nitrogen, heat to 100°C and stir overnight, then cool and concentrate. The residue is purified by silica gel column chromatography to obtain a mixture of compound 116D and compound 118D (0.5 g).
  • Step 5 The mixture of compound 116E and compound 118E (0.4 g) and triethylamine (0.16 mg, 1.58 mmol) were dissolved in DMF (8 mL), and then compound 1C (0.15 g, 1.19 mmol) was added. After the addition was completed, the mixture was stirred at room temperature overnight. After the reaction was completed, water (50 mL) was added to the system, and then extracted with ethyl acetate (50 mL) 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 116F (80 mg) and compound 118F (51 mg).
  • Step 6 Compound 116F was separated by chiral SFC to obtain compound 116 (pre-SFC peak, 22 mg) and compound 117 (post-SFC peak, 29 mg).
  • SFC preparation method Instrument: Waters 150 Prep-SFC, column: Chiral IK column; Mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol; Gradient: 5-40% B in A; Flow rate: 120 mL/min Column temperature: 35°C Wavelength: 220 nm, Cycle time: 6.8 min; Sample preparation: Sample concentration 2 mg/mL, Methanol solution injection: 2 mL each time.
  • Compound 118F was separated by chiral SFC to obtain compound 118 (pre-SFC preparation peak, 16 mg) and compound 119 (post-SFC preparation peak, 16 mg).
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral IK column; mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; gradient: 5-40% B in A; flow rate: 100 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 3.6 min; sample preparation: sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.
  • Step 2 Compound 120B (1.9 g, 6.62 mmol) and hydrazine hydrate (3.31 g, 52.96 mmol, 80% content) were added to anhydrous ethanol (50 mL), and heated to 80°C with nitrogen protection and stirred for 4 hours. The mixture was cooled, filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 120C (1.5 g, yield: 76%).
  • LC-MS (ESI): m/z 301.0 [M+H] + .
  • Step 4 Compound 120D (600 mg, 1.09 mmol) and triisopropylsilyl acetylene (800 mg, 4.36 mmol) were dissolved in tetrahydrofuran (25 mL), and Pd(PPh 3 ) 2 Cl 2 (77 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol) and triethylamine (550 mg, 5.45 mmol) were added in sequence. After nitrogen replacement three times, the mixture was reacted at 60° C. under nitrogen protection for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 120E (200 mg, yield: 28%).
  • LC-MS (ESI): m/z 654.2[M+H] + .
  • Step 8 Compound 120H was further separated by chiral SFC to obtain compound 120 (SFC analysis retention time: 1.957 min, 31 mg) and compound 121 (SFC analysis retention time: 2.091 min, 20 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 3.8 min Sample preparation: Sample concentration 10 mg/mL, methanol solution injection: 2.0 mL each time.
  • Example 122 and Example 123
  • Step 4 Compound 122D was further separated by chiral SFC to obtain compound 122 (SFC analysis retention time: 0.831 min, 98.0 mg) and compound 123 (SFC analysis retention time: 1.276 min, 96.9 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD SFC, column: Chiral IX column; mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol; gradient: 5%-40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO 2 , B: methanol; Gradient: 45% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 6.5 min Sample preparation: Sample concentration 10 mg/mL, Ethanol solution injection: 2.0 mL each time.
  • Step 4 Compound 124D (1.0 g, 2.99 mmol) was dissolved in ethanol (35 mL), and then hydrazine hydrate (0.94 g, 14.95 mmol) was added and reacted at 80° C. for 4 hours. After the reaction was completed, it was directly concentrated to obtain compound 124E (1.2 g crude product), which was directly used in the next step.
  • Step 8 Compound 124H (80 mg) was subjected to chiral SFC separation to obtain compound 124 (SFC analysis retention time: 2.130 min, 20 mg) and compound 125 (SFC analysis retention time: 2.628 min, 21 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35° C. wavelength: 220 nm.
  • SFC preparation method instrument: Waters 150 Prep-SFC, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: for ethanol; gradient: 50% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.0 min; sample preparation: sample concentration 4 mg/mL, acetonitrile ethanol mixed solution injection: 3.0 mL each time.
  • Example 126 Example 126, Example 127, Example 128 and Example 129
  • Step 2 Compound 126B (1.1 g, 2.36 mmol) and NIS (586 mg, 2.60 mmol) were dissolved in 20 mL of anhydrous DCM and stirred at -10 °C for 10 min under nitrogen protection. Then, hydrogen fluoride pyridine solution (270 mg, 260 mmol) was slowly added dropwise at -10 °C, and the mixture was slowly restored from -10 °C to room temperature and continued to react for 1 h. After the reaction was complete, 20 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise under an ice bath, and the liquids were separated. The aqueous phase was extracted once with 20 mL of dichloromethane, and the organic phases were combined and dried.
  • Step 3 The mixture of compound 126C and 126B (510 mg, equivalent weight calculated based on 126C: 0.83 mmol) was dissolved in 10 mL of DCM, and DBU (253 mg, 1.67 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was complete, 10 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise under an ice bath, and the liquids were separated. The aqueous phase was extracted once with 10 mL of dichloromethane, and the organic phases were combined, dried, and concentrated to obtain compound 126D (320 mg, a mixture containing 126B), which was directly used for the next step.
  • LC-MS (ESI): m/z 481.9 [MH] - & 464.3 [MH] - .
  • Step 4 Toluene (5 mL) was added to a 25 mL single-mouth bottle, followed by a mixture of compounds 126D and 126B (320 mg, equivalent weight calculated based on 126D: 0.69 mmol) and DIPEA (100 mg, 0.76 mmol), and then phosphorus oxychloride (113 mg, 0.76 mmol) was slowly added dropwise. After the addition was completed, the system was heated to 100 ° C and stirred for 1 h under nitrogen protection. After the raw materials disappeared, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a mixture of compounds 126E and 126F (120 mg).
  • Step 5 Compound 1C (121 mg, 0.50 mmol) was dissolved in dichloromethane (5 mL), triethylamine (198 mg, 1.00 mmol) was added and stirred for half an hour, then a mixture of 126E and 126F (120 mg, equivalent weight calculated based on 126F: 0.25 mmol) was added and stirred at room temperature overnight. Water (5 mL) was added to quench the reaction, the mixture was separated, and extracted twice with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a mixture of compounds 126G and 126H (60 mg).
  • Step 6 The mixture of compounds 126G and 126H (60 mg) was subjected to chiral SFC separation to obtain compound 126 (SFC analysis retention time: 0.959 min, 6.1 mg), compound 127 (SFC analysis retention time: 1.155 min, 14.2 mg), compound 128 (SFC analysis retention time: 1.392 min, 5.3 mg) and compound 129 (SFC analysis retention time: 1.700 min, 13.6 mg).
  • SFC analysis method instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 40% B in A; flow rate: 3 mL/min; column temperature: 35°C; detection wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 8.0 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.
  • reaction solution was concentrated to 1/3 of the original volume, 100 mL of saturated ammonium chloride aqueous solution was added to quench the reaction, and extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 130B (3.5 g, yield: 81%).
  • LC-MS (ESI): m/z 336.1[MH] - .
  • Step 4 Disperse compound 130D (250 mg, 0.40 mmol) in anhydrous toluene, add phosphorus oxychloride (122 mg, 0.8 mmol) and DIPEA (155 mg, 1.2 mmol), and react at 100° C. for 1 h. After the reaction is completed, concentrate the residue, and purify it by silica gel column chromatography to obtain compound 130E (150 mg, yield: 58%).
  • Step 5 Dissolve compound 1C (111 mg, 0.46 mmol) in dichloromethane (5 mL), add triethylamine (93 mg, 0.92 mmol) and stir for half an hour, then add compound 130E (150 mg, 0.23 mmol) and stir at room temperature overnight. Add water (5 mL) to quench the reaction, separate the liquids, extract twice with dichloromethane (5 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure.
  • Step 2 Compound 131B (1 g, 2.92 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 16 h, and concentrated under reduced pressure to obtain compound 131C (600 mg, crude product), which was directly used in the next step.
  • LC-MS (ESI): m/z 143.1 [M+H] + .
  • Step 3 Compound 131C (220 mg, 1.52 mmol) was processed according to the third step of Example 40 to obtain compound 131D (200 mg).
  • LC-MS (ESI): m/z 632.2 [M+H] + .
  • Step 4 Compound 131D was separated by chiral SFC to obtain compounds 131 (SFC analysis retention time: 2.125min, 8mg) and 132 (SFC analysis retention time: 2.229min, 5mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3mL/min Column temperature: 35°C Wavelength: 220nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B: ethanol; Gradient: 30% B gradient elution flow rate: 120mL/min, Column temperature: 25°C Wavelength: 254nm Cycle time: 8.1min; Sample preparation: Sample concentration 2mg/mL, ethanol solution injection: 2mL each time.
  • Example 133 and Example 134
  • Step 2 Compound 133B (150 mg, 0.67 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (0.3 g, 2.82 mmol) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 24 h under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 133C (40 mg), which was directly used in the next step.
  • LC-MS (ESI): m/z 135.1 [M+H] + .
  • Step 4 Compound 133D was subjected to chiral SFC separation to obtain compounds 133 (SFC analysis retention time: 0.75 min, 3.19 mg) and 134 (SFC analysis retention time: 1.10 min, 2.2 mg).
  • SFC analysis method Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B for 0.05% DEA in isopropanol and acetonitrile; Gradient: 40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm.
  • SFC preparation method Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile; Gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 6.0 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.
  • the synthetic routes of the compounds in other embodiments refer to the synthetic routes of Examples 1 and 2.
  • the compounds of the present invention have an IC 50 value of less than 1000 nM for the cAMP signaling pathway downstream of the CB1 receptor, some preferred compounds have an IC 50 ⁇ 100 nM, some more preferred compounds have an IC 50 ⁇ 50 nM, some more preferred compounds have an IC 50 ⁇ 10 nM, and some more preferred compounds have an IC 50 ⁇ 1 nM.
  • IC 50 values of some specific compounds are shown in Table 1, wherein AA represents IC 50 ⁇ 1 nM, A represents 1 nM ⁇ IC 50 ⁇ 10 nM, B represents 10 nM ⁇ IC 50 ⁇ 50 nM, C represents 50 nM ⁇ IC 50 ⁇ 100 nM, and D represents 100 nM ⁇ IC 50 ⁇ 1000 nM.
  • the compounds of the present invention have a strong antagonistic effect on the cAMP signaling pathway downstream of the CB1 receptor.
  • the IC 50 of some compounds is less than 1 nM, for example, the IC 50 of compound 2 is 0.4744 nM, the IC 50 of compound 5 is 0.75 nM, the IC 50 of compound 9 is 0.6693 nM, the IC 50 of compound 14 is 0.46 nM, the IC 50 of compound 21 is 0.44 nM, the IC 50 of compound 23 is 0.38 nM, the IC 50 of compound 25 is 0.357 nM, the IC 50 of compound 27 is 0.46 nM, the IC 50 of compound 30 is 0.41 nM, the IC 50 of compound 31 is 0.389 nM, the IC 50 of compound 32 is 0.2196 nM, the IC 50 of compound 35 is 0.734 nM, and the IC 50 of compound 43 is 0.
  • the IC 50 of compound 46 was 0.6745 nM, the IC 50 of compound 47 was 0.4382 nM, the IC 50 of compound 51 was 0.5359 nM, the IC 50 of compound 53 was 0.834 nM, the IC 50 of compound 59 was 0.3883 nM, the IC 50 of compound 62 was 0.607 nM, the IC 50 of compound 63 was 0.8594 nM, the IC 50 of compound 64 was 0.8295 nM, the IC 50 of compound 73 was 0.8538 nM, the IC 50 of compound 74 was 0.7239 nM, the IC 50 of compound 77 was 0.4387 nM, the IC 50 of compound 79 was 0.5482 nM, the IC 50 of compound 81 was The IC 50 of compound 83 was 0.6728 nM, the IC 50 of compound 84 was 0.9576 nM, the IC 50 of compound 86 was 0.2643 nM, the IC 50 of compound 88 was 0.
  • HEK293T cells were cultured to 80% confluence, and the cells were collected by trypsin digestion and counted and inoculated into 6-well plates.
  • the cell density reached about 70%, and the receptor and ⁇ arrestin2 plasmids were co-transfected by Lipo3000.
  • the cells were digested and re-plated into 96-well plates overnight.
  • 10 ⁇ working solution of the test substance was prepared, and the detection substrate and the prepared compound were added. Incubate in 96-well plates, and read the luminescence signal value with an enzyme reader. IC 50 value was calculated using GraphPad Prism software.
  • IC 50 values of some specific compounds are shown in Table 2, wherein AA represents IC 50 ⁇ 1 nM, A represents 1 nM ⁇ IC 50 ⁇ 10 nM, B represents 10 nM ⁇ IC 50 ⁇ 50 nM, C represents 50 nM ⁇ IC 50 ⁇ 100 nM, and D represents 100 nM ⁇ IC 50 ⁇ 1000 nM.
  • the compounds of the present invention have a strong antagonistic effect on the ⁇ -arrestin signaling pathway downstream of the CB1 receptor.
  • a Chinese hamster ovary (CHO) cell line that stably expresses CB2 receptors was used.
  • the positive compound and the test substance were first diluted in series, and then the treated cells were counted and inoculated in a 384-well plate. Next, the diluted compound was added to the corresponding experimental wells and incubated at 37°C for 10 minutes. After the incubation, 4 ⁇ L of agonist solution was added to the corresponding experimental wells and incubated for 30 minutes to induce cAMP production.
  • the compounds of the present invention such as the compounds in the examples, have a weak antagonistic effect on the cAMP signaling pathway downstream of the CB2 receptor.
  • mice Male C57 mice, 18-25 g, purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • mice were randomly divided into two groups according to body weight, namely, IV and PO. The mice were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • the brain tissue was rinsed with cold saline to remove residual blood on the surface, and after absorbing the water, it was weighed and homogenized; the adipose tissue was rinsed with cold saline to remove residual blood and hair on the surface, and after absorbing the water, it was weighed and homogenized. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention have good pharmacokinetic characteristics in mice. Moreover, the example compounds have low exposure in the brain tissue of mice, with a lower brain/plasma ratio, and high exposure in the adipose tissue, with a very high fat/plasma ratio.
  • Experimental animals Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in rats.
  • mice Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • test method On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% [1-(I/Io)] ⁇ 100%.
  • Inhibition% represents the percentage of inhibition of hERG potassium current by the compound
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention have no inhibition on the hERG potassium channel current.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC 50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the compounds of the present invention have no inhibition on the five isozymes of human liver microsomal cytochrome P450 (CYP), especially compound 2 has only weak inhibition on 1A2, 2C19, 2D6, and 3A4.
  • liver microsomes from five species including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) were further calculated.
  • the experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate.
  • a transport buffer solution (HBSS, 10mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (2 ⁇ M) or the control compounds digoxin (10 ⁇ M), nadolol (2 ⁇ M) and metoprolol (2 ⁇ M) was added to the dosing port well on the apical side or the basolateral side.
  • a transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ⁇ 1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate.
  • acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention such as the compounds of the examples, showed good permeability in the Caco-2 permeability test.
  • mice were fed a high-fat diet purchased from Research Diets, catalog number D12492, with 60% of calories being fat. After 14 weeks of continuous induction, obese mice were induced, weighing approximately 50 grams. After the induction was completed, compound administration began, 3 mg/kg QD for 20 consecutive days, and body weight was measured once a day.
  • INV-202 is Table Compound 72 in patent US20180273485A1.

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Abstract

Disclosed are a cannabinoid receptor 1 antagonist and a use thereof, and in particular, disclosed are a compound represented by formula (I), formula (IV), formula (IV-a), or formula (IV-b), and a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, and a use thereof as a CB1 antagonist in preparation of drugs for treating related diseases, wherein each group in formula (I), formula (IV), formula (IV-a), and formula (IV-b) is as defined in the description.

Description

一种大麻素受体1拮抗剂及其应用Cannabinoid receptor 1 antagonist and its application 技术领域Technical Field

本发明涉及一种大麻素受体1(CB1)拮抗剂，其立体异构体、互变异构体、药学上可接受的盐、溶剂化物、共晶或氘代物，及其在制备治疗CB1介导的相关疾病的药物中的用途。The present invention relates to a cannabinoid receptor 1 (CB1) antagonist, its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, cocrystal or deuterated substance, and use thereof in preparing a drug for treating CB1-mediated related diseases.

背景技术Background Art

CB1不仅在脑中表达，在外周细胞和组织中也表达，是内源性大麻素系统的组成部分。CB1通过大麻素及其衍生物刺激或结合，激活胞内信号，发挥广泛的生物学作用。该系统的激活可以增加食欲，促进脂质的合成和储存等。CB1的拮抗剂可以通过抑制内源性大麻素系统，降低食欲，减少摄食，从而减轻体重。目前已有CB1拮抗剂已被证明有减肥效果，如利莫那班，并具有胰岛素增敏和改善脂代谢紊乱的作用。但因其具有中枢副作用而撤市。目前仍存在需求，开发可用于代谢综合征、肥胖、糖尿病肾病、胰岛素依赖性糖尿病或非胰岛素依赖型糖尿病等疾病的药物。CB1 is expressed not only in the brain, but also in peripheral cells and tissues, and is a component of the endocannabinoid system. CB1 activates intracellular signals through stimulation or binding of cannabinoids and their derivatives, and exerts a wide range of biological effects. Activation of this system can increase appetite, promote the synthesis and storage of lipids, etc. CB1 antagonists can reduce weight by inhibiting the endocannabinoid system, reducing appetite, and reducing food intake. Currently, CB1 antagonists have been shown to have weight loss effects, such as rimonabant, and have the effects of sensitizing insulin and improving lipid metabolism disorders. However, it was withdrawn from the market because of its central side effects. There is still a demand to develop drugs that can be used for diseases such as metabolic syndrome, obesity, diabetic nephropathy, insulin-dependent diabetes or non-insulin-dependent diabetes.

发明内容Summary of the invention

本发明的目的是提供一种CB1拮抗剂，具有结构新颖、药效好、生物利用度高、副作用小、起效快、长效等优点。The purpose of the present invention is to provide a CB1 antagonist with the advantages of novel structure, good efficacy, high bioavailability, small side effects, rapid onset and long-term effect.

本发明涉及一种式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，
The present invention relates to a compound represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), and a stereoisomer or a pharmaceutically acceptable salt thereof.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、-SF5、-SCF3、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-O-C3-6环烷基或-O-(3-6元杂环烷基)，其中所述的烷基、烯基、炔基任选进一步被1-5个Ra取代；在某些实施方案中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基，其中所述的烷基、烯基、炔基任选进一步被1-5个Ra取代；在某些实施方案中，R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C1-4卤代烷基，其中所述的烷基任选进一步被1-5个Ra取代；在某些实施方案中，R1、R3各自独立地选自氘、卤素、C1-4烷基、C1-4卤代烷基，其中所述的烷基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C In some embodiments, R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen , hydroxy , cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-( 3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra; in certain embodiments, R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C In some embodiments, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, wherein the alkyl, alkenyl, alkynyl are optionally further substituted with 1-5 Ra; In some embodiments, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, wherein the alkyl, alkenyl, alkynyl are optionally further substituted with 1-5 Ra; In some embodiments, R 1 , R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, wherein the alkyl is optionally further substituted with 1-5 Ra; In some embodiments, R 1 , R 3 are each independently selected from deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, wherein the alkyl is optionally further substituted with 1-5 Ra; 1-4 haloalkyl, wherein the alkyl is optionally further substituted with 1-5 Ra;

在某些实施方案中，R2选自氢；In certain embodiments, R 2 is selected from hydrogen;

在某些实施方案中，R1选自卤素；R3选自C1-4卤代烷基；在某些实施方案中，R1选自卤素、C1-4烷基、C2-4炔基；在某些实施方案中，R1选自F、Cl、Br、甲基、乙基、乙炔；In certain embodiments, R 1 is selected from halogen; R 3 is selected from C 1-4 haloalkyl; in certain embodiments, R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl; in certain embodiments, R 1 is selected from F, Cl, Br, methyl, ethyl, acetylene;

在某些实施方案中，R3选自氘、卤素、C1-4卤代烷基、-SF5、C2-4烯基、C2-4炔基，其中所述的烯基、炔基任选进一步被1-3个Ra取代；In certain embodiments, R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

在某些实施方案中，R1选自F、Cl、Br；R3选自-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F；在某些实施方案中，R1选自F、Cl、Br、甲基；R3选自-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、乙烯基、乙炔基、1-氟乙烯基；在某些实施方案中，R1选自Cl；R3选自-CF3；在某些实施方案中，R1选自卤素、C1-3烷基；在某些实施方案中，R1选自Cl；在某些实施方案中，R1选自-CH3；在某些实施方案中，R1选自乙炔；In certain embodiments, R 1 is selected from F, Cl, Br; R 3 is selected from -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F; In certain embodiments, R 1 is selected from F, Cl, Br, methyl; R 3 is selected from -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, vinyl, ethynyl, 1-fluorovinyl; In certain embodiments, R 1 is selected from Cl; R 3 is selected from -CF 3 ; In certain embodiments, R 1 is selected from halogen, C 1-3 alkyl; In certain embodiments, R 1 is selected from Cl; In certain embodiments, R 1 is selected from -CH 3 ; In certain embodiments, R 1 is selected from acetylene;

在某些实施方案中，R3选自卤素、SF5、C1-4卤代烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基；在某些实施方案中，R3选自F、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、乙烯基、乙炔基、1-氟乙烯基、SF5；In certain embodiments, R 3 is selected from halogen, SF 5 , C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl; In certain embodiments, R 3 is selected from F, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, vinyl, ethynyl, 1-fluorovinyl, SF 5 ;

RA选自-L1-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1；在某些实施方案中，RA选自-L1-W1-L2-W2-RA1；在某些实施方案中，RA选自-W1-L2-W2-RA1；在某些实施方案中，RA选自-W1-W2-RA1；在某些实施方案中，RA选自-N＝C(NH2)-NRW1C(O)-RA1、-NRW1-RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1；在某些实施方案中，RA1选自C1-4烷基、C3-6环烷基、3-6元杂环烷基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，RW1选自H、C1-2烷基； RA is selected from -L1- W1 -L2 - W2 - RA1 , -C3-6 cycloalkyl- RA1 or -3-6 membered heterocycloalkyl- RA1 ; in certain embodiments, RA is selected from -L1 - W1 - L2 - W2 - RA1 ; in certain embodiments, RA is selected from -W1 - L2 - W2 - RA1 ; in certain embodiments, RA is selected from -W1 - W2 - RA1 ; in certain embodiments, RA is selected from -N＝C( NH2 ) -NRW1C(O)-RA1 , -NRW1 - RA1 , -N＝C( NH2 ) -NRW1 - NRW1C (O) -RA1 ; in certain embodiments, RA is selected from C1-4 alkyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R W1 is selected from H, C 1-2 alkyl;

在某些实施方案中，Ra选自氘、卤素、氧代基、C1-4烷基、-C(O)C1-4烷基、-NRW1C(O)C1-4烷基、-S(O)2NH2、-C(O)C3-6环烷基、-NRW1C(O)C3-6环烷基、-S(O)2C1-4烷基、-S(＝O)(＝NH)-C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基的基团所取代；In certain embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, -C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 alkyl, -S(O) 2 NH 2 , -C(O)C 3-6 cycloalkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, -S(＝O)(＝NH)-C 1-4 alkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-5 groups selected from halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, and deuterated C 1-4 alkyl;

在某些实施方案中，RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；In certain embodiments, R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy;

L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ;

在某些实施方案中，L1选自键；In certain embodiments, L 1 is selected from a bond;

在某些实施方案中，L2选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、3-6元环烷基，所述的烷基、环烷基任选进一步被1-4个选自卤素的取代基取代；在某些实施方案中，L2选自键、C1-2亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自F、Cl、＝O、甲基、乙基、环丙基、环丁基，所述的甲基、乙基、环丙基、环丁基任选进一步被1-4个选自F、Cl的取代基取代；在某些实施方案中，L2选自键；In certain embodiments, L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C1-4 alkyl, 3-6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen; in certain embodiments, L2 is selected from a bond, C1-2 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from F, Cl, =O, methyl, ethyl, cyclopropyl, cyclobutyl, and the methyl, ethyl, cyclopropyl, cyclobutyl are optionally further substituted with 1-4 substituents selected from F and Cl; in certain embodiments, L2 is selected from a bond;

W1、W2各自独立地选自键、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W1、W2各自独立地选自键、-O-、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W1、W2各自独立地选自键、-NRW1-、-(C＝O)NRW1-、-NRW1(C＝O)-、-NRW1-NRw1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W1、W2各自独立地选自键、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W1、W2各自独立地选自键、-NRW1-、-NRW1-NRw1(C＝O)-、-NRW1(C＝O)-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W1选自-NRW1-、-NRW1S(O)2-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-；在某些实施方案中，W2选自键、-NRW1-、-NRW1(C＝O)-、-NRW1-NRw1(C＝O)-； W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C(=O)O-, -OC(=O)-, -S(O) 2- , -S(O) 2 NR W1 -, -NR W1 S(O) 2- , -S(=O)(=NH)-, -N=C( NH2 )-, -N=S(=O)( C1-6 alkyl)-, -N=C( CH3 )-; in certain embodiments, W1 and W2 are each independently selected from a bond, -O-, -NR W1 -, -NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -, -NR W1 (C=O)-, -C (=O)O-, -OC(=O)-, -S(O) 2- , -S(O) 2 NR W1 -, -NR W1 S(O) 2 -, -S(＝O)(＝NH)-, -N＝C(NH 2 )-, -N＝S(＝O)(C 1-6 alkyl)-, -N＝C(CH 3 )-; in certain embodiments, W 1 , W 2 are each independently selected from a bond, -NR W1 -, -(C＝O)NR W1 -, -NR W1 (C＝O)-, -NR W1 -NR w1 (C＝O)-, -S(O) 2 -, -S(O) 2 NR W1 -, -NR W1 S(O) 2 -, -S(O)(＝NH)-, -N＝C(NH 2 )-, -N＝S(＝O)(C 1-6 alkyl)-, -N＝C(CH 3 )-; in certain embodiments, W 1 , W 2 are each independently selected from a bond, -NR W1 -, -NR W1 -NR w1 In some embodiments, W1 and W2 are each independently selected from a bond, -NRW1-, -NRW1- NRW1 (C=O)-, -NRW1 (C=O)-, -NRW1 (C=O)-, -S(O) 2- , -S ( O) 2NRW1- , -NRW1 S(O) 2- , -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-; In some embodiments, W1 and W2 are each independently selected from a bond, -NRW1-, -NRW1-NRW1 (C=O)-, -NRW1 (C=O)-, -NRW1 S (O) 2- , -S( O )(=NH)-, -N= C (NH2)-, -N=S(=O)( C1-6alkyl )-, -N=C(CH3)-; In some embodiments, W1 and W2 are each independently selected from a bond, -NRW1-, -NRW1-NRW1 (C=O)-, -NRW1 (C =O )-, -NRW1 S(O) 2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C1-6alkyl)-, -N = C ( CH3 ) - S(O) 2 -, -N=C(NH 2 )-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH 3 )-; In certain embodiments, W 2 is selected from a bond, -NR W1 -, -NR W1 (C=O)-, -NR W1 -NR w1 (C=O)-;

在某些实施方案中，条件是，L1、L2、W1、W2不同时为键；在某些实施方案中，条件是，L2、W1、W2不同时为键；在某些实施方案中，条件是，W1、W2不同时为键；In certain embodiments, with the proviso that L 1 , L 2 , W 1 , and W 2 are not simultaneously a bond; In certain embodiments, with the proviso that L 2 , W 1 , and W 2 are not simultaneously a bond; In certain embodiments, with the proviso that W 1 , and W 2 are not simultaneously a bond;

RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，RA1选自氘、卤素、羟基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-4烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，RA1选自氘、卤素、氰基、C1-4烷基、C2-4烯基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、烯基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；在某些实施方案中，RA1选自氘、卤素、氰基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C In some embodiments, RA1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in some embodiments, RA1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in some embodiments, RA1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 membered aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

在某些实施方案中，RA1选自氰基、C1-4烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；In certain embodiments, R A1 is selected from cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

在某些实施方案中，RA1选自氰基、甲基、乙基、丙基、乙烯基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、氧杂环丁基、氧杂环戊基、氧杂环己基、硫杂环己基、氮杂环戊基、氮杂环己基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噁唑基、 任选进一步被1-5个Ra取代；In certain embodiments, R A1 is selected from cyano, methyl, ethyl, propyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolyl, oxhexyl, thiazole, azetyl, azohexyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, Optionally further substituted with 1-5 Ra;

在某些实施方案中，RA1选自氰基、甲基、乙基、丙基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环戊基、氮杂环己基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、任选进一步被1-5个Ra取代；In certain embodiments, R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl, azopentyl, azohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, Optionally further substituted with 1-5 Ra;

在某些实施方案中，RA1选自氰基、甲基、乙基、丙基、环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、 任选进一步被1-5个Ra取代；In certain embodiments, R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, aziridine, azohexyl, phenyl, Optionally further substituted with 1-5 Ra;

RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano;

在某些实施方案中，RW1选自H、C1-2烷基、卤素、氰基；在某些实施方案中，RW1选自H、C1-2烷基、氰基；在某些实施方案中，RW1选自H、氰基；In certain embodiments, R W1 is selected from H, C 1-2 alkyl, halogen, cyano; In certain embodiments, R W1 is selected from H, C 1-2 alkyl, cyano; In certain embodiments, R W1 is selected from H, cyano;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C1-6烷基亚基、C1-6卤代烷基亚基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、羟基、氰基、氧代基、C1-4烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-6环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-6环烷基、-S(O)2C3-6环烷基、-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、羟基、氧代基、C1-4烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-6环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-6环烷基、-S(O)2C3-6环烷基或-S(O)2C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O) C3-8cycloalkyl , -S(O ) 2C3-8cycloalkyl or -S(O ) 2C1-4alkyl , wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxyl, cyano, amino, oxo, C1-6alkyl , haloC1-6alkyl , deuteratedC1-6alkyl, C1-6alkoxy , haloC1-6alkoxy or deuteratedC1-6alkoxy ; in certain embodiments, Ra is selected from deuterium, halogen, hydroxyl, cyano, oxo, C1-4alkyl, C1-3alkyl substituent, C1-3 haloalkyl substituent, C2-4alkenyl , C2-4alkynyl , C1-4 deuteratedalkyl , C1-4 haloalkyl, C C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 halogen, oxo, C 1-4 alkyl, haloC 2 In some embodiments, Ra is selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O) NR W1 C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C -S(O) 2C3-6cycloalkyl , -S( O ) 2C3-6cycloalkyl or -S (O) 2C1-4alkyl , wherein the alkyl or cycloalkyl is optionally further substituted with 1-5 groups selected from halogen, oxo, C1-4alkyl , halo- substituted C1-4alkyl , deuterated C1-4alkyl , C1-4alkoxy, halo-substituted C1-4alkoxy or deuterated C1-4alkoxy ;

在某些实施方案中，Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2或-S(O)2NHC1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、氧代基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2或-S(O)2NHC1-4烷基，其中所述的烷基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；在某些实施方案中，Ra选自氘、卤素、氧代基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基；在某些实施方案中，Ra选自氧代基、甲基、乙基、丙基、-CD3、-CHD2、-CH2D、-CH2CD3、-CH2CHD2、-CH2CH2D、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、甲亚基、乙亚基、1-甲基乙亚基；In certain embodiments, Ra is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 members selected from halogen, hydroxyl, cyano, amino, oxo, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, In some embodiments, Ra is selected from deuterium, halogen, cyano, oxo , C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl , 5-6 membered heteroaryl, -C(O )C 1-4 alkyl , -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O) C 1-4 deuterated alkyl, -S( O ) 2 NH 2 , -S(O) 2 NHC wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halo-C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy or deuterated C 1-4 alkoxy; in certain embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl , C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl , -S(O) 2 NH 2 or -S (O) 2 NHC In some embodiments, R is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl , alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or deuterated C 1-4 alkoxy. In some embodiments, R is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 halogen, oxo, C 1-4 alkyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or deuterated C In some embodiments, Ra is substituted with a C 1-4 alkoxy group; in some embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl; in some embodiments, Ra is selected from oxo, methyl, ethyl, propyl, -CD 3 , -CHD 2 , -CH 2 D, -CH 2 CD 3 , -CH 2 CHD 2 , -CH 2 CH 2 D, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, methylidene, ethylidene, 1-methylethylidene;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;

在某些实施方案中，作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-6环烷基；在某些实施方案中，作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基；在某些实施方案中，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基；在某些实施方案中，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基；In certain embodiments, alternatively, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl; in certain embodiments, alternatively, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl; in certain embodiments, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl, C 2-6 alkynyl; in certain embodiments, two Ra on the same carbon atom are taken together with the carbon atom to which they are attached to form C 2-6 alkenyl;

在某些实施方案中，RA选自 In certain embodiments, RA is selected from

在某些实施方案中，RA选自 In certain embodiments, RA is selected from

在某些实施方案中，RA选自: In certain embodiments, RA is selected from:

RA2选自C3-8环烷基、3-8元杂环烷基、5-10元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-6烷氧基的基团所取代；R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;

在某些实施方案中，RA2选自C3-6环烷基、3-6元杂环烷基、5-6元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；In certain embodiments, R A2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;

在某些实施方案中，RA2选自环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基，所述的环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基任选进一步被1-5个选自氘、羟基、氰基、氨基、甲基、乙基、异丙基、甲氧基、乙氧基、F、Cl、氧代基、甲亚基、乙亚基、1-甲基乙亚基、氟甲亚基、二氟甲亚基、-CH2D、-CHD2、-CD3、-CH2CH2D、-CH2CHD2、-CH2CD3、-CHDCH2D、-CHDCHD2、-CHDCD3、-CD2CH2D、-CD2CHD2、-CD2CD3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-OCHF2、-OCH2F、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCHFCH2F、-OCHFCHF2、-OCHFCF3、-OCF2CH2F、-OCF2CHF2、-OCF2CF3、-OCHD2、-OCH2D、-OCD3、-OCH2CH2D、-OCH2CHD2、-OCH2CD3、-OCHDCH2D、-OCHDCHD2、-OCHDCD3、-OCD2CH2D、-OCD2CHD2、-OCD2CD3的基团所取代；In certain embodiments, RA2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl , ethyl, isopropyl, methoxy, ethoxy, F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D , -CHD2 , -CD3 , -CH2CH2D , -CH2CHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDCD3 , -CD2CH2 D. -CD 2 CHD 2 , -CD 2 CD 3 , -CH 2 F , -CHF 2 , -CF 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F , -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F , -CF 2 CHF 2 , -CF 2 CF 3 , -OCHF 2 , -OCH 2 F , -OCF 3 , -OCH 2 CH 2 F , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 2 F , -OCHFCHF 2 , -OCHFCF 3 , -OCF 2 CH 2 F , -OCF 2 CHF 2 , -OCF 2 CF 3 , -OCHD 2 , -OCH 2 D, -OCD 3 , -OCH 2 CH 2 D, -OCH 2 CHD 2 , -OCH 2 CD 3 , -OCHDCH 2 D, -OCHDCHD 2 , -OCHDCD 3 , -OCD 2 CH 2 D, -OCD 2 CHD 2 , -OCD 2 CD 3 groups substituted;

RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-4 alkoxy;

在某些实施方案中，RA2选自C3-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；In certain embodiments, R A2 is selected from C 3-6 cycloalkyl, which is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;

在某些实施方案中，RA2选自环丙基、环丁基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、氧杂环丁基、氮杂环丁基、氧杂环戊基、氮杂环戊基、氧杂环己基、氮杂环己基、吗啉基、哌嗪基，所述的环丙基、环丁基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、氧杂环丁基、氮杂环丁基、氧杂环戊基、氮杂环戊基、氧杂环己基、氮杂环己基、吗啉基、哌嗪基任选进一步被1-3个选自甲基、乙基、F、Cl、氧代基、甲亚基、乙亚基、1-甲基乙亚基、氟甲亚基、二氟甲亚基、-CH2D、-CHD2、-CD3、-CH2CH2D、-CH2CHD2、-CH2CD3、-CHDCH2D、-CHDCHD2、-CHDCD3、-CD2CH2D、-CD2CHD2、-CD2CD3的基团所取代；In certain embodiments, RA2 is selected from cyclopropyl, cyclobutyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxacyclohexyl, azohexyl, morpholinyl, piperazinyl, the ... oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxhexyl, azohexyl, morpholinyl, piperazinyl are optionally further substituted with 1-3 groups selected from methyl, ethyl, F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene , -CH2D, -CHD2 , -CD3 , -CH2CH2D , -CH2CHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDCD3 , -CD2CH2D , -CD2CHHD2 , -CD2CD3 ;

X1、X2、X3、X4选自CH或N；在一些实施方案中，X1、X2、X3、X4选自CH或N，且X1、X2、X3、X4中至少1个选自N；在某些实施方案中，X1、X2选自CH，X3、X4选自N；在某些实施方案中，X1、X2选自N，X3、X4选自CH；在某些实施方案中，X1选自N，X2、X3、X4选自CH；在某些实施方案中，X2选自N，X1、X3、X4选自CH；在某些实施方案中，X3选自N，X1、X2、X4选自CH；在某些实施方案中，X4选自N，X1、X2、X3选自CH； X1 , X2 , X3 , X4 are selected from CH or N; in some embodiments, X1 , X2 , X3 , X4 are selected from CH or N, and at least one of X1 , X2 , X3 , X4 is selected from N; in certain embodiments, X1 , X2 are selected from CH, X3 , X4 are selected from N; in certain embodiments, X1 , X2 are selected from N, X3 , X4 are selected from CH; in certain embodiments, X1 is selected from N, X2 , X3 , X4 are selected from CH; in certain embodiments, X2 is selected from N, X1 , X3 , X4 are selected from CH; in certain embodiments, X3 is selected from N, X1 , X2 , X4 are selected from CH; in certain embodiments, X4 is selected from N, X1 , X2 , X3 are selected from CH;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

在某些实施方案中，作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-6环烷基、3-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；In certain embodiments, alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy;

在某些实施方案中，作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C4-6环烷基、4-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；In certain embodiments, alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or a 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy;

在某些实施方案中，作为选择，不同碳原子两个R3与其相连的碳原子一起形成C4-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、C1-4烷基的基团所取代；In certain embodiments, alternatively, two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;

n选自0、1、2、3、4或5；在某些实施方案中，n选自0、1、2或3；在某些实施方案中，n选自0或1；在某些实施方案中，n选自0；n is selected from 0, 1, 2, 3, 4 or 5; in certain embodiments, n is selected from 0, 1, 2 or 3; in certain embodiments, n is selected from 0 or 1; in certain embodiments, n is selected from 0;

m选自1、2、3、4或5；在某些实施方案中，m选自1、2或3；在某些实施方案中，m选自1或2；在某些实施方案中，m选自1；m is selected from 1, 2, 3, 4 or 5; in certain embodiments, m is selected from 1, 2 or 3; in certain embodiments, m is selected from 1 or 2; in certain embodiments, m is selected from 1;

k选自1、2、3、4或5；在某些实施方案中，k选自1、2或3；在某些实施方案中，k选自1或2；在某些实施方案中，k选自1；k is selected from 1, 2, 3, 4 or 5; in certain embodiments, k is selected from 1, 2 or 3; in certain embodiments, k is selected from 1 or 2; in certain embodiments, k is selected from 1;

本发明式(I)化合物满足如下条件：The compound of formula (I) of the present invention satisfies the following conditions:

(1)RA不为 (1) R A does not

(2)RA选自时，R3不为C2-6炔基和C1-6氘代烷基；(2) R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;

(3)当m、k同时选自1时，R1、R3不同时选自卤素；(3) When m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen;

在一些实施方案中，本发明化合物不选自如下结构 In some embodiments, the compounds of the present invention are not selected from the following structures

具体而言，本发明其中一种实施方案，涉及一种式(I)、式(IV)、式(IV-a)、式(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，
Specifically, one embodiment of the present invention relates to a compound represented by formula (I), formula (IV), formula (IV-a), formula (IV-b), and stereoisomers and pharmaceutically acceptable salts thereof.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

RA选自-L1-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;

L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ;

W1、W2各自独立地选自键、-O-、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -O-, -NRW1-, -NRW1- NRw1 (C=O)-, -(C=O) NRW1- , -NRW1 (C=O)-, -C (=O)O-, -OC(=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(=O)(=NH)-, -N=C( NH2 )-, -N=S( = O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L1、L2、W1、W2不同时为键；Provided that L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C1-6烷基亚基、C1-6卤代烷基亚基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-8 cycloalkyl, -S(O) 2 C 3-8 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

RA2选自C3-8环烷基、3-8元杂环烷基、5-10元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-6烷氧基的基团所取代；R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;

X1、X2、X3、X4选自CH或N；X 1 , X 2 , X 3 , X 4 are selected from CH or N;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;

m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5;

k选自1、2、3、4或5；k is selected from 1, 2, 3, 4 or 5;

并且式(I)化合物满足如下条件：And the compound of formula (I) satisfies the following conditions:

(1)RA不为 (1) R A does not

(2)RA选自时，R3不为C2-6炔基和C1-6氘代烷基；(2) R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;

(3)当m、k同时选自1时，R1、R3不同时选自卤素。(3) When m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen.

具体而言，本发明其中一种实施方案，涉及一种式(I)、式(IV)所示的化合物，其立体异构体、药学上可接受的盐，
Specifically, one embodiment of the present invention relates to a compound represented by formula (I) or formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

RA选自-L1-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;

L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ;

W1、W2各自独立地选自键、-O-、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -O-, -NRW1-, -NRW1- NRw1 (C=O)-, -(C=O) NRW1- , -NRW1 (C=O)-, -C (=O)O-, -OC(=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(=O)(=NH)-, -N=C( NH2 )-, -N=S( = O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L1、L2、W1、W2不同时为键；Provided that L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C1-6烷基亚基、C1-6卤代烷基亚基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-8 cycloalkyl, -S(O) 2 C 3-8 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

RA2选自C3-8环烷基、3-8元杂环烷基、5-10元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-6烷氧基的基团所取代；R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy;

X1、X2、X3、X4选自CH或N，且X1、X2、X3、X4中至少1个选自N；X 1 , X 2 , X 3 , and X 4 are selected from CH or N, and at least one of X 1 , X 2 , X 3 , and X 4 is selected from N;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;

m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5;

k选自1、2、3、4或5；k is selected from 1, 2, 3, 4 or 5;

并且式(I)化合物满足如下条件：And the compound of formula (I) satisfies the following conditions:

(1)RA不为 (1) R A does not

(2)RA选自时，R3不为C2-6炔基和C1-6氘代烷基；(2) R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl;

(3)当m、k同时选自1时，R1、R3不同时选自卤素。(3) When m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen.

本发明涉及的另一个实施方案，涉及一种式(I)所示的化合物，其立体异构体、药学上可接受的盐，
Another embodiment of the present invention relates to a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

条件是：当m、k同时选自1时，R1、R3不同时选自卤素；Provided that: when m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen;

RA选自-L1-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;

L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ;

W1、W2各自独立地选自键、-O-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -O-, -NRW1-, -CONRW1-, -NRW1CO- , -C (=O) O- , -OC(=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S(O) 2- , -S (=O)(=NH)-, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L1、L2、W1、W2不同时为键；Provided that L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, -C(O) C1-4 alkyl, -C(O) C1-4 deuterated alkyl, -NRW1C(O) C1-4 alkyl, -NRW1C(O) C1-4 deuterated alkyl, -S(O) 2NH2 , -S ( O) 2NHC1-4 alkyl , -C(O) C3-8 cycloalkyl , -C(O ) NRW1C1-4 alkyl , -NRW1C(O) C3-8 cycloalkyl , -S(O) 2C 3-8 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;

m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5;

k选自1、2、3、4或5；k is selected from 1, 2, 3, 4 or 5;

条件是：The conditions are:

(1)RA不为 (1) R A does not

(2)RA选自时，R3不为C2-6炔基和C1-6氘代烷基。(2) R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl.

本发明涉及的另一个实施方案，涉及一种式(IV)所示的化合物，其立体异构体、药学上可接受的盐，
Another embodiment of the present invention relates to a compound represented by formula (IV), its stereoisomers, and pharmaceutically acceptable salts.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C1-6烷基亚基、C1-6卤代烷基亚基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-8 cycloalkyl, -S(O) 2 C 3-8 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

RA2选自C3-8环烷基、3-8元杂环烷基、、5-10元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy or deuterated C 1-6 alkoxy;

X1、X2、X3、X4选自CH或N；在一些实施方案中，X1、X2、X3、X4选自CH或N，且X1、X2、X3、X4中至少1个选自N；X 1 , X 2 , X 3 , X 4 are selected from CH or N; in some embodiments, X 1 , X 2 , X 3 , X 4 are selected from CH or N, and at least one of X 1 , X 2 , X 3 , X 4 is selected from N;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;

m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5;

k选自1、2、3、4或5。k is selected from 1, 2, 3, 4 or 5.

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、-SF5、-SCF3、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-O-C3-6环烷基或-O-(3-6元杂环烷基)，其中所述的烷基、烯基、炔基任选进一步被1-5个Ra取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -SF 5 , -SCF 3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

m选自1、2或3；m is selected from 1, 2 or 3;

k选自1、2或3。k is selected from 1, 2 or 3.

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -W1 - L2 - W2 - RA1, -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;

L2选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、3-6元环烷基，所述的烷基、环烷基任选进一步被1-4个选自卤素的取代基取代； L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C1-4 alkyl, 3-6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally further substituted by 1-4 substituents selected from halogen;

W1、W2各自独立地选自键、-NRW1-、-(C＝O)NRW1-、-NRW1(C＝O)-、-NRW1-NRw1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -(C=O) NRW1- , -NRW1(C=O)-, -NRW1 - NRw1 (C=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(O)(=NH)-, -N = C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L2、W1、W2不同时为键；The condition is that L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-4烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、卤素、氰基；R W1 is selected from H, C 1-2 alkyl, halogen, cyano;

Ra选自氘、卤素、羟基、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基、-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C C 3-8 cycloalkyl, -S(O) 2 C 3-8 cycloalkyl, -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy;

RA2选自C3-6环烷基、3-6元杂环烷基、5-6元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；R A2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-6环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-6环烷基、3-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy.

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自-W1-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1,优选RA选自-N＝C(NH2)-NRW1C(O)-RA1、-N＝C(NH2)-NRW1RA1、-N＝C(NH2)-RA1、-NRW1-RA1、-N＝S(＝O)(C1-6烷基)-RA1、-NRW1S(O)2-NRW1C(O)-RA1、-NRW1-S(O)(＝NH)-RA1、-N＝C(CH3)-NRW1RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1、-C3-6环烷基-RA1、-3-6元杂环烷基-RA1； RA is selected from -W1 - W2 - RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 . Preferably RA is selected from -N＝C( NH2 )-NRW1C(O) -RA1 , -N＝C( NH2 ) -NRW1RA1 , -N＝C( NH2 ) -RA1 , -NRW1 -RA1 , -N＝S(＝O)( C1-6alkyl ) -RA1 , -NRW1S(O) 2- NRW1C (O )-RA1 , -NRW1 - S (O)(＝NH) -RA1 , -N＝C( CH3 ) -NRW1RA1 , -N＝C( NH2 ) -NRW1 - NRW1C (O) -RA1 , -C3-6cycloalkyl - RA1 , -3-6 membered heterocycloalkyl-R A1 ;

W1、W2各自独立地选自键、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1-, -NRW1 - NRw1 (C=O)-, -(C=O) NRW1- , -NRW1 ( C=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(O)(=NH)-, -N = C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，W1、W2不同时为键；The condition is that W 1 and W 2 are not bonds at the same time;

RA1选自氘、卤素、氰基、C1-4烷基、C2-4烯基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、烯基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、氰基；R W1 is selected from H, C 1-2 alkyl, cyano;

Ra选自氘、卤素、羟基、氧代基、C1-4烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-6环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-6环烷基、-S(O)2C3-6环烷基或-S(O)2C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl or cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy;

RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-4 alkoxy;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C3-6环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or a C 3-6 cycloalkyl;

作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C4-6环烷基、4-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy.

在一些具体实施方案中，式(I)、(II)、(III)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -W1 - L2 - W2 - RA1, -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ;

L2选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、3-6元环烷基，所述的烷基、环烷基任选进一步被1-4个选自卤素的取代基取代； L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C1-4 alkyl, 3-6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally further substituted by 1-4 substituents selected from halogen;

W1、W2各自独立地选自键、-NRW1-、-CONRW1-、-NRW1CO-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -CONRW1-, -NRW1CO- , -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S( O )(=NH ) -, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L2、W1、W2不同时为键；The condition is that L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-4烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、卤素、氰基；R W1 is selected from H, C 1-2 alkyl, halogen, cyano;

Ra选自氘、卤素、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 members selected from halogen, oxo, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl substituted by a C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy group;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基。Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or C 2-6 alkynyl.

在一些具体实施方案中，式(I)、(II)、(III)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自-W1-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1,优选RA选自-N＝C(NH2)-NRW1C(O)-RA1、-N＝C(NH2)-NRW1RA1、-N＝C(NH2)-RA1、-NRW1-RA1、-N＝S(＝O)(C1-6烷基)-RA1、-NRW1S(O)2-NRW1C(O)-RA1、-NRW1-S(O)(＝NH)-RA1、-N＝C(CH3)-NRW1RA1、-C3-6环烷基-RA1、-3-6元杂环烷基-RA1； RA is selected from -W1 - W2 - RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 , preferably RA is selected from -N＝C( NH2 )-NRW1C ( O) -RA1 , -N＝C(NH2) -NRW1RA1 , -N＝C( NH2 ) -RA1 , -NRW1 - RA1 , -N＝S(＝O)( C1-6alkyl ) -RA1 , -NRW1S(O) 2 - NRW1C (O) -RA1 , -NRW1- S (O)(＝NH) -RA1 , -N ＝C( CH3 ) -NRW1RA1 , -C3-6cycloalkyl - RA1 and -3-6memberedheterocycloalkyl- RA1 ;

W1、W2各自独立地选自键、-NRW1-、-CONRW1-、-NRW1CO-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -CONRW1-, -NRW1CO- , -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S( O )(=NH ) -, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，W1、W2不同时为键；The condition is that W 1 and W 2 are not bonds at the same time;

RA1选自氘、卤素、氰基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、氰基；R W1 is selected from H, C 1-2 alkyl, cyano;

Ra选自氘、卤素、氧代基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2或-S(O)2NHC1-4烷基；Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基。Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl group.

在一些具体实施方案中，式(I)、(II)、(III)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自-N＝C(NH2)-NRW1C(O)-RA1、-N＝C(NH2)-NRW1RA1、-N＝C(NH2)-RA1、-NRW1-RA1、-N＝S(＝O)(C1-6烷基)-RA1、-NRW1S(O)2-NRW1C(O)-RA1、-NRW1-S(O)(＝NH)-RA1、-N＝C(CH3)-NRW1RA1、、-C3-6环烷基-RA1、-3-6元杂环烷基-RA1； RA is selected from -N＝C( NH2 )-NRW1C(O) -RA1 , -N＝C( NH2 ) -NRW1RA1 , -N＝C( NH2 ) -RA1 , -NRW1 - RA1 , -N＝S(＝O)( C1-6alkyl ) -RA1 , -NRW1S ( O) 2 - NRW1C (O) -RA1 , -NRW1 - S (O)(＝NH) -RA1 , -N ＝C( CH3 ) -NRW1RA1 , -C3-6cycloalkyl - RA1 , -3-6memberedheterocycloalkyl- RA1 ;

RA1选自氘、卤素、氰基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、氰基；R W1 is selected from H, C 1-2 alkyl, cyano;

Ra选自氘、卤素、氧代基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2或-S(O)2NHC1-4烷基。Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 or -S(O) 2 NHC 1-4 alkyl.

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

R1选自卤素、C1-4烷基、C2-4炔基；R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;

R2选自氢； R2 is selected from hydrogen;

R3选自氘、卤素、C1-4卤代烷基、-SF5、C2-4烯基、C2-4炔基，其中所述的烯基、炔基任选进一步被1-3个Ra取代；R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

作为选择，不同碳原子两个R3与其相连的碳原子一起形成C4-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、C1-4烷基的基团所取代；Alternatively, two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;

X1、X2、X3、X4选自CH或N；X 1 , X 2 , X 3 , X 4 are selected from CH or N;

RA选自-N＝C(NH2)-NRW1C(O)-RA1、-NRW1-RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1； RA is selected from -N=C( NH2 ) -NRW1C (O) -RA1 , -NRW1 - RA1 , -N=C(NH2)-NRW1 - NRW1C (O) -RA1 ;

RA1选自C1-4烷基、C3-6环烷基、3-6元杂环烷基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基；R W1 is selected from H, C 1-2 alkyl;

Ra选自氘、卤素、氧代基、C1-4烷基、-C(O)C1-4烷基、-NRW1C(O)C1-4烷基、-S(O)2NH2、-C(O)C3-6环烷基、-NRW1C(O)C3-6环烷基、-S(O)2C1-4烷基、-S(＝O)(＝NH)-C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基的基团所取代；Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, -C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 alkyl, -S(O) 2 NH 2 , -C(O)C 3-6 cycloalkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, -S(＝O)(＝NH)-C 1-4 alkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-5 groups selected from halogen, C 1-4 alkyl, halogenated C 1-4 alkyl and deuterated C 1-4 alkyl;

RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, and the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy.

在一些具体实施方案中，式(I)、(II)、(III)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), their stereoisomers, and pharmaceutically acceptable salts, wherein

R1选自卤素、C1-4烷基、C2-4炔基；R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;

R2选自氢； R2 is selected from hydrogen;

R3选自氘、卤素、C1-4卤代烷基、-SF5、C2-4烯基、C2-4炔基，其中所述的烯基、炔基任选进一步被1-3个Ra取代；R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

作为选择，不同碳原子两个R3与其相连的碳原子一起形成C4-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、C1-4烷基的基团所取代；Alternatively, two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;

RA选自-N＝C(NH2)-NRW1C(O)-RA1、-NRW1-RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1； RA is selected from -N=C( NH2 ) -NRW1C (O) -RA1 , -NRW1 - RA1 , -N=C(NH2)-NRW1 - NRW1C (O) -RA1 ;

RA1选自C1-4烷基、C3-6环烷基、3-6元杂环烷基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基；R W1 is selected from H, C 1-2 alkyl;

Ra选自氘、卤素、氧代基、C1-4烷基、-C(O)C1-4烷基、-NRW1C(O)C1-4烷基、-S(O)2NH2、-C(O)C3-6环烷基、-NRW1C(O)C3-6环烷基、-S(O)2C1-4烷基、-S(＝O)(＝NH)-C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基的基团所取代。Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, -C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 alkyl, -S(O) 2 NH 2 , -C(O)C 3-6 cycloalkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, -S(＝O)(＝NH)-C 1-4 alkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-5 groups selected from halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterated C 1-4 alkyl.

在一些具体实施方案中，式(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

R1选自卤素、C1-4烷基、C2-4炔基；R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl;

R2选自氢； R2 is selected from hydrogen;

R3选自氘、卤素、C1-4卤代烷基、-SF5、C2-4烯基、C2-4炔基，其中所述的烯基、炔基任选进一步被1-3个Ra取代；R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

作为选择，不同碳原子两个R3与其相连的碳原子一起形成C4-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、C1-4烷基的基团所取代；Alternatively, two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl;

X1、X2、X3、X4选自CH或N；X 1 , X 2 , X 3 , X 4 are selected from CH or N;

RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, and the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy.

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自: R A is selected from:

RA2选自环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基，所述的环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基任选进一步被1-5个选自氘、羟基、氰基、氨基、甲基、乙基、异丙基、甲氧基、乙氧基、F、Cl、氧代基、甲亚基、乙亚基、1-甲基乙亚基、氟甲亚基、二氟甲亚基、-CH2D、-CHD2、-CD3、-CH2CH2D、-CH2CHD2、-CH2CD3、-CHDCH2D、-CHDCHD2、-CHDCD3、-CD2CH2D、-CD2CHD2、-CD2CD3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-OCHF2、-OCH2F、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCHFCH2F、-OCHFCHF2、-OCHFCF3、-OCF2CH2F、-OCF2CHF2、-OCF2CF3、-OCHD2、-OCH2D、-OCD3、-OCH2CH2D、-OCH2CHD2、-OCH2CD3、-OCHDCH2D、-OCHDCHD2、-OCHDCD3、-OCD2CH2D、-OCD2CHD2、-OCD2CD3的基团所取代。R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy , F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene , -CH2D , -CHD2 , -CD3 , -CH2CH2D , -CH2CHHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDCD3 , -CD2CH2D , -CD 2 CHD 2 , -CD 2 CD 3 , -CH 2 F , -CHF 2 , -CF 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F , -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F , -CF 2 CHF 2 , -CF 2 CF 3 , -OCHF 2 , -OCH 2 F , -OCF 3 , -OCH 2 CH 2 F , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 2 F , -OCHFCHF 2 , -OCHFCF 3 , -OCF 2 CH 2 F , -OCF 2 CHF 2 , -OCF 2 CF 3 , -OCHD 2 , -OCH 2 D, -OCD 3 , -OCH 2 CH 2 D, -OCH 2 CHD 2 , -OCH 2 CD 3 , -OCHDCH 2 D, -OCHDCHD 2 , -OCHDCD 3 , -OCD 2 CH 2 D, -OCD 2 CHD 2 , -OCD 2 CD 3 .

在一些具体实施方案中，式(I)、(II)、(III)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (I), (II), (III), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA选自: R A is selected from:

在一些具体实施方案中，式(IV)、(IV-a)、(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compounds represented by formula (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

RA2选自环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基，所述的环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基任选进一步被1-5个选自氘、羟基、氰基、氨基、甲基、乙基、异丙基、甲氧基、乙氧基、F、Cl、氧代基、甲亚基、乙亚基、1-甲基乙亚基、氟甲亚基、二氟甲亚基、-CH2D、-CHD2、-CD3、-CH2CH2D、-CH2CHD2、-CH2CD3、-CHDCH2D、-CHDCHD2、-CHDCD3、-CD2CH2D、-CD2CHD2、-CD2CD3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-OCHF2、-OCH2F、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCHFCH2F、-OCHFCHF2、-OCHFCF3、-OCF2CH2F、-OCF2CHF2、-OCF2CF3、-OCHD2、-OCH2D、-OCD3、-OCH2CH2D、-OCH2CHD2、-OCH2CD3、-OCHDCH2D、-OCHDCHD2、-OCHDCD3、-OCD2CH2D、-OCD2CHD2、-OCD2CD3的基团所取代。R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy , F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene , -CH2D , -CHD2 , -CD3 , -CH2CH2D , -CH2CHHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDCD3 , -CD2CH2D , -CD 2 CHD 2 , -CD 2 CD 3 , -CH 2 F , -CHF 2 , -CF 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F , -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F , -CF 2 CHF 2 , -CF 2 CF 3 , -OCHF 2 , -OCH 2 F , -OCF 3 , -OCH 2 CH 2 F , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 2 F , -OCHFCHF 2 , -OCHFCF 3 , -OCF 2 CH 2 F , -OCF 2 CHF 2 , -OCF 2 CF 3 , -OCHD 2 , -OCH 2 D, -OCD 3 , -OCH 2 CH 2 D, -OCH 2 CHD 2 , -OCH 2 CD 3 , -OCHDCH 2 D, -OCHDCHD 2 , -OCHDCD 3 , -OCD 2 CH 2 D, -OCD 2 CHD 2 , -OCD 2 CD 3 .

本发明涉及的另一个实施方案，一种式(I)所示的化合物，其立体异构体、药学上可接受的盐，
Another embodiment of the present invention is a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.

其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra;

条件是：当m、k同时选自1时，R1、R3不同时选自卤素；Provided that: when m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen;

RA选自-L1-W1-L2-W2-RA1； RA is selected from -L1-W1 - L2 - W2 - RA1 ;

L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ;

W1、W2各自独立地选自键、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -O-, -S-, -NRW1-, -CONRW1- , -NRW1CO- , -C(=O) O- , -OC(=O)-, -S(O) 2- , -S(O)2NRW1- , -NRW1S (O) 2- , -S(=O)(=NH ) -, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L1、L2、W1、W2不同时为键；Provided that L 1 , L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano;

Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；R is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, C 2-6 alkynyl;

n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5;

m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5;

k选自1、2、3、4或5；k is selected from 1, 2, 3, 4 or 5;

条件是：所述化合物不选自如下结构 The condition is that the compound is not selected from the following structures

在一些具体实施方案中，式(I)化合物，其立体异构体、药学上可接受的盐，其中In some specific embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein

R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、-SF5、-SCF3、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-O-C3-6环烷基或-O-(3-6元杂环烷基)，其中所述的烷基、烯基、炔基任选进一步被1-5个Ra取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -SF 5 , -SCF 3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra;

n选自0、1、2或3；n is selected from 0, 1, 2 or 3;

m选自1、2或3；m is selected from 1, 2 or 3;

k选自1、2或3；k is selected from 1, 2 or 3;

条件是：当m、k选自1时，R1、R3不同时选自卤素。Provided that: when m and k are selected from 1, R 1 and R 3 are not simultaneously selected from halogen.

在一些具体实施方案中，式(I)化合物，其立体异构体、药学上可接受的盐，其中，In some specific embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein:

RA选自-W1-L2-W2-RA1； RA is selected from -W1 - L2 - W2 - RA1 ;

L2选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、3-6元环烷基，所述的烷基、环烷基任选进一步被1-4个选自卤素的取代基取代； L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C1-4 alkyl, 3-6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally further substituted by 1-4 substituents selected from halogen;

W1、W2各自独立地选自键、-NRW1-、-CONRW1-、-NRW1CO-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -CONRW1-, -NRW1CO- , -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S( O )(=NH ) -, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，L2、W1、W2不同时为键；The condition is that L 2 , W 1 , and W 2 are not bonds at the same time;

RA1选自氘、卤素、羟基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-4烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、卤素、氰基；R W1 is selected from H, C 1-2 alkyl, halogen, cyano;

Ra选自氘、卤素、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；R is selected from deuterium, halogen, cyano, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基。Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or C 2-6 alkynyl.

在一些具体实施方案中，式(I)化合物，其立体异构体、药学上可接受的盐，其中，In some specific embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein:

RA选自-W1-W2-RA1； RA is selected from -W1 - W2 - RA1 ;

W1、W2各自独立地选自键、-NRW1-、-CONRW1-、-NRW1CO-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -CONRW1-, -NRW1CO- , -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S( O )(=NH ) -, -N=C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-;

条件是，W1、W2不同时为键；The condition is that W 1 and W 2 are not bonds at the same time;

RA1选自氘、卤素、氰基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

RW1选自H、C1-2烷基、氰基；R W1 is selected from H, C 1-2 alkyl, cyano;

Ra选自氘、卤素、氧代基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基；Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl;

作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基。Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl group.

在一些具体实施方案中，式(I)的化合物，其立体异构体、药学上可接受的盐，其中，In some specific embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein:

RA选自: R A is selected from:

在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)的化合物，其立体异构体、药学上可接受的盐，其中所述化合物选自表一结构之一：In some specific embodiments, the compound of formula (I), (II), (III), (IV), (IV-a), (IV-b), its stereoisomers, pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table 1:

表一



Table 1



在一些具体实施方案中，式(I)、(II)、(III)、(IV)、(IV-a)、(IV-b)的化合物，其立体异构体、药学上可接受的盐，其中所述化合物选自表二结构之一：In some specific embodiments, the compound of formula (I), (II), (III), (IV), (IV-a), (IV-b), its stereoisomers, pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table 2:

表二





Table 2





本发明还涉及一种药物组合物，所述的组合物包括：含有上述所述的化合物、其立体异构体、药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。The present invention also relates to a pharmaceutical composition, which comprises: the above-mentioned compound, its stereoisomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and/or excipient.

本发明还涉及通式(I)所示的化合物及其立体异构体、药学上可接受的盐或者含本发明化合物的组合物在制备用于治疗由CB1受体介导的疾病的药物中的用途。The present invention also relates to the use of the compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or compositions containing the compound of the present invention in the preparation of drugs for treating diseases mediated by CB1 receptors.

本发明涉及通式(I)所示的化合物及其立体异构体、药学上可接受的盐或者含本发明化合物的组合物在制备CB1拮抗剂中的用途。The present invention relates to the use of a compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or a composition containing the compound of the present invention in the preparation of a CB1 antagonist.

在本发明一些具体实施方案中，所述CB1介导的疾病为肥胖症、糖尿病、非酒精性和酒精性脂肪肝疾病、糖尿病性肾病、代谢综合征、高血脂或痛风。In some specific embodiments of the present invention, the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

本发明还涉及一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明任意一项所述的化合物或者其立体异构体或药学上可接受的盐，治疗有效量优选1-1000mg，所述的疾病优选肥胖症、糖尿病、非酒精性和酒精性脂肪肝疾病、糖尿病性肾病、代谢综合征、高血脂或痛风。一些实施方案中，本发明中所述哺乳动物包括人。The present invention also relates to a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the compounds of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1-1000 mg, the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout. In some embodiments, the mammal in the present invention includes a human.

本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统任何其它希望改变的。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于：1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-50mg、1-40mg、1-25mg、1-20mg、5-1000mg、5-900mg、5-800mg、5-700mg、5-600mg、5-500mg、5-400mg、5-300mg、5-250mg、5-200mg、5-150mg、5-125mg、5-100mg、5-90mg、5-70mg、5-80mg、5-60mg、5-50mg、5-40mg、5-30mg、5-25mg、5-20mg、10-1000mg、10-900mg、10-800mg、10-700mg、10-600mg、10-500mg、10-450mg、10-400mg、10-300mg、10-250mg、10-200mg、10-150mg、10-125mg、10-100mg、10-90mg、10-80mg、10-70mg、10-60mg、10-50mg、10-40mg、10-30mg、10-20mg；20-1000mg、20-900mg、20-800mg、20-700mg、20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、20-200mg、20-150mg、20-125mg、20-100mg、20-90mg、20-80mg、20-70mg、20-60mg、20-50mg、20-40mg、20-30mg；50-1000mg、50-900mg、50-800mg、50-700mg、50-600mg、50-500mg、50-400mg、50-300mg、50-250mg、50-200mg、50-150mg、50-125mg、50-100mg；100-1000mg、100-900mg、100-800mg、100-700mg、100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg；"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-2 50mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1000mg, 10-90 0mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-9 0mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-4 0mg, 20-30mg; 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50- 125mg, 50-100mg; 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

在一些实施方案中，该药物组合物包括但不限于:1-1000mg、5-500mg、10-250mg、50-250mg、100-200mg、1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、60mg、70mg、80mg、90mg、100mg、120mg、125mg、150mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg的本发明化合物或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐。In some embodiments, the pharmaceutical composition includes but is not limited to: 1-1000 mg, 5-500 mg, 10-250 mg, 50-250 mg, 100-200 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg of a compound of the invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐，治疗有效量优选1-1000mg，所述的疾病优选肥胖症、糖尿病、非酒精性和酒精性脂肪肝疾病、糖尿病性肾病、代谢综合征、高血脂或痛风。A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1-1000 mg, and the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia, or gout.

一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐以1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于：1-1000mg/天、1-300mg/天、5-500mg/天、10-500mg/天、10-400mg/天、10-300mg/天、10-100mg/天、20-400mg/天、20-200mg/天、20-100mg/天、50-500mg/天、50-250mg/天、50-200mg/天、50-150mg/天、50-100mg/天、100-500mg/天、100-300mg/天、100-200mg/天；A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof to a subject at a daily dose of 1-1000 mg/day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to: 1-1000 mg/day, 1-300 mg/day, 5-500 mg/day, 10-500 mg/day , 10-400 mg/day, 10-300 mg/day, 10-100 mg/day, 20-400 mg/day, 20-200 mg/day, 20-100 mg/day, 50-500 mg/day, 50-250 mg/day, 50-200 mg/day, 50-150 mg/day, 50-100 mg/day, 100-500 mg/day, 100-300 mg/day, 100-200 mg/day;

在一些实施方案中，日剂量包括但不限于：1mg/天、2.5mg/天、5mg/天、10mg/天、12.5mg/天、15mg/天、20mg/天、25mg/天、30mg/天、35mg/天、40mg/天、45mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、120mg/天、150mg/天、200mg/天、250mg/天、300mg/天、400mg/天、500mg/天、1000mg/天。In some embodiments, daily doses include but are not limited to: 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 12.5 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 120 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 1000 mg/day.

本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐，本发明化合物的或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐量与上述药物组合物中其量相同。The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains the compound of the present invention or its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt, and the amount of the compound of the present invention or its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

本发明中本发明化合物或者其立体异构体、互变异构体、溶剂化物、药学上可接受的盐的量在每种情况下以游离碱的形式换算。The amount of the compound of the present invention or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt in the present invention is in each case calculated based on the free base form.

“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。"Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

合成路线Synthetic route

本领域技术人员可以结合已知的有机合成技术制备本发明的化合物，其起始原料为市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, and the starting materials are commercially available chemicals and/or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and Bailingwei Technology.

通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。Specific and similar reactants can be selectively identified through indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services.

术语the term

除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

术语“烷基”是指饱和的直链或带有支链的脂肪族烃基团，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子，即“C1-20烷基”。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至8个碳原子的烷基(即C1-8烷基)，进一步优选具有1至6个碳原子的烷基(即C1-6烷基)，最优选具有1至3个碳原子的烷基(即C1-3烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述烷基被取代基取代时，所述取代基不再被进一步取代。The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., " C1-20 alkyl". The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C1-8 alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C1-3 alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment. When the alkyl group is substituted with a substituent, the substituent may not be further substituted.

术语“亚烷基”是指二价的直链和支链饱和烷基。亚烷基实施例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)等。The term "alkylene" refers to divalent straight and branched chain saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the like.

术语“烯基”是指包含至少一个碳碳双键(C＝C)的直链烃基或支链烃基，通常包含2至18个碳原子，如2至8个碳原子，进一步如2至6个碳原子，再进一步如2至4个碳原子，其示例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；烯基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述烯基被取代基取代时，所述取代基不再被进一步取代。The term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms, examples of which include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; alkenyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment. When the alkenyl is substituted with a substituent, the substituent is no longer substituted further.

术语“炔基”是指含有至少一个碳碳三键(C≡C)的直链烃基或支链烃基，通常包含2至18个碳原子，进一步包含2至8个碳原子，进一步包含2至6个碳原子，再进一步包含2至4个的碳原子，其示例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等；炔基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述炔基被取代基取代时，所述取代基不再被进一步取代。The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), generally containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms, examples of which include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; alkynyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment. When the alkynyl is substituted by a substituent, the substituent is no longer further substituted.

术语“环烷基”指饱和或部分不饱和单环环状烃取代基(即单环环烷基)或多环环状烃取代基(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子，即C3-20环烷基。所述环烷基优选具有3至12个碳原子的环烷基(即C3-12环烷基)，更优选具有3至8个碳原子的环烷基(即C3-8环烷基)，进一步优选具有3至6个碳原子的环烷基(即C3-6环烷基)，最优选具有3至5个碳原子的环烷基(即C3-5环烷基)。所述的单环环烷基的非限制性实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。所述的多环环烷基的非限制性实例包括：螺环烷基、稠环烷基和桥环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., a C3-20 cycloalkyl. The cycloalkyl is preferably a cycloalkyl having 3 to 12 carbon atoms (i.e., a C3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., a C3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., a C3-6 cycloalkyl), and most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., a C3-5 cycloalkyl). Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl, etc. Non-limiting examples of the polycyclic cycloalkyl include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

术语“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20螺环烷基)。所述的螺环烷基优选具有6至14个环原子的螺环烷基(即C6-14螺环烷基)，更优选具有7至10个环原子的螺环烷基(即C7-10螺环烷基)。根据环与环之间共用的螺原子的数目将所述螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基或双螺环烷基，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。The term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C5-20 spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., C6-14 spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., C7-10 spirocycloalkyl). The spirocycloalkyl group is divided into monospirocycloalkyl group, bispirocycloalkyl group or polyspirocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospirocycloalkyl group or bispirocycloalkyl group, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered monospirocycloalkyl group.

术语“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20稠环烷基)。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的稠环烷基优选具有6至14个环原子的稠环烷基(即C6-14稠环烷基)，更优选具有7至10个环原子的稠环烷基(即C7-10稠环烷基)。根据组成环的数目分为双环、三环、四环或多环稠环烷基，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。The term "fused cycloalkyl" refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C5-20 fused cycloalkyl). It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused cycloalkyl preferably has a fused cycloalkyl having 6 to 14 ring atoms (i.e., C6-14 fused cycloalkyl), and more preferably has a fused cycloalkyl having 7 to 10 ring atoms (i.e., C7-10 fused cycloalkyl). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic condensed cycloalkyl groups or tricyclic condensed cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic condensed cycloalkyl groups.

术语“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20桥环烷基)。其含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的桥环烷基优选具有6至14个环原子的桥环烷基(即C6-14桥环烷基)，更优选具有7至10个环原子的桥环烷基(即C7-10桥环烷基)。根据组成环的数目分为双环、三环、四环或多环桥环烷基，优选为双环桥环烷基或三环桥环烷基。The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 bridged cycloalkyl). It contains one or more double bonds, but no ring has a completely conjugated π electron system. The bridged cycloalkyl preferably has a bridged cycloalkyl with 6 to 14 ring atoms (i.e., C 6-14 bridged cycloalkyl), and more preferably has a bridged cycloalkyl with 7 to 10 ring atoms (i.e., C 7-10 bridged cycloalkyl). According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl.

所述的环烷基可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基。所述环烷基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述环烷基被取代基取代时，所述取代基不再被进一步取代。The cycloalkyl may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the cycloalkyl is substituted with a substituent, the substituent is no longer substituted further.

术语“杂环烷基”指饱和或部分不饱和的单环杂环状烃取代基(即单环杂环烷基)或多环杂环状烃取代基(即多环杂环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3-20元杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。所述杂环烷基优选具有3至12个环原子(即3-12元杂环烷基)，其中含1-4个选自N、O和S原子的杂原子，更优选具有3至8个环原子(即3-8元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子，进一步优选具有3至6个环原子(即3-6元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子，最优选具有5至6个环原子(即5-6元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子。所述的单环杂环烷基的非限制性实例包括：氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、哌啶基、哌嗪基、吗啉基、1,3-二氧环戊基、2,2-二氟-1,3-二氧环戊基、环戊酮基、2,2-二氟环戊酮基、吖庚基、氧杂环戊基或氮杂环戊基等。所述的多环杂环烷基的非限制性实例包括：螺杂环烷基、稠杂环烷基和桥杂环烷基。The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., a monocyclic heterocycloalkyl) or a polycyclic heterocyclic hydrocarbon substituent (i.e., a polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12-membered heterocycloalkyl), wherein 1-4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., 3-8-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., 3-6-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., 5-6-membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocycloalkyl include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl, etc. Non-limiting examples of the polycyclic heterocycloalkyl include: spiroheterocycloalkyl, fused heterocycloalkyl and bridged heterocycloalkyl.

术语“螺杂环烷基”指单环之间共用一个原子(称螺原子)的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元螺杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的螺杂环烷基优选具有6至14个环原子的螺杂环烷基(即6-14元螺杂环烷基)，更优选具有7至10个环原子的螺杂环烷基(即7-10元螺杂环烷基)。根据环与环之间共用的螺原子的数目将所述螺杂环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基，优选为单螺杂环烷基或双螺杂环烷基，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环烷基。The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which one atom (called spiro atom) is shared between monocyclic rings, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20 membered spiroheterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The spiroheterocycloalkyl preferably has a spiroheterocycloalkyl having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), and more preferably has a spiroheterocycloalkyl having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiro heterocycloalkyl group is divided into monospiro heterocycloalkyl group, bispiro heterocycloalkyl group or polyspiro heterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiro heterocycloalkyl group or bispiro heterocycloalkyl group, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered monospiro heterocycloalkyl group.

术语“稠杂环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元稠杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的稠杂环烷基优选具有6至14个环原子的稠杂环烷基(即6-14元稠杂环烷基)，更优选具有7至10个环原子的稠杂环烷基(即7-10元稠杂环烷基)。根据组成环的数目分为双环、三环、四环或多环稠杂环烷基，优选双环稠杂环烷基或三环稠杂环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环烷基。The term "fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20-membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused heterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6-14-membered fused heterocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7-10-membered fused heterocycloalkyl). According to the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, preferably bicyclic fused heterocycloalkyl groups or tricyclic fused heterocycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocycloalkyl groups.

术语“桥杂环烷基”指任意两个环共用两个不直接连接的原子的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元桥杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的桥杂环烷基优选具有6至14个环原子的桥杂环烷基(即6-14元桥杂环烷基)，更优选具有7至10个环原子的桥杂环烷基(即7-10元桥杂环烷基)。根据组成环的数目分为双环、三环、四环或多环桥杂环烷基，优选为双环桥杂环烷基或三环桥杂环烷基。The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5-20-membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. The bridged heterocycloalkyl preferably has a bridged heterocycloalkyl having 6 to 14 ring atoms (i.e., 6-14-membered bridged heterocycloalkyl), and more preferably has a bridged heterocycloalkyl having 7 to 10 ring atoms (i.e., 7-10-membered bridged heterocycloalkyl). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, and preferably bicyclic or tricyclic bridged heterocycloalkyl groups.

所述的杂环烷基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环烷基。所述的杂环烷基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代)。当所述杂环烷基被取代基取代时，所述取代基不再被进一步取代。The heterocycloalkyl may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocycloalkyl. The heterocycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment). When the heterocycloalkyl is substituted by a substituent, the substituent is no longer substituted further.

术语“芳基”指具有共轭的π电子体系的全碳单环基团(即单环芳基)或稠合多环基团(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)碳原子(即C6-14芳基)。所述芳基优选具有6至12个碳原子的芳基(即C6-12芳基)，更优选具有6至10个碳原子的芳基(即C6-10芳基)，进一步优选苯基或萘基，最优选苯基。所述的单环芳基，例如苯基。所述的多环芳基的非限制性的实例包括：萘基、蒽基、菲基等。The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 aryl). The aryl preferably has an aryl having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., C 6-10 aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl, for example, phenyl. Non-limiting examples of the polycyclic aryl include: naphthyl, anthracenyl, phenanthrenyl, etc.

所述的芳基可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，优选苯并C3-8环烷基、苯并3-8元杂环烷基、苯并5-6元杂芳基，更优选苯并C4-6环烷基、苯并4-6元杂环烷基、苯并5-6元杂芳基，进一步优选苯并环丁基、苯并环戊基、苯并环己基、苯并氮杂环丁基、苯并氧杂环丁基、苯并氧杂环戊基、苯并氮杂环戊基、苯并氧杂环己基、苯并氮杂环己基、苯并噻吩基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并吡啶基、苯并嘧啶基、苯并吡啶酮基、苯并吡嗪基、苯并哒嗪基。所述的芳基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述芳基被取代基取代时，所述取代基不再被进一步取代。The aryl group may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, preferably a benzo C 3-8 cycloalkyl, a benzo 3-8 membered heterocycloalkyl, a benzo 5-6 membered heteroaryl, more preferably a benzo C 4-6 cycloalkyl, a benzo 4-6 membered heterocycloalkyl, a benzo 5-6 membered heteroaryl, further preferably a benzocyclobutyl, a benzocyclopentyl, a benzocyclohexyl, a benzoazetidinyl, a benzoxe ... The aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the aryl group is substituted with a substituent, the substituent may not be further substituted.

术语“杂芳基”指具有共轭的π电子体系的单环杂芳基团(即单环杂芳基)或稠合多环杂芳基团(即多环杂芳基)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5-14元杂芳基)，其中一个或多个(例如1、2、3或4个)环原子为选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，优选为选自氮、氧、或硫的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。所述杂芳基优选具有5至10个环原子的杂芳基(即5-10元杂芳基)。所述的单环杂芳基，优选具有5至6个环原子的杂芳基(即5-6元杂芳基)，非限制性的实例包括：呋喃基、吡喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、吡咯基、吡啶基、嘧啶基、吡啶酮基、吡嗪基、哒嗪基等。所述的多环杂芳基，优选5-6元杂芳基并5-6元杂芳基、5-10元杂芳基并C6-10芳基或C6-10芳基并5-10元杂芳基，进一步优选5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并苯基或苯基并5-6元杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、噻吩并苯基、喹唑啉基、苯并噻唑基、咔唑基、噻吩并吡啶基、吡啶并噻吩基、吡啶并吡咯基等。The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14-membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m , and S(O) n (wherein m and n are integers of 0-2), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10-membered heteroaryl). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, and the like. The polycyclic heteroaryl group is preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-10-membered heteroaryl and a C 6-10 aryl, or a C 6-10 aryl and a 5-10-membered heteroaryl, and is further preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-6-membered heteroaryl and a phenyl group, or a phenyl and a 5-6-membered heteroaryl group. Non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl, and the like.

所述的杂芳基可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，优选5-6元杂芳基并C3-8环烷基、5-6元杂芳基并3-8元杂环烷基、5-6元杂芳基并苯基，更优选5-6元杂芳基并C4-6环烷基、5-6元杂芳基并4-6元杂环烷基、5-6元杂芳基并苯基。所述的杂芳基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述杂芳基被取代基取代时，所述取代基不再被进一步取代。The heteroaryl group may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, preferably a 5-6-membered heteroaryl and C 3-8 cycloalkyl, a 5-6-membered heteroaryl and 3-8-membered heterocycloalkyl, a 5-6-membered heteroaryl and phenyl, more preferably a 5-6-membered heteroaryl and C 4-6 cycloalkyl, a 5-6-membered heteroaryl and 4-6-membered heterocycloalkyl, a 5-6-membered heteroaryl and phenyl. The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the heteroaryl group is substituted by a substituent, the substituent is no longer substituted further.

术语“烷氧基”指-O-(烷基)或-O-(非取代的环烷基)，其中烷基、环烷基的定义如上所述，其具有1至10个(例如1、2、3、4、5、6、7、8、9或10个)碳原子(即C1-10烷氧基)。所述烷氧基优选具有1至8个碳原子的烷氧基(即C1-8烷氧基)，更优选具有1至6个碳原子的烷氧基(即C1-6烷氧基)，最更优具有1至3个碳原子的烷氧基(即C1-3烷氧基)。非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。所述烷氧基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述烷氧基被取代基取代时，所述取代基不再被进一步取代。The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkoxy preferably has an alkoxy with 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably an alkoxy with 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably an alkoxy with 1 to 3 carbon atoms (i.e., C 1-3 alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the alkoxy is substituted by a substituent, the substituent is no longer further substituted.

术语“烷硫基”指-S-(烷基)或-S-(非取代的环烷基)，其中烷基、环烷基的定义如上所述，其具有1至10个(例如1、2、3、4、5、6、7、8、9或10个)碳原子(即C1-10烷硫基)。所述烷硫基优选具有1至8个碳原子的烷硫基(即C1-8烷硫基)，更优选具有1至6个碳原子的烷硫基(即C1-6烷硫基)，最更优具有1至3个碳原子的烷硫基(即C1-3烷硫基)。非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基等。所述烷硫基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。当所述烷硫基被取代基取代时，所述取代基不再被进一步取代。The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio is preferably an alkylthio having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), and most preferably an alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 alkylthio). Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. The alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point. When the alkylthio group is substituted with a substituent, the substituent may not be further substituted.

术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴原子。The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。非限制性实例包括：氟甲基、氯甲基、溴甲基、碘甲基、二氟甲基、氯氟甲基、二氯甲基、溴氟甲基、三氟甲基、氯二氟甲基、二氯氟甲基、三氯甲基、溴二氟甲基、溴氯氟甲基、二溴氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、2,2-二氟乙基、2-氯-2-氟乙基、2,2-二氯乙基、2-溴-2-氟乙基、2,2,2-三氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、2-溴-2,2-二氟乙基、2-溴-2-氯-2-氟乙基、2-溴-2,2-二氯乙基、1,1,2,2-四氟乙基、五氟乙基、1-氯-1,2,2,2-四氟乙基、2-氯-1,1,2,2-四氟乙基、1,2-二氯-1,2,2-三氟乙基、2-溴-1,1,2,2-四氟乙基等，优选氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、2,2-二氟乙基。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl and the like, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl and 2,2-difluoroethyl.

术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。非限制性实例包括：氟甲氧基、氯甲氧基、溴甲氧基、碘甲氧基、二氟甲氧基、氯氟甲氧基、二氯甲氧基、溴氟甲氧基、三氟甲氧基、氯二氟甲氧基、二氯氟甲氧基、三氯甲氧基、溴二氟甲氧基、溴氯氟甲氧基、二溴氟甲氧基等；优选氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2-氯乙氧基、2-溴乙氧基、2,2-二氟乙氧基、2-氯-2-氟乙氧基、2,2-二氯乙氧基、2-溴-2-氟乙氧基、2,2,2-三氟乙氧基、2-氯-2,2-二氟乙氧基、2,2-二氯-2-氟乙氧基、2,2,2-三氯乙氧基、2-溴-2,2-二氟乙氧基、2-溴-2-氯-2-氟乙氧基、2-溴-2,2-二氯乙氧基、1,1,2,2-四氟乙氧基、五氟乙氧基、1-氯-1,2,2,2-四氟乙氧基、2-氯-1,1,2,2-四氟乙氧基、1,2-二氯-1,2,2-三氟乙氧基、2-溴-1,1,2,2-四氟乙氧基，优选氟甲氧基、二氟甲氧基、三氟甲氧、2-氟乙氧基、2-氯乙氧基、2-溴乙氧基、2,2-二氟乙氧基。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 , 2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

术语“巯基”指-SH。The term "thiol" refers to -SH.

术语“羟基”指-OH。The term "hydroxy" refers to -OH.

术语“硝基”指-NO2。The term "nitro" refers to -NO2 .

术语“氨基”指-NH2。The term "amino" refers to -NH2 .

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.

术语“氧代”或“氧代基”指＝O。The term "oxo" or "oxo" refers to =0.

术语“羰基”指C＝O；本文描述中C＝O与C(O)同义；The term "carbonyl" refers to C=O; C=O is synonymous with C(O) in the present description;

术语“氨酰基”指-C(O)NH2。The term "aminoacyl" refers to -C(O) NH2 .

术语“磺酰基”指-S(O)2；本文描述中-S(O)2与-S(＝O)2同义；The term "sulfonyl" refers to -S(O) 2 ; in the present description, -S(O) 2 is synonymous with -S(=O) 2 ;

术语“氘代烷基”指被一个或多个氘取代的烷基，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.

术语“氘代烷氧基”指被一个或多个氘取代的烷氧基，其中烷氧基如上所定义。The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium, wherein alkoxy is as defined above.

术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

术语“烷胺基”指烷基-NH-，其中烷基如上所定义。The term "alkylamino" refers to an alkyl-NH- group, wherein alkyl is as defined above.

术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".

术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range is specifically disclosed. In particular, each range of values disclosed herein should be understood to mean each value and range encompassed within the broader range.

在本文中，“Z”和“-Z-”均表示为同一特定的基团，其可以互换使用。Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C2-C8”或“C2-8”涵盖2-8个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C2-C6、C3-C6、C4-C6、C4-C7、C4-C8等，以及C2、C3、C4、C5、C6、C7、C8等。例如，表述“C3-C10”或“C3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-C9、C6-C9、C6-C8、C6-C7、C7-C10、C7-C9、C7-C8、C8-C9等以及C3、C4、C5、C6、C7、C8、C9、C10等。又例如，表述“C1-C6”或“C1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6等，以及C1、C2、C3、C4、C5、C6等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及每个点值，例如三元至五元、三元至六元、三元至七元、三元至八元、四元至五元、四元至六元、四元至七元、四元至八元、五元至七元、五元至八元、六元至七元、六元至八元、九元至十元，等，以及三、四、五、六、七、八、九、十元，等。本文中其他类似的表述也应当以类似的方式理解。The expression mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values. For example, the expression " C2 - C8 " or " C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2 - C5 , C3 - C4 , C2 - C6 , C3 - C6 , C4 - C6 , C4 - C7 , C4 - C8, etc., as well as C2 , C3 , C4 , C5 , C6 , C7 , C8, etc. For example, the expression " C3 - C10 " or " C3-10 " should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8-C9, etc. , as well as C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , etc. For another example, the expression "C 1 -C 6 " or "C 1-6 " encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc. For another example, the expression "three yuan to ten yuan" should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this document should also be understood in a similar manner.

本文所用的表述“X选自A、B或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。Different expressions used herein such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选(地)被烷基取代的环烷基”意味着烷基可以但不必须存在，该说明包括环烷基被烷基取代的情形和环烷基不被烷基取代的情形。The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.

术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。示例性的取代基包括但不限于：C1-6烷基、C2-6烯基、C2-6炔基、C3-8杂烷基、C5-12芳基、5-12元杂芳基、羟基、C1-6烷氧基、C5-12芳氧基、硫醇基、C1-6烷硫基、氰基、卤素、C1-6烷硫代羰基、C1-6烷氨基甲酰基、N-氨基甲酰基、硝基、甲硅烷基、亚磺酰基、磺酰基、亚砜、卤代C1-6烷基、卤代C1-6烷氧基、氨基、膦酸、-CO2(C1-6烷基)，-OC(＝O)(C1-6烷基)，-OCO2(C1-6烷基)，-C(＝O)NH2，-C(＝O)N(C1-6烷基)2，-OC(＝O)NH(C1-6烷基)，-NHC(＝O)(C1-6烷基)，-N(C1-6烷基)C(＝O)(C1-6烷基)，-NHCO2(C1-6烷基)，-NHC(＝O)N(C1-6烷基)2，-HC(＝O)NH(C1-6烷基)，-NHC(＝O)NH2，-NHSO2(C1-6烷基)，-SO2N(C1-6烷基)2，-SO2NH(C1-6烷基)，-SO2NH2，-SO2C1-6烷基等。The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds. When describing that a substituent does not exist, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When describing that each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed. Exemplary substituents include, but are not limited to, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 heteroalkyl, C5-12 aryl, 5-12 membered heteroaryl, hydroxy, C1-6 alkoxy, C5-12 aryloxy, thiol, C1-6 alkylthio, cyano, halogen, C1-6 alkylthiocarbonyl, C1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, amino, phosphonic acid, -CO2( C1-6 alkyl), -OC (=O)( C1-6 alkyl), -OCO2( C1-6 alkyl), -C(=O) NH2 , -C(=O)N( C1-6 alkyl) 2 , -OC(=O)NH( C1-6 alkyl) -NHC(＝O)(C 1-6 alkyl), -NHC(＝O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(＝O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(＝O)N(C 1-6 alkyl) 2 , -HC(＝O)NH(C 1-6 alkyl), -NHC(＝O)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl and the like.

如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被替代。当取代基为氢时，这也可以表示对应的基团为“非取代”或者“未被取代”的。除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。If a substituent is described as "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as optionally substituted with one or more of the substituent list, one or more hydrogens on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also mean that the corresponding group is "non-substituted" or "unsubstituted". Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代环中的任一成环原子。When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

当任何变量(例如R)，以及带有标记的变量(例如R1、R2、R3、R4、R5、R6、R7等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。When any variable (e.g., R), as well as variables with labels (e.g., R1 , R2 , R3 , R4 , R5 , R6 , R7 , etc.) occurs more than once in a compound composition or structure, its definition at each occurrence is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。本发明化合物的取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

本发明的化合物还包括其互变异构体，存在的本文公开的化合物的互变异构体可以是“NH2”互变异构体，或“NH”互变异构体，或二者的组合。例如：
The compounds of the present invention also include their tautomers. The tautomers of the compounds disclosed herein may be "NH 2 " tautomers, or "NH" tautomers, or a combination of the two. For example:

本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

本发明的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。Compounds of the present invention include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses. Examples of isotopes that can be introduced into compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P , 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.

相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

在本发明化合物中，当一个位置被特别地指定为氘D时，该位置应理解为氘的丰度比天然丰度(其为0.015％)大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即，至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍的丰度的氘(即，至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即，至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即，至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即，至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即，至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即，至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即，至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即，至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即，至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即，至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即，至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即，至少99.5％的氘掺入)。In the compounds of the invention, when a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

术语“药学上可接受”的物质指这样的物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

术语“药学上可接受的盐”指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.

术语“药物组合物”指含有一种或多种本发明所述的化合物或其生理学上/药学上可接受的盐或前体药物，以及其他组分例如生理学上/药学上可接受的载体或赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。The term "pharmaceutical composition" refers to a composition containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标紊乱、疾病或病症。术语“神经精神类疾病”是指神经类疾病与精神类疾病的总称，包含神经类疾病和/或精神类疾病。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition. The term "neuropsychiatric disease" refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.

针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

术语“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由15℃到30℃；在另一些实施例中，“室温”指的是温度由18℃到25℃。The term "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C to 25°C.

“当量”或其缩写“eq”，是按照化学反应的当量关系，以每步中所用基本原料为基准(1当量)，所需要的其他原材料的当量用量。"Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，均表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。In the context of the present invention, when or whether the words "about" or "approximately" are used, they all mean within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.

下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为化合物在饮食诱导肥胖模型中的减重药效试验结果。FIG1 shows the weight loss efficacy test results of the compound in a diet-induced obesity model.

具体实施方式DETAILED DESCRIPTION

以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的，按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明，但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。The content of the present invention will be described in detail below through examples. If no specific conditions are specified in the examples, the experimental method according to conventional conditions is carried out. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Those skilled in the art can make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still belongs to the protection scope of the present invention.

无特殊说明，原料购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。Unless otherwise specified, raw materials were purchased from Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and J&K Technology.

化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

实施例1和实施例2
Example 1 and Example 2

第一步：将化合物1A(2.00g,7.71mmol)溶于二氯甲烷(20mL)中，加入三乙胺(1.17g,11.57mmol)，抽换氮气三次后在冰浴下缓慢滴加环丙甲酰氯(1.05g，10.02mmol)，加料完成后反应保持冰浴搅拌2h。加水(30mL)淬灭反应，用二氯甲烷(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝90:10)纯化得到化合物1B(2.2g，收率：100％)。LC-MS(ESI):m/z＝328.2[M+H]+。Step 1: Dissolve compound 1A (2.00 g, 7.71 mmol) in dichloromethane (20 mL), add triethylamine (1.17 g, 11.57 mmol), replace nitrogen three times, and slowly add cyclopropanecarbonyl chloride (1.05 g, 10.02 mmol) dropwise in an ice bath. After the addition is complete, keep the reaction in an ice bath and stir for 2 h. Add water (30 mL) to quench the reaction, extract twice with dichloromethane (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue is purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 90: 10) to obtain compound 1B (2.2 g, yield: 100%). LC-MS (ESI): m/z = 328.2 [M+H] + .

第二步：将化合物1B(400mg,1.22mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(4mL)，在室温下搅拌6h。将反应液减压浓缩得化合物1C(600mg)，直接用于下一步反应。LC-MS(ESI):m/z＝128.1[M+H]+。Step 2: Dissolve compound 1B (400 mg, 1.22 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 6 h. Concentrate the reaction solution under reduced pressure to obtain compound 1C (600 mg), which is directly used in the next step. LC-MS (ESI): m/z = 128.1 [M+H] + .

第三步：将化合物1D(230mg，0.44mmol,参考专利WO2022245627合成)溶于二氯甲烷(30mL)中，分别加入化合物1C(390mg,1.1mmol)和三乙胺(220mg,2.17mmol)，在室温下搅拌过夜。加水(40mL)淬灭反应，以二氯甲烷(50mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯＝60:40)纯化得到化合物1E(200mg)。Step 3: Compound 1D (230 mg, 0.44 mmol, synthesized by referring to patent WO2022245627) was dissolved in dichloromethane (30 mL), and compound 1C (390 mg, 1.1 mmol) and triethylamine (220 mg, 2.17 mmol) were added respectively, and stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, and dichloromethane (50 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 60:40) to obtain compound 1E (200 mg).

第四步：化合物1E经手性拆分得到化合物1(SFC分析保留时间：0.942min，70mg)和1-2(SFC分析保留时间：1.635min，80mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:254nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:35％B梯度洗脱流速:100mL/min，柱温:25℃波长:254nm循环时间:6.0min；样品制备:样品浓度10mg/mL，乙醇溶液进样:每次1.5mL。Step 4: Compound 1E was subjected to chiral separation to obtain compounds 1 (SFC analysis retention time: 0.942 min, 70 mg) and 1-2 (SFC analysis retention time: 1.635 min, 80 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 35% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 254 nm Cycle time: 6.0 min; Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 1.5 mL each time.

化合物1(SFC分析保留时间：0.942min)：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.03-8.01(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.38(m,2H),7.33-7.22(m,5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.89-3.86(m,1H),1.99-1.97(m,1H),0.92-0.84(m,4H)；LC-MS(ESI):m/z＝617.1[M+H]+。Compound 1 (SFC analysis retention time: 0.942 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.03-8.01 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 7.33-7.22 (m, 5H), 5.05-5.01 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.86 (m, 1H), 1.99-1.97 (m, 1H), 0.92-0.84 (m, 4H); LC-MS (ESI): m/z=617.1 [M+H] + .

化合物2(SFC分析保留时间：1.635min)：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.03-8.01(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.38(m,2H),7.33-7.22(m,5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.89-3.86(m,1H),1.99-1.97(m,1H),0.92-0.84(m,4H)；LC-MS(ESI):m/z＝617.1[M+H]+。Compound 2 (SFC analysis retention time: 1.635 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.03-8.01 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 7.33-7.22 (m, 5H), 5.05-5.01 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.86 (m, 1H), 1.99-1.97 (m, 1H), 0.92-0.84 (m, 4H); LC-MS (ESI): m/z=617.1 [M+H] + .

实施例3
Example 3

第一步：将化合物3A(99.17mg，0.78mmol,参考专利WO201711552合成)溶解于异丙醇(6mL)中，并加入N,N-二异丙基乙胺(201.61mg，1.56mmol)，于室温下反应3h。然后于-25℃下加入化合物1D(207mg，0.39mmol)的二氯甲烷(10mL)溶液，滴加完毕后于室温下反应过夜。待反应完全后，将反应液浓缩，所得残余物送制备HPLC纯化，得到化合物3(210mg，收率：87％)。Step 1: Dissolve compound 3A (99.17 mg, 0.78 mmol, synthesized according to patent WO201711552) in isopropanol (6 mL), add N,N-diisopropylethylamine (201.61 mg, 1.56 mmol), and react at room temperature for 3 h. Then add a dichloromethane (10 mL) solution of compound 1D (207 mg, 0.39 mmol) at -25 ° C, and react overnight at room temperature after the addition is complete. After the reaction is complete, the reaction solution is concentrated, and the residue is purified by preparative HPLC to obtain compound 3 (210 mg, yield: 87%).

1H NMR(400MHz,DMSO-d6)δ8.01-7.99(d,2H),7.88-7.86(d,2H),7.54-7.51(d,2H),7.39-7.37(d,2H),7.34-7.28(m,4H),7.26-7.22(m,1H),5.07-5.02(m,1H),4.53(s,1H),3.88(s,1H),3.43(s,2H),2.62-2.58(t,2H),1.94-1.87(m,2H)；LC-MS(ESI):m/z＝617.3[M+H]+。 1 H NMR (400MHz, DMSO-d 6 )δ8.01-7.99(d,2H),7.88-7.86(d,2H),7.54-7.51(d,2H),7.39-7.37(d,2H),7.34-7.28(m,4H),7.26-7.22(m,1H),5.07 -5.02(m,1H),4.53(s,1H),3.88(s,1H),3.43(s,2H),2.62-2.58(t,2H),1.94-1.87(m,2H); LC-MS(ESI):m/z＝617.3[M+H] + .

实施例4和实施例5
Example 4 and Example 5

第一步：将化合物4A(5.00g,39.65mmol)溶于DMF(40mL)中，加入碳酸钾(13.70g,99.12mmol)，抽换氮气三次后在冰浴下缓慢滴加氘代碘甲烷(5.75g,39.65mmol)。加料完成后反应在室温下搅拌2h。加水(100mL)稀释反应，并用二氯甲烷(100mL)萃取三次，合并有机相，经无水硫酸钠干燥后浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝80:20)纯化得到化合物4B(2.00g,收率：35.24％)。LC-MS(ESI):m/z＝144.1[M+H]+。Step 1: Dissolve compound 4A (5.00 g, 39.65 mmol) in DMF (40 mL), add potassium carbonate (13.70 g, 99.12 mmol), replace nitrogen three times, and then slowly add deuterated iodomethane (5.75 g, 39.65 mmol) dropwise in an ice bath. After the addition is completed, the reaction is stirred at room temperature for 2 h. Add water (100 mL) to dilute the reaction, and extract it three times with dichloromethane (100 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 80: 20) to obtain compound 4B (2.00 g, yield: 35.24%). LC-MS (ESI): m/z = 144.1 [M+H] + .

第二步：将化合物4B(2.00g,13.97mmol)溶于四氢呋喃(15mL)和水(5mL)中，加入氢氧化锂一水合物(1.76g,41.91mmol)，反应在室温下搅拌3h。反应液中加水(10mL)稀释，用稀盐酸调pH＝5，以乙酸乙酯(20mL)萃取三次，合并有机相，经无水硫酸钠干燥后真空减压浓缩，得化合物4C(1.20g,收率：66.52％)。LC-MS(ESI):m/z＝130.1[M+H]+。Step 2: Compound 4B (2.00 g, 13.97 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5 mL), and lithium hydroxide monohydrate (1.76 g, 41.91 mmol) was added. The reaction was stirred at room temperature for 3 h. Water (10 mL) was added to dilute the reaction solution, pH was adjusted to 5 with dilute hydrochloric acid, and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4C (1.20 g, yield: 66.52%). LC-MS (ESI): m/z=130.1[M+H] + .

第三步：将化合物4C(1.20g,9.29mmol)溶于DMF(40mL)中，加入HATU(3.89g,10.22mmol)和三乙胺(2.35g,23.23mmol)，抽换氮气并在室温搅拌15min后加入1,3-二(叔丁氧基羰基)胍(2.89g,11.15mmol)。加料完成后反应在室温下搅拌16h。反应液中加水(100mL)稀释反应，用二氯甲烷(100mL)萃取三次，合并有机相经无水硫酸钠干燥后真空浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝80:20)纯化得到化合物4D(1.50g,收率：43.58％)。LC-MS(ESI):m/z＝371.3[M+H]+。Step 3: Compound 4C (1.20 g, 9.29 mmol) was dissolved in DMF (40 mL), HATU (3.89 g, 10.22 mmol) and triethylamine (2.35 g, 23.23 mmol) were added, nitrogen was replaced and stirred at room temperature for 15 min, then 1,3-di(tert-butoxycarbonyl)guanidine (2.89 g, 11.15 mmol) was added. After the addition was completed, the reaction was stirred at room temperature for 16 h. Water (100 mL) was added to the reaction solution to dilute the reaction, and it was extracted three times with dichloromethane (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 80:20) to obtain compound 4D (1.50 g, yield: 43.58%). LC-MS (ESI): m/z = 371.3 [M+H] + .

第四步：将化合物4D(1.50g,4.05mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(5mL)，在室温下搅拌4h。将反应液减压浓缩得化合物4E(1.2g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝171.1[M+H]+。Step 4: Dissolve compound 4D (1.50 g, 4.05 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 4 h. Concentrate the reaction solution under reduced pressure to obtain compound 4E (1.2 g crude product), which is directly used in the next step. LC-MS (ESI): m/z = 171.1 [M+H] + .

第五步：化合物4E(200mg,0.95mmol)参照实施例1第三步合成操作得到化合物4F(450mg,收率：71.77％)。LC-MS(ESI):m/z＝660.2[M+H]+。Step 5: Compound 4E (200 mg, 0.95 mmol) was synthesized by referring to the third step of Example 1 to obtain compound 4F (450 mg, yield: 71.77%). LC-MS (ESI): m/z = 660.2 [M+H] + .

第六步：化合物4F经手性拆分得到化合物4(SFC分析保留时间：2.033min，169.8mg)和化合物5(SFC分析保留时间：2.235min，145.1mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:2.5min；样品制备:样品浓度10mg/mL，乙醇溶液进样:每次3.0mL。Step 6: Compound 4F was subjected to chiral separation to obtain Compound 4 (SFC analysis retention time: 2.033 min, 169.8 mg) and Compound 5 (SFC analysis retention time: 2.235 min, 145.1 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 2.5 min; Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 3.0 mL each time.

化合物4(SFC分析保留时间：2.033min)：1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.48(s,1H),8.14(s,1H),8.04-8.02(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.38-7.36(m,2H),7.33-7.30(m,2H),7.26-7.24(m,3H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.93-3.89(m,1H)；LC-MS(ESI):m/z＝660.6[M+H]+。Compound 4 (SFC analysis retention time: 2.033 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 8.04-8.02 (m, 2H), 7.81-7.79 (m, 2H), 7.51-7.49 (m, 2H), 7.38-7.36 (m, 2H), 7.33-7.30 (m, 2H), 7.26-7.24 (m, 3H), 5.06-5.02 (m, 1H), 4.54-4.48 (m, 1H), 3.93-3.89 (m, 1H); LC-MS (ESI): m/z=660.6 [M+H] + .

化合物5(SFC分析保留时间：2.235min)：1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.48(s,1H),8.14(s,1H),8.04-8.02(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.26-7.24(m,3H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.93-3.89(m,1H)；LC-MS(ESI):m/z＝660.5[M+H]+。Compound 5 (SFC analysis retention time: 2.235 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 8.04-8.02 (m, 2H), 7.81-7.79 (m, 2H), 7.51-7.49 (m, 2H), 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.26-7.24 (m, 3H), 5.06-5.02 (m, 1H), 4.54-4.48 (m, 1H), 3.93-3.89 (m, 1H); LC-MS (ESI): m/z=660.5 [M+H] + .

实施例6和实施例7
Example 6 and Example 7

第一步：将化合物4H-1,2,4-三唑-3-羧酸(1.13g，10mmol)溶于N,N-二甲基甲酰胺(20mL)，依次加入HATU(5.7g，15mmol)、1,3-二(叔丁氧基羰基)胍(2.59g，10mmol)和N,N-二异丙基乙胺(3.9g，30mmol)，室温下反应2h。反应结束后向体系中加入100mL乙酸乙酯，饱和食盐水洗涤(50mL×4)，收集有机相，无水硫酸钠干燥，浓缩，残余物经硅胶柱层析分离(二氯甲烷：无水甲醇(v:v)＝20:1)后得到化合物6A(443mg，收率：12.5％)。LC-MS(ESI):m/z＝355.5[M+H]+。Step 1: Dissolve compound 4H-1,2,4-triazole-3-carboxylic acid (1.13 g, 10 mmol) in N,N-dimethylformamide (20 mL), add HATU (5.7 g, 15 mmol), 1,3-di(tert-butoxycarbonyl)guanidine (2.59 g, 10 mmol) and N,N-diisopropylethylamine (3.9 g, 30 mmol) in sequence, and react at room temperature for 2 h. After the reaction, add 100 mL of ethyl acetate to the system, wash with saturated brine (50 mL×4), collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and separate the residue by silica gel column chromatography (dichloromethane: anhydrous methanol (v:v) = 20:1) to obtain compound 6A (443 mg, yield: 12.5%). LC-MS (ESI): m/z = 355.5 [M+H] + .

第二步：将化合物6A(443mg,1.25mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(4mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物6B(371mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝155.5[M+H]+。Step 2: Dissolve compound 6A (443 mg, 1.25 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature overnight. Concentrate the reaction solution under reduced pressure to obtain compound 6B (371 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 155.5 [M+H] + .

第三步：化合物6B(371mg粗品)参照实施例1第三步合成操作得到化合物6C(224mg，收率：61％)。Step 3: Compound 6B (371 mg crude product) was synthesized by referring to the third step of Example 1 to obtain compound 6C (224 mg, yield: 61%).

第四步：化合物6C经手性拆分得到化合物6(SFC分析保留时间：2.323min，58.3mg)和化合物7(SFC分析保留时间：2.668min，56.5mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇；梯度:45％B梯度洗脱流速:100mL/min，柱温:室温波长:220nm循环时间:5.0min；样品制备:样品浓度3mg/mL，甲醇溶液进样:每次5mL。Step 4: Compound 6C was subjected to chiral separation to obtain compound 6 (SFC analysis retention time: 2.323 min, 58.3 mg) and compound 7 (SFC analysis retention time: 2.668 min, 56.5 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 3 mg/mL, Methanol solution injection: 5 mL each time.

化合物6(SFC分析保留时间：2.323min)：1H NMR(400MHz,DMSO-d6)δ14.92(s,1H),9.67(s,1H),8.78(s,1H),8.08-7.85(m,4H),7.83-7.77(m,2H),7.57-7.50(m,2H),7.40-7.34(m,2H),7.32-7.20(m,5H),5.09-4.99(m,1H),4.58-4.46(m,1H),3.96-3.83(m,1H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 6 (SFC analysis retention time: 2.323 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.92 (s, 1H), 9.67 (s, 1H), 8.78 (s, 1H), 8.08-7.85 (m, 4H), 7.83-7.77 (m, 2H), 7.57-7.50 (m, 2H), 7.40-7.34 (m, 2H), 7.32-7.20 (m, 5H), 5.09-4.99 (m, 1H), 4.58-4.46 (m, 1H), 3.96-3.83 (m, 1H); LC-MS (ESI): m/z=644.2 [M+H] + .

化合物7(SFC分析保留时间：2.668min)：1H NMR(400MHz,DMSO-d6)δ14.92(s,1H),9.67(s,1H),8.78(s,1H),8.08-7.85(m,4H),7.83-7.77(m,2H),7.57-7.50(m,2H),7.40-7.34(m,2H),7.32-7.20(m,5H),5.09-4.99(m,1H),4.58-4.46(m,1H),3.96-3.83(m,1H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 7 (SFC analysis retention time: 2.668 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.92 (s, 1H), 9.67 (s, 1H), 8.78 (s, 1H), 8.08-7.85 (m, 4H), 7.83-7.77 (m, 2H), 7.57-7.50 (m, 2H), 7.40-7.34 (m, 2H), 7.32-7.20 (m, 5H), 5.09-4.99 (m, 1H), 4.58-4.46 (m, 1H), 3.96-3.83 (m, 1H); LC-MS (ESI): m/z=644.2 [M+H] + .

实施例8和实施例9
Example 8 and Example 9

第一步：将化合物1A(2.2g,8.57mmol)和8A(0.8g,7.14mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(2.76g,21.4mmol)和HATU(3.26g,8.57mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(二氯甲烷:甲醇(v:v)＝10:1)纯化得到化合物8B(0.8g，收率：31.7％)。LC-MS(ESI):m/z＝354.2[M+H]+。Step 1: Dissolve compound 1A (2.2 g, 8.57 mmol) and 8A (0.8 g, 7.14 mmol) in N,N-dimethylformamide (20 mL), add diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by column chromatography (dichloromethane: methanol (v: v) = 10: 1) to obtain compound 8B (0.8 g, yield: 31.7%). LC-MS (ESI): m/z = 354.2 [M+H] + .

第二步：将化合物8B(400mg,1.12mmol)溶于二氯甲烷(12mL)中，加入三氟乙酸(3mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物8C(600mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.0[M+H]+。Step 2: Dissolve compound 8B (400 mg, 1.12 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (3 mL), and stir at room temperature overnight. Concentrate the reaction solution under reduced pressure to obtain compound 8C (600 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 154.0 [M+H] + .

第三步：化合物8C(600mg,1.12mmol)参照实施例1第三步操作(溶剂为DMF)得到化合物8D(170mg,收率：63.0％)。Step 3: Compound 8C (600 mg, 1.12 mmol) was subjected to the third step of Example 1 (solvent: DMF) to obtain compound 8D (170 mg, yield: 63.0%).

第四步：化合物8D经手性拆分得到化合物8(SFC分析保留时间：2.118min，50mg)和化合物9(SFC分析保留时间：2.498min，60mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:6.2min；样品制备:样品浓度10mg/mL，乙腈甲醇混合溶液进样:每次3.0mL。Step 4: Compound 8D was subjected to chiral separation to obtain compound 8 (SFC analysis retention time: 2.118 min, 50 mg) and compound 9 (SFC analysis retention time: 2.498 min, 60 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 6.2 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 3.0 mL each time.

化合物8(SFC分析保留时间：2.118min)：1H NMR(400MHz,DMSO-d6)δ13.01-12.80(m,1H),8.03-7.99(m,4H),7.89(s,1H),7.80-7.76(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.30-7.16(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 8 (SFC analysis retention time: 2.118 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01-12.80 (m, 1H), 8.03-7.99 (m, 4H), 7.89 (s, 1H), 7.80-7.76 (m, 2H), 7.52-7.50 (m, 2H), 7.37-7.35 (m, 2H), 7.30-7.16 (m, 5H), 5.06-5.02 (m, 1H), 4.54-4.48 (m, 1H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

化合物9(SFC分析保留时间：2.498min)：1H NMR(400MHz,DMSO-d6)δ13.01-12.80(m,1H),8.03-7.99(m,4H),7.89(s,1H),7.80-7.78(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.30-7.21(m,5H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 9 (SFC analysis retention time: 2.498 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.01-12.80 (m, 1H), 8.03-7.99 (m, 4H), 7.89 (s, 1H), 7.80-7.78 (m, 2H), 7.52-7.50 (m, 2H), 7.37-7.35 (m, 2H), 7.30-7.21 (m, 5H), 5.06-5.02 (m, 1H), 4.54-4.49 (m, 1H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

实施例10和实施例11
Example 10 and Example 11

第一步：将化合物1A(2.77g,10.7mmol)和10A(0.8g,7.14mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(2.76g,21.4mmol)和HATU(3.26g,8.57mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝5:1)纯化得到化合物10B(1.6g，收率：63.4％)。1H NMR(400MHz,CDCl3)δ4.84-4.83(m,2H),3.37(s,1H),3.09-2.93(m,4H),1.50(s,18H)。Step 1: Compound 1A (2.77 g, 10.7 mmol) and 10A (0.8 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol) were added. After the addition was completed, the mixture was stirred at room temperature overnight. Water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 5:1) to obtain compound 10B (1.6 g, yield: 63.4%). 1 H NMR (400 MHz, CDCl 3 ) δ 4.84-4.83 (m, 2H), 3.37 (s, 1H), 3.09-2.93 (m, 4H), 1.50 (s, 18H).

第二步：将化合物10B(600mg,1.70mmol)溶于二氯甲烷(12mL)中，加入三氟乙酸(4mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物10C(800mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.2[M+H]+。Step 2: Dissolve compound 10B (600 mg, 1.70 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 10C (800 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 154.2 [M+H] + .

第三步：化合物1D(250mg，0.47mmol)参照实施例1第三步操作得到化合物10D(180mg,收率：59.6％)。Step 3: Compound 1D (250 mg, 0.47 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain Compound 10D (180 mg, yield: 59.6%).

第四步：化合物10D经手性拆分得到化合物10(SFC分析保留时间：2.305min，70mg)和化合物11(SFC分析保留时间：2.547min，80mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral Whelk Column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral Whelk Column；流动相:A:CO2,B:异丙醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:4.3min；样品制备:样品浓度10mg/mL，乙腈甲醇混合溶液进样:每次2.0mL。Step 4: Compound 10D was subjected to chiral separation to obtain compound 10 (SFC analysis retention time: 2.305 min, 70 mg) and compound 11 (SFC analysis retention time: 2.547 min, 80 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral Whelk Column; Mobile phase: A: CO 2 , B: Isopropanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.3 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.

化合物10(SFC分析保留时间：2.305min)：1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.33-7.22(m,5H),5.04-5.00(m,1H),4.79-4.78(m,2H),4.51-4.45(m,1H),3.89-3.85(m,1H),3.33-3.29(m,1H),2.84-2.82(m,4H)；LC-MS(ESI):m/z＝643.2[M+H]+。Compound 10 (SFC analysis retention time: 2.305 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.01-7.99 (m, 2H), 7.81-7.79 (m, 2H), 7.51-7.49 (m, 2H), 7.39-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.04-5.00 (m, 1H), 4.79-4.78 (m, 2H), 4.51-4.45 (m, 1H), 3.89-3.85 (m, 1H), 3.33-3.29 (m, 1H), 2.84-2.82 (m, 4H); LC-MS (ESI): m/z=643.2 [M+H] + .

化合物11(SFC分析保留时间：2.547min)：1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.01-7.99(m,2H),7.82-7.79(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.33-7.22(m,5H),5.05-5.00(m,1H),4.79-4.78(m,2H),4.51-4.45(m,1H),3.89-3.84(m,1H),3.33-3.29(m,1H),2.84-2.82(m,4H)；LC-MS(ESI):m/z＝643.2[M+H]+。Compound 11 (SFC analysis retention time: 2.547 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.01-7.99 (m, 2H), 7.82-7.79 (m, 2H), 7.51-7.49 (m, 2H), 7.39-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.05-5.00 (m, 1H), 4.79-4.78 (m, 2H), 4.51-4.45 (m, 1H), 3.89-3.84 (m, 1H), 3.33-3.29 (m, 1H), 2.84-2.82 (m, 4H); LC-MS (ESI): m/z=643.2 [M+H] + .

实施例12和实施例13
Example 12 and Example 13

第一步：将化合物1A(2.78g,10.70mmol)和化合物12A(1.0g,8.92mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(4.7mL,26.76mmol)和HATU(4.10g,10.70mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相并干燥，减压浓缩，所得残余物经柱层析纯化(二氯甲烷:甲醇(v:v)＝10:1)纯化得到化合物12B(0.45g，产率：14.27％)。LC-MS(ESI):m/z＝354.1[M+H]+。Step 1: Dissolve compound 1A (2.78 g, 10.70 mmol) and compound 12A (1.0 g, 8.92 mmol) in N,N-dimethylformamide (20 mL), add diisopropylethylamine (4.7 mL, 26.76 mmol) and HATU (4.10 g, 10.70 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases and dry, concentrate under reduced pressure, and purify the residue by column chromatography (dichloromethane: methanol (v: v) = 10: 1) to obtain compound 12B (0.45 g, yield: 14.27%). LC-MS (ESI): m/z = 354.1 [M+H] + .

第二步：将化合物12B(450mg,1.27mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(2mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物12C(190mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.1[M+H]+。Step 2: Compound 12B (450 mg, 1.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 12C (190 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 154.1 [M+H] + .

第三步：化合物12C(190mg,1.14mmol)参照实施例3第一步操作(溶剂为DMF)得到化合物12D(120mg,收率：49.28％)。Step 3: Compound 12C (190 mg, 1.14 mmol) was subjected to the same operation as in the first step of Example 3 (solvent: DMF) to obtain compound 12D (120 mg, yield: 49.28%).

第四步：化合物12D经手性拆分得到化合物12(SFC分析保留时间：2.118min，50mg)和化合物13(SFC分析保留时间：2.498min，60mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:45％B梯度洗脱流速:100mL/min，柱温:25℃波长:220nm循环时间:5.0min；样品制备:样品浓度5mg/mL，乙腈乙醇混合溶液进样:每次2.0mL。Step 4: Compound 12D was subjected to chiral separation to obtain compound 12 (SFC analysis retention time: 2.118 min, 50 mg) and compound 13 (SFC analysis retention time: 2.498 min, 60 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 5 mg/mL, acetonitrile ethanol mixed solution injection: 2.0 mL each time.

化合物12(SFC分析保留时间：2.136min)：1H NMR(400MHz,DMSO-d6)δ8.01-7.85(m,2H),7.81-7.77(m,1H),7.54-7.50(m,1H),7.37-7.34(m,1H),7.30-7.20(m,6H),7.16-7.10(m,3H),7.04-6.97(m,3H),5.08-4.99(m,1H),4.55-4.46(m,1H),3.93-3.86(m,1H)；LC-MS(ESI):m/z＝643.2[M+H]+。Compound 12 (SFC analysis retention time: 2.136 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01-7.85 (m, 2H), 7.81-7.77 (m, 1H), 7.54-7.50 (m, 1H), 7.37-7.34 (m, 1H), 7.30-7.20 (m, 6H), 7.16-7.10 (m, 3H), 7.04-6.97 (m, 3H), 5.08-4.99 (m, 1H), 4.55-4.46 (m, 1H), 3.93-3.86 (m, 1H); LC-MS (ESI): m/z=643.2 [M+H] + .

化合物13(SFC分析保留时间：2.594min)：1H NMR(400MHz,DMSO-d6)δ8.06-7.85(m,2H),7.82-7.78(m,1H),7.55-7.50(m,1H),7.37-7.34(m,1H),7.39-7.21(m,6H),7.16-7.10(m,3H),7.04-6.97(m,3H),5.08-4.99(m,1H),4.55-4.46(m,1H),3.93-3.86(m,1H)；LC-MS(ESI):m/z＝643.2[M+H]+。Compound 13 (SFC analysis retention time: 2.594 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.06-7.85 (m, 2H), 7.82-7.78 (m, 1H), 7.55-7.50 (m, 1H), 7.37-7.34 (m, 1H), 7.39-7.21 (m, 6H), 7.16-7.10 (m, 3H), 7.04-6.97 (m, 3H), 5.08-4.99 (m, 1H), 4.55-4.46 (m, 1H), 3.93-3.86 (m, 1H); LC-MS (ESI): m/z=643.2 [M+H] + .

实施例14和实施例15
Example 14 and Example 15

第一步：将化合物1D(0.5g，0.95mmol)溶于二氯甲烷(10mL)中，并加入N,N-二异丙基乙胺(0.96g，9.5mmol)，然后于0℃下加入化合物14A(0.5g，4.37mmol,参考专利WO2020181952合成)的四氢呋喃(5mL)溶液，滴加完毕后在室温下搅拌1h。反应结束后加入水(50mL)，用二氯甲烷萃取(100mL×3)，合并有机相后用饱和食盐水洗(40mL×1)，无水硫酸钠干燥后过滤，减压浓缩，所得残余物经柱层析(二氯甲烷:甲醇(v/v)＝50:1)纯化后得到化合物14B(0.52g，收率：91％)。LC-MS(ESI):m/z＝604.1[M+H]+。Step 1: Dissolve compound 1D (0.5 g, 0.95 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (0.96 g, 9.5 mmol), then add a tetrahydrofuran (5 mL) solution of compound 14A (0.5 g, 4.37 mmol, synthesized according to patent WO2020181952) at 0 ° C, and stir at room temperature for 1 h after the addition is complete. After the reaction is completed, add water (50 mL), extract with dichloromethane (100 mL × 3), combine the organic phases and wash with saturated brine (40 mL × 1), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by column chromatography (dichloromethane: methanol (v/v) = 50: 1) to obtain compound 14B (0.52 g, yield: 91%). LC-MS (ESI): m/z = 604.1 [M + H] + .

第二步：化合物14B(0.52g)经手性拆分得到化合物14(SFC分析保留时间：1.744min，220mg)和化合物15(SFC分析保留时间：1.948min，206mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf；柱:Chiral AS column；流动相:A for CO2；B for 0.05％DEA in甲醇；梯度:B for 5-40％；流速:3mL/min；背压:100bar；柱温:35℃；波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC；柱:Chiral AS column；流动相:A for CO2；B for 0.1％NH3·H2O in乙醇；梯度:B for 35％；洗脱流速:120mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:6.0min；样品制备:样品浓度为15mg/mL，溶于乙腈和甲醇中。注射：每次注射3.0毫升。Step 2: Compound 14B (0.52 g) was subjected to chiral separation to obtain compound 14 (SFC analysis retention time: 1.744 min, 220 mg) and compound 15 (SFC analysis retention time: 1.948 min, 206 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf; column: Chiral AS column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 5-40%; flow rate: 3 mL/min; back pressure: 100 bar; column temperature: 35°C; wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC; Column: Chiral AS column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in ethanol; Gradient: B for 35%; Elution flow rate: 120mL/min; Back pressure: 100bar; Column temperature: room temperature; Wavelength: 220nm; Cycle time: 6.0min; Sample preparation: Sample concentration is 15mg/mL, dissolved in acetonitrile and methanol. Injection: 3.0ml per injection.

化合物14(SFC分析保留时间：1.744min)：1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.18(m,2H),5.07(dd,1H),4.69-4.60(m,1H),4.49(td,1H),4.29(td,1H),4.16-4.08(m,1H),4.06-3.99(m,1H),3.98-3.84(m,2H),1.75(d,3H)；LC-MS(ESI):m/z＝604.1[M+H]+。Compound 14 (SFC analysis retention time: 1.744 min): 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.18(m,2H),5.07(dd,1H),4.69-4.6 0(m,1H),4.49(td,1H),4.29(td,1H),4.16-4.08(m,1H),4.06-3.99(m,1H),3.98-3.84(m,2H),1.75(d,3H); LC-MS(ESI):m/z＝604.1[M+H] + .

化合物15(SFC分析保留时间：1.948min)：1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.19(m,2H),5.07(dd,1H),4.70-4.60(m,1H),4.49(dt,1H),4.29(td,1H),4.16-4.07(m,1H),4.06-3.99(m,1H),3.97-3.84(m,2H),1.75(d,3H)；LC-MS(ESI):m/z＝604.1[M+H]+。Compound 15 (SFC analysis retention time: 1.948 min): 1 H NMR (400 MHz, DMSO-d 6 )δ8.61(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.19(m,2H),5.07(dd,1H),4.70-4.6 0(m,1H),4.49(dt,1H),4.29(td,1H),4.16-4.07(m,1H),4.06-3.99(m,1H),3.97-3.84(m,2H),1.75(d,3H); LC-MS(ESI):m/z＝604.1[M+H] + .

实施例16和实施例17
Example 16 and Example 17

第一步：将化合物1D(500mg，0.95mmol)溶于DMF(8mL)中，并加入N,N-二异丙基乙胺(429.72mg，3.32mmol)，然后于-0℃下加入化合物16A(188mg，1.09mmol)的DMF(2mL)溶液，滴加完毕后在室温下搅拌1h。反应结束后体系中加入水(50mL)，用乙酸乙酯萃取(100mL×3)，合并有机相后用饱和食盐水洗(40mL×1)，无水硫酸钠干燥后过滤，减压浓缩后得到化合物16B(620mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝607.2[M+H-56]+。Step 1: Dissolve compound 1D (500 mg, 0.95 mmol) in DMF (8 mL), add N,N-diisopropylethylamine (429.72 mg, 3.32 mmol), then add a DMF (2 mL) solution of compound 16A (188 mg, 1.09 mmol) at -0°C, and stir at room temperature for 1 h after the addition is complete. After the reaction is completed, add water (50 mL) to the system, extract with ethyl acetate (100 mL×3), combine the organic phases and wash with saturated brine (40 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 16B (620 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z＝607.2[M+H-56] + .

第二步：将化合物16B(620mg,0.94mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(2mL)，在室温下搅拌1.5h。将反应液减压浓缩得化合物16C(529mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝562.3[M+H]+。Step 2: Dissolve compound 16B (620 mg, 0.94 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 16C (529 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 562.3 [M+H] + .

第三步：将化合物16C(530mg,0.94mmol)溶于二氯甲烷(5mL)与四氢呋喃(5mL)中，加入三乙胺(333mg,3.29mmol)，抽换氮气三次后在冰浴下缓慢滴加乙酰氯(111mg，1.41mmol)，加料完成后反应保持冰浴搅拌1h。加水(30mL)淬灭反应，用二氯甲烷(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(二氯甲烷:甲醇(v/v)＝50:1)纯化得到化合物16D(490mg，收率：86％)。LC-MS(ESI):m/z＝604.3[M+H]+。Step 3: Compound 16C (530 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL), triethylamine (333 mg, 3.29 mmol) was added, nitrogen was replaced three times, and acetyl chloride (111 mg, 1.41 mmol) was slowly added dropwise in an ice bath. After the addition was completed, the reaction was kept in an ice bath and stirred for 1 h. Water (30 mL) was added to quench the reaction, and dichloromethane (50 mL) was used to extract twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol (v/v) = 50: 1) to obtain compound 16D (490 mg, yield: 86%). LC-MS (ESI): m/z = 604.3 [M+H] + .

第四步：化合物16D(490mg)经手性拆分得到化合物16(SFC分析保留时间：1.210min，153mg)和化合物17(SFC分析保留时间：1.335min，151mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf；柱:Chiral OJ column；流动相:A for CO2；B for 0.05％DEA in甲醇；梯度:B for 5-40％；流速:3mL/min；背压:100bar；柱温:35℃；波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC；柱:Chiral OJ column；流动相:A for CO2；B for 0.1％NH3·H2O in甲醇；梯度:B for 25％；洗脱流速:70mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:7.0min；样品制备:样品浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射3.0毫升。Step 4: Compound 16D (490 mg) was subjected to chiral separation to obtain compound 16 (SFC analysis retention time: 1.210 min, 153 mg) and compound 17 (SFC analysis retention time: 1.335 min, 151 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf; column: Chiral OJ column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 5-40%; flow rate: 3 mL/min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC; Column: Chiral OJ column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in methanol; Gradient: B for 25%; Elution flow rate: 70mL/min; Back pressure: 100bar; Column temperature: room temperature; Wavelength: 220nm; Cycle time: 7.0min; Sample preparation: Sample concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 3.0ml per injection.

化合物16(SFC分析保留时间：1.210min)：1H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.99(d,2H),7.83(d,2H),7.64(d,2H),7.43(d,2H),7.32(t,2H),7.27-7.20(m,3H),4.95(dd,1H),4.89-4.74(m,2H),4.54-4.32(m,4H),3.84(dd,1H),1.86(s,3H)；LC-MS(ESI):m/z＝604.3[M+H]+。Compound 16 (SFC analysis retention time: 1.210 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.64 (d, 2H), 7.43 (d, 2H), 7.32 (t, 2H), 7.27-7.20 (m, 3H), 4.95 (dd, 1H), 4.89-4.74 (m, 2H), 4.54-4.32 (m, 4H), 3.84 (dd, 1H), 1.86 (s, 3H); LC-MS (ESI): m/z=604.3 [M+H] + .

化合物17(SFC分析保留时间：1.335min)：1H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.99(d,2H),7.82(d,2H),7.64(d,2H),7.43(d,2H),7.32(t,2H),7.27-7.20(m,3H),4.95(dd,1H),4.89-4.74(m,2H),4.55-4.31(m,4H),3.84(dd,1H),1.86(s,3H)；LC-MS(ESI):m/z＝604.3[M+H]+。Compound 17 (SFC analysis retention time: 1.335 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 7.64 (d, 2H), 7.43 (d, 2H), 7.32 (t, 2H), 7.27-7.20 (m, 3H), 4.95 (dd, 1H), 4.89-4.74 (m, 2H), 4.55-4.31 (m, 4H), 3.84 (dd, 1H), 1.86 (s, 3H); LC-MS (ESI): m/z=604.3 [M+H] + .

实施例18、实施例19、实施例20和实施例21
Example 18, Example 19, Example 20 and Example 21

第一步：将化合物1D(1.05g，1.99mmol)溶于DMF(15mL)中，并加入N,N-二异丙基乙胺(0.90g，6.96mmol)，然后于0℃下加入化合物18A(0.25g，2.49mmol)的DMF(5mL)溶液，滴加完毕后在室温下搅拌1h。反应结束后体系中加入水(50mL)，用乙酸乙酯萃取(100mL×3)，合并有机相后用饱和食盐水洗(40mL×1)，无水硫酸钠干燥后过滤，减压浓缩，所得残余物经柱层析(二氯甲烷:甲醇(v/v)＝50:1)纯化后得到化合物18B(985mg，收率：83％)。LC-MS(ESI):m/z＝590.1[M+H]+。Step 1: Compound 1D (1.05 g, 1.99 mmol) was dissolved in DMF (15 mL), and N,N-diisopropylethylamine (0.90 g, 6.96 mmol) was added. Then, a DMF (5 mL) solution of compound 18A (0.25 g, 2.49 mmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was completed, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol (v/v) = 50: 1) to obtain compound 18B (985 mg, yield: 83%). LC-MS (ESI): m/z = 590.1 [M+H] + .

第二步：化合物18B(985mg)经手性拆分得到化合物18(SFC分析保留时间：2.420min，226mg)、化合物19(SFC分析保留时间：2.769min，170mg)、化合物20(SFC分析保留时间：3.279min，180mg)和化合物21(SFC分析保留时间：3.537min，204mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf；柱:Chiral OD column；流动相:A for CO2；B for 0.05％DEA in甲醇；梯度:B for 20-30％；流速:1.5mL/min；背压:100bar；柱温:35℃；波长:254nm。SFC拆分方法：第一次拆分:仪器:Waters 150Prep-SFC；柱:Chiral OD column；流动相:A for CO2；B for 0.1％NH3·H2O in甲醇；梯度:B for 35％；洗脱流速:120mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:5.0min；样品制备:化合物浓度为20mg/mL，溶于乙腈和甲醇中。注射：每次注射5.0毫升。分离得到组分A和组分B。将上述组分A再进行SFC拆分，纯化方法:仪器:Waters 150 Prep-SFC；柱:Chiral AD column；流动相:A for CO2；B for 0.1％NH3·H2O in异丙醇和乙腈；梯度:B for 35％；洗脱流速:100mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:4.0min；样品制备:化合物浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射5.0毫升。分离得到化合物18和化合物19。Step 2: Compound 18B (985 mg) was subjected to chiral separation to obtain compound 18 (SFC analysis retention time: 2.420 min, 226 mg), compound 19 (SFC analysis retention time: 2.769 min, 170 mg), compound 20 (SFC analysis retention time: 3.279 min, 180 mg) and compound 21 (SFC analysis retention time: 3.537 min, 204 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf; column: Chiral OD column; mobile phase: A for CO 2 ; B for 0.05% DEA in methanol; gradient: B for 20-30%; flow rate: 1.5 mL/min; back pressure: 100 bar; column temperature: 35° C.; wavelength: 254 nm. SFC separation method: First separation: Instrument: Waters 150Prep-SFC; Column: Chiral OD column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in methanol; Gradient: B for 35%; Elution flow rate: 120mL/min; Back pressure: 100bar; Column temperature: Room temperature; Wavelength: 220nm; Cycle time: 5.0min; Sample preparation: Compound concentration is 20mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Component A and component B are separated. The above component A was further subjected to SFC separation, purification method: instrument: Waters 150 Prep-SFC; column: Chiral AD column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; gradient: B for 35%; elution flow rate: 100mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 4.0min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Compound 18 and compound 19 were separated.

将上述组分B再进行SFC拆分，纯化方法:仪器:Waters 150 Prep-SFC；柱:Chiral WHEIK column；流动相:A for CO2；B for 0.1％NH3·H2O in甲醇；梯度:B for 40％；洗脱流速:120mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:3.0min；样品制备:化合物浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射5.0毫升。分离得到化合物20和化合物21。The above component B was further subjected to SFC separation and purification method: instrument: Waters 150 Prep-SFC; column: Chiral WHEIK column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in methanol; gradient: B for 40%; elution flow rate: 120mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 3.0min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Compound 20 and compound 21 were separated.

化合物18(SFC分析保留时间：2.420min)：1H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.00(d,2H),7.87(s,1H),7.83(d,2H),7.75(d,2H),7.44(d,2H),7.33(t,2H),7.28-7.19(m,3H),5.11(dd,1H),4.60(t,1H),4.48(d,1H),4.01(dd,1H),3.14-3.02(m,2H),2.23(s,1H),2.04(dd,1H)；LC-MS(ESI):m/z＝590.1[M+H]+。Compound 18 (SFC analysis retention time: 2.420 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (d, 1H), 8.00 (d, 2H), 7.87 (s, 1H), 7.83 (d, 2H), 7.75 (d, 2H), 7.44 (d, 2H), 7.33 (t, 2H), 7.28-7.19 (m, 3H), 5.11 (dd, 1H), 4.60 (t, 1H), 4.48 (d, 1H), 4.01 (dd, 1H), 3.14-3.02 (m, 2H), 2.23 (s, 1H), 2.04 (dd, 1H); LC-MS (ESI): m/z=590.1 [M+H] + .

化合物19(SFC分析保留时间：2.769min)：1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.02(d,2H),7.87(t,3H),7.75(d,2H),7.44(d,2H),7.34(t,2H),7.29-7.20(m,3H),5.11(dd,1H),4.55(dd,2H),4.17(d,1H),3.10(dq,2H),2.25(s,1H),2.02-1.90(m,1H)；LC-MS(ESI):m/z＝590.1[M+H]+。Compound 19 (SFC analysis retention time: 2.769 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, 1H), 8.02 (d, 2H), 7.87 (t, 3H), 7.75 (d, 2H), 7.44 (d, 2H), 7.34 (t, 2H), 7.29-7.20 (m, 3H), 5.11 (dd, 1H), 4.55 (dd, 2H), 4.17 (d, 1H), 3.10 (dq, 2H), 2.25 (s, 1H), 2.02-1.90 (m, 1H); LC-MS (ESI): m/z=590.1 [M+H] + .

化合物20(SFC分析保留时间：3.279min)：1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.02(d,2H),7.87(t,3H),7.75(d,2H),7.44(d,2H),7.34(t,2H),7.29-7.20(m,3H),5.11(dd,1H),4.54(dd,2H),4.17(d,1H),3.09(dq,2H),2.26(s,1H),2.02-1.89(m,1H)；LC-MS(ESI):m/z＝590.1[M+H]+.Compound 20 (SFC analysis retention time: 3.279 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, 1H), 8.02 (d, 2H), 7.87 (t, 3H), 7.75 (d, 2H), 7.44 (d, 2H), 7.34 (t, 2H), 7.29-7.20 (m, 3H), 5.11 (dd, 1H), 4.54 (dd, 2H), 4.17 (d, 1H), 3.09 (dq, 2H), 2.26 (s, 1H), 2.02-1.89 (m, 1H); LC-MS (ESI): m/z=590.1 [M+H] + .

化合物21(SFC分析保留时间：3.537min)：1H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.00(d,2H),7.87(s,1H),7.83(d,2H),7.75(d,2H),7.44(d,2H),7.33(t,2H),7.28-7.19(m,3H),5.11(dd,1H),4.60(t,1H),4.48(d,1H),4.01(dd,1H),3.14-3.05(m,2H),2.24(s,1H),2.04(dd,1H)；LC-MS(ESI):m/z＝590.1[M+H]+。Compound 21 (SFC analysis retention time: 3.537 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (d, 1H), 8.00 (d, 2H), 7.87 (s, 1H), 7.83 (d, 2H), 7.75 (d, 2H), 7.44 (d, 2H), 7.33 (t, 2H), 7.28-7.19 (m, 3H), 5.11 (dd, 1H), 4.60 (t, 1H), 4.48 (d, 1H), 4.01 (dd, 1H), 3.14-3.05 (m, 2H), 2.24 (s, 1H), 2.04 (dd, 1H); LC-MS (ESI): m/z=590.1 [M+H] + .

实施例22和实施例23
Example 22 and Example 23

第一步：往化合物22A(0.8g,2.64mmol，制备参考文献：ChemMedChem,2015,vol.10,#3,p.461-469)中加入氨的1,4-二氧六环溶液(0.5M，20mL)，室温搅拌16小时，直接减压浓缩得到化合物22B(0.75g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝282.0[M-H]-。Step 1: Add ammonia 1,4-dioxane solution (0.5M, 20mL) to compound 22A (0.8g, 2.64mmol, preparation reference: ChemMedChem, 2015, vol.10, #3, p.461-469), stir at room temperature for 16 hours, and directly concentrate under reduced pressure to obtain compound 22B (0.75g crude product), which is directly used in the next step. LC-MS (ESI): m/z=282.0[MH] - .

第二步：将化合物22B(0.75g,2.65mmol)加入二氯甲烷(20mL)中，冰浴下加入三乙胺(0.8g,7.95mmol)和氯甲酸异丙酯(0.65g,5.30mmol)，室温搅拌2小时，加水稀释后，DCM萃取两次，合并有机相，干燥过滤，滤液浓缩所得残余物通过柱层析纯化(石油醚:乙酸乙酯(v:v)＝2:1)得到化合物22C(0.5g,收率：51％)。LC-MS(ESI):m/z＝368.0[M-H]-。Step 2: Compound 22B (0.75 g, 2.65 mmol) was added to dichloromethane (20 mL), triethylamine (0.8 g, 7.95 mmol) and isopropyl chloroformate (0.65 g, 5.30 mmol) were added under ice bath, stirred at room temperature for 2 hours, diluted with water, extracted with DCM twice, the organic phases were combined, dried and filtered, and the residue obtained by concentrating the filtrate was purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 2: 1) to obtain compound 22C (0.5 g, yield: 51%). LC-MS (ESI): m/z = 368.0 [MH] - .

第三步：将化合物22C(0.4g,1.08mmol)和中间体22D(0.36g,1.40mmol，参考专利WO2022245627合成)加入甲苯(20mL)中，氮气保护，加热至100℃搅拌10小时，然后冷却，浓缩，所得残余物通过硅胶柱层析(石油醚:乙酸乙酯＝1:1)分离纯化得到化合物22E(0.3g,收率:49％)。LC-MS(ESI):m/z＝566.0[M+H]+。Step 3: Compound 22C (0.4 g, 1.08 mmol) and intermediate 22D (0.36 g, 1.40 mmol, synthesized according to patent WO2022245627) were added to toluene (20 mL), and heated to 100°C with nitrogen protection and stirred for 10 hours, then cooled and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 22E (0.3 g, yield: 49%). LC-MS (ESI): m/z = 566.0 [M+H] + .

第四步：向50mL的单口瓶中加入甲苯(15mL)，随后加入化合物22E(0.30g，0.53mmol)和N,N-二异丙基乙基胺(0.14g，1.06mmol)，然后缓慢滴加入三氯氧磷(0.16g，1.06mmol)，加料完毕后体系氮气保护并100℃搅拌1h，反应液减压浓缩所得残余物通过硅胶柱层析(石油醚:乙酸乙酯(v:v)＝2:1)纯化分离得到化合物22F(0.16g,收率：52％)。LC-MS(ESI):m/z＝584.0[M+H]+。Step 4: Add toluene (15 mL) to a 50 mL single-mouth bottle, then add compound 22E (0.30 g, 0.53 mmol) and N,N-diisopropylethylamine (0.14 g, 1.06 mmol), then slowly dropwise add phosphorus oxychloride (0.16 g, 1.06 mmol), after the addition is complete, the system is protected by nitrogen and stirred at 100 ° C for 1 h, the reaction solution is concentrated under reduced pressure, and the residue is purified and separated by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 2: 1) to obtain compound 22F (0.16 g, yield: 52%). LC-MS (ESI): m/z = 584.0 [M+H] + .

第五步:化合物22F(160mg，0.27mmol)和牛磺酰胺盐酸盐(87mg，0.54mmol)参照实施例1操作得到化合物22G(150mg,收率：82％)。LC-MS(ESI):m/z＝672.1[M+H]+。Step 5: Compound 22F (160 mg, 0.27 mmol) and taurine hydrochloride (87 mg, 0.54 mmol) were treated with the same method as in Example 1 to obtain compound 22G (150 mg, yield: 82%). LC-MS (ESI): m/z = 672.1 [M+H] + .

第六步：将化合物22G进一步经手性拆分得到化合物22(SFC分析保留时间：0.732min，73mg)和化合物23(SFC分析保留时间：1.339min，71mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral Whelk Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IC Column；流动相:A:CO2,B:0.1％NH3·H2O in EtOH；梯度:40％B梯度洗脱流速:100mL/min，柱温:25℃波长:220nm循环时间:4.0min样品制备:样品浓度10mg/mL，甲醇溶液进样:每次1.5mL。Step 6: Compound 22G was further subjected to chiral separation to obtain compound 22 (SFC analysis retention time: 0.732 min, 73 mg) and compound 23 (SFC analysis retention time: 1.339 min, 71 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in EtOH; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.0 min Sample preparation: Sample concentration 10 mg/mL, methanol solution injection: 1.5 mL each time.

化合物22(SFC分析保留时间：0.732min)：1H NMR(400MHz,DMSO-d6)δ8.30-8.22(m,1H),8.07-7.99(m,4H),7.73-7.66(m,2H),7.48-7.42(m,2H),7.36-7.30(m,2H),7.28-7.21(m,3H),7.04(s,2H),5.15-5.07(m,1H),4.55(t,1H),4.12-4.03(m,1H),3.79-3.67(m,2H),3.30-3.26(m,2H)；LC-MS(ESI):m/z＝672.1[M+H]+。Compound 22 (SFC analysis retention time: 0.732 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30-8.22 (m, 1H), 8.07-7.99 (m, 4H), 7.73-7.66 (m, 2H), 7.48-7.42 (m, 2H), 7.36-7.30 (m, 2H), 7.28-7.21 (m, 3H), 7.04 (s, 2H), 5.15-5.07 (m, 1H), 4.55 (t, 1H), 4.12-4.03 (m, 1H), 3.79-3.67 (m, 2H), 3.30-3.26 (m, 2H); LC-MS (ESI): m/z=672.1 [M+H] + .

化合物23(SFC分析保留时间：1.339min)：1H NMR(400MHz,DMSO-d6)δ8.30-8.22(m,1H),8.07-7.99(m,4H),7.73-7.66(m,2H),7.48-7.42(m,2H),7.36-7.30(m,2H),7.28-7.21(m,3H),7.04(s,2H),5.15-5.07(m,1H),4.55(t,1H),4.12-4.03(m,1H),3.79-3.67(m,2H),3.30-3.26(m,2H)；LC-MS(ESI):m/z＝672.1[M+H]+。Compound 23 (SFC analysis retention time: 1.339 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30-8.22 (m, 1H), 8.07-7.99 (m, 4H), 7.73-7.66 (m, 2H), 7.48-7.42 (m, 2H), 7.36-7.30 (m, 2H), 7.28-7.21 (m, 3H), 7.04 (s, 2H), 5.15-5.07 (m, 1H), 4.55 (t, 1H), 4.12-4.03 (m, 1H), 3.79-3.67 (m, 2H), 3.30-3.26 (m, 2H); LC-MS (ESI): m/z=672.1 [M+H] + .

实施例24和实施例25
Example 24 and Example 25

第一步：将化合物24A(1.20g,5.66mmol)溶于DMF(20mL)中，加入三乙胺(1.72g,16.98mmol)，然后加入HATU(2.20g,8.49mmol)，氮气保护下室温搅拌2h。加水(30mL)淬灭反应，用二氯甲烷(30mL)萃取两次，合并有机相，经无水硫酸钠干燥后浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝3:1)纯化得到化合物24B(1.7g,收率：66％)。LC-MS(ESI):m/z＝454.2[M+H]+。Step 1: Compound 24A (1.20 g, 5.66 mmol) was dissolved in DMF (20 mL), triethylamine (1.72 g, 16.98 mmol) was added, and then HATU (2.20 g, 8.49 mmol) was added, and the mixture was stirred at room temperature for 2 h under nitrogen protection. Water (30 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 3: 1) to obtain compound 24B (1.7 g, yield: 66%). LC-MS (ESI): m/z = 454.2 [M+H] + .

第二步：将化合物24B(700mg,1.54mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)，反应在室温下搅拌10h。将反应液真空减压浓缩得化合物24C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.1[M+H]+。Step 2: Compound 24B (700 mg, 1.54 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the reaction was stirred at room temperature for 10 h. The reaction solution was concentrated under vacuum to obtain compound 24C (500 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 154.1 [M+H] + .

第三步：化合物24C(870mg,3.26mmol)参照实施例1第三步操作得到化合物24D(200mg)。Step 3: Compound 24C (870 mg, 3.26 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain compound 24D (200 mg).

第四步：将化合物24D经SFC手性拆分得到化合物24(SFC分析保留时间：0.836min，70mg)和25(SFC分析保留时间：1.437min，70mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral Cellulose-2column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral Cellulose-2column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇；梯度:45％B梯度洗脱流速:100mL/min，柱温:25℃，波长:254nm，循环时间:4.5min。样品制备:样品浓度10mg/mL，乙醇溶液进样:每次2.0mL。Step 4: Compound 24D was subjected to chiral separation by SFC to obtain compounds 24 (SFC analysis retention time: 0.836 min, 70 mg) and 25 (SFC analysis retention time: 1.437 min, 70 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C, wavelength: 254 nm, cycle time: 4.5 min. Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 2.0 mL each time.

化合物24(SFC分析保留时间：0.836min)：1H NMR(400MHz,DMSO-d6)δ13.41(s,1H),10.57(s,1H),8.70-8.40(m,1H),8.23-8.09(m,1H),8.03(d,2H),7.80(d,2H),7.55-7.44(m,2H),7.39-7.28(m,4H),7.27-7.20(m,3H),5.08-4.99(m,1H),4.51(t,1H),3.95-3.87(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 24 (SFC analysis retention time: 0.836 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.41 (s, 1H), 10.57 (s, 1H), 8.70-8.40 (m, 1H), 8.23-8.09 (m, 1H), 8.03 (d, 2H), 7.80 (d, 2H), 7.55-7.44 (m, 2H), 7.39-7.28 (m, 4H), 7.27-7.20 (m, 3H), 5.08-4.99 (m, 1H), 4.51 (t, 1H), 3.95-3.87 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

化合物25(SFC分析保留时间：1.437min)：1H NMR(400MHz,DMSO-d6)δ13.41(s,1H),10.57(s,1H),8.70-8.40(m,1H),8.23-8.09(m,1H),8.03(d,2H),7.80(d,2H),7.55-7.44(m,2H),7.39-7.28(m,4H),7.27-7.20(m,3H),5.08-4.99(m,1H),4.51(t,1H),3.95-3.87(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 25 (SFC analysis retention time: 1.437 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.41 (s, 1H), 10.57 (s, 1H), 8.70-8.40 (m, 1H), 8.23-8.09 (m, 1H), 8.03 (d, 2H), 7.80 (d, 2H), 7.55-7.44 (m, 2H), 7.39-7.28 (m, 4H), 7.27-7.20 (m, 3H), 5.08-4.99 (m, 1H), 4.51 (t, 1H), 3.95-3.87 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

实施例26和实施例27
Example 26 and Example 27

第一步：将化合物1A(2.38g,9.19mmol)和化合物26A(1.50g,7.07mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入二异丙基乙胺(1.79g,17.67mmol)和HATU(2.96g,7.78mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯＝5:1)纯化得到化合物26B(1.20g,收率:37.43％)。LC-MS(ESI):m/z＝454.2[M+H]+。Step 1: Dissolve compound 1A (2.38 g, 9.19 mmol) and compound 26A (1.50 g, 7.07 mmol) in N,N-dimethylformamide (30 mL), add diisopropylethylamine (1.79 g, 17.67 mmol) and HATU (2.96 g, 7.78 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, the residue obtained is purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 26B (1.20 g, yield: 37.43%). LC-MS (ESI): m/z = 454.2 [M+H] + .

第二步：将化合物26B(1.20g,2.65mmol)溶于二氯甲烷(24mL)中，加入三氟乙酸(6mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物26C(1.00g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.2[M+H]+。Step 2: Compound 26B (1.20 g, 2.65 mmol) was dissolved in dichloromethane (24 mL), trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 26C (1.00 g crude product), which was directly used in the next step. LC-MS (ESI): m/z = 154.2 [M+H] + .

第三步：化合物26C(1.00g,2.65mmol)参照实施例1第三步操作得到化合物26D(600mg,收率：81.85％)。LC-MS(ESI):m/z＝643.3[M+H]+。Step 3: Compound 26C (1.00 g, 2.65 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 26D (600 mg, yield: 81.85%). LC-MS (ESI): m/z = 643.3 [M+H] + .

第四步：化合物26D经手性拆分得到化合物26(SFC分析保留时间：2.004min，218.2mg)和化合物27(SFC分析保留时间：2.433min，212.1mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3.H2O in甲醇；梯度:40％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:5.9min；样品制备:样品浓度10mg/mL，乙腈二氯甲烷混合溶液进样:每次8.0mL。Step 4: Compound 26D was subjected to chiral separation to obtain compound 26 (SFC analysis retention time: 2.004 min, 218.2 mg) and compound 27 (SFC analysis retention time: 2.433 min, 212.1 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 40% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.9 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 8.0 mL each time.

化合物26(SFC分析保留时间：2.004min)：1H NMR(400MHz,CDCl3)δ12.11(s,1H),9.76(s,1H),9.03(br s,2H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.64(s,1H),7.57-7.55(m,2H),7.21-7.16(m,5H),6.97-6.96(m,2H),6.88-6.86(m,1H),4.63-4.61(m,1H),4.57-4.51(m,1H),4.31-4.28(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 26 (SFC analysis retention time: 2.004 min): 1 H NMR (400 MHz, CDCl 3 ) δ 12.11 (s, 1H), 9.76 (s, 1H), 9.03 (br s, 2H), 8.14-8.12 (m, 2H), 7.76-7.74 (m, 2H), 7.64 (s, 1H), 7.57-7.55 (m, 2H), 7.21-7.16 (m, 5H), 6.97-6.96 (m, 2H), 6.88-6.86 (m, 1H), 4.63-4.61 (m, 1H), 4.57-4.51 (m, 1H), 4.31-4.28 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

化合物27(SFC分析保留时间：2.433min)：1H NMR(400MHz,CDCl3)δ12.11(s,1H),9.76(s,1H),9.03(br s,2H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.64-7.63(m,1H),7.57-7.55(m,2H),7.21-7.14(m,5H),7.00-6.96(m,2H),6.88-6.85(m,1H),4.63-4.61(m,1H),4.57-4.51(m,1H),4.31-4.28(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 27 (SFC analysis retention time: 2.433 min): 1 H NMR (400 MHz, CDCl 3 ) δ 12.11 (s, 1H), 9.76 (s, 1H), 9.03 (br s, 2H), 8.14-8.12 (m, 2H), 7.76-7.74 (m, 2H), 7.64-7.63 (m, 1H), 7.57-7.55 (m, 2H), 7.21-7.14 (m, 5H), 7.00-6.96 (m, 2H), 6.88-6.85 (m, 1H), 4.63-4.61 (m, 1H), 4.57-4.51 (m, 1H), 4.31-4.28 (m, 1H); LC-MS (ESI): m/z=643.1 [M+H] + .

实施例28、实施例29、实施例30和实施例31
Example 28, Example 29, Example 30 and Example 31

第一步：将化合物1A(1.00g,3.86mmol)溶于二氯甲烷(20mL)中，加入三乙胺(1.17g,11.57mmol)，3-四氢呋喃甲酸(0.45g,3.86mmol)，抽换氮气三次后在冰浴下加入HATU(1.76g，4.63mmol)，加料完成后反应室温搅拌12h。加水(30mL)淬灭反应，用二氯甲烷(20mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝3:1)纯化得到化合物28A(0.60g，收率：43.53％)。LC-MS(ESI):m/z＝257.2[M-101+H]+。Step 1: Dissolve compound 1A (1.00 g, 3.86 mmol) in dichloromethane (20 mL), add triethylamine (1.17 g, 11.57 mmol), 3-tetrahydrofurancarboxylic acid (0.45 g, 3.86 mmol), replace nitrogen three times, add HATU (1.76 g, 4.63 mmol) in an ice bath, and stir the reaction at room temperature for 12 h after the addition is complete. Add water (30 mL) to quench the reaction, extract twice with dichloromethane (20 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The resulting residue is purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 3: 1) to obtain compound 28A (0.60 g, yield: 43.53%). LC-MS (ESI): m/z = 257.2 [M-101+H] + .

第二步：将化合物28A(600mg,1.68mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(4mL)，在室温下搅拌6h。将反应液减压浓缩得化合物28B(600mg)，直接用于下一步反应。LC-MS(ESI):m/z＝158.1[M+H]+。Step 2: Dissolve compound 28A (600 mg, 1.68 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 6 h. Concentrate the reaction solution under reduced pressure to obtain compound 28B (600 mg), which is directly used in the next step. LC-MS (ESI): m/z = 158.1 [M+H] + .

第三步：化合物28B(130mg,0.29mmol)参照实施例1第三步操作得到化合物28C(160mg)。Step 3: Compound 28B (130 mg, 0.29 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain compound 28C (160 mg).

第四步：将化合物28C经手性拆分得到化合物28(SFC分析保留时间：0.680min，35mg)、化合物29(SFC分析保留时间：0.749min，30mg)、化合物30(SFC分析保留时间：1.411min，32mg)和化合物31(SFC分析保留时间：2.517min，36mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral OX Column；流动相:A:CO2,B:0.05％DEA in甲醇和乙腈；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:254nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral OX Column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇和乙腈；梯度:35％B梯度洗脱流速:100mL/min，柱温:25℃波长:254nm循环时间:10.0min；样品制备:样品浓度10mg/mL，乙醇溶液进样:每次5mL。Step 4: Compound 28C was subjected to chiral separation to obtain compound 28 (SFC analysis retention time: 0.680 min, 35 mg), compound 29 (SFC analysis retention time: 0.749 min, 30 mg), compound 30 (SFC analysis retention time: 1.411 min, 32 mg) and compound 31 (SFC analysis retention time: 2.517 min, 36 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol and acetonitrile; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol and acetonitrile; Gradient: 35% B gradient elution flow rate: 100 mL/min, column temperature: 25°C wavelength: 254 nm cycle time: 10.0 min; Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 5 mL each time.

化合物28(SFC分析保留时间：0.680min)：1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.38(d,2H),7.33-7.22(m,5H),5.05-5.02(m,1H),4.49(t,1H),3.89-3.84(m,2H),3.78-3.65(m,3H),3.27-3.21(m,1H),2.11-1.94(m,2H)；LC-MS(ESI):m/z＝647.1[M+H]+。Compound 28 (SFC analysis retention time: 0.680 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.50 (d, 2H), 7.38 (d, 2H), 7.33-7.22 (m, 5H), 5.05-5.02 (m, 1H), 4.49 (t, 1H), 3.89-3.84 (m, 2H), 3.78-3.65 (m, 3H), 3.27-3.21 (m, 1H), 2.11-1.94 (m, 2H); LC-MS (ESI): m/z=647.1 [M+H] + .

化合物29(SFC分析保留时间：0.749min)：1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.33-7.23(m,5H),5.06-5.02(m,1H),4.49(t,1H),3.90-3.85(m,2H),3.77-3.64(m,3H),3.28-3.22(m,1H),2.10-1.95(m,2H)；LC-MS(ESI):m/z＝647.1[M+H]+。Compound 29 (SFC analysis retention time: 0.749 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.51 (d, 2H), 7.39 (d, 2H), 7.33-7.23 (m, 5H), 5.06-5.02 (m, 1H), 4.49 (t, 1H), 3.90-3.85 (m, 2H), 3.77-3.64 (m, 3H), 3.28-3.22 (m, 1H), 2.10-1.95 (m, 2H); LC-MS (ESI): m/z=647.1 [M+H] + .

化合物30(SFC分析保留时间：1.411min)：1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.34-7.23(m,5H),5.06-5.02(m,1H),4.49(t,1H),3.90-3.84(m,2H),3.77-3.64(m,3H),3.28-3.23(m,1H),2.09-1.96(m,2H)；LC-MS(ESI):m/z＝647.1[M+H]+。Compound 30 (SFC analysis retention time: 1.411 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.51 (d, 2H), 7.39 (d, 2H), 7.34-7.23 (m, 5H), 5.06-5.02 (m, 1H), 4.49 (t, 1H), 3.90-3.84 (m, 2H), 3.77-3.64 (m, 3H), 3.28-3.23 (m, 1H), 2.09-1.96 (m, 2H); LC-MS (ESI): m/z=647.1 [M+H] + .

化合物31(SFC分析保留时间：2.517min)：1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.38(d,2H),7.34-7.22(m,5H),5.06-5.02(m,1H),4.49(t,1H),3.90-3.85(m,2H),3.77-3.65(m,3H),3.28-3.23(m,1H),2.08-1.95(m,2H)；LC-MS(ESI):m/z＝647.1[M+H]+。Compound 31 (SFC analysis retention time: 2.517 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.51 (d, 2H), 7.38 (d, 2H), 7.34-7.22 (m, 5H), 5.06-5.02 (m, 1H), 4.49 (t, 1H), 3.90-3.85 (m, 2H), 3.77-3.65 (m, 3H), 3.28-3.23 (m, 1H), 2.08-1.95 (m, 2H); LC-MS (ESI): m/z=647.1 [M+H] + .

实施例32和实施例33
Example 32 and Example 33

第一步：将化合物32A(10.0g,77.19mmol)和DMAP(4.72g,38.59mmol)加入THF(200mL)中，然后加入BOC酸酐(42.12g,192.97mmol)，室温搅拌过夜，加水稀释后，EA萃取，收集有机相，以无水硫酸钠干燥，过滤，滤液浓缩所得残余物通过硅胶柱层析纯化(石油醚:乙酸乙酯(v:v)＝5:1)得到化合物32B(22g,收率：86％)。LC-MS(ESI):m/z＝330.1[M+H]+。Step 1: Compound 32A (10.0 g, 77.19 mmol) and DMAP (4.72 g, 38.59 mmol) were added to THF (200 mL), followed by BOC anhydride (42.12 g, 192.97 mmol), stirred at room temperature overnight, diluted with water, extracted with EA, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5: 1) to obtain compound 32B (22 g, yield: 86%). LC-MS (ESI): m/z = 330.1 [M+H] + .

第二步：将化合物32B(5.0g,15.16mmol)、乙酰胺(1.79g,30.32mmol)、醋酸钯(0.68g,3.03mmol)、Xant phos(3.51g,6.06mmol)和碳酸钾(4.19g,30.32mmol)先后加入1,4-二氧六环(80mL)中，氮气保护，加热至100℃搅拌过夜。冷却后过滤，滤液加水稀释后，EA萃取，有机相以无水硫酸钠干燥，过滤，滤液浓缩所得残余物通过硅胶柱层析纯化(PE:EA(v:v)＝2:1)得到化合物32C(4.7g,收率：88％)。LC-MS(ESI):m/z＝353.2[M+H]+。Step 2: Compound 32B (5.0 g, 15.16 mmol), acetamide (1.79 g, 30.32 mmol), palladium acetate (0.68 g, 3.03 mmol), Xant phos (3.51 g, 6.06 mmol) and potassium carbonate (4.19 g, 30.32 mmol) were added to 1,4-dioxane (80 mL) successively, and the mixture was heated to 100°C and stirred overnight under nitrogen protection. After cooling, the mixture was filtered, and the filtrate was diluted with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (PE:EA (v:v) = 2:1) to obtain compound 32C (4.7 g, yield: 88%). LC-MS (ESI): m/z = 353.2 [M+H] + .

第三步：将化合物32C(1.0g,2.84mmol)加入二氯甲烷(6mL)中，然后加入3mL三氟乙酸，室温下搅拌10小时。浓缩后，残余物中加入饱和碳酸氢钠溶液，以EA萃取，有机相经无水硫酸钠干燥，过滤，滤液浓缩得到化合物32D(粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝153.1[M+H]+。Step 3: Compound 32C (1.0 g, 2.84 mmol) was added to dichloromethane (6 mL), and then 3 mL of trifluoroacetic acid was added, and stirred at room temperature for 10 hours. After concentration, saturated sodium bicarbonate solution was added to the residue, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32D (crude product), which was directly used in the next step. LC-MS (ESI): m/z = 153.1 [M+H] + .

第四步：将化合物32D(0.2g,1.31mmol)和化合物1D(0.52g,0.98mmol)加入干燥的THF(15mL)中，氮气保护，冰浴下缓慢LiHMDS(3.93mL,3.93mmol)，加完后，搅拌1小时。加入饱和的氯化铵溶液淬灭反应，以EA萃取，收集有机相经无水硫酸钠干燥，过滤，滤液浓缩所得残余物通过硅胶柱层析纯化(PE:EA(v:v)＝1:1)得到体化合物32E(300mg)。Step 4: Compound 32D (0.2 g, 1.31 mmol) and compound 1D (0.52 g, 0.98 mmol) were added to dry THF (15 mL), and LiHMDS (3.93 mL, 3.93 mmol) was slowly added under nitrogen protection in an ice bath. After the addition, the mixture was stirred for 1 hour. A saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with EA. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (PE: EA (v: v) = 1: 1) to obtain the compound 32E (300 mg).

第五步：化合物32E进一步经手性SFC拆分得到化合物32(SFC分析保留时间：2.002min，120mg)和33(SFC分析保留时间：2.314min，120mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral AD column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral AD column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇；梯度:40％B梯度洗脱流速:100mL/min，柱温:25℃波长:254nm循环时间:4.5min样品制备:样品浓度10mg/mL，乙醇溶液进样:每次2.0mL。Step 5: Compound 32E was further resolved by chiral SFC to obtain compounds 32 (SFC analysis retention time: 2.002 min, 120 mg) and 33 (SFC analysis retention time: 2.314 min, 120 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, Column: Chiral AD column; Mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; Gradient: 5-40% B; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 254 nm Cycle time: 4.5 min Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 2.0 mL each time.

化合物32(SFC分析保留时间：2.002min)：1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.14(s,1H),8.96(s,1H),8.24(s,1H),7.99(d,2H),7.83(d,2H),7.50-7.30(m,6H),7.30-7.18(m,3H),5.11-5.07(m,1H),4.59(t,1H),3.97-3.93(m,1H),2.08(s,3H)；LC-MS(ESI):m/z＝642.1[M+H]+。Compound 32 (SFC analysis retention time: 2.002 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 10.14 (s, 1H), 8.96 (s, 1H), 8.24 (s, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.50-7.30 (m, 6H), 7.30-7.18 (m, 3H), 5.11-5.07 (m, 1H), 4.59 (t, 1H), 3.97-3.93 (m, 1H), 2.08 (s, 3H); LC-MS (ESI): m/z=642.1 [M+H] + .

化合物33(SFC分析保留时间：2.314min)：1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.14(s,1H),8.96(s,1H),8.24(s,1H),7.99(d,2H),7.83(d,2H),7.50-7.30(m,6H),7.30-7.18(m,3H),5.11-5.07(m,1H),4.59(t,1H),3.97-3.93(m,1H),2.08(s,3H)；LC-MS(ESI):m/z＝642.1[M+H]+。Compound 33 (SFC analysis retention time: 2.314 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 10.14 (s, 1H), 8.96 (s, 1H), 8.24 (s, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.50-7.30 (m, 6H), 7.30-7.18 (m, 3H), 5.11-5.07 (m, 1H), 4.59 (t, 1H), 3.97-3.93 (m, 1H), 2.08 (s, 3H); LC-MS (ESI): m/z=642.1 [M+H] + .

实施例34和实施例35
Example 34 and Example 35

第一步：化合物34A(60mg,0.40mmol)参照实施例1第三步操作得到化合物34B(130mg,收率：53.37％)。LC-MS(ESI):m/z＝641.1[M+H]+。Step 1: Compound 34A (60 mg, 0.40 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 34B (130 mg, yield: 53.37%). LC-MS (ESI): m/z = 641.1 [M+H] + .

第二步：化合物34B经手性拆分得到化合物34(SFC分析保留时间：2.392min，15.4mg)和化合物35(SFC分析保留时间：2.847min，19.2mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.1％NH3.H2O in甲醇；梯度:45％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:5.1min；样品制备:样品浓度5mg/mL，乙腈二氯甲烷混合溶液进样:每次2.0mL。Step 2: Compound 34B was subjected to chiral separation to obtain compound 34 (SFC analysis retention time: 2.392 min, 15.4 mg) and compound 35 (SFC analysis retention time: 2.847 min, 19.2 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 45% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.1 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.

化合物34(SFC分析保留时间：2.392min)：1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.98(s,1H),7.97-7.92(m,4H),7.82-7.80(m,2H),7.65-7.63(m,2H),7.43-7.41(m,2H),7.37-7.33(m,2H),7.29-7.25(m,3H),6.89-6.87(m,1H),5.18-5.14(m,1H),4.75-4.70(m,1H),4.11-4.07(m,1H),2.05(s,3H)；LC-MS(ESI):m/z＝641.1[M+H]+。Compound 34 (SFC analysis retention time: 2.392 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.98 (s, 1H), 7.97-7.92 (m, 4H), 7.82-7.80 (m, 2H), 7.65-7.63 (m, 2H), 7.43-7.41 (m, 2H), 7.37-7.33 (m, 2H), 7.29-7.25 (m, 3H), 6.89-6.87 (m, 1H), 5.18-5.14 (m, 1H), 4.75-4.70 (m, 1H), 4.11-4.07 (m, 1H), 2.05 (s, 3H); LC-MS (ESI): m/z=641.1 [M+H] + .

化合物35(SFC分析保留时间：2.847min)：1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.98(s,1H),7.97-7.92(m,4H),7.82-7.80(m,2H),7.65-7.63(m,2H),7.43-7.41(m,2H),7.35-7.33(m,2H),7.29-7.27(m,3H),6.89-6.87(m,1H),5.18-5.14(m,1H),4.75-4.70(m,1H),4.11-4.07(m,1H),2.05(s,3H)；LC-MS(ESI):m/z＝641.1[M+H]+。Compound 35 (SFC analysis retention time: 2.847 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.98 (s, 1H), 7.97-7.92 (m, 4H), 7.82-7.80 (m, 2H), 7.65-7.63 (m, 2H), 7.43-7.41 (m, 2H), 7.35-7.33 (m, 2H), 7.29-7.27 (m, 3H), 6.89-6.87 (m, 1H), 5.18-5.14 (m, 1H), 4.75-4.70 (m, 1H), 4.11-4.07 (m, 1H), 2.05 (s, 3H); LC-MS (ESI): m/z=641.1 [M+H] + .

实施例36和实施例37
Example 36 and Example 37

第一步：将化合物1A(2.00g,7.71mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(10mL)，在室温下搅拌反应6小时。将反应液减压浓缩得化合物36A(1.00g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝60.2[M+H]+。Step 1: Dissolve compound 1A (2.00 g, 7.71 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 6 hours. Concentrate the reaction solution under reduced pressure to obtain compound 36A (1.00 g crude product), which is directly used in the next step. LC-MS (ESI): m/z = 60.2 [M+H] + .

第二步：化合物36A(1.00g粗品)参照实施例1第三步操作得到化合物36B(350mg,收率：33.56％)。LC-MS(ESI):m/z＝549.2[M+H]+。Step 2: Compound 36A (1.00 g crude product) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 36B (350 mg, yield: 33.56%). LC-MS (ESI): m/z = 549.2 [M+H] + .

第三步：将化合物36B(350mg，0.64mmol)溶于二氯甲烷(50mL)，分别加入化合物36C(100mg,0.75mmol,参照专利CN107759587合成)和三乙胺(130mg,1.28mmol)，反应液在室温下搅拌1.5小时。加水(40mL)淬灭反应，以二氯甲烷(50mL)萃取二次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(石油醚:乙酸乙酯(v:v)＝50:50)纯化得到化合物36D(400mg,收率：97.11％)。LC-MS(ESI):m/z＝646.4[M+H]+。Step 3: Compound 36B (350 mg, 0.64 mmol) was dissolved in dichloromethane (50 mL), and compound 36C (100 mg, 0.75 mmol, synthesized according to patent CN107759587) and triethylamine (130 mg, 1.28 mmol) were added respectively, and the reaction solution was stirred at room temperature for 1.5 hours. Water (40 mL) was added to quench the reaction, and dichloromethane (50 mL) was used for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 50:50) to obtain compound 36D (400 mg, yield: 97.11%). LC-MS (ESI): m/z = 646.4 [M+H] + .

第四步：化合物36D经手性拆分得到化合物36(SFC分析保留时间：0.856min，56.4mg)和化合物37(SFC分析保留时间：1.160min，94.8mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral OX Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:50％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral OX Column；流动相:A:CO2,B:0.1％NH3.H2O in甲醇；梯度:55％B梯度；洗脱流速:100mL/min；柱温:25℃；波长:220nm；循环时间:7.0min；样品制备:样品浓度5mg/mL，乙腈二氯甲烷混合溶液进样:每次3.0mL。Step 4: Compound 36D was subjected to chiral separation to obtain compound 36 (SFC analysis retention time: 0.856 min, 56.4 mg) and compound 37 (SFC analysis retention time: 1.160 min, 94.8 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 50% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 55% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 7.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

化合物36(SFC分析保留时间：0.856min)：1H NMR(400MHz,DMSO-d6)δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7.60-7.53(m,1H),7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.22(m,3H),5.10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H),3.57-3.38(m,2H),3.13-3.11(m,2H),2.92(s,3H)；LC-MS(ESI):m/z＝646.1[M+H]+。Compound 36 (SFC analysis retention time: 0.856 min): 1 H NMR (400 MHz, DMSO-d 6 )δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7.60-7.53(m,1H) ,7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.22(m,3H),5 .10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H),3. 57-3.38(m,2H),3.13-3.11(m,2H),2.92(s,3H); LC-MS(ESI):m/z＝646.1[M+H] + .

化合物37(SFC分析保留时间：1.160min)：1H NMR(400MHz,DMSO-d6)δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7.60-7.53(m,1H),7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.22(m,3H),5.10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H),3.57-3.41(m,2H),3.13-3.11(m,2H),2.92(s,3H)；LC-MS(ESI):m/z＝646.2[M+H]+。Compound 37 (SFC analysis retention time: 1.160 min): 1 H NMR (400 MHz, DMSO-d 6 )δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7.60-7.53(m,1H) ,7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.22(m,3H),5 .10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H),3. 57-3.41(m,2H),3.13-3.11(m,2H),2.92(s,3H); LC-MS(ESI):m/z=646.2[M+H] + .

实施例38和实施例39
Example 38 and Example 39

第一步：将化合物38A(1.00g,9.08mmol)溶于二氧六环(20mL)中，加入吡啶(2.15g,27.24mmol)，反应液置换氮气保护后室温下缓慢滴加乙酰氯(750mg,9.55mmol)。完成加料后反应液在室80℃下搅拌反应3小时。将反应液减压浓缩，所得残余物经柱层析(二氯甲烷:甲醇(v:v)＝90:10)纯化得到化合物38B(420mg,收率：30.40％)。1H NMR(400MHz,DMSO-d6)δ12.50(br s,2H),8.73-8.72(m,1H),8.47(s,1H),6.15-6.13(s,1H),1.92(s,3H)。Step 1: Dissolve compound 38A (1.00 g, 9.08 mmol) in dioxane (20 mL), add pyridine (2.15 g, 27.24 mmol), replace the nitrogen atmosphere in the reaction solution, slowly add acetyl chloride (750 mg, 9.55 mmol) at room temperature. After the addition is completed, the reaction solution is stirred at 80°C for 3 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography (dichloromethane: methanol (v:v) = 90:10) to obtain compound 38B (420 mg, yield: 30.40%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.50 (br s, 2H), 8.73-8.72 (m, 1H), 8.47 (s, 1H), 6.15-6.13 (s, 1H), 1.92 (s, 3H).

第二步：将化合物1D(500mg，0.95mmol)溶于四氢呋喃(20mL)，分别加入化合物38B(290mg,1.90mmol)和叔丁醇钾(320mg,2.85mmol)，反应液在75℃搅拌2小时。加水(40mL)淬灭反应，以乙酸乙酯(40mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析(乙酸乙酯)纯化得到化合物38C(140mg,收率：22.95％)。LC-MS(ESI):m/z＝642.1[M+H]+。Step 2: Compound 1D (500 mg, 0.95 mmol) was dissolved in tetrahydrofuran (20 mL), and compound 38B (290 mg, 1.90 mmol) and potassium tert-butoxide (320 mg, 2.85 mmol) were added respectively, and the reaction solution was stirred at 75°C for 2 hours. Water (40 mL) was added to quench the reaction, and ethyl acetate (40 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate) to obtain compound 38C (140 mg, yield: 22.95%). LC-MS (ESI): m/z=642.1[M+H] + .

第三步：化合物38C经手性SFC拆分得到化合物38(SFC分析保留时间：2.408min，11.20mg)和化合物39(SFC分析保留时间：2.607min，14.30mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.1％NH3.H2O in甲醇；梯度:35％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:6.5min；样品制备:样品浓度3.3mg/mL，乙腈二氯甲烷混合溶液进样:每次2.0mL。Step 3: Compound 38C was separated by chiral SFC to obtain compound 38 (SFC analysis retention time: 2.408 min, 11.20 mg) and compound 39 (SFC analysis retention time: 2.607 min, 14.30 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in methanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 6.5 min; sample preparation: sample concentration 3.3 mg/mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.

化合物38(SFC分析保留时间：2.408min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.24-8.22(m,1H),7.99-7.97(m,2H),7.78-7.76(m,2H),7.49-7.47(m,1H),7.36-7.24(m,10H),4.99-4.95(m,1H),4.53-4.45(m,1H),3.87-3.83(m,1H),2.10(s,3H)；LC-MS(ESI):m/z＝642.1[M+H]+。Compound 38 (SFC analysis retention time: 2.408 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.24-8.22 (m, 1H), 7.99-7.97 (m, 2H), 7.78-7.76 (m, 2H), 7.49-7.47 (m, 1H), 7.36-7.24 (m, 10H), 4.99-4.95 (m, 1H), 4.53-4.45 (m, 1H), 3.87-3.83 (m, 1H), 2.10 (s, 3H); LC-MS (ESI): m/z=642.1 [M+H] + .

化合物39(SFC分析保留时间：2.607min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.24-8.22(m,1H),7.99-7.97(m,2H),7.78-7.76(m,2H),7.49-7.47(m,1H),7.36-7.24(m,10H),4.99-4.95(m,1H),4.53-4.45(m,1H),3.87-3.83(m,1H),2.10(s,3H)；LC-MS(ESI):m/z＝642.1[M+H]+。Compound 39 (SFC analysis retention time: 2.607 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.24-8.22 (m, 1H), 7.99-7.97 (m, 2H), 7.78-7.76 (m, 2H), 7.49-7.47 (m, 1H), 7.36-7.24 (m, 10H), 4.99-4.95 (m, 1H), 4.53-4.45 (m, 1H), 3.87-3.83 (m, 1H), 2.10 (s, 3H); LC-MS (ESI): m/z=642.1 [M+H] + .

实施例40和实施例41
Example 40 and Example 41

第一步：将化合物40A(0.5g,4.46mmol)和N-Boc-胍(1.06g,6.7mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入二异丙基乙胺(1.72g,13.38mmol)和HATU(2.0g,5.35mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物40B(1.0g，收率：88.6％)。LC-MS(ESI):m/z＝254.2[M+H]+。Step 1: Dissolve compound 40A (0.5 g, 4.46 mmol) and N-Boc-guanidine (1.06 g, 6.7 mmol) in N,N-dimethylformamide (10 mL), add diisopropylethylamine (1.72 g, 13.38 mmol) and HATU (2.0 g, 5.35 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 40B (1.0 g, yield: 88.6%). LC-MS (ESI): m/z=254.2[M+H] + .

第二步：将化合物40B(300mg,1.18mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(4mL)，在室温下搅拌反应5小时。将反应液减压浓缩得化合物40C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝154.1[M+H]+。Step 2: Compound 40B (300 mg, 1.18 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 40C (500 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 154.1 [M+H] + .

第三步：将化合物1D(200mg，0.38mmol)溶于二氯甲烷(10mL)，分别加入化合物40C粗品(500mg,1.18mmol)和二异丙基乙胺(765mg,5.9mmol)，在室温下搅拌过夜。加水(40mL)淬灭反应，以二氯甲烷(50mL)萃取二次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物40D(230mg,收率：94.2％)。Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), and crude compound 40C (500 mg, 1.18 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added respectively, and stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, and the mixture was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 40D (230 mg, yield: 94.2%).

第四步：化合物40D经手性SFC拆分得到化合物40(SFC分析保留时间：0.913min，90mg)和化合物41(SFC分析保留时间：1.370min，39mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral OX Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral OX Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:30％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:4.0min；样品制备:样品浓度7.0mg/mL，乙腈乙醇混合溶液进样:每次2.0mL。Step 4: Compound 40D was separated by chiral SFC to obtain compound 40 (SFC analysis retention time: 0.913 min, 90 mg) and compound 41 (SFC analysis retention time: 1.370 min, 39 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral OX Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 30% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.0 min; Sample preparation: Sample concentration 7.0 mg/mL, acetonitrile ethanol mixed solution injection: 2.0 mL each time.

化合物40(SFC分析保留时间：0.913min)：1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.48(m,2H),7.39-7.37(m,2H),7.32-7.21(m,5H),5.94(s,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.89-3.84(m,1H),3.10-3.07(m,2H),2.86-2.83(m,2H),2.08-2.04(m,2H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 40 (SFC analysis retention time: 0.913 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.48(m,2H),7.39-7.37(m,2H),7.32-7.21(m,5H),5.94(s,1H),5.04-5.0 0(m,1H),4.51-4.45(m,1H),3.89-3.84(m,1H),3.10-3.07(m,2H),2.86-2.83(m,2H),2.08-2.04(m,2H); LC-MS(ESI):m/z＝643.1[M+H] + .

化合物41(SFC分析保留时间：1.370min)：1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.48(m,2H),7.40-7.36(m,2H),7.32-7.21(m,5H),5.94(s,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.89-3.85(m,1H),3.10-3.07(m,2H),2.86-2.83(m,2H),2.10-2.04(m,2H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 41 (SFC analysis retention time: 1.370 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.48(m,2H),7.40-7.36(m,2H),7.32-7.21(m,5H),5.94(s,1H),5.04-5.0 0(m,1H),4.51-4.45(m,1H),3.89-3.85(m,1H),3.10-3.07(m,2H),2.86-2.83(m,2H),2.10-2.04(m,2H); LC-MS(ESI):m/z＝643.1[M+H] + .

实施例42和实施例43
Example 42 and Example 43

第一步：将化合物42A(2.0g,15.37mmol)和BOC-胍(3.67g,23.05mmol)溶于DMF(50mL)中，加入三乙胺(4.67g,46.11mmol)，然后加入HATU(7.60g,19.98mmol)，氮气保护,室温搅拌2h。加水(50mL)淬灭反应，并用乙酸乙酯(30mL)萃取两次，收集有机相，经饱和食盐水洗涤，无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物42B(3.5g,收率：84％)。LC-MS(ESI):m/z＝272.2[M+H]+。Step 1: Dissolve compound 42A (2.0 g, 15.37 mmol) and BOC-guanidine (3.67 g, 23.05 mmol) in DMF (50 mL), add triethylamine (4.67 g, 46.11 mmol), then add HATU (7.60 g, 19.98 mmol), protect with nitrogen, and stir at room temperature for 2 h. Add water (50 mL) to quench the reaction, and extract twice with ethyl acetate (30 mL), collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain compound 42B (3.5 g, yield: 84%). LC-MS (ESI): m/z=272.2[M+H] + .

第二步：将化合物42B(500mg,1.84mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(2.5mL)，在室温搅拌10h。将反应液浓缩得化合物42C(320mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝172.1[M+H]+。Step 2: Compound 42B (500 mg, 1.84 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added, and the mixture was stirred at room temperature for 10 h. The reaction solution was concentrated to obtain compound 42C (320 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 172.1 [M+H] + .

第三步：化合物42C(320mg,1.12mmol)参照实施例1第三步操作得到化合物42D(180mg)。Step 3: Compound 42C (320 mg, 1.12 mmol) was subjected to the procedure of Step 3 of Example 1 to obtain compound 42D (180 mg).

第四步：将化合物42D进一步经手性SFC拆分得到化合物42(SFC分析保留时间：0.736min，70mg)和化合物43(SFC分析保留时间：1.429min，70mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral Cellulose-2column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法：仪器:Waters 150 Prep-SFC，柱:Chiral Cellulose-2column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇；梯度:45％B梯度洗脱流速:100mL/min，柱温:25℃波长:254nm循环时间:4.5min样品制备:样品浓度10mg/mL，乙醇溶液进样:每次2.0mL。Step 4: Compound 42D was further separated by chiral SFC to obtain compound 42 (SFC analysis retention time: 0.736 min, 70 mg) and compound 43 (SFC analysis retention time: 1.429 min, 70 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral Cellulose-2 column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol; Gradient: 45% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 254 nm Cycle time: 4.5 min Sample preparation: Sample concentration 10 mg/mL, ethanol solution injection: 2.0 mL each time.

化合物42(SFC分析保留时间：0.736min):1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.01(d,2H),7.82(d,2H),7.52-7.46(m,2H),7.41-7.36(m,2H),7.34-7.21(m,5H),5.07-4.98(m,1H),4.49(t,1H),3.92-3.81(m,3H),3.34-3.31(m,1H),3.28-3.25(m,1H),2.78-2.65(m,1H),1.72-1.48(m,4H)；LC-MS(ESI):m/z＝661.2[M+H]+。Compound 42 (SFC analysis retention time: 0.736 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.52-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.21 (m, 5H), 5.07-4.98 (m, 1H), 4.49 (t, 1H), 3.92-3.81 (m, 3H), 3.34-3.31 (m, 1H), 3.28-3.25 (m, 1H), 2.78-2.65 (m, 1H), 1.72-1.48 (m, 4H); LC-MS (ESI): m/z=661.2 [M+H] + .

化合物43(SFC分析保留时间：1.429min):1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.01(d,2H),7.82(d,2H),7.46-7.52(m,2H),7.41-7.36(m,2H),7.34-7.21(m,5H),5.07-4.98(m,1H),4.49(t,1H),3.92-3.81(m,3H),3.34-3.31(m,1H),3.28-3.25(m,1H),2.78-2.65(m,1H),1.72-1.48(m,4H)；LC-MS(ESI):m/z＝661.2[M+H]+。Compound 43 (SFC analysis retention time: 1.429 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.46-7.52 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.21 (m, 5H), 5.07-4.98 (m, 1H), 4.49 (t, 1H), 3.92-3.81 (m, 3H), 3.34-3.31 (m, 1H), 3.28-3.25 (m, 1H), 2.78-2.65 (m, 1H), 1.72-1.48 (m, 4H); LC-MS (ESI): m/z=661.2 [M+H] + .

实施例44、实施例45、实施例46和实施例47
Example 44, Example 45, Example 46 and Example 47

第一步：将2-甲巯基乙胺碳酸叔丁酯(3.00g,15.68mmol)加入到氨甲醇溶液中(7mol/L,50mL)，冰浴降温至0～10℃，缓慢加入碘苯二乙酸(12.63g,39.20mmol)，而后恢复室温搅拌4小时。反应完成后加入乙酸乙酯(200mL)和饱和碳酸氢钠水溶液(200mL)进行分液，有机相用饱和食盐水洗涤，经无水硫酸钠干燥后浓缩，残余物经硅胶柱层析纯化得化合物44B(2.54g,收率：72.85％)。LC-MS(ESI):m/z＝223.1[M+H]+。Step 1: Add tert-butyl 2-methylmercaptoethylamine carbonate (3.00 g, 15.68 mmol) to ammonia methanol solution (7 mol/L, 50 mL), cool to 0-10°C in an ice bath, slowly add iodophenyl diacetic acid (12.63 g, 39.20 mmol), and then stir at room temperature for 4 hours. After the reaction is completed, add ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL) for separation, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate, and purify the residue by silica gel column chromatography to obtain compound 44B (2.54 g, yield: 72.85%). LC-MS (ESI): m/z = 223.1 [M+H] + .

第二步：将化合物44B加入到4mol/L的盐酸1,4-二氧六环(30mL)溶液中，室温反应4小时。反应完成后过滤，收集滤饼并用乙腈洗涤，干燥得化合物44C(1.6g,收率：89.69％)。LC-MS(ESI):m/z＝123.1[M+H]+。Step 2: Compound 44B was added to a 4 mol/L hydrochloric acid 1,4-dioxane solution (30 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the filter cake was collected and washed with acetonitrile and dried to obtain compound 44C (1.6 g, yield: 89.69%). LC-MS (ESI): m/z = 123.1 [M+H] + .

第三步：化合物44C(0.14g,0.91mmol)参照实施例1第三步操作得化合物44D(331mg,收率：71.16％)。LC-MS(ESI):m/z＝612.0[M+H]+。Step 3: Compound 44C (0.14 g, 0.91 mmol) was treated with the same method as in Step 3 of Example 1 to obtain Compound 44D (331 mg, yield: 71.16%). LC-MS (ESI): m/z = 612.0 [M+H] + .

第四步：将化合物44D(331mg,0.54mmol)进行手性SFC拆分得化合物44(SFC分析保留时间：0.882min，63.8mg)、化合物45(SFC分析保留时间：1.082min，65.7mg)、化合物46(SFC分析保留时间：1.385min，76.4mg)和化合物47(SFC分析保留时间：1.586min，77.6mg)。SFC分析方法：仪器：SHIMADZU LC-30AD sf；色谱柱：Chiral OX column；流动相:A for CO2；B for 0.05％DEA in乙醇；梯度:B 5-40％；流速:3.0mL/min；柱压:100bar；柱温:35℃；波长:220nm)。SFC手性拆分方法：仪器：Waters 150 Prep-SFC；色谱柱：Chiral OX column；流动相:A for CO2；B for 0.1％NH3·H2Oin甲醇；梯度:B 40％；流速:120mL/min；柱压:100bar；柱温:室温；波长:220nm)循环时间：～3.5min。样品制备：将化合物溶于乙腈中，浓度为3.0mg/mL；注射:每次进样2mL。Step 4: Compound 44D (331 mg, 0.54 mmol) was subjected to chiral SFC separation to obtain compound 44 (SFC analysis retention time: 0.882 min, 63.8 mg), compound 45 (SFC analysis retention time: 1.082 min, 65.7 mg), compound 46 (SFC analysis retention time: 1.385 min, 76.4 mg) and compound 47 (SFC analysis retention time: 1.586 min, 77.6 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf; chromatographic column: Chiral OX column; mobile phase: A for CO 2 ; B for 0.05% DEA in ethanol; gradient: B 5-40%; flow rate: 3.0 mL/min; column pressure: 100 bar; column temperature: 35° C.; wavelength: 220 nm). SFC chiral separation method: Instrument: Waters 150 Prep-SFC; Chromatographic column: Chiral OX column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in methanol; Gradient: B 40%; Flow rate: 120 mL/min; Column pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm) Cycle time: ~3.5 min. Sample preparation: Dissolve the compound in acetonitrile at a concentration of 3.0 mg/mL; Injection: 2 mL each time.

化合物44(SFC分析保留时间：0.882min)：1H NMR(400MHz,CDCl3)δ8.15-8.09(m,1H),8.05-8.02(m,2H),7.68-7.66(m,2H),7.58-7.51(m,2H),7.35-7.20(m,4H),7.16-7.06(m,2H),4.72-4.68(m,1H),4.56-4.51(m,1H),4.22-4.18(m,2H),4.09-4.04(m,1H),3.65-3.50(m,2H),3.17(s,3H)；LC-MS(ESI):m/z＝612.0[M+H]+。Compound 44 (SFC analysis retention time: 0.882 min): 1 H NMR (400 MHz, CDCl 3 ) δ 8.15-8.09 (m, 1H), 8.05-8.02 (m, 2H), 7.68-7.66 (m, 2H), 7.58-7.51 (m, 2H), 7.35-7.20 (m, 4H), 7.16-7.06 (m, 2H), 4.72-4.68 (m, 1H), 4.56-4.51 (m, 1H), 4.22-4.18 (m, 2H), 4.09-4.04 (m, 1H), 3.65-3.50 (m, 2H), 3.17 (s, 3H); LC-MS (ESI): m/z=612.0 [M+H] + .

化合物45(SFC分析保留时间：1.082min)：1H NMR(400MHz,CDCl3)δ8.15-8.09(m,1H),8.06-8.01(m,2H),7.70-7.65(m,2H),7.60-7.50(m,2H),7.37-7.20(m,4H),7.16-7.07(m,2H),4.79-4.63(m,1H),4.59-4.45(m,1H),4.28-4.15(m,2H),4.13-4.04(m,1H),3.67-3.48(m,2H),3.17(s,3H)；LC-MS(ESI):m/z＝612.0[M+H]+。Compound 45 (SFC analysis retention time: 1.082 min): 1 H NMR (400 MHz, CDCl 3 ) δ 8.15-8.09 (m, 1H), 8.06-8.01 (m, 2H), 7.70-7.65 (m, 2H), 7.60-7.50 (m, 2H), 7.37-7.20 (m, 4H), 7.16-7.07 (m, 2H), 4.79-4.63 (m, 1H), 4.59-4.45 (m, 1H), 4.28-4.15 (m, 2H), 4.13-4.04 (m, 1H), 3.67-3.48 (m, 2H), 3.17 (s, 3H); LC-MS (ESI): m/z=612.0 [M+H] + .

化合物46(SFC分析保留时间：1.385min)：1H NMR(400MHz,CDCl3)δ8.14-8.07(m,1H),8.06-8.00(m,2H),7.72-7.63(m,2H),7.58-7.50(m,2H),7.34-7.21(m,4H),7.15-7.08(m,2H),4.75-4.66(m,1H),4.58-4.49(m,1H),4.25-4.16(m,2H),4.10-4.03(m,1H),3.67-3.50(m,2H),3.18(s,3H)；LC-MS(ESI):m/z＝612.0[M+H]+。Compound 46 (SFC analysis retention time: 1.385 min): 1 H NMR (400 MHz, CDCl 3 ) δ 8.14-8.07 (m, 1H), 8.06-8.00 (m, 2H), 7.72-7.63 (m, 2H), 7.58-7.50 (m, 2H), 7.34-7.21 (m, 4H), 7.15-7.08 (m, 2H), 4.75-4.66 (m, 1H), 4.58-4.49 (m, 1H), 4.25-4.16 (m, 2H), 4.10-4.03 (m, 1H), 3.67-3.50 (m, 2H), 3.18 (s, 3H); LC-MS (ESI): m/z=612.0 [M+H] + .

化合物47(SFC分析保留时间：1.586min)：1H NMR(400MHz,CDCl3)δ8.17-8.08(m,1H),8.07-8.00(m,2H),7.72-7.65(m,2H),7.56-7.50(m,2H),7.37-7.19(m,4H),7.17-7.06(m,2H),4.76-4.63(m,1H),4.57-4.46(m,1H),4.24-4.14(m,2H),4.14-4.04(m,1H),3.60-3.39(m,2H),3.12(s,3H)；LC-MS(ESI):m/z＝612.0[M+H]+。Compound 47 (SFC analysis retention time: 1.586 min): 1 H NMR (400 MHz, CDCl 3 ) δ 8.17-8.08 (m, 1H), 8.07-8.00 (m, 2H), 7.72-7.65 (m, 2H), 7.56-7.50 (m, 2H), 7.37-7.19 (m, 4H), 7.17-7.06 (m, 2H), 4.76-4.63 (m, 1H), 4.57-4.46 (m, 1H), 4.24-4.14 (m, 2H), 4.14-4.04 (m, 1H), 3.60-3.39 (m, 2H), 3.12 (s, 3H); LC-MS (ESI): m/z=612.0 [M+H] + .

实施例48和实施例49
Example 48 and Example 49

第一步：将化合物48A(1.0g,5.61mmol)和N-Boc-胍(1.01g,6.73mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入二异丙基乙胺(2.18g,16.83mmol)和HATU(3.20g,8.42mmol)，加料完毕，室温搅拌过夜。加水(100mL)，乙酸乙酯(50mL)萃取，合并有机相，无水硫酸钠干燥后减压浓缩，残余物经硅胶柱层析纯化得到化合物48B(0.80g，收率：44.6％)。LC-MS(ESI):m/z＝320.2[M+H]+。Step 1: Dissolve compound 48A (1.0 g, 5.61 mmol) and N-Boc-guanidine (1.01 g, 6.73 mmol) in N,N-dimethylformamide (10 mL), add diisopropylethylamine (2.18 g, 16.83 mmol) and HATU (3.20 g, 8.42 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 48B (0.80 g, yield: 44.6%). LC-MS (ESI): m/z=320.2[M+H] + .

第二步：将化合物48B(800mg,2.50mmol)溶于二氯甲烷(9mL)中，加入三氟乙酸(3mL)，在室温下搅拌反应5小时。将反应液减压浓缩得化合物48C(600mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝220.1[M+H]+。Step 2: Compound 48B (800 mg, 2.50 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 48C (600 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 220.1 [M+H] + .

第三步：化合物48C粗品(150mg,0.68mmol)参照实施例40第三步操作得到化合物48D(50mg)。Step 3: The crude product of compound 48C (150 mg, 0.68 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 48D (50 mg).

第四步：化合物48D经手性SFC拆分得到化合物48(SFC分析保留时间：2.228min，11mg)和化合物49(SFC分析保留时间：2.661min，15mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:254nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:7.5min；样品制备:样品浓度2mg/mL，乙醇溶液进样:每次2mL。Step 4: Compound 48D was separated by chiral SFC to obtain compound 48 (SFC analysis retention time: 2.228 min, 11 mg) and compound 49 (SFC analysis retention time: 2.661 min, 15 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 7.5 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.

化合物48(SFC分析保留时间：2.228min)：1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.39(d,2H),7.34-7.22(m,5H),5.05-4.99(m,1H),4.52-4.46(m,1H),3.90-3.85(m,1H),3.17-3.11(m,4H),2.82-2.75(m,1H),2.20-2.12(m,2H),2.06-1.94(m,2H)；LC-MS(ESI):m/z＝709.1[M+H]+。Compound 48 (SFC analysis retention time: 2.228 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.50 (d, 2H), 7.39 (d, 2H), 7.34-7.22 (m, 5H), 5.05-4.99 (m, 1H), 4.52-4.46 (m, 1H), 3.90-3.85 (m, 1H), 3.17-3.11 (m, 4H), 2.82-2.75 (m, 1H), 2.20-2.12 (m, 2H), 2.06-1.94 (m, 2H); LC-MS (ESI): m/z=709.1 [M+H] + .

化合物49(SFC分析保留时间：2.661min)：1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.39(d,2H),7.34-7.22(m,5H),5.05-5.00(m,1H),4.52-4.46(m,1H),3.90-3.85(m,1H),3.17-3.10(m,4H),2.83-2.75(m,1H),2.20-2.12(m,2H),2.05-1.94(m,2H)；LC-MS(ESI):m/z＝709.1[M+H]+。Compound 49 (SFC analysis retention time: 2.661 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.01 (d, 2H), 7.82 (d, 2H), 7.50 (d, 2H), 7.39 (d, 2H), 7.34-7.22 (m, 5H), 5.05-5.00 (m, 1H), 4.52-4.46 (m, 1H), 3.90-3.85 (m, 1H), 3.17-3.10 (m, 4H), 2.83-2.75 (m, 1H), 2.20-2.12 (m, 2H), 2.05-1.94 (m, 2H); LC-MS (ESI): m/z=709.1 [M+H] + .

实施例50和实施例51
Example 50 and Example 51

第一步：将化合物50A(1.0g,6.98mmol)和N-Boc-胍(1.67g,10.47mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入二异丙基乙胺(2.71g,20.94mmol)和HATU(3.98g,10.47mmol)，加料完毕，室温搅拌过夜。加水(100mL)，乙酸乙酯(50mL)萃取，合并有机相，无水硫酸钠干燥后减压浓缩，残余物经硅胶柱层析纯化得到化合物50B(1.2g，收率：60.4％)。LC-MS(ESI):m/z＝285.2[M+H]+。Step 1: Dissolve compound 50A (1.0 g, 6.98 mmol) and N-Boc-guanidine (1.67 g, 10.47 mmol) in N,N-dimethylformamide (10 mL), add diisopropylethylamine (2.71 g, 20.94 mmol) and HATU (3.98 g, 10.47 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 50B (1.2 g, yield: 60.4%). LC-MS (ESI): m/z=285.2[M+H] + .

第二步：将化合物50B(600mg,2.11mmol)溶于二氯甲烷(9mL)中，加入三氟乙酸(3mL)，在室温下搅拌反应5小时。将反应液减压浓缩得化合物50C(600mg粗品)，直接用于下一步反应。Step 2: Compound 50B (600 mg, 2.11 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 50C (600 mg crude product), which was directly used in the next step.

第三步：化合物50C粗品(100mg,0.54mmol)参照实施例40第三步操作得到化合物50D(80mg)。Step 3: The crude product of compound 50C (100 mg, 0.54 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 50D (80 mg).

第四步：化合物50D经手性SFC拆分得到化合物50(SFC分析保留时间：0.855min，51mg)和化合物51(SFC分析保留时间：1.642min，45mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:50％B梯度洗脱流速:100mL/min，柱温:25℃波长:220nm循环时间:2.5min；样品制备:样品浓度5mg/mL，乙醇溶液进样:每次5mL。Step 4: Compound 50D was separated by chiral SFC to obtain compound 50 (SFC analysis retention time: 0.855 min, 51 mg) and compound 51 (SFC analysis retention time: 1.642 min, 45 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 50% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 2.5 min; Sample preparation: Sample concentration 5 mg/mL, ethanol solution injection: 5 mL each time.

化合物50(SFC分析保留时间：0.855min):1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.01(d,2H),7.81(d,2H),7.49(d,2H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3.86(m,1H),2.81-2.75(m,2H),2.50-2.38(m,1H),2.16(s,3H),1.87-1.82(m,2H),1.72-1.67(m,2H),1.60-1.50(m,2H)；LC-MS(ESI):m/z＝674.1[M+H]+。Compound 50 (SFC analysis retention time: 0.855 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.49(s,1H),8.01(d,2H),7.81(d,2H),7.49(d,2H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3.86(m,1H) ,2.81-2.75(m,2H),2.50-2.38(m,1H),2.16(s,3H),1.87-1.82(m,2H),1.72-1.67(m,2H),1.60-1.50(m,2H); LC-MS(ESI):m/z＝674.1[M+H] + .

化合物51(SFC分析保留时间：1.642min):1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.00(d,2H),7.81(d,2H),7.49(d,2H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3.86(m,1H),2.79-2.72(m,2H),2.49-2.37(m,1H),2.13(s,3H),1.84-1.78(m,2H),1.71-1.66(m,2H),1.59-1.49(m,2H)；LC-MS(ESI):m/z＝674.1[M+H]+。Compound 51 (SFC analysis retention time: 1.642 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.48(s,1H),8.00(d,2H),7.81(d,2H),7.49(d,2H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3.86(m,1H) ,2.79-2.72(m,2H),2.49-2.37(m,1H),2.13(s,3H),1.84-1.78(m,2H),1.71-1.66(m,2H),1.59-1.49(m,2H); LC-MS(ESI):m/z＝674.1[M+H] + .

实施例52和实施例53
Example 52 and Example 53

第一步：将化合物52A(1.00g,7.19mmol)溶于二氯甲烷(20mL)中，加入三乙胺(1.86g,14.38mmol)，反应液置换氮气保护后，冰浴下缓慢滴加乙酰氯(680mg,8.64mmol)，完成加料后反应液在室温下搅拌反应2小时。加水(10mL)淬灭反应，以二氯甲烷(15mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物52B(700mg,收率：53.76％)。Step 1: Compound 52A (1.00 g, 7.19 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.86 g, 14.38 mmol) was added, and the reaction solution was replaced with nitrogen protection, and acetyl chloride (680 mg, 8.64 mmol) was slowly added dropwise under ice bath, and the reaction solution was stirred at room temperature for 2 hours after the addition was completed. Water (10 mL) was added to quench the reaction, and dichloromethane (15 mL) was used for extraction three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 52B (700 mg, yield: 53.76%).

1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.98(s,1H),8.90(s,1H),7.68(br s,1H),2.29(s,3H)；LC-MS(ESI):m/z＝182.1[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ9.16 (s, 1H), 8.98 (s, 1H), 8.90 (s, 1H), 7.68 (br s, 1H), 2.29 (s, 3H); LC-MS (ESI): m/z=182.1[M+H] + .

第二步：将化合物52B(700mg，3.86mmol)溶于甲醇(20mL)，加入钯碳(690mg,0.58mmol,10％wt)，反应液置换氢气后，在室温下搅拌16小时。将反应液过滤，滤液减压浓缩后得到化合物52C(400mg粗品)，直接用于下一步反应。Step 2: Compound 52B (700 mg, 3.86 mmol) was dissolved in methanol (20 mL), palladium carbon (690 mg, 0.58 mmol, 10% wt) was added, the reaction solution was replaced with hydrogen, and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 52C (400 mg crude product), which was directly used in the next step reaction.

1H NMR(400MHz,CDCl3)δ7.83-7.82(m,1H),7.78(s,1H),7.75-7.74(m,1H),7.14(br s,1H),3.74(br s,1H),2.19(s,3H)；LC-MS(ESI):m/z＝152.2[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ7.83-7.82(m,1H),7.78(s,1H),7.75-7.74(m,1H),7.14(br s,1H),3.74(br s, 1H), 2.19 (s, 3H); LC-MS (ESI): m/z=152.2[M+H] + .

第三步：将化合物1D(200mg，0.38mmol)溶于四氢呋喃(25mL)，分别加入化合物52C(70mg,0.46mmol)和DIPEA(100mg,0.76mmol)，反应液在室温下搅拌16小时。加水(40mL)淬灭反应，以乙酸乙酯(40mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物52D(140mg,收率：57.47％)。LC-MS(ESI):m/z＝641.2[M+H]+。Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in tetrahydrofuran (25 mL), and compound 52C (70 mg, 0.46 mmol) and DIPEA (100 mg, 0.76 mmol) were added respectively. The reaction solution was stirred at room temperature for 16 hours. Water (40 mL) was added to quench the reaction, and ethyl acetate (40 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 52D (140 mg, yield: 57.47%). LC-MS (ESI): m/z=641.2[M+H] + .

第四步：化合物52D经手性SFC拆分后得到化合物52(SFC分析保留时间：0.848min，24.3mg)和化合物53(SFC分析保留时间：1.133min，24.0mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHEIK Column；流动相:A:CO2,B:0.1％NH3.H2O in异丙醇；梯度:45％B梯度；洗脱流速:100mL/min；柱温:25℃；波长:220nm；循环时间:5.0min；样品制备:样品浓度5mg/mL，乙腈二氯甲烷混合溶液进样:每次3.0mL。Step 4: Compound 52D was subjected to chiral SFC separation to obtain compound 52 (SFC analysis retention time: 0.848 min, 24.3 mg) and compound 53 (SFC analysis retention time: 1.133 min, 24.0 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHEIK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 45% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

化合物52(SFC分析保留时间：0.848min)：1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8.10(m,1H),7.99(s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H),7.44-7.42(m,2H),7.37-7.34(m,2H),7.29-7.26(m,3H),5.19-5.15(m,1H),4.75-4.70(m,1H),4.19-4.15(m,1H),2.04(s,3H)；LC-MS(ESI):m/z＝641.1[M+H]+。Compound 52 (SFC analysis retention time: 0.848 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8.10(m,1H),7.99( s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H),7.44-7.4 2(m,2H),7.37-7.34(m,2H),7.29-7.26(m,3H),5.19-5.15(m,1H),4.75-4 .70(m,1H),4.19-4.15(m,1H),2.04(s,3H); LC-MS(ESI):m/z＝641.1[M+H] + .

化合物53(SFC分析保留时间：1.133min)：1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8.10(m,1H),7.99(s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H),7.45-7.42(m,2H),7.37-7.34(m,2H),7.29-7.25(m,3H),5.19-5.14(m,1H),4.75-4.69(m,1H),4.19-4.15(m,1H),2.04(s,3H)；LC-MS(ESI):m/z＝641.0[M+H]+。Compound 53 (SFC analysis retention time: 1.133 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8.10(m,1H),7.99( s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H),7.45-7.4 2(m,2H),7.37-7.34(m,2H),7.29-7.25(m,3H),5.19-5.14(m,1H),4.75-4 .69(m,1H),4.19-4.15(m,1H),2.04(s,3H); LC-MS(ESI):m/z＝641.0[M+H] + .

实施例54和实施例55
Example 54 and Example 55

第一步：将化合物54A(1.00g,7.19mmol)溶于二氯甲烷(20mL)中，加入三乙胺(1.86g,14.38mmol)，反应液置换氮气保护后冰浴下缓慢滴加乙酰氯(680mg,8.64mmol)。完成加料后反应液在室温下搅拌反应2小时。加水(10mL)淬灭反应，以二氯甲烷(15mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物54B(230mg,收率：17.66％)。LC-MS(ESI):m/z＝182.1[M+H]+。Step 1: Dissolve compound 54A (1.00 g, 7.19 mmol) in dichloromethane (20 mL), add triethylamine (1.86 g, 14.38 mmol), replace the nitrogen protection in the reaction solution, slowly add acetyl chloride (680 mg, 8.64 mmol) in an ice bath. After the addition is completed, the reaction solution is stirred at room temperature for 2 hours. Add water (10 mL) to quench the reaction, extract with dichloromethane (15 mL) three times, combine the organic phases, dry with anhydrous sodium sulfate and concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 54B (230 mg, yield: 17.66%). LC-MS (ESI): m/z = 182.1 [M + H] + .

第二步：将化合物54B(230mg，1.27mmol)溶于甲醇(10mL)，加入钯碳(130mg,0.19mmol,10％wt)，反应液置换氢气保护后，在室温下搅拌16小时。将反应液过滤，滤液减压浓缩后得到化合物54C(120mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝152.2[M+H]+。Step 2: Compound 54B (230 mg, 1.27 mmol) was dissolved in methanol (10 mL), palladium carbon (130 mg, 0.19 mmol, 10% wt) was added, and the reaction solution was replaced with hydrogen protection and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 54C (120 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 152.2 [M+H] + .

第三步：化合物54C(120mg,0.79mmol)参照实施例52第三步操作得到化合物54D(300mg,收率：82.11％)。LC-MS(ESI):m/z＝641.2[M+H]+。Step 3: Compound 54C (120 mg, 0.79 mmol) was processed according to the third step of Example 52 to obtain Compound 54D (300 mg, yield: 82.11%). LC-MS (ESI): m/z = 641.2 [M+H] + .

第四步：化合物54D经手性SFC拆分后得到化合物54(SFC分析保留时间：1.951min，36.4mg)和化合物55(SFC分析保留时间：2.193min，50.1mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral AD Column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral AD Column；流动相:A:CO2,B:0.1％NH3.H2O in异丙醇；梯度:35％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:7.5min；样品制备:样品浓度5mg/mL，乙腈二氯甲烷混合溶液进样:每次3.0mL。Step 4: Compound 54D was subjected to chiral SFC separation to obtain compound 54 (SFC analysis retention time: 1.951 min, 36.4 mg) and compound 55 (SFC analysis retention time: 2.193 min, 50.1 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral AD Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral AD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 7.5 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

化合物54(SFC分析保留时间：1.951min)：1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.89(s,1H),7.97-7.95(m,3H),7.77-7.75(m,2H),7.39-7.22(m,10H),7.10-7.01(m,1H),5.00-4.98(m,1H),4.57-4.51(m,1H),3.92-3.88(m,1H),2.08(s,3H)；LC-MS(ESI):m/z＝641.0[M+H]+。Compound 54 (SFC analysis retention time: 1.951 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 9.89 (s, 1H), 7.97-7.95 (m, 3H), 7.77-7.75 (m, 2H), 7.39-7.22 (m, 10H), 7.10-7.01 (m, 1H), 5.00-4.98 (m, 1H), 4.57-4.51 (m, 1H), 3.92-3.88 (m, 1H), 2.08 (s, 3H); LC-MS (ESI): m/z=641.0 [M+H] + .

化合物55(SFC分析保留时间：2.193min)：1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.89(s,1H),7.97-7.95(m,3H),7.77-7.75(m,2H),7.39-7.24(m,10H),7.11-6.98(m,1H),5.00-4.98(m,1H),4.57-4.51(m,1H),3.92-3.88(m,1H),2.08(s,3H)；LC-MS(ESI):m/z＝641.1[M+H]+。Compound 55 (SFC analysis retention time: 2.193 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 9.89 (s, 1H), 7.97-7.95 (m, 3H), 7.77-7.75 (m, 2H), 7.39-7.24 (m, 10H), 7.11-6.98 (m, 1H), 5.00-4.98 (m, 1H), 4.57-4.51 (m, 1H), 3.92-3.88 (m, 1H), 2.08 (s, 3H); LC-MS (ESI): m/z=641.1 [M+H] + .

实施例56和实施例57
Example 56 and Example 57

第一步：将化合物56A(2.0g,19.59mmol)和BOC-胍(3.43g,21.55mmol)溶于N,N-二甲基甲酰胺(50mL)中，加入三乙胺(3.96g,39.18mmol)和HATU(8.94g,23.51mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物56B(1.2g，收率：25％)。LC-MS(ESI):m/z＝244.1[M+H]+。Step 1: Dissolve compound 56A (2.0 g, 19.59 mmol) and BOC-guanidine (3.43 g, 21.55 mmol) in N,N-dimethylformamide (50 mL), add triethylamine (3.96 g, 39.18 mmol) and HATU (8.94 g, 23.51 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 56B (1.2 g, yield: 25%). LC-MS (ESI): m/z=244.1[M+H] + .

第二步：将化合物56B(600mg,1.70mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(4mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物56C(800mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝144.1[M+H]+。Step 2: Compound 56B (600 mg, 1.70 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 56C (800 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 144.1 [M+H] + .

第三步：化合物56C(480mg,1.87mmol)参照实施例1第三步得到化合物56D(150mg,收率：46％)。Step 3: Compound 56C (480 mg, 1.87 mmol) was prepared by referring to the third step of Example 1 to obtain compound 56D (150 mg, yield: 46%).

第四步：化合物56D经手性SFC拆分得到化合物56(SFC分析保留时间：2.305min，50mg)和化合物57(SFC分析保留时间：2.547min，45mg)。SFC分析方法:仪器:SHIMADZU LC-20AP，柱:C18 column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral Whelk Column；流动相:A:CO2,B:异丙醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:4.3min；样品制备:样品浓度10mg/mL，乙腈甲醇混合溶液进样:每次2.0mL。Step 4: Compound 56D was subjected to chiral SFC separation to obtain compound 56 (SFC analysis retention time: 2.305 min, 50 mg) and compound 57 (SFC analysis retention time: 2.547 min, 45 mg). SFC analysis method: instrument: SHIMADZU LC-20AP, column: C18 column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral Whelk Column; Mobile phase: A: CO 2 , B: Isopropanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 4.3 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.

化合物56(SFC分析保留时间：1.708min)：1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.01(d,2H),7.84(d,2H),7.55-7.49(m,2H),7.42-7.36(m,2H),7.34-7.21(m,5H),6.90(s,1H),5.08-5.00(m,1H),4.50(t,1H),3.90-3.83(m,1H),1.22-1.09(m,4H)；LC-MS(ESI):m/z＝633.2[M+H]+。Compound 56 (SFC analysis retention time: 1.708 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 1H), 8.01 (d, 2H), 7.84 (d, 2H), 7.55-7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.21 (m, 5H), 6.90 (s, 1H), 5.08-5.00 (m, 1H), 4.50 (t, 1H), 3.90-3.83 (m, 1H), 1.22-1.09 (m, 4H); LC-MS (ESI): m/z=633.2 [M+H] + .

化合物57(SFC分析保留时间：2.087min)：1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.01(d,2H),7.84(d,2H),7.55-7.49(m,2H),7.42-7.36(m,2H),7.34-7.21(m,5H),6.90(s,1H),5.08-5.00(m,1H),4.50(t,1H),3.90-3.83(m,1H),1.22-1.09(m,4H)；LC-MS(ESI):m/z＝633.2[M+H]+。Compound 57 (SFC analysis retention time: 2.087 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 1H), 8.01 (d, 2H), 7.84 (d, 2H), 7.55-7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.21 (m, 5H), 6.90 (s, 1H), 5.08-5.00 (m, 1H), 4.50 (t, 1H), 3.90-3.83 (m, 1H), 1.22-1.09 (m, 4H); LC-MS (ESI): m/z=633.2 [M+H] + .

实施例58和实施例59
Example 58 and Example 59

第一步：将化合物58A(2.0g,19.61mmol)和BOC-胍(3.74g,23.53mmol)溶于二氯甲烷(50mL)中，加入三乙胺(5.94g,58.83mmol)，然后加入HATU(8.94g,23.53mmol)，氮气保护,室温搅拌2h。加水(50mL)淬灭反应，并用乙酸乙酯(30mL)萃取两次，收集有机相，经饱和食盐水洗涤，无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物58B(3.5g,收率：74％)。LC-MS(ESI):m/z＝244.2[M+H]+。Step 1: Dissolve compound 58A (2.0 g, 19.61 mmol) and BOC-guanidine (3.74 g, 23.53 mmol) in dichloromethane (50 mL), add triethylamine (5.94 g, 58.83 mmol), then add HATU (8.94 g, 23.53 mmol), protect with nitrogen, and stir at room temperature for 2 h. Add water (50 mL) to quench the reaction, and extract twice with ethyl acetate (30 mL), collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain compound 58B (3.5 g, yield: 74%). LC-MS (ESI): m/z=244.2[M+H] + .

第二步：将化合物58B(3.5g,14.41mmol)溶于二氯甲烷(35mL)中，加入三氟乙酸(10mL)，在室温搅拌16h。将反应液浓缩得化合物58C(6.4g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝144.1[M+H]+。Step 2: Dissolve compound 58B (3.5 g, 14.41 mmol) in dichloromethane (35 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 16 h. Concentrate the reaction solution to obtain compound 58C (6.4 g crude product), which is directly used in the next step. LC-MS (ESI): m/z = 144.1 [M+H] + .

第三步：化合物58C(500mg,1.77mmol)参照实施例第三步操作得到化合物58D(200mg)。Step 3: Compound 58C (500 mg, 1.77 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 58D (200 mg).

第四步：将化合物58D进一步经手性SFC拆分得到化合物58(SFC分析保留时间：0.944min，73.7mg)和化合物59(SFC分析保留时间：1.781min，78.6mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral IK column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法：仪器:Waters 150 Prep-SFC，柱:Chiral IK column；流动相:A:CO2,B:异丙醇；梯度:50％B梯度洗脱流速:100mL/min，柱温:室温波长:220nm循环时间:7min样品制备:样品浓度5mg/mL，乙醇溶液进样:每次3.0mL。Step 4: Compound 58D was further separated by chiral SFC to obtain compound 58 (SFC analysis retention time: 0.944 min, 73.7 mg) and compound 59 (SFC analysis retention time: 1.781 min, 78.6 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, column: Chiral IK column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, column: Chiral IK column; mobile phase: A: CO 2 , B: isopropanol; gradient: 50% B gradient elution flow rate: 100 mL/min, column temperature: room temperature wavelength: 220 nm cycle time: 7 min sample preparation: sample concentration 5 mg/mL, ethanol solution injection: 3.0 mL each time.

化合物58(SFC分析保留时间：0.944min):1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.00(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.35-7.20(m,5H),5.05-5.01(m,1H),4.69-4.65(m,2H),4.62-4.56(m,2H),4.52-4.46(m,1H),4.05-3.99(m,1H),3.89-3.84(m,1H)；LC-MS(ESI):m/z＝633.1[M+H]+。Compound 58 (SFC analysis retention time: 0.944 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.00 (d, 2H), 7.82 (d, 2H), 7.51 (d, 2H), 7.39 (d, 2H), 7.35-7.20 (m, 5H), 5.05-5.01 (m, 1H), 4.69-4.65 (m, 2H), 4.62-4.56 (m, 2H), 4.52-4.46 (m, 1H), 4.05-3.99 (m, 1H), 3.89-3.84 (m, 1H); LC-MS (ESI): m/z=633.1 [M+H] + .

化合物59(SFC分析保留时间：1.781min):1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.00(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.35-7.20(m,5H),5.05-5.01(m,1H),4.69-4.65(m,2H),4.62-4.56(m,2H),4.52-4.46(m,1H),4.05-3.99(m,1H),3.89-3.84(m,1H)；LC-MS(ESI):m/z＝633.1[M+H]+。Compound 59 (SFC analysis retention time: 1.781 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.00 (d, 2H), 7.82 (d, 2H), 7.51 (d, 2H), 7.39 (d, 2H), 7.35-7.20 (m, 5H), 5.05-5.01 (m, 1H), 4.69-4.65 (m, 2H), 4.62-4.56 (m, 2H), 4.52-4.46 (m, 1H), 4.05-3.99 (m, 1H), 3.89-3.84 (m, 1H); LC-MS (ESI): m/z=633.1 [M+H] + .

实施例60、实施例61、实施例62和实施例63
Example 60, Example 61, Example 62 and Example 63

第一步：将化合物60A(500mg,3.87mmol)和BOC-胍(575mg,4.64mmol)溶于四氢呋喃(10mL)中，加入三乙胺(1.5g,19.35mmol)，然后加入1-正丙基磷酸酐(1.45g,5.81mmol)，氮气保护，室温搅拌2h。加水(50mL)淬灭反应，并用乙酸乙酯(30mL)萃取两次，收集有机相，经饱和食盐水洗涤，无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物60B(800mg,收率：76％)。LC-MS(ESI):m/z＝271.2[M+H]+。Step 1: Dissolve compound 60A (500 mg, 3.87 mmol) and BOC-guanidine (575 mg, 4.64 mmol) in tetrahydrofuran (10 mL), add triethylamine (1.5 g, 19.35 mmol), then add 1-n-propylphosphoric anhydride (1.45 g, 5.81 mmol), protect with nitrogen, and stir at room temperature for 2 h. Add water (50 mL) to quench the reaction, and extract twice with ethyl acetate (30 mL), collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain compound 60B (800 mg, yield: 76%). LC-MS (ESI): m/z=271.2[M+H] + .

第二步：将化合物60B(800mg,2.96mmol)溶于二氯甲烷(35mL)中，加入三氟乙酸(10mL)，在室温搅拌16h。将反应液浓缩得化合物60C(1g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝171.2[M+H]+。Step 2: Dissolve compound 60B (800 mg, 2.96 mmol) in dichloromethane (35 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 16 h. Concentrate the reaction solution to obtain compound 60C (1 g crude product), which is directly used in the next step. LC-MS (ESI): m/z = 171.2 [M+H] + .

第三步：化合物60C(1g)参照实施例1第三步操作得到化合物60D(1g,收率：80％)。LC-MS(ESI):m/z＝660.1[M+H]+。Step 3: Compound 60C (1 g) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 60D (1 g, yield: 80%). LC-MS (ESI): m/z = 660.1 [M+H] + .

第四步：将化合物60D进一步经手性SFC拆分得到化合物60(SFC分析保留时间：0.795min，41.6mg)、化合物61(SFC分析保留时间：0.826min，27.9mg)、化合物62(SFC分析保留时间：1.265min，64.8mg)和化合物63(SFC分析保留时间：1.312min，68.3mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral OX column；流动相:A:CO2,B:0.05％DEA in m乙醇和乙腈；梯度:40％B；流速:3mL/min柱温:35℃波长:220nm.Step 4: Compound 60D was further separated by chiral SFC to obtain compound 60 (SFC analysis retention time: 0.795 min, 41.6 mg), compound 61 (SFC analysis retention time: 0.826 min, 27.9 mg), compound 62 (SFC analysis retention time: 1.265 min, 64.8 mg) and compound 63 (SFC analysis retention time: 1.312 min, 68.3 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral OX column; mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol and acetonitrile; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm.

SFC拆分方法：SFC split method:

第一次拆分:仪器:Waters 150 Prep-SFC；柱:Chiral OX column；流动相:A for CO2；B for 0.1％NH3·H2O in甲醇和乙腈；梯度:B for 50％；洗脱流速:100mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:5.0min；样品制备:化合物浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射5.0毫升。分离得到组分A和组分B。First separation: Instrument: Waters 150 Prep-SFC; Column: Chiral OX column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in methanol and acetonitrile; Gradient: B for 50%; Elution flow rate: 100mL/min; Back pressure: 100bar; Column temperature: Room temperature; Wavelength: 220nm; Cycle time: 5.0min; Sample preparation: Compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0ml each time. Component A and component B are separated.

将上述组分A再进行SFC拆分，纯化方法:仪器:SHIMADZU LC-20AP；柱:Chiral IA column；流动相:A for n-Hexane；B for 0.1％NH3·H2O in异丙醇和乙腈；梯度:B for 17％；洗脱流速:80mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:14min；样品制备:化合物浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射5.0毫升。分离得到化合物60和化合物61。The above component A was further subjected to SFC separation and purification method: instrument: SHIMADZU LC-20AP; column: Chiral IA column; mobile phase: A for n-Hexane; B for 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; gradient: B for 17%; elution flow rate: 80mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 14min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 5.0 ml each time. Compound 60 and compound 61 were separated.

将上述组分B再进行SFC拆分，纯化方法:仪器:Waters 150 Prep-SFC；柱:Chiral IC column；流动相:A for CO2；B for 0.1％NH3·H2O in异丙醇和乙腈；梯度:B for 40％；洗脱流速:120mL/min；背压:100bar；柱温:室温；波长:220nm；循环时间:7.5min；样品制备:化合物浓度为10mg/mL，溶于乙腈和甲醇中。注射：每次注射4.0毫升。分离得到化合物62和化合物63。The above component B was further subjected to SFC separation and purification method: instrument: Waters 150 Prep-SFC; column: Chiral IC column; mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; gradient: B for 40%; elution flow rate: 120mL/min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm; cycle time: 7.5min; sample preparation: compound concentration is 10mg/mL, dissolved in acetonitrile and methanol. Injection: 4.0 ml each time. Compound 62 and compound 63 were separated.

化合物60(SFC分析保留时间：0.795min)：1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H)；LC-MS(ESI):m/z＝660.1[M+H]+。Compound 60 (SFC analysis retention time: 0.795 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.01-7.99 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.06-5.02 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.85 (m, 1H), 3.10-3.06 (m, 1H), 2.70-2.66 (m 1H), 2.48-2.36 (m, 3H), 2.20 (s, 3H), 1.97-1.86 (m, 2H); LC-MS (ESI): m/z=660.1[M+H] + .

化合物61(SFC分析保留时间：0.826min)：1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H)；LC-MS(ESI):m/z＝660.1[M+H]+。Compound 61 (SFC analysis retention time: 0.826 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.01-7.99 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.06-5.02 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.85 (m, 1H), 3.10-3.06 (m, 1H), 2.70-2.66 (m 1H), 2.48-2.36 (m, 3H), 2.20 (s, 3H), 1.97-1.86 (m, 2H); LC-MS (ESI): m/z=660.1[M+H] + .

化合物62(SFC分析保留时间：1.265min)：1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H)；LC-MS(ESI):m/z＝660.1[M+H]+。Compound 62 (SFC analysis retention time: 1.265 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.01-7.99 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.06-5.02 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.85 (m, 1H), 3.10-3.06 (m, 1H), 2.70-2.66 (m 1H), 2.48-2.36 (m, 3H), 2.20 (s, 3H), 1.97-1.86 (m, 2H); LC-MS (ESI): m/z=660.1[M+H] + .

化合物63(SFC分析保留时间：1.312min)：1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H)；LC-MS(ESI):m/z＝660.1[M+H]+。Compound 63 (SFC analysis retention time: 1.312 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.01-7.99 (m, 2H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.22 (m, 5H), 5.06-5.02 (m, 1H), 4.52-4.46 (m, 1H), 3.89-3.85 (m, 1H), 3.10-3.06 (m, 1H), 2.70-2.66 (m 1H), 2.48-2.36 (m, 3H), 2.20 (s, 3H), 1.97-1.86 (m, 2H); LC-MS (ESI): m/z=660.1[M+H] + .

实施例64和实施例65
Example 64 and Example 65

第一步：化合物64A(1.4g，6.19mmol)溶于二氯甲烷(20mL)，加入三乙胺(1.89g，18.77mmol),氮气置换三次，冰浴条件下缓慢滴加氯甲酸甲酯(664mg,7.06mmol)，加料完毕后缓慢恢复室温搅拌1h。TLC监测反应完全后，加入水(10mL)搅拌5min，以稀盐酸溶液(1mol/L)洗涤有机相两次，再二以氯甲烷(100mL)萃取水相三次，合并有机相，以无水硫酸钠干燥，减压浓缩得到化合物64B(1.63g，收率：93％)。Step 1: Compound 64A (1.4 g, 6.19 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.89 g, 18.77 mmol) was added, nitrogen was replaced three times, methyl chloroformate (664 mg, 7.06 mmol) was slowly added dropwise under ice bath conditions, and the mixture was slowly returned to room temperature and stirred for 1 h. After TLC monitoring, water (10 mL) was added and stirred for 5 min, the organic phase was washed twice with dilute hydrochloric acid solution (1 mol/L), and the aqueous phase was extracted three times with chloromethane (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 64B (1.63 g, yield: 93%).

1HNMR(400MHz,CDCl3)δ9.01(s,1H),8.60(s,1H),8.37-8.35(m,1H),8.25-8.23(m,1H),3.72(s,3H)。 1 HNMR (400MHz, CDCl 3 ) δ9.01 (s, 1H), 8.60 (s, 1H), 8.37-8.35 (m, 1H), 8.25-8.23 (m, 1H), 3.72 (s, 3H).

第二步：化合物64B(1.63g，5.74mmol)和化合物22D(1.47g,5.74mmol)溶于甲苯(20mL),加料完毕后体系氮气保护，加热至110℃搅拌4h。冷却后减压浓缩,所得残余物经硅胶柱层析纯化得化合物64D(2.24g，收率：77％)。LCMS(ESI)：m/z＝509.1[M+H]+。Step 2: Compound 64B (1.63 g, 5.74 mmol) and compound 22D (1.47 g, 5.74 mmol) were dissolved in toluene (20 mL). After the addition was completed, the system was protected by nitrogen and heated to 110°C and stirred for 4 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 64D (2.24 g, yield: 77%). LCMS (ESI): m/z = 509.1 [M+H] + .

第三步：向100mL的单口瓶中加入甲苯(20mL)，随后加入化合物64D(2.24g，4.41mmol)和N,N-二异丙基乙胺(1.42g，11.03mmol)，然后缓慢滴加入三氯氧磷(1.01g，6.62mmol)，加料完毕后体系氮气保护，加热至100℃搅拌1h。TLC监测反应完全后，反应液减压浓缩得到化合物64E(3g粗品)，直接用于下一步反应。LCMS(ESI)：m/z＝527.2[M+H]+。Step 3: Add toluene (20 mL) to a 100 mL single-mouth bottle, then add compound 64D (2.24 g, 4.41 mmol) and N,N-diisopropylethylamine (1.42 g, 11.03 mmol), then slowly dropwise add phosphorus oxychloride (1.01 g, 6.62 mmol), after the addition is complete, the system is protected by nitrogen, heated to 100 ° C and stirred for 1 h. After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure to obtain compound 64E (3 g crude product), which is directly used in the next step. LCMS (ESI): m/z = 527.2 [M+H] + .

第四步:将化合物64E(350mg,0.66mmol)溶于二氯甲烷(30mL)中，分别加入化合物1C(320mg,1.12mmol)和三乙胺(200mg,1.98mmol)。加料完成后反应在室温下搅拌过夜，加水(40mL)淬灭反应，并用二氯甲烷(50mL)萃取三次，合并有机相，经无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物64F(180mg)。Step 4: Compound 64E (350 mg, 0.66 mmol) was dissolved in dichloromethane (30 mL), and compound 1C (320 mg, 1.12 mmol) and triethylamine (200 mg, 1.98 mmol) were added respectively. After the addition was completed, the reaction was stirred at room temperature overnight, water (40 mL) was added to quench the reaction, and it was extracted three times with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 64F (180 mg).

第五步：化合物64F经手性SFC拆分得到化合物64(SFC分析保留时间：5.85min，50mg)和化合物65(SFC分析保留时间：7.05min，40mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral Cellulose-2column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法：仪器:SFC Prep 150AP；色谱柱:AD(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：a.流动相A,B组成：流动相A：CO2，流动相B：异丙醇；b.等度洗脱，流动相B含量40％；c.流量40mL/min。Step 5: Compound 64F was subjected to chiral SFC separation to obtain compound 64 (SFC analysis retention time: 5.85 min, 50 mg) and compound 65 (SFC analysis retention time: 7.05 min, 40 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral Cellulose-2 column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: SFC Prep 150AP; chromatographic column: AD (19 mm×250 mm); the sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 40%; c. Flow rate 40 mL/min.

化合物64(SFC分析保留时间：5.85min):1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.01(s,1H),8.38(d,1H),8.14(d,1H),7.60-7.46(m,2H),7.44-7.36(m,2H),7.36-7.20(m,5H),5.13-4.98(m,1H),4.54(t,1H),4.02-3.88(m,1H),1.97-1.86(m,1H),0.96-0.76(m,4H)；Compound 64 (SFC analysis retention time: 5.85 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.70(s,1H),9.01(s,1H),8.38(d,1H),8.14(d,1H),7.60-7.46(m,2H),7.44-7.36(m,2H),7.36-7.20(m,5H),5.13-4.98(m,1H),4.54(t,1H),4.02-3.88(m,1H),1.97-1.86(m,1H),0.96-0.76(m,4H);

LC-MS(ESI):m/z＝618.2[M+H]+。LC-MS (ESI): m/z=618.2[M+H] + .

化合物65(SFC分析保留时间：7.05min):1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.01(s,1H),8.38(d,1H),8.14(d,1H),7.60-7.46(m,2H),7.44-7.36(m,2H),7.36-7.20(m,5H),5.13-4.98(m,1H),4.54(t,1H),4.02-3.88(m,1H),1.97-1.86(m,1H),0.96-0.76(m,4H)；Compound 65 (SFC analysis retention time: 7.05 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.70 (s, 1H), 9.01 (s, 1H), 8.38 (d, 1H), 8.14 (d, 1H), 7.60-7.46 (m, 2H), 7.44-7.36 (m, 2H), 7.36-7.20 (m, 5H), 5.13-4.98 (m, 1H), 4.54 (t, 1H), 4.02-3.88 (m, 1H), 1.97-1.86 (m, 1H), 0.96-0.76 (m, 4H);

LC-MS(ESI):m/z＝618.2[M+H]+。LC-MS (ESI): m/z=618.2[M+H] + .

实施例66和实施例67
Example 66 and Example 67

第一步：将化合物1D(900mg，1.71mmol)溶于DMF(20mL)，分别加入化合物4,6-二氨基嘧啶(380mg,3.42mmol)和三乙胺(520mg,5.13mmol)，在室温下搅拌过夜。加水(40mL)淬灭反应，以乙酸乙酯(50mL)萃取二次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物66A(1g,收率：97％)。LC-MS(ESI):m/z＝600.1[M+H]+。Step 1: Compound 1D (900 mg, 1.71 mmol) was dissolved in DMF (20 mL), and compound 4,6-diaminopyrimidine (380 mg, 3.42 mmol) and triethylamine (520 mg, 5.13 mmol) were added respectively, and stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 66A (1 g, yield: 97%). LC-MS (ESI): m/z=600.1[M+H] + .

第二步：将化合物66A(1.0g,1.67mmol)和三乙胺(0.42g,4.17mmol)加入干燥的二氯甲烷(30mL)中，冰浴下缓慢加入乙酰氯(0.20g,2.50mmol)，加料完毕，室温搅拌2小时。加水(30mL)，用二氯甲烷(30mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物66B(130mg，收率：12％)。LC-MS(ESI):m/z＝642.2[M+H]+。Step 2: Add compound 66A (1.0 g, 1.67 mmol) and triethylamine (0.42 g, 4.17 mmol) to dry dichloromethane (30 mL), slowly add acetyl chloride (0.20 g, 2.50 mmol) under ice bath, stir at room temperature for 2 hours after addition. Add water (30 mL), extract twice with dichloromethane (30 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, the residue is purified by silica gel column chromatography to obtain compound 66B (130 mg, yield: 12%). LC-MS (ESI): m/z=642.2[M+H] + .

第三步：化合物66B经手性SFC拆分得到化合物66(SFC制备前出峰，30mg)和化合物67(SFC制备后出峰，35mg)。SFC制备方法:仪器:SFC Prep 150AP；色谱柱:IK(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：a.流动相A,B组成：流动相A：CO2；流动相B：异丙醇；b.等度洗脱，流动相B含量50％；c.流量38mL/min。Step 3: Compound 66B was separated by chiral SFC to obtain compound 66 (pre-SFC preparation peak, 30 mg) and compound 67 (post-SFC preparation peak, 35 mg). SFC preparation method: Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 50%; c. Flow rate 38 mL/min.

化合物66(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.38(s,1H),8.33-8.19(m,1H),7.96(d,2H),7.76(d,2H),7.46-7.29(m,9H),7.27-7.21(m,1H),5.08-4.97(m,1H),4.63-4.46(m,1H),3.94-3.82(m,1H),2.11(s,3H)；LC-MS(ESI):m/z＝642.2[M+H]+。Compound 66 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 10.38 (s, 1H), 8.33-8.19 (m, 1H), 7.96 (d, 2H), 7.76 (d, 2H), 7.46-7.29 (m, 9H), 7.27-7.21 (m, 1H), 5.08-4.97 (m, 1H), 4.63-4.46 (m, 1H), 3.94-3.82 (m, 1H), 2.11 (s, 3H); LC-MS (ESI): m/z=642.2 [M+H] + .

化合物67(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.38(s,1H),8.33-8.19(m,1H),7.96(d,2H),7.76(d,2H),7.46-7.29(m,9H),7.27-7.21(m,1H),5.08-4.97(m,1H),4.63-4.46(m,1H),3.94-3.82(m,1H),2.11(s,3H)；LC-MS(ESI):m/z＝642.2[M+H]+。Compound 67 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 10.38 (s, 1H), 8.33-8.19 (m, 1H), 7.96 (d, 2H), 7.76 (d, 2H), 7.46-7.29 (m, 9H), 7.27-7.21 (m, 1H), 5.08-4.97 (m, 1H), 4.63-4.46 (m, 1H), 3.94-3.82 (m, 1H), 2.11 (s, 3H); LC-MS (ESI): m/z=642.2 [M+H] + .

实施例68和实施例69
Example 68 and Example 69

第一步：将化合物68A(500mg,4.23mmol)和BOC-胍(1.01g,6.35mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入DIPEA(1.64g,12.69mmol)和HATU(2.09g,5.55mmol)，加料完毕，室温搅拌3小时。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物68B(800mg)和化合物68C(200mg)。LC-MS(ESI):m/z＝260.1[M+H]+。Step 1: Dissolve compound 68A (500 mg, 4.23 mmol) and BOC-guanidine (1.01 g, 6.35 mmol) in N,N-dimethylformamide (20 mL), add DIPEA (1.64 g, 12.69 mmol) and HATU (2.09 g, 5.55 mmol), stir at room temperature for 3 hours after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 68B (800 mg) and compound 68C (200 mg). LC-MS (ESI): m/z=260.1[M+H] + .

第二步：将化合物68B(800mg,3.09mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(3mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物68D(800mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝160.1[M+H]+。Step 2: Compound 68B (800 mg, 3.09 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 68D (800 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 160.1 [M+H] + .

第三步：化合物68D(150mg,0.56mmol)参照实施例40第三步得到化合物68E(120mg,收率：65％)。Step 3: Compound 68D (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 68E (120 mg, yield: 65%).

第四步：化合物68E经手性SFC拆分得到化合物68(SFC制备前出峰，35mg)和化合物69(SFC制备后出峰，40mg)。SFC制备方法:仪器:SFC Prep 150AP；色谱柱:IK(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：a.流动相A,B组成：流动相A：CO2，流动相B：异丙醇；b.等度洗脱，流动相B含量50％；c.流量38mL/min。Step 4: Compound 68E was separated by chiral SFC to obtain compound 68 (pre-SFC preparation peak, 35 mg) and compound 69 (post-SFC preparation peak, 40 mg). SFC preparation method: Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content 50%; c. Flow rate 38 mL/min.

化合物68(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.00(d,2H),7.81(d,2H),7.53-7.46(m,2H),7.42-7.36(m,2H),7.35-7.21(m,5H),5.25-5.17(m,0.5H),5.11-4.98(m,1.5H),4.54-4.42(m,1H),3.92-3.83(m,1H),3.38-3.31(m,1H),2.48-2.30(m,4H).Compound 68 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.00 (d, 2H), 7.81 (d, 2H), 7.53-7.46 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.21 (m, 5H), 5.25-5.17 (m, 0.5H), 5.11-4.98 (m, 1.5H), 4.54-4.42 (m, 1H), 3.92-3.83 (m, 1H), 3.38-3.31 (m, 1H), 2.48-2.30 (m, 4H).

LC-MS(ESI):m/z＝649.2[M+H]+。LC-MS (ESI): m/z=649.2[M+H] + .

化合物69(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.00(d,2H),7.81(d,2H),7.53-7.46(m,2H),7.42-7.36(m,2H),7.35-7.21(m,5H),5.25-5.17(m,0.5H),5.11-4.98(m,1.5H),4.54-4.42(m,1H),3.92-3.83(m,1H),3.38-3.31(m,1H),2.48-2.30(m,4H).Compound 69 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.00 (d, 2H), 7.81 (d, 2H), 7.53-7.46 (m, 2H), 7.42-7.36 (m, 2H), 7.35-7.21 (m, 5H), 5.25-5.17 (m, 0.5H), 5.11-4.98 (m, 1.5H), 4.54-4.42 (m, 1H), 3.92-3.83 (m, 1H), 3.38-3.31 (m, 1H), 2.48-2.30 (m, 4H).

LC-MS(ESI):m/z＝649.2[M+H]+。LC-MS (ESI): m/z=649.2[M+H] + .

实施例70和实施例71
Example 70 and Example 71

第一步：将化合物70A(1.00g,9.99mmol)和叔丁氧羰基胍(1.67g,10.49mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(3.03g,29.96mmol)和HATU(4.56g,11.99mmol)，加料完毕后反应液在室温下搅拌16h。加水(100mL)稀释并用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物70B(1.10g，收率：45.64％)。LC-MS(ESI):m/z＝186.1[M-56+H]+。Step 1: Compound 70A (1.00 g, 9.99 mmol) and tert-butyloxycarbonylguanidine (1.67 g, 10.49 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (3.03 g, 29.96 mmol) and HATU (4.56 g, 11.99 mmol) were added. After the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (100 mL) was added to dilute and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 70B (1.10 g, yield: 45.64%). LC-MS (ESI): m/z=186.1[M-56+H] + .

第二步：将化合物70B(500mg,2.07mmol)溶于二氯甲烷(24mL)中，加入三氟乙酸(6mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物70C(420mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝142.2[M+H]+。Step 2: Dissolve compound 70B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 70C (420 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 142.2 [M+H] + .

第三步：化合物70C(420mg粗品,2.07mmol)参照实施例1第三步操作得到化合物70D(550mg,收率：91.75％)。LC-MS(ESI):m/z＝631.2[M+H]+。Step 3: Compound 70C (420 mg crude product, 2.07 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 70D (550 mg, yield: 91.75%). LC-MS (ESI): m/z = 631.2 [M+H] + .

第四步：化合物70D经手性SFC拆分得到化合物70(SFC分析保留时间：2.217min，203.8mg)和化合物71(SFC分析保留时间：2.485min，153.5mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHELK Column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHELK Column；流动相:A:CO2,B:0.1％NH3.H2O in异丙醇；梯度:35％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:4.5min；样品制备:样品浓度10mg/mL，乙腈二氯甲烷混合溶液进样:每次5.0mL。Step 4: Compound 70D was separated by chiral SFC to obtain compound 70 (SFC analysis retention time: 2.217 min, 203.8 mg) and compound 71 (SFC analysis retention time: 2.485 min, 153.5 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 4.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

化合物70(SFC分析保留时间：2.217min)：1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.22-2.07(m,4H),1.97-1.86(m,1H),1.83-1.75(m,1H)；LC-MS(ESI):m/z＝643.1[M+H]+。Compound 70 (SFC analysis retention time: 2.217 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m,1H),4.52- 4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.22-2.07(m,4H),1.97-1.86(m,1H),1.83-1.75(m,1H); LC-MS(ESI):m/z＝643.1[M+H] + .

化合物71(SFC分析保留时间：2.485min)：1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.19-2.07(m,4H),1.97-1.88(m,1H),1.83-1.75(m,1H)；LC-MS(ESI):m/z＝643.0[M+H]+。Compound 71 (SFC analysis retention time: 2.485 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m,1H),4.52- 4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.19-2.07(m,4H),1.97-1.88(m,1H),1.83-1.75(m,1H); LC-MS(ESI):m/z＝643.0[M+H] + .

实施例72和实施例73
Example 72 and Example 73

第一步：将化合物72A(1.00g,7.93mmol)和叔丁氧羰基胍(1.64g,10.31mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(2.41g,23.79mmol)和HATU(3.32g,8.72mmol)，加料完毕后反应液在室温下搅拌16h。加水(100mL)稀释并用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物72B(1.00g，收率：47.18％)。LC-MS(ESI):m/z＝268.2[M+H]+。Step 1: Compound 72A (1.00 g, 7.93 mmol) and tert-butyloxycarbonylguanidine (1.64 g, 10.31 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (2.41 g, 23.79 mmol) and HATU (3.32 g, 8.72 mmol) were added. After the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (100 mL) was added to dilute and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 72B (1.00 g, yield: 47.18%). LC-MS (ESI): m/z=268.2[M+H] + .

第二步：将化合物72B(500mg,1.87mmol)溶于二氯甲烷(24mL)中，加入三氟乙酸(6mL)，在室温下搅拌反应5小时。将反应液减压浓缩得化合物72C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝168.1[M+H]+。Step 2: Dissolve compound 72B (500 mg, 1.87 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 72C (500 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 168.1 [M+H] + .

第三步：化合物72C(500mg粗品,1.87mmol)参照实施例1第三步操作得到化合物72D(600mg,收率：96.13％)。LC-MS(ESI):m/z＝657.2[M+H]+。Step 3: Compound 72C (500 mg crude product, 1.87 mmol) was processed according to the third step of Example 1 to obtain compound 72D (600 mg, yield: 96.13%). LC-MS (ESI): m/z = 657.2 [M+H] + .

第四步：化合物72D经手性SFC拆分得到化合物72(SFC分析保留时间：1.884min，265.0mg)和化合物73(SFC分析保留时间：2.165min，262.2mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral OD Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral OD Column；流动相:A:CO2,B:0.1％NH3.H2O in乙醇；梯度:35％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:4.3min；样品制备:样品浓度10mg/mL，乙腈二氯甲烷混合溶液进样:每次5.0mL。Step 4: Compound 72D was separated by chiral SFC to obtain compound 72 (SFC analysis retention time: 1.884 min, 265.0 mg) and compound 73 (SFC analysis retention time: 2.165 min, 262.2 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in ethanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 4.3 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

化合物72(SFC分析保留时间：1.884min)：1H NMR(400MHz,DMSO-d6)δ9.26(br s,1H),8.03-7.92(m,5H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.31-7.22(m,5H),6.89-6.88(m,1H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.95(s,3H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝657.0[M+H]+。Compound 72 (SFC analysis retention time: 1.884 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (br s, 1H), 8.03-7.92 (m, 5H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.37-7.35 (m, 2H), 7.31-7.22 (m, 5H), 6.89-6.88 (m, 1H), 5.06-5.02 (m, 1H), 4.54-4.49 (m, 1H), 3.95 (s, 3H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=657.0 [M+H] + .

化合物73(SFC分析保留时间：2.165min)：1H NMR(400MHz,DMSO-d6)δ9.26(br s,1H),8.06-7.92(m,5H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.31-7.24(m,5H),6.89-6.88(m,1H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.95(s,3H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝657.1[M+H]+。Compound 73 (SFC analysis retention time: 2.165 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (br s, 1H), 8.06-7.92 (m, 5H), 7.83-7.81 (m, 2H), 7.52-7.50 (m, 2H), 7.37-7.35 (m, 2H), 7.31-7.24 (m, 5H), 6.89-6.88 (m, 1H), 5.06-5.02 (m, 1H), 4.54-4.49 (m, 1H), 3.95 (s, 3H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=657.1 [M+H] + .

实施例74和实施例75
Example 74 and Example 75

第一步：将化合物68C(200mg,0.77mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(3mL)，在室温下搅拌反应1.5小时。将反应液减压浓缩得化合物74A(200mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝160.1[M+H]+。Step 1: Dissolve compound 68C (200 mg, 0.77 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 1.5 hours. Concentrate the reaction solution under reduced pressure to obtain compound 74A (200 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 160.1 [M+H] + .

第二步：化合物74A(150mg,0.56mmol)参照实施例40第三步得到化合物74B(120mg,收率：65％)。Step 2: Compound 74A (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 74B (120 mg, yield: 65%).

第三步：化合物74B经手性SFC拆分得到化合物74(SFC制备前出峰，45mg)和化合物75(SFC制备后出峰，35mg)。SFC制备方法:仪器:SFC Prep 150AP；色谱柱:IG(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：a.流动相A,B组成：流动相A：CO2，流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量30％；c.流量40mL/min。Step 3: Compound 74B was separated by chiral SFC to obtain compound 74 (pre-SFC preparation peak, 45 mg) and compound 75 (post-SFC preparation peak, 35 mg). SFC preparation method: Instrument: SFC Prep 150AP; Chromatographic column: IG (19 mm × 250 mm); The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 30%; c. Flow rate 40 mL/min.

化合物74(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.00(d,2H),7.80(d,2H),7.53-7.46(m,2H),7.41-7.36(m,2H),7.35-7.21(m,5H),5.12-4.99(m,1.5H),4.98-4.90(m,0.5H),4.55-4.43(m,1H),3.91-3.82(m,1H),2.86-2.74(m,1H),2.59-2.51(m,2H),2.33-2.17(m,2H)；LC-MS(ESI):m/z＝649.2[M+H]+。Compound 74 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.00 (d, 2H), 7.80 (d, 2H), 7.53-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.35-7.21 (m, 5H), 5.12-4.99 (m, 1.5H), 4.98-4.90 (m, 0.5H), 4.55-4.43 (m, 1H), 3.91-3.82 (m, 1H), 2.86-2.74 (m, 1H), 2.59-2.51 (m, 2H), 2.33-2.17 (m, 2H); LC-MS (ESI): m/z=649.2 [M+H] + .

化合物75(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.00(d,2H),7.80(d,2H),7.53-7.46(m,2H),7.41-7.36(m,2H),7.35-7.21(m,5H),5.12-4.99(m,1.5H),4.98-4.90(m,0.5H),4.55-4.43(m,1H),3.91-3.82(m,1H),2.86-2.74(m,1H),2.59-2.51(m,2H),2.33-2.17(m,2H)；LC-MS(ESI):m/z＝649.2[M+H]+。Compound 75 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.00 (d, 2H), 7.80 (d, 2H), 7.53-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.35-7.21 (m, 5H), 5.12-4.99 (m, 1.5H), 4.98-4.90 (m, 0.5H), 4.55-4.43 (m, 1H), 3.91-3.82 (m, 1H), 2.86-2.74 (m, 1H), 2.59-2.51 (m, 2H), 2.33-2.17 (m, 2H); LC-MS (ESI): m/z=649.2 [M+H] + .

实施例76和实施例77
Example 76 and Example 77

第一步：化合物76A(1.0g，4.42mmol)溶于二氯甲烷(20mL)，加入三乙胺(1.34g，13.26mmol),氮气置换三次，冰浴条件下缓慢滴加氯甲酸异丙酯(810mg,6.63mmol)，加料完毕后缓慢恢复室温搅拌1h。TLC监测反应完全后，加入水(10mL)搅拌5min，以稀盐酸溶液(1mol/L)洗涤有机相两次，再二以氯甲烷(100mL)萃取水相三次，合并有机相，以无水硫酸钠干燥，减压浓缩得到化合物76B(1.0g，收率：72％)。Step 1: Compound 76A (1.0 g, 4.42 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.34 g, 13.26 mmol) was added, and the atmosphere was replaced with nitrogen three times. Isopropyl chloroformate (810 mg, 6.63 mmol) was slowly added dropwise under ice bath conditions. After the addition was completed, the mixture was slowly returned to room temperature and stirred for 1 h. After TLC monitoring of the reaction was complete, water (10 mL) was added and stirred for 5 min. The organic phase was washed twice with dilute hydrochloric acid solution (1 mol/L), and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 76B (1.0 g, yield: 72%).

第二步：化合物76B(0.6g，1.92mmol)和化合物22D(0.49g,1.92mmol)溶于甲苯(20mL),加料完毕后体系氮气保护，加热至110℃搅拌4h。冷却后减压浓缩,所得残余物经硅胶柱层析纯化得化合物76C(0.6g，收率：61％)。LCMS(ESI)：m/z＝509.1[M+H]+。Step 2: Compound 76B (0.6 g, 1.92 mmol) and compound 22D (0.49 g, 1.92 mmol) were dissolved in toluene (20 mL). After the addition was completed, the system was protected by nitrogen and heated to 110°C and stirred for 4 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 76C (0.6 g, yield: 61%). LCMS (ESI): m/z = 509.1 [M+H] + .

第三步：向100mL的单口瓶中加入甲苯(20mL)，随后加入化合物76C(0.6g，1.18mmol)和N,N-二异丙基乙胺(0.31g，2.36mmol)，然后缓慢滴加入三氯氧磷(0.36g，2.36mmol)，加料完毕后体系氮气保护，加热至100℃搅拌1h。TLC监测反应完全后，反应液减压浓缩，所得残余物经硅胶柱层析纯化得化合物76D(0.39g，收率：63％)。LCMS(ESI)：m/z＝527.2[M+H]+。Step 3: Add toluene (20 mL) to a 100 mL single-mouth bottle, then add compound 76C (0.6 g, 1.18 mmol) and N,N-diisopropylethylamine (0.31 g, 2.36 mmol), then slowly dropwise add phosphorus oxychloride (0.36 g, 2.36 mmol), after the addition is complete, the system is protected by nitrogen, heated to 100 ° C and stirred for 1 h. After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 76D (0.39 g, yield: 63%). LCMS (ESI): m/z = 527.2 [M+H] + .

第四步:将化合物76D(220mg,0.42mmol)溶于二氯甲烷(20mL)中，分别加入化合物1C(200mg,0.84mmol)和三乙胺(130mg,1.26mmol)。加料完成后反应在室温下搅拌过夜，将反应液浓缩，粗品经硅胶柱层析纯化得到化合物76E(150mg)。Step 4: Compound 76D (220 mg, 0.42 mmol) was dissolved in dichloromethane (20 mL), and compound 1C (200 mg, 0.84 mmol) and triethylamine (130 mg, 1.26 mmol) were added respectively. After the addition was completed, the reaction was stirred at room temperature overnight, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 76E (150 mg).

第五步：将上一步得到的化合物76E进一步经手性SFC拆分得到化合物76(SFC制备前出峰，55mg)和77(SFC制备后出峰，50mg)。SFC制备方法:1.仪器:SFC Prep 150AP；色谱柱:IK(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：a.流动相A,B组成：流动相A：CO2,流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量52％。Step 5: Compound 76E obtained in the previous step was further resolved by chiral SFC to obtain compounds 76 (SFC pre-preparation peak, 55 mg) and 77 (SFC post-preparation peak, 50 mg). SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 , Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 52%.

化合物76(SFC制备前出峰):1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35-7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H)；LC-MS(ESI):m/z＝618.1[M+H]+。Compound 76 (eluting peak before SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35-7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H); LC-MS(ESI):m/z＝618.1[M+H] + .

化合物77(SFC制备后出峰):1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35-7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H)；LC-MS(ESI):m/z＝618.1[M+H]+。Compound 77 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35-7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H); LC-MS(ESI):m/z＝618.1[M+H] + .

实施例78和实施例79
Example 78 and Example 79

第一步：将化合物78A(1.00g,6.53mmol)和叔丁氧羰基胍(1.35g,8.49mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入二异丙基乙胺(1.98g,19.59mmol)和HATU(2.98g,7.84mmol)，加料完毕后反应液在室温下搅拌16h。加水(100mL)稀释并用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物78B(1.00g，收率：52.03％)。LC-MS(ESI):m/z＝295.2[M+H]+。Step 1: Compound 78A (1.00 g, 6.53 mmol) and tert-butyloxycarbonylguanidine (1.35 g, 8.49 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (1.98 g, 19.59 mmol) and HATU (2.98 g, 7.84 mmol) were added. After the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (100 mL) was added to dilute and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 78B (1.00 g, yield: 52.03%). LC-MS (ESI): m/z=295.2[M+H] + .

第二步：将化合物78B(500mg,1.70mmol)溶于二氯甲烷(24mL)中，加入三氟乙酸(6mL)，在室温下搅拌反应4小时。将反应液减压浓缩得化合物78C(400mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝195.1[M+H]+。Step 2: Dissolve compound 78B (500 mg, 1.70 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 4 hours. Concentrate the reaction solution under reduced pressure to obtain compound 78C (400 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 195.1 [M+H] + .

第三步：化合物78C(200mg粗品,0.85mmol)参照实施例1第三步操作得到化合物78D(250mg,收率：96.18％)。LC-MS(ESI):m/z＝684.2[M+H]+。Step 3: Compound 78C (200 mg crude product, 0.85 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 78D (250 mg, yield: 96.18%). LC-MS (ESI): m/z = 684.2 [M+H] + .

第四步：化合物78D经手性SFC拆分得到化合物78(SFC分析保留时间：2.135min，62.6mg)和化合物79(SFC分析保留时间：2.366min，62.1mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral OD Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral OD Column；流动相:A:CO2,B:0.1％NH3.H2O in乙醇；梯度:35％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:3.5min；样品制备:样品浓度10mg/mL，乙腈二氯甲烷混合溶液进样:每次3.0mL。Step 4: Compound 78D was separated by chiral SFC to obtain compound 78 (SFC analysis retention time: 2.135 min, 62.6 mg) and compound 79 (SFC analysis retention time: 2.366 min, 62.1 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral OD Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in ethanol; gradient: 35% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 3.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

化合物78(SFC分析保留时间：2.135min)：1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05-8.03(m,2H),7.95(br s,2H),7.84-7.79(m,3H),7.54-7.52(m,2H),7.39-7.37(m,2H),7.30-7.24(m,5H),6.87-6.86(m,1H),6.49-6.47(m,1H),5.06-5.02(m,1H),4.53-4.47(m,1H),3.91-3.87(m,1H),3.47(s,3H)；LC-MS(ESI):m/z＝684.1[M+H]+。Compound 78 (SFC analysis retention time: 2.135 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.05-8.03 (m, 2H), 7.95 (br s, 2H), 7.84-7.79 (m, 3H), 7.54-7.52 (m, 2H), 7.39-7.37 (m, 2H), 7.30-7.24 (m, 5H), 6.87-6.86 (m, 1H), 6.49-6.47 (m, 1H), 5.06-5.02 (m, 1H), 4.53-4.47 (m, 1H), 3.91-3.87 (m, 1H), 3.47 (s, 3H); LC-MS (ESI): m/z=684.1 [M+H] + .

化合物79(SFC分析保留时间：2.366min)：1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05-8.03(m,2H),7.95(br s,2H),7.84-7.79(m,3H),7.54-7.52(m,2H),7.39-7.37(m,2H),7.32-7.22(m,5H),6.87-6.86(m,1H),6.49-6.47(m,1H),5.06-5.02(m,1H),4.53-4.47(m,1H),3.91-3.87(m,1H),3.47(s,3H)；LC-MS(ESI):m/z＝684.0[M+H]+。Compound 79 (SFC analysis retention time: 2.366 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.05-8.03 (m, 2H), 7.95 (br s, 2H), 7.84-7.79 (m, 3H), 7.54-7.52 (m, 2H), 7.39-7.37 (m, 2H), 7.32-7.22 (m, 5H), 6.87-6.86 (m, 1H), 6.49-6.47 (m, 1H), 5.06-5.02 (m, 1H), 4.53-4.47 (m, 1H), 3.91-3.87 (m, 1H), 3.47 (s, 3H); LC-MS (ESI): m/z=684.0 [M+H] + .

实施例80和实施例81
Example 80 and Example 81

第一步：将化合物80A(1.00g,9.99mmol)和叔丁氧羰基胍(2.07g,12.98mmol)溶于N,N-二甲基甲酰胺(25mL)中，加入二异丙基乙胺(3.03g,29.96mmol)和HATU(4.56g,11.99mmol)，加料完毕后反应液在室温下搅拌16h。加水(100mL)稀释并用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物80B(2.00g，收率：82.98％)。LC-MS(ESI):m/z＝186.1[M-56+H]+。Step 1: Compound 80A (1.00 g, 9.99 mmol) and tert-butyloxycarbonylguanidine (2.07 g, 12.98 mmol) were dissolved in N,N-dimethylformamide (25 mL), and diisopropylethylamine (3.03 g, 29.96 mmol) and HATU (4.56 g, 11.99 mmol) were added. After the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (100 mL) was added to dilute and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 80B (2.00 g, yield: 82.98%). LC-MS (ESI): m/z=186.1[M-56+H] + .

第二步：将化合物80B(500mg,2.07mmol)溶于二氯甲烷(24mL)中，加入三氟乙酸(6mL)，在室温下搅拌反应3小时。将反应液减压浓缩得化合物80C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝142.1[M+H]+。Step 2: Dissolve compound 80B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain compound 80C (500 mg crude product), which is directly used in the next step. LC-MS (ESI): m/z = 142.1 [M+H] + .

第三步：化合物80C(250mg粗品,1.03mmol)参照实施例1第三步操作得到化合物80D(230mg,收率：95.92％)。LC-MS(ESI):m/z＝631.2[M+H]+。Step 3: Compound 80C (250 mg crude product, 1.03 mmol) was subjected to the same operation as in Step 3 of Example 1 to obtain Compound 80D (230 mg, yield: 95.92%). LC-MS (ESI): m/z = 631.2 [M+H] + .

第四步：化合物80D经手性SFC拆分得到化合物80(SFC分析保留时间：0.525min，84.2mg)和化合物81(SFC分析保留时间：0.797min，62.3mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3.H2O in异丙醇；梯度:40％B梯度；洗脱流速:120mL/min；柱温:25℃；波长:220nm；循环时间:2.5min；样品制备:样品浓度10mg/mL，乙腈二氯甲烷混合溶液进样:每次5.0mL。Step 4: Compound 80D was separated by chiral SFC to obtain compound 80 (SFC analysis retention time: 0.525 min, 84.2 mg) and compound 81 (SFC analysis retention time: 0.797 min, 62.3 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 40% B in A; flow rate: 3.0 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 .H 2 O in isopropanol; gradient: 40% B gradient; elution flow rate: 120 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 2.5 min; sample preparation: sample concentration 10 mg/mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

化合物80(SFC分析保留时间：0.525min)：1H NMR(400MHz,DMSO-d6)δ8.03-8.01(m,2H),7.837.81(m,2H),7.46-7.44(m,2H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.25-7.22(m,3H),5.03-4.99(m,1H),4.52-4.46(m,1H),3.92-3.88(m,1H),1.35(s,3H),1.15-1.14(m,2H),0.76-0.73(m,2H)；LC-MS(ESI):m/z＝631.1[M+H]+。Compound 80 (SFC analysis retention time: 0.525 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03-8.01 (m, 2H), 7.83-7.81 (m, 2H), 7.46-7.44 (m, 2H), 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 5.03-4.99 (m, 1H), 4.52-4.46 (m, 1H), 3.92-3.88 (m, 1H), 1.35 (s, 3H), 1.15-1.14 (m, 2H), 0.76-0.73 (m, 2H); LC-MS (ESI): m/z=631.1 [M+H] + .

化合物81(SFC分析保留时间：0.797min)：1H NMR(400MHz,DMSO-d6)δ8.03-8.01(m,2H),7.837.81(m,2H),7.47-7.44(m,2H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.25-7.22(m,3H),5.03-4.99(m,1H),4.52-4.46(m,1H),3.92-3.88(m,1H),1.35(s,3H),1.15-1.14(m,2H),0.76-0.73(m,2H)；LC-MS(ESI):m/z＝631.2[M+H]+。Compound 81 (SFC analysis retention time: 0.797 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03-8.01 (m, 2H), 7.83-7.81 (m, 2H), 7.47-7.44 (m, 2H), 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 5.03-4.99 (m, 1H), 4.52-4.46 (m, 1H), 3.92-3.88 (m, 1H), 1.35 (s, 3H), 1.15-1.14 (m, 2H), 0.76-0.73 (m, 2H); LC-MS (ESI): m/z=631.2 [M+H] + .

实施例82和实施例83
Example 82 and Example 83

第一步：将化合物82A(2.0g,16.12mmol)和N-Boc-胍(3.85g,24.18mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入二异丙基乙胺(6.25g,48.36mmol)和HATU(9.19g,24.18mmol)，加料完毕，室温搅拌过夜。加水(100mL)，乙酸乙酯(50mL)萃取，合并有机相，无水硫酸钠干燥后减压浓缩，残余物经硅胶柱层析纯化得到化合物82B(1.50g，收率：35.1％)。LC-MS(ESI):m/z＝266.1[M+H]+。Step 1: Dissolve compound 82A (2.0 g, 16.12 mmol) and N-Boc-guanidine (3.85 g, 24.18 mmol) in N,N-dimethylformamide (30 mL), add diisopropylethylamine (6.25 g, 48.36 mmol) and HATU (9.19 g, 24.18 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 82B (1.50 g, yield: 35.1%). LC-MS (ESI): m/z=266.1[M+H] + .

第二步：将化合物82B(500mg,1.88mmol)溶于二氯甲烷(9mL)中，加入三氟乙酸(3mL)，在室温下搅拌反应5小时。将反应液减压浓缩得化合物82C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝166.1[M+H]+。Step 2: Compound 82B (500 mg, 1.88 mmol) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 82C (500 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 166.1 [M+H] + .

第三步：化合物82C粗品(200mg,1.22mmol)参照实施例40第三步操作得到化合物82D(80mg)。Step 3: The crude product of compound 82C (200 mg, 1.22 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 82D (80 mg).

第四步：化合物82D经手性SFC拆分得到化合物82(SFC制备前出峰，20mg)和化合物83(SFC制备后出峰，25mg)。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇；梯度:50％B梯度洗脱流速:40mL/min，柱温:25℃波长:220nm循环时间:20min；样品制备:样品浓度2mg/mL，甲醇溶液进样:每次2mL。Step 4: Compound 82D was separated by chiral SFC to obtain compound 82 (pre-SFC preparation peak, 20 mg) and compound 83 (post-SFC preparation peak, 25 mg). SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; Gradient: 50% B gradient elution flow rate: 40 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 20 min; Sample preparation: Sample concentration 2 mg/mL, methanol solution injection: 2 mL each time.

化合物82(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.28(s,1H),9.02(s,1H),8.78(s,1H),8.02(d,4H),7.80(d,2H),7.53(d,2H),7.36(d,2H),7.30-7.22(m,5H),5.07-5.03(m,1H),4.53(t,1H),3.93-3.88(m,1H)；LC-MS(ESI):m/z＝655.3[M+H]+。Compound 82 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 9.28 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.02 (d, 4H), 7.80 (d, 2H), 7.53 (d, 2H), 7.36 (d, 2H), 7.30-7.22 (m, 5H), 5.07-5.03 (m, 1H), 4.53 (t, 1H), 3.93-3.88 (m, 1H); LC-MS (ESI): m/z=655.3 [M+H] + .

化合物83(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.28(s,1H),9.02(s,1H),8.78(s,1H),8.02(d,4H),7.80(d,2H),7.53(d,2H),7.36(d,2H),7.30-7.21(m,5H),5.07-5.03(m,1H),4.53(t,1H),3.93-3.88(m,1H)；LC-MS(ESI):m/z＝655.3[M+H]+。Compound 83 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ9.90 (s, 1H), 9.28 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.02 (d, 4H), 7.80 (d, 2H), 7.53 (d, 2H), 7.36 (d, 2H), 7.30-7.21 (m, 5H), 5.07-5.03 (m, 1H), 4.53 (t, 1H), 3.93-3.88 (m, 1H); LC-MS (ESI): m/z=655.3 [M+H] + .

实施例84和实施例85
Example 84 and Example 85

第一步：化合物84A(358mg，2.55mmol)参照实施例18第一步操作得到化合物84B(0.48g，收率：80％)。LC-MS(ESI):m/z＝630.3[M+H]+。First step: Compound 84A (358 mg, 2.55 mmol) was subjected to the same operation as in the first step of Example 18 to obtain compound 84B (0.48 g, yield: 80%). LC-MS (ESI): m/z = 630.3 [M+H] + .

第二步：化合物84B(0.48g)经手性SFC拆分得到化合物84(SFC制备前出峰，160mg)和化合物85(SFC制备后出峰，156mg)。SFC制备方法:1.仪器:SFC Prep 150AP；色谱柱:AS(19mm×250mm)；2.样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：CO2；流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量45％；c.流速38mL/min。Step 2: Compound 84B (0.48 g) was subjected to chiral SFC separation to obtain compound 84 (pre-SFC preparation peak, 160 mg) and compound 85 (post-SFC preparation peak, 156 mg). SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 45%; c. Flow rate 38 mL/min.

化合物84(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H),7.45(d,2H),7.33(t,2H),7.26(t,1H),7.22(d,2H),5.07(dd,1H),4.76-4.66(m,1H),4.53-4.41(m,2H),4.32-4.20(m,1H),4.12-4.00(m,1H),3.97-3.86(m,2H),1.56-1.47(m,1H),0.76-0.65(m,4H)；LC-MS(ESI):m/z＝630.3[M+H]+。Compound 84 (pre-SFC peak): 1 H NMR (400 MHz, DMSO-d 6 )δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H),7.45(d,2H),7. 33(t,2H),7.26(t,1H),7.22(d,2H),5.07(dd,1H),4.76-4.66(m,1H),4 .53-4.41(m,2H),4.32-4.20(m,1H),4.12-4.00(m,1H),3.97-3.86(m,2 H),1.56-1.47(m,1H),0.76-0.65(m,4H); LC-MS(ESI):m/z＝630.3[M+H] + .

化合物85(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H),7.45(t,2H),7.33(t,2H),7.26(t,1H),7.22(d,2H),5.08(dd,1H),4.76-4.65(m,1H),4.54-4.40(m,2H),4.31-4.20(m,1H),4.10-4.01(m,1H),3.98-3.85(m,2H),1.56-1.47(m,1H),0.80-0.63(m,4H)；LC-MS(ESI):m/z＝630.3[M+H]+。Compound 85 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H),7.45(t,2H),7. 33(t,2H),7.26(t,1H),7.22(d,2H),5.08(dd,1H),4.76-4.65(m,1H),4 .54-4.40(m,2H),4.31-4.20(m,1H),4.10-4.01(m,1H),3.98-3.85(m,2 H),1.56-1.47(m,1H),0.80-0.63(m,4H); LC-MS(ESI):m/z＝630.3[M+H] + .

实施例86和实施例87
Example 86 and Example 87

第一步：将化合物86A(5.0g,29.03mmol)溶于二氯甲烷(100mL)中，加入三乙胺(8.8g,87.09mmol)，抽换氮气三次后冰浴下缓慢滴加甲胺基甲酰氯(4.07g，43.55mmol)的二氯甲烷(10mL)溶液，加料完成后反应保持冰浴搅拌30min。加水(100mL)淬灭反应，用二氯甲烷(100mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物86B(4.2g，收率：63％)。LC-MS(ESI):m/z＝174.2[M+H-56]+。Step 1: Dissolve compound 86A (5.0 g, 29.03 mmol) in dichloromethane (100 mL), add triethylamine (8.8 g, 87.09 mmol), replace nitrogen three times, and slowly drop a dichloromethane (10 mL) solution of methylaminoformyl chloride (4.07 g, 43.55 mmol) under ice bath. After the addition is complete, keep the reaction in ice bath and stir for 30 min. Add water (100 mL) to quench the reaction, extract twice with dichloromethane (100 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 86B (4.2 g, yield: 63%). LC-MS (ESI): m/z=174.2[M+H-56] + .

第二步：将化合物86B(1.0g,4.36mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(4mL)，在室温下搅拌1.5h。将反应液减压浓缩得化合物86C(1.15g，粗品)，直接用于下一步反应。Step 2: Dissolve compound 86B (1.0 g, 4.36 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 86C (1.15 g, crude product), which is directly used in the next step.

第三步：化合物86C(1.15g，4.36mmol)参照实施例18第一步操作得到化合物86D(0.35g，收率：60％)。LC-MS(ESI):m/z＝619.3[M+H]+。Step 3: Compound 86C (1.15 g, 4.36 mmol) was processed by referring to the first step of Example 18 to obtain compound 86D (0.35 g, yield: 60%). LC-MS (ESI): m/z = 619.3 [M+H] + .

第四步：化合物86D(0.35g)经手性SFC拆分得到化合物86(SFC制备前出峰，102mg)和化合物87(SFC制备后出峰，95mg)。SFC制备方法:1.仪器:SFC Prep 150AP；色谱柱:AS(19mm×250mm)；2.样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：CO2；流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量28％；c.流速42mL/min。Step 4: Compound 86D (0.35 g) was subjected to chiral SFC separation to obtain compound 86 (SFC pre-preparation peak, 102 mg) and compound 87 (SFC post-preparation peak, 95 mg). SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 28%; c. Flow rate 42 mL/min.

化合物86(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.00(d,2H),7.85(d,2H),7.75(d,2H),7.45(d,2H),7.32(t,2H),7.25(dd,1H),7.22(dd,2H),6.28(q,1H),5.06(dd,1H),4.69-4.54(m,1H),4.48(t,1H),3.97(td,2H),3.94-3.80(m,3H),2.55(d,3H)；LC-MS(ESI):m/z＝619.3[M+H]+。Compound 86 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, 1H), 8.00 (d, 2H), 7.85 (d, 2H), 7.75 (d, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.25 (dd, 1H), 7.22 (dd, 2H), 6.28 (q, 1H), 5.06 (dd, 1H), 4.69-4.54 (m, 1H), 4.48 (t, 1H), 3.97 (td, 2H), 3.94-3.80 (m, 3H), 2.55 (d, 3H); LC-MS (ESI): m/z=619.3 [M+H] + .

化合物87(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.00(d,2H),7.85(d,2H),7.75(d,2H),7.45(d,2H),7.32(t,2H),7.25(dd,1H),7.22(dd,2H),6.27(q,1H),5.06(dd,1H),4.68-4.55(m,1H),4.47(t,1H),3.98(td,2H),3.94-3.80(m,3H),2.55(d,3H)；LC-MS(ESI):m/z＝619.3[M+H]+。Compound 87 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, 1H), 8.00 (d, 2H), 7.85 (d, 2H), 7.75 (d, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.25 (dd, 1H), 7.22 (dd, 2H), 6.27 (q, 1H), 5.06 (dd, 1H), 4.68-4.55 (m, 1H), 4.47 (t, 1H), 3.98 (td, 2H), 3.94-3.80 (m, 3H), 2.55 (d, 3H); LC-MS (ESI): m/z=619.3 [M+H] + .

实施例88和实施例89
Example 88 and Example 89

第一步：将化合物88A(600mg,3.22mmol)溶于二氯甲烷(10mL)中，加入三乙胺(1.47g,14.50mmol)，抽换氮气三次后冰浴下缓慢滴加环丙基甲酰氯(505mg，4.83mmol)的二氯甲烷(10mL)溶液，加料完成后反应保持冰浴搅拌30min。加水(50mL)淬灭反应，用二氯甲烷(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物88B(665mg，收率：81％)。LC-MS(ESI):m/z＝199.3[M+H-56]+。Step 1: Dissolve compound 88A (600 mg, 3.22 mmol) in dichloromethane (10 mL), add triethylamine (1.47 g, 14.50 mmol), replace nitrogen three times, and slowly add cyclopropylcarbonyl chloride (505 mg, 4.83 mmol) in dichloromethane (10 mL) under ice bath. After the addition is complete, keep the reaction in ice bath and stir for 30 min. Add water (50 mL) to quench the reaction, extract twice with dichloromethane (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 88B (665 mg, yield: 81%). LC-MS (ESI): m/z=199.3[M+H-56] + .

第二步：将化合物88B(665mg,2.61mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(4mL)，在室温下搅拌1.5h。将反应液减压浓缩得化合物88C(645mg，粗品)，直接用于下一步反应。Step 2: Dissolve compound 88B (665 mg, 2.61 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. Concentrate the reaction solution under reduced pressure to obtain compound 88C (645 mg, crude product), which is directly used in the next step.

第三步：化合物88C(645mg，2.61mmol)参照实施例18第一步操作得到化合物88D(0.48g，收率：78％)。LC-MS(ESI):m/z＝644.2[M+H]+。Step 3: Compound 88C (645 mg, 2.61 mmol) was processed by referring to the first step of Example 18 to obtain compound 88D (0.48 g, yield: 78%). LC-MS (ESI): m/z = 644.2 [M+H] + .

第四步：化合物88D(0.48g)经手性SFC拆分得到化合物88(SFC制备前出峰，204mg)和化合物89(SFC制备后出锋，195mg)。SFC制备方法:1.仪器:SFC Prep 150AP；色谱柱:AS(19mm×250mm)；2.样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：CO2；流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量20％；c.流速40mL/min。Step 4: Compound 88D (0.48 g) was separated by chiral SFC to obtain compound 88 (SFC preparative front peak, 204 mg) and compound 89 (SFC preparative rear peak, 195 mg). SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 20%; c. Flow rate 40 mL/min.

化合物88(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7.72(d,2H),7.44(d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd,1H),4.54-4.41(m,2H),4.28-4.15(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2.24-2.12(m,2H),1.50(dq,1H),0.68-0.60(m,4H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 88 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 )δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7.72(d,2H),7.44 (d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd,1H),4.54- 4.41(m,2H),4.28-4.15(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2.24-2. 12(m,2H),1.50(dq,1H),0.68-0.60(m,4H); LC-MS(ESI):m/z＝644.2[M+H] + .

化合物89(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7.72(d,2H),7.44(d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd,1H),4.57-4.40(m,2H),4.28-4.14(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2.24-2.11(m,2H),1.50(dq,1H),0.68-0.60(m,4H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 89 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7.72(d,2H),7.44 (d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd,1H),4.57- 4.40(m,2H),4.28-4.14(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2.24-2. 11(m,2H),1.50(dq,1H),0.68-0.60(m,4H); LC-MS(ESI):m/z＝644.2[M+H] + .

实施例90和实施例91
Example 90 and Example 91

第一步：将化合物90A(600mg,3.22mmol)溶于二氯甲烷(10mL)中，加入三乙胺(1.47g,14.50mmol)，抽换氮气三次后冰浴下缓慢滴加环丙基甲酰氯(505mg，4.83mmol)的二氯甲烷(10mL)溶液，加料完成后反应保持冰浴搅拌30min。加水(50mL)淬灭反应，用二氯甲烷(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物90B(650mg，收率：79％)。LC-MS(ESI):m/z＝199.3[M+H-56]+。Step 1: Dissolve compound 90A (600 mg, 3.22 mmol) in dichloromethane (10 mL), add triethylamine (1.47 g, 14.50 mmol), replace nitrogen three times, and slowly add cyclopropylcarbonyl chloride (505 mg, 4.83 mmol) in dichloromethane (10 mL) dropwise under ice bath. After the addition is complete, keep the reaction in ice bath and stir for 30 min. Add water (50 mL) to quench the reaction, extract twice with dichloromethane (50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 90B (650 mg, yield: 79%). LC-MS (ESI): m/z=199.3[M+H-56] + .

第二步：将化合物90B(650mg,2.56mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(4mL)，在室温下搅拌1.5h。将反应液减压浓缩得化合物90C(660mg，粗品)，直接用于下一步反应。Step 2: Compound 90B (650 mg, 2.56 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 90C (660 mg, crude product), which was directly used in the next step.

第三步：化合物90C(660mg，2.56mmol)参照实施例18第一步操作得到化合物90D(0.41g，收率：67％)。LC-MS(ESI):m/z＝644.2[M+H]+。Step 3: Compound 90C (660 mg, 2.56 mmol) was subjected to the same operation as in the first step of Example 18 to obtain compound 90D (0.41 g, yield: 67%). LC-MS (ESI): m/z = 644.2 [M+H] + .

第四步：化合物90D(0.41g)经手性SFC拆分得到化合物90(SFC制备前出峰，135mg)和化合物91(SFC制备后出峰，128mg)。SFC制备方法:1.仪器:SFC Prep 150AP；色谱柱:AS(19mm×250mm)；2.样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a.流动相A,B组成：流动相A：CO2；流动相B：异丙醇(0.01％氨水)；b.等度洗脱，流动相B含量25％；c.流速40mL/min。Step 4: Compound 90D (0.41 g) was subjected to chiral SFC separation to obtain compound 90 (pre-SFC preparation peak, 135 mg) and compound 91 (post-SFC preparation peak, 128 mg). SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A, B: Mobile phase A: CO 2 ; Mobile phase B: isopropanol (0.01% ammonia water); b. Isocratic elution, mobile phase B content 25%; c. Flow rate 40 mL/min.

化合物90(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73(d,2H),7.47-7.41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd,1H),4.50(t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H),2.10-1.93(m,2H),1.50(dq,1H),0.71-0.56(m,4H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 90 (pre-SFC peak): 1 H NMR (400 MHz, DMSO-d 6 )δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73(d,2H),7.47-7 .41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd,1H),4.50 (t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H),2.10- 1.93(m,2H),1.50(dq,1H),0.71-0.56(m,4H); LC-MS(ESI):m/z＝644.2[M+H] + .

化合物91(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73(d,2H),7.48-7.41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd,1H),4.50(t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H),2.10-1.93(m,2H),1.50(dq,1H),0.72-0.54(m,4H)；LC-MS(ESI):m/z＝644.2[M+H]+。Compound 91 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73(d,2H),7.48-7 .41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd,1H),4.50 (t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H),2.10- 1.93(m,2H),1.50(dq,1H),0.72-0.54(m,4H); LC-MS(ESI):m/z＝644.2[M+H] + .

实施例92、实施例93、实施例94和实施例95
Example 92, Example 93, Example 94 and Example 95

第一步：将化合物1-甲基-2-氧代哌啶-4-羧酸(314mg，2mmol)溶于N,N-二甲基甲酰胺(10mL)，依次加入HATU(1.14g，3mmol)、叔丁氧羰基胍(477mg，3mmol)和N,N-二异丙基乙胺(1.3g，10mmol)，室温下反应2h。反应结束后向体系中加入40mL乙酸乙酯，饱和食盐水洗涤(50mL×4)，收集有机相，无水硫酸钠干燥，浓缩，残余物经硅胶柱层析纯化得到化合物92A(368mg，收率：61.7％)。LC-MS(ESI):m/z＝299.1[M+H]+。Step 1: Dissolve the compound 1-methyl-2-oxopiperidine-4-carboxylic acid (314 mg, 2 mmol) in N,N-dimethylformamide (10 mL), add HATU (1.14 g, 3 mmol), tert-butyloxycarbonylguanidine (477 mg, 3 mmol) and N,N-diisopropylethylamine (1.3 g, 10 mmol) in sequence, and react at room temperature for 2 h. After the reaction, add 40 mL of ethyl acetate to the system, wash with saturated brine (50 mL×4), collect the organic phase, dry it with anhydrous sodium sulfate, concentrate it, and purify the residue by silica gel column chromatography to obtain compound 92A (368 mg, yield: 61.7%). LC-MS (ESI): m/z=299.1[M+H] + .

第二步：将化合物92A(368mg,1.23mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(4mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物92B(247mg，粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝199.1[M+H]+。Step 2: Compound 92A (368 mg, 1.23 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 92B (247 mg, crude product), which was directly used in the next step. LC-MS (ESI): m/z = 199.1 [M+H] + .

第三步：将化合物1D(525mg，1mmol)溶于无水乙腈(30mL)中，分别加入化合物92B(247mg,粗品)和N,N-二异丙基乙胺(2mL)，40℃下反应0.5h。LCMS监测反应完全后直接浓缩，所得残余物经硅胶柱层析纯化得到化合物92C(256mg，收率：37.2％)。Step 3: Compound 1D (525 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL), and compound 92B (247 mg, crude product) and N,N-diisopropylethylamine (2 mL) were added respectively, and the mixture was reacted at 40° C. for 0.5 h. After the reaction was completed as monitored by LCMS, the residue was directly concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 92C (256 mg, yield: 37.2%).

第四步：化合物92C经手性SFC拆分得到化合物92(SFC分析保留时间：2.907min，28.6mg)、化合物93(SFC分析保留时间：3.303min，22.1mg)、化合物94(SFC分析保留时间：4.183min，29.9mg)和化合物95(SFC分析保留时间：4.955min，29.7mg)。SFC分析方法:仪器:SHIMADZU LC-20AD，柱:Chiral IK Column；流动相:A:n-Hexane,B:0.1％IPAmin异丙醇和乙腈；梯度:35％B in A；流速:1mL/min柱温:35℃波长:220nm。Step 4: Compound 92C was separated by chiral SFC to obtain compound 92 (SFC analysis retention time: 2.907min, 28.6mg), compound 93 (SFC analysis retention time: 3.303min, 22.1mg), compound 94 (SFC analysis retention time: 4.183min, 29.9mg) and compound 95 (SFC analysis retention time: 4.955min, 29.7mg). SFC analysis method: instrument: SHIMADZU LC-20AD, column: Chiral IK Column; mobile phase: A: n-Hexane, B: 0.1% IPAmin isopropanol and acetonitrile; gradient: 35% B in A; flow rate: 1mL/min column temperature: 35℃ wavelength: 220nm.

SFC第一次制备得到化合物92和化合物93，方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHELK column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇和乙腈；梯度:40％B in A；流速:120mL/min柱温:室温波长:220nm循环时间:4.8min；样品制备:样品浓度5mg/mL，乙腈和甲醇溶液进样:每次3mL。Compound 92 and compound 93 were prepared by SFC for the first time. Method: instrument: Waters 150 Prep-SFC, column: Chiral WHELK column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; gradient: 40% B in A; flow rate: 120 mL/min, column temperature: room temperature, wavelength: 220 nm, cycle time: 4.8 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and methanol solution injection: 3 mL each time.

其余混合物回收进行第二次SFC制备得到化合物94和化合物95，方法:仪器:Waters 150Prep-SFC，柱:Chiral WHELK column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇和乙腈；梯度:40％B in A；流速:120mL/min柱温:室温波长:220nm循环时间:3.5min；样品制备:样品浓度5mg/mL，乙腈和甲醇溶液进样:每次3mL。The remaining mixture was recovered for a second SFC preparation to obtain compound 94 and compound 95. Method: instrument: Waters 150Prep-SFC, column: Chiral WHELK column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; gradient: 40% B in A; flow rate: 120 mL/min, column temperature: room temperature, wavelength: 220 nm, cycle time: 3.5 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and methanol solution injection: 3 mL each time.

化合物92(SFC分析保留时间：2.907min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H)；LC-MS(ESI):m/z＝688.3[M+H]+。Compound 92 (SFC analysis retention time: 2.907 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36( m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.8 1(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m ,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m/z＝688.3[M+H] + .

化合物93(SFC分析保留时间：3.303min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H)；LC-MS(ESI):m/z＝688.3[M+H]+。Compound 93 (SFC analysis retention time: 3.303 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36( m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.8 1(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m ,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m/z＝688.3[M+H] + .

化合物94(SFC分析保留时间：4.183min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H)；LC-MS(ESI):m/z＝688.3[M+H]+。Compound 94 (SFC analysis retention time: 4.183 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36( m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.8 1(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m ,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m/z＝688.3[M+H] + .

化合物95(SFC分析保留时间：4.955min)：1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H)；LC-MS(ESI):m/z＝688.3[M+H]+。Compound 95 (SFC analysis retention time: 4.955 min): 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m,2H),7.41-7.36( m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H),3.96-3.8 1(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2.26(m ,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m/z＝688.3[M+H] + .

实施例96和实施例97
Example 96 and Example 97

第一步：将化合物96A(3.1g,14mmol)(合成参考文献：ACS Catalysis(2021),11(15),9715-9721)溶于140mL无水乙醇中，加入过量水合肼，回流反应6h。反应结束后，直接浓缩，得到化合物96B(3.3g，粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝237.1[M+H]+。Step 1: Dissolve compound 96A (3.1 g, 14 mmol) (synthesis reference: ACS Catalysis (2021), 11 (15), 9715-9721) in 140 mL of anhydrous ethanol, add excess hydrazine hydrate, and reflux for 6 h. After the reaction, directly concentrate to obtain compound 96B (3.3 g, crude product), which is directly used in the next step. LC-MS (ESI): m/z = 237.1 [M+H] + .

第二步：将化合物96B(3.3g，粗品)分散于无水甲苯中，加入化合物(4-(三氟甲基)苯基)磺酰基)氨基甲酸乙酯(3.86g,13mmol)，100℃下反应4h。反应结束后，浓缩，向所得残余物中加入100mL石油醚和乙酸乙酯的混合溶液(v/v＝3:1)，充分震荡后过滤，干燥滤饼即得到化合物96C(3.1g，两步收率：45.5％)。LC-MS(ESI):m/z＝488.2[M+H]+。Step 2: Disperse compound 96B (3.3 g, crude product) in anhydrous toluene, add compound (4-(trifluoromethyl)phenyl)sulfonyl)carbamic acid ethyl ester (3.86 g, 13 mmol), and react at 100°C for 4 h. After the reaction is completed, concentrate, add 100 mL of a mixed solution of petroleum ether and ethyl acetate (v/v=3:1) to the obtained residue, shake well, filter, and dry the filter cake to obtain compound 96C (3.1 g, two-step yield: 45.5%). LC-MS (ESI): m/z=488.2[M+H] + .

第三步：将化合物96C(3.1g,6.3mmol)分散于无水甲苯中，加入三氯氧磷(1.53g，10mmol)和N,N-二异丙基乙胺(3.87g，30mmol)，100℃下反应1h。反应结束后，浓缩，所得残余物经硅胶柱层析纯化得到化合物96D(2.8g，收率：88.1％)。LC-MS(ESI):m/z＝506.1[M+H]+。Step 3: Disperse compound 96C (3.1 g, 6.3 mmol) in anhydrous toluene, add phosphorus oxychloride (1.53 g, 10 mmol) and N,N-diisopropylethylamine (3.87 g, 30 mmol), and react at 100°C for 1 h. After the reaction, concentrate the residue, and purify it by silica gel column chromatography to obtain compound 96D (2.8 g, yield: 88.1%). LC-MS (ESI): m/z=506.1[M+H] + .

第四步：将化合物1C(127mg,1mmol)溶于无水乙腈(30mL)中，分别加入化合物96D(505mg,1mmol)和N,N-二异丙基乙胺(2mL)，40℃下反应0.5h。LCMS监测反应完全后直接浓缩，所得残余物经硅胶柱层析纯化得到化合物96E(384mg，收率：64.4％)。Step 4: Compound 1C (127 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL), and compound 96D (505 mg, 1 mmol) and N,N-diisopropylethylamine (2 mL) were added respectively, and the mixture was reacted at 40°C for 0.5 h. After the reaction was completed as monitored by LCMS, the mixture was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 96E (384 mg, yield: 64.4%).

第五步：化合物96E经手性SFC拆分得到化合物96(SFC分析保留时间：1.747min，183.8mg)和化合物97(SFC分析保留时间：2.147min，181.6mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:35％B梯度洗脱流速:120mL/min，柱温:室温波长:220nm循环时间:4.0min；样品制备:样品浓度10mg/mL，乙腈和乙醇溶液进样:每次5mL。Step 5: Compound 96E was separated by chiral SFC to obtain compound 96 (SFC analysis retention time: 1.747 min, 183.8 mg) and compound 97 (SFC analysis retention time: 2.147 min, 181.6 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 35% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 4.0 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile and ethanol solution injection: 5 mL each time.

化合物96(SFC分析保留时间：1.747min)：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.03(d,2H),7.82(d,2H),7.47-7.39(m,2H),7.35-7.18(m,5H),7.11(d,2H),5.05-4.95(m,1H),5.53-4.41(m,1H),3.90-3.83(m,1H),2.23(s,3H),2.07-1.93(m,1H),0.97-0.80(m,4H)；LC-MS(ESI):m/z＝597.3[M+H]+。Compound 96 (SFC analysis retention time: 1.747 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 8.03 (d, 2H), 7.82 (d, 2H), 7.47-7.39 (m, 2H), 7.35-7.18 (m, 5H), 7.11 (d, 2H), 5.05-4.95 (m, 1H), 5.53-4.41 (m, 1H), 3.90-3.83 (m, 1H), 2.23 (s, 3H), 2.07-1.93 (m, 1H), 0.97-0.80 (m, 4H); LC-MS (ESI): m/z=597.3 [M+H] + .

化合物97(SFC分析保留时间：2.147min)：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.03(d,2H),7.82(d,2H),7.47-7.39(m,2H),7.35-7.18(m,5H),7.11(d,2H),5.05-4.95(m,1H),5.53-4.41(m,1H),3.90-3.83(m,1H),2.23(s,3H),2.07-1.93(m,1H),0.97-0.80(m,4H)；LC-MS(ESI):m/z＝597.3[M+H]+。Compound 97 (SFC analysis retention time: 2.147 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 8.03 (d, 2H), 7.82 (d, 2H), 7.47-7.39 (m, 2H), 7.35-7.18 (m, 5H), 7.11 (d, 2H), 5.05-4.95 (m, 1H), 5.53-4.41 (m, 1H), 3.90-3.83 (m, 1H), 2.23 (s, 3H), 2.07-1.93 (m, 1H), 0.97-0.80 (m, 4H); LC-MS (ESI): m/z=597.3 [M+H] + .

实施例98和实施例99

Example 98 and Example 99

第一步：在100mL茄形瓶中，依次加入化合物98A(530mg,2.37mmol)(按照专利WO2023169481合成)、苄硫醇(440mg，3.5mmol)、1,1-双(二苯基膦)二茂铁二氯化钯(87.7mg，0.12mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(138mg，0.24mmol)和N,N-二异丙基乙胺(2mL)，再加入20mL无水甲苯，氮气置换后于100℃下反应4h。反应结束后，浓缩，所得残余物经硅胶柱层析纯化得到化合物98B(472mg，收率：72.1％)。Step 1: In a 100 mL eggplant-shaped bottle, compound 98A (530 mg, 2.37 mmol) (synthesized according to patent WO2023169481), benzyl mercaptan (440 mg, 3.5 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (87.7 mg, 0.12 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (138 mg, 0.24 mmol) and N,N-diisopropylethylamine (2 mL) were added in sequence, and then 20 mL of anhydrous toluene was added, and the reaction was carried out at 100 ° C for 4 hours after nitrogen replacement. After the reaction was completed, it was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 98B (472 mg, yield: 72.1%).

第二步：在50mL茄形瓶中，加入98B(472mg，1.71mmol)和N-氯代丁二酰亚胺(0.9g，6.84mmol)再加入10mL无水乙酸和2mL水。室温下反应2h。反应结束后，加入50mL水，乙酸乙酯萃取(50mL×3)，合并有机相，浓缩，所得残余物经硅胶柱层析纯化得到化合物98C(296mg，收率：69.1％)。Step 2: In a 50 mL eggplant-shaped bottle, add 98B (472 mg, 1.71 mmol) and N-chlorosuccinimide (0.9 g, 6.84 mmol), then add 10 mL of anhydrous acetic acid and 2 mL of water. React at room temperature for 2 h. After the reaction, add 50 mL of water, extract with ethyl acetate (50 mL×3), combine the organic phases, concentrate, and purify the residue by silica gel column chromatography to obtain compound 98C (296 mg, yield: 69.1%).

第三步：将化合物98C(296mg，1.2mmol)溶于二氯甲烷(10mL)中，加入0.1M胺的1,4-二氧六环溶液(16mL)，室温下反应2h。反应结束后，浓缩，即得到化合物98D(287mg，粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝234.0[M+H]+。Step 3: Compound 98C (296 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), and a 0.1 M amine solution in 1,4-dioxane (16 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction, the mixture was concentrated to obtain compound 98D (287 mg, crude product), which was directly used in the next step. LC-MS (ESI): m/z = 234.0 [M+H] + .

第四步：将化合物98D(287mg，粗品)溶于二氯甲烷(10mL)中，加入氯甲酸乙酯(194mg，1.8mmol)和三乙胺(1mL)，室温下反应过夜。反应结束后，用1M氯化氢溶液调节pH至1～3。分液，分离有机相，浓缩，所得残余物经硅胶柱层析纯化得到化合物98E(267mg，收率：72.9％)。LC-MS(ESI):m/z＝306.1[M+H]+。Step 4: Compound 98D (287 mg, crude product) was dissolved in dichloromethane (10 mL), ethyl chloroformate (194 mg, 1.8 mmol) and triethylamine (1 mL) were added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the pH was adjusted to 1-3 with 1M hydrogen chloride solution. The organic phase was separated and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 98E (267 mg, yield: 72.9%). LC-MS (ESI): m/z=306.1[M+H] + .

第五步：将化合物98E(267mg，0.87mmol)分散于无水甲苯中，加入化合物22D(257mg,1mmol)，100℃下反应4h。反应结束后，浓缩，向所得残余物中加入100mL石油醚和乙酸乙酯的混合溶液(v/v＝3:1)，充分震荡后过滤，干燥滤饼即得到化合物98H(355mg，收率：79.1％)。LC-MS(ESI):m/z＝514.3[M-H]- Step 5: Disperse compound 98E (267 mg, 0.87 mmol) in anhydrous toluene, add compound 22D (257 mg, 1 mmol), and react at 100°C for 4 h. After the reaction is completed, concentrate, add 100 mL of a mixed solution of petroleum ether and ethyl acetate (v/v=3:1) to the residue, shake well, filter, and dry the filter cake to obtain compound 98H (355 mg, yield: 79.1%). LC-MS (ESI): m/z=514.3 [MH] -

第六步：将化合物98H(355mg,0.68mmol)分散于无水甲苯中，加入三氯氧磷(153mg，1mmol)和N,N-二异丙基乙胺(387mg，3mmol)，100℃下反应1h。反应结束后，浓缩，所得残余物经硅胶柱层析纯化得到化合物98I(318mg，收率：87.6％)。LC-MS(ESI):m/z＝612.2[M-H]-。Step 6: Disperse compound 98H (355 mg, 0.68 mmol) in anhydrous toluene, add phosphorus oxychloride (153 mg, 1 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol), and react at 100°C for 1 h. After the reaction, concentrate the residue, and purify it by silica gel column chromatography to obtain compound 98I (318 mg, yield: 87.6%). LC-MS (ESI): m/z=612.2[MH] - .

第七步：将化合物1C(127mg,1mmol)溶于无水乙腈(10mL)中，分别加入化合物98I(318mg,0.6mmol)和N,N-二异丙基乙胺(2mL)，40℃下反应0.5h。LCMS监测反应完全后直接浓缩，所得残余物经硅胶柱层析纯化得到化合物98J(187mg，收率：49.8％)。LC-MS(ESI):m/z＝625.3[M+H]+。Step 7: Compound 1C (127 mg, 1 mmol) was dissolved in anhydrous acetonitrile (10 mL), and compound 98I (318 mg, 0.6 mmol) and N,N-diisopropylethylamine (2 mL) were added respectively, and the mixture was reacted at 40°C for 0.5 h. After the reaction was completed as monitored by LCMS, the product was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 98J (187 mg, yield: 49.8%). LC-MS (ESI): m/z=625.3[M+H] + .

第八步：化合物98J经手性SFC拆分得到化合物98(SFC制备前出峰，84.1mg)和化合物99(SFC制备后出峰，86.1mg)。SFC制备方法:仪器:SFC Prep 150AP，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇；梯度:50％B梯度洗脱流速:40mL/min，柱温:室温波长:220nm循环时间:4.0min；样品制备:样品浓度5mg/mL，DMF溶液进样:每次5mL。Step 8: Compound 98J was separated by chiral SFC to obtain compound 98 (SFC pre-preparation peak, 84.1 mg) and compound 99 (SFC post-preparation peak, 86.1 mg). SFC preparation method: instrument: SFC Prep 150AP, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol; gradient: 50% B gradient elution flow rate: 40 mL/min, column temperature: room temperature wavelength: 220 nm cycle time: 4.0 min; sample preparation: sample concentration 5 mg/mL, DMF solution injection: 5 mL each time.

化合物98(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.85-7.80(m,2H),7.62(d,1H),7.54-7.50(m,2H),7.42-7.37(m,2H),7.34-7.21(m,5H),5.08-4.98(m,1H),4.54-4.43(m,1H),3.92-3.82(m,1H),3.16-3.04(m,2H),2.70-2.54(m,2H),2.05-1.92(m,1H),0.98-0.78(m,4H)；LC-MS(ESI):m/z＝625.3[M+H]+。Compound 98 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 7.85-7.80 (m, 2H), 7.62 (d, 1H), 7.54-7.50 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.21 (m, 5H), 5.08-4.98 (m, 1H), 4.54-4.43 (m, 1H), 3.92-3.82 (m, 1H), 3.16-3.04 (m, 2H), 2.70-2.54 (m, 2H), 2.05-1.92 (m, 1H), 0.98-0.78 (m, 4H); LC-MS (ESI): m/z=625.3 [M+H] + .

化合物99(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.85-7.80(m,2H),7.62(d,1H),7.54-7.50(m,2H),7.42-7.37(m,2H),7.34-7.21(m,5H),5.08-4.98(m,1H),4.54-4.43(m,1H),3.92-3.82(m,1H),3.16-3.04(m,2H),2.70-2.54(m,2H),2.05-1.92(m,1H),0.98-0.78(m,4H)；LC-MS(ESI):m/z＝625.3[M+H]+。Compound 99 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 7.85-7.80 (m, 2H), 7.62 (d, 1H), 7.54-7.50 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.21 (m, 5H), 5.08-4.98 (m, 1H), 4.54-4.43 (m, 1H), 3.92-3.82 (m, 1H), 3.16-3.04 (m, 2H), 2.70-2.54 (m, 2H), 2.05-1.92 (m, 1H), 0.98-0.78 (m, 4H); LC-MS (ESI): m/z=625.3 [M+H] + .

实施例100和实施例101
Example 100 and Example 101

第一步：将化合物100A(3.5g，29.63mmol)加入反应瓶，用THF(50mL)溶解，冷却到-15℃，然后滴加苄基溴化镁(37mL，37.04mmol)，滴加完成后，升到室温反应3小时，然后再加入2mol/L的盐酸(30mL)室温搅拌30min。TLC监测反应完成后，加水(200mL)稀释，用乙酸乙酯萃取两次(100mL*2)，合并有机相并干燥，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100B(2.2g，收率：35.15％)。LC-MS(ESI):m/z＝212.1[M+H]+。Step 1: Add compound 100A (3.5 g, 29.63 mmol) to a reaction flask, dissolve it with THF (50 mL), cool it to -15 °C, then drop benzylmagnesium bromide (37 mL, 37.04 mmol), after the dropwise addition is complete, warm to room temperature for reaction for 3 hours, then add 2 mol/L hydrochloric acid (30 mL) and stir at room temperature for 30 min. After TLC monitoring, dilute with water (200 mL), extract twice with ethyl acetate (100 mL*2), combine the organic phases and dry, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 100B (2.2 g, yield: 35.15%). LC-MS (ESI): m/z=212.1[M+H] + .

第二步：将化合物100B(1.2g，5.68mmol)加入反应瓶，用甲醇(20mL)溶解，然后加入甲醛溶液(670mg，17.04mmol)、乙酸(680mg，11.36mmol)和哌啶(970mg，11.36mmol)，氮气置换三次，在60℃反应2小时。TLC监测反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100C(0.6g，收率：47.31％)。LC-MS(ESI)：m/z＝224.2[M+H]+。Step 2: Compound 100B (1.2 g, 5.68 mmol) was added to a reaction bottle, dissolved with methanol (20 mL), then added with formaldehyde solution (670 mg, 17.04 mmol), acetic acid (680 mg, 11.36 mmol) and piperidine (970 mg, 11.36 mmol), replaced with nitrogen three times, and reacted at 60°C for 2 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain compound 100C (0.6 g, yield: 47.31%). LC-MS (ESI): m/z=224.2[M+H] + .

第三步：将化合物100C(0.6g，2.69mmol)加入反应瓶，用乙醇(10mL)溶解，然后加入水合肼(336mg，5.38mmol)，在80℃反应1小时。TLC监测反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100D(0.5g，收率：78.37％)。LC-MS(ESI):m/z＝238.1[M+H]+。Step 3: Compound 100C (0.6 g, 2.69 mmol) was added to a reaction bottle, dissolved with ethanol (10 mL), and then hydrazine hydrate (336 mg, 5.38 mmol) was added and reacted at 80°C for 1 hour. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 100D (0.5 g, yield: 78.37%). LC-MS (ESI): m/z=238.1[M+H] + .

第四步：将化合物100D(0.5g，2.11mmol)和化合物100H(627mg，2.11mmol，参考专利WO2020236411A1合成)加入反应瓶，用甲苯(10mL)混匀，在120℃反应4小时。TLC监测反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100E(240mg，收率：23.30％)。LC-MS(ESI):m/z＝489.1[M+H]+。Step 4: Add compound 100D (0.5 g, 2.11 mmol) and compound 100H (627 mg, 2.11 mmol, synthesized according to patent WO2020236411A1) to the reaction bottle, mix with toluene (10 mL), and react at 120 ° C for 4 hours. After the reaction is completed by TLC monitoring, cool to room temperature, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 100E (240 mg, yield: 23.30%). LC-MS (ESI): m/z=489.1[M+H] + .

第五步：将化合物100E(200mg，0.41mmol)加入反应瓶，用甲苯(10mL)溶解，然后加入DIPEA(0.18mL，1.02mmol)和三氯氧磷(94mg，0.61mmol)，然后在100℃反应1小时。TLC监测反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100F(100mg，收率：48.18％)。LC-MS(ESI):m/z＝507.0[M+H]+。Step 5: Compound 100E (200 mg, 0.41 mmol) was added to a reaction bottle, dissolved with toluene (10 mL), and then DIPEA (0.18 mL, 1.02 mmol) and phosphorus oxychloride (94 mg, 0.61 mmol) were added, and then reacted at 100°C for 1 hour. After the reaction was completed by TLC monitoring, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 100F (100 mg, yield: 48.18%). LC-MS (ESI): m/z=507.0[M+H] + .

第六步：将化合物100F(100mg，0.20mmol)、化合物1C(101mg，0.80mmol)和DIPEA(0.35mL，2.0mmol)加入反应瓶，用DCM(10mL)溶解，然后室温反应2小时。TLC监测反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物100G(80mg，收率：66.93％)。LC-MS(ESI):m/z＝598.3[M+H]+。Step 6: Compound 100F (100 mg, 0.20 mmol), compound 1C (101 mg, 0.80 mmol) and DIPEA (0.35 mL, 2.0 mmol) were added to a reaction bottle, dissolved with DCM (10 mL), and then reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 100G (80 mg, yield: 66.93%). LC-MS (ESI): m/z=598.3[M+H] + .

第七步：化合物100G经手性SFC拆分得到化合物100(SFC分析保留时间：0.473min，12mg)和化合物101(SFC分析保留时间：0.714min，11mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral IK Column；流动相:A:CO2，B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2，B:0.1％NH3·H2O in甲醇；梯度:40％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:6.2min；样品制备:样品浓度10mg/mL，乙腈甲醇混合溶液进样:每次3.0mL。Step 7: Compound 100G was separated by chiral SFC to obtain compound 100 (SFC analysis retention time: 0.473 min, 12 mg) and compound 101 (SFC analysis retention time: 0.714 min, 11 mg). SFC analysis method: instrument: SHIMADZU LC-30AD, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; Gradient: 40% B gradient elution flow rate: 120 mL/min, column temperature: 25°C wavelength: 220 nm cycle time: 6.2 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 3.0 mL each time.

化合物100(SFC分析保留时间：0.473min)：1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.28(s,1H),8.05-8.00(m,2H),7.84-7.80(m,2H),7.67-7.58(m,2H),7.28-7.15(m,6H),5.05-4.99(m,1H),4.51-4.43(m,1H),3.93-3.87(m,1H),2.23(s,3H),2.02-1.95(m,1H),0.92-0.82(m,4H)。Compound 100 (SFC analysis retention time: 0.473 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.28 (s, 1H), 8.05-8.00 (m, 2H), 7.84-7.80 (m, 2H), 7.67-7.58 (m, 2H), 7.28-7.15 (m, 6H), 5.05-4.99 (m, 1H), 4.51-4.43 (m, 1H), 3.93-3.87 (m, 1H), 2.23 (s, 3H), 2.02-1.95 (m, 1H), 0.92-0.82 (m, 4H).

化合物101(SFC分析保留时间：0.714min):1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.28(s,1H),8.05-8.00(m,2H),7.84-7.79(m,2H),7.67-7.58(m,2H),7.28-7.15(m,6H),5.05-4.99(m,1H),4.51-4.43(m,1H),3.93-3.87(m,1H),2.23(s,3H),2.02-1.94(s,1H),0.92-0.82(m,4H)。Compound 101 (SFC analysis retention time: 0.714 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.28 (s, 1H), 8.05-8.00 (m, 2H), 7.84-7.79 (m, 2H), 7.67-7.58 (m, 2H), 7.28-7.15 (m, 6H), 5.05-4.99 (m, 1H), 4.51-4.43 (m, 1H), 3.93-3.87 (m, 1H), 2.23 (s, 3H), 2.02-1.94 (s, 1H), 0.92-0.82 (m, 4H).

实施例102和实施例103
Example 102 and Example 103

第一步：将化合物102A(0.5g,4.8mmol)和N-Boc-胍(1.14g,7.2mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入二异丙基乙胺(1.86g,14.4mmol)和HATU(2.19g,5.76mmol)，加料完毕，室温搅拌过夜。加水(100mL)，用乙酸乙酯(50mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物102B(1.0g，收率：85.0％)。LC-MS(ESI):m/z＝190.1[M-56+H]+。Step 1: Dissolve compound 102A (0.5 g, 4.8 mmol) and N-Boc-guanidine (1.14 g, 7.2 mmol) in N,N-dimethylformamide (15 mL), add diisopropylethylamine (1.86 g, 14.4 mmol) and HATU (2.19 g, 5.76 mmol), stir at room temperature overnight after the addition is complete. Add water (100 mL), extract twice with ethyl acetate (50 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 102B (1.0 g, yield: 85.0%). LC-MS (ESI): m/z=190.1[M-56+H] + .

第二步：将化合物102B(300mg,1.22mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(4mL)，在室温下搅拌反应3小时。将反应液减压浓缩得化合物102C(500mg粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝146.1[M+H]+。Step 2: Compound 102B (300 mg, 1.22 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 102C (500 mg crude product), which was directly used in the next step. LC-MS (ESI): m/z = 146.1 [M+H] + .

第三步：将化合物1D(200mg，0.38mmol)溶于乙腈(10mL)，分别加入化合物40C(500mg,1.22mmol)和二异丙基乙胺(765mg,5.9mmol)，加热至40℃反应2小时。减压浓缩，所得残余物经硅胶柱层析纯化得到化合物102D(150mg,收率：62.2％)。Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in acetonitrile (10 mL), and compound 40C (500 mg, 1.22 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added respectively, and heated to 40°C for 2 hours. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain compound 102D (150 mg, yield: 62.2%).

第四步：化合物102D经手性SFC拆分得到化合物102(SFC分析保留时间：1.903min，61mg)和化合物103(SFC分析保留时间：2.181min，70mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral AD column；流动相:A:CO2,B:0.05％DEA in异丙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral AD column；流动相:A:CO2,B:0.1％NH3·H2O in异丙醇；梯度:35％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:6.0min；样品制备:样品浓度10mg/mL，乙腈甲醇混合溶液进样:每次2.0mL。Step 4: Compound 102D was separated by chiral SFC to obtain compound 102 (SFC analysis retention time: 1.903 min, 61 mg) and compound 103 (SFC analysis retention time: 2.181 min, 70 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral AD column; mobile phase: A: CO 2 , B: 0.05% DEA in isopropanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in isopropanol; Gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 6.0 min; Sample preparation: Sample concentration 10 mg/mL, acetonitrile methanol mixed solution injection: 2.0 mL each time.

化合物102(SFC分析保留时间：1.903min)：1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.04-8.02(m,2H),7.82-7.80(m,2H),7.54-7.51(m,2H),7.40-7.38(m,2H),7.32-7.20(m,5H),5.05-5.01(m,1H),4.51-4.44(m,1H),3.90-3.86(m,1H),1.50-1.41(m,2H),1.40-1.32(m,2H)；LC-MS(ESI):m/z＝635.3[M+H]+。Compound 102 (SFC analysis retention time: 1.903 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.04-8.02 (m, 2H), 7.82-7.80 (m, 2H), 7.54-7.51 (m, 2H), 7.40-7.38 (m, 2H), 7.32-7.20 (m, 5H), 5.05-5.01 (m, 1H), 4.51-4.44 (m, 1H), 3.90-3.86 (m, 1H), 1.50-1.41 (m, 2H), 1.40-1.32 (m, 2H); LC-MS (ESI): m/z=635.3 [M+H] + .

化合物103(SFC分析保留时间：2.181min)：1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.04-8.02(m,2H),7.82-7.80(m,2H),7.54-7.51(m,2H),7.40-7.38(m,2H),7.32-7.19(m,5H),5.05-5.01(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.50-1.41(m,2H),1.40-1.32(m,2H)；LC-MS(ESI):m/z＝635.3[M+H]+。Compound 103 (SFC analysis retention time: 2.181 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.04-8.02 (m, 2H), 7.82-7.80 (m, 2H), 7.54-7.51 (m, 2H), 7.40-7.38 (m, 2H), 7.32-7.19 (m, 5H), 5.05-5.01 (m, 1H), 4.51-4.45 (m, 1H), 3.90-3.85 (m, 1H), 1.50-1.41 (m, 2H), 1.40-1.32 (m, 2H); LC-MS (ESI): m/z=635.3 [M+H] + .

实施例104和实施例105
Example 104 and Example 105

第一步：化合物104A(6g，40.50mmol)溶于二氯甲烷(50mL)中在冰水浴下缓慢加入草酰氯(12.85g，101.25mmol)，反应1h，直接浓缩得到酰氯粗品。然后将N,O-二甲基羟胺盐酸盐(7.11g，72.9mmol)和三乙胺(12.29g，121.5mmol)溶于二氯甲烷(50mL)中，将得到的酰氯溶于二氯甲烷中缓慢加入到上述反应中，室温反应2小时。反应完成后直接浓缩，所得残余经硅胶柱层析纯化得到化合物104B(5.5g，收率：71％)。Step 1: Compound 104A (6 g, 40.50 mmol) was dissolved in dichloromethane (50 mL) and oxalyl chloride (12.85 g, 101.25 mmol) was slowly added under an ice-water bath, reacted for 1 h, and directly concentrated to obtain a crude acyl chloride. Then N, O-dimethylhydroxylamine hydrochloride (7.11 g, 72.9 mmol) and triethylamine (12.29 g, 121.5 mmol) were dissolved in dichloromethane (50 mL), and the obtained acyl chloride was dissolved in dichloromethane and slowly added to the above reaction, and reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104B (5.5 g, yield: 71%).

LC-MS(ESI):m/z＝192.1[M+H]+。LC-MS (ESI): m/z=192.1[M+H] + .

第二步：将化合物104B(5.4g，28.24mmol)溶于四氢呋喃(60mL)中，氮气置换3次后，于0℃下分批缓慢加入苄基溴化镁(16.55g，84.72mmol)，室温反应过夜。反应完成后加水稀释，乙酸乙酯萃取3次，合并有机相，浓缩所得残余物经硅胶柱层析纯化得到化合物104C(4.2g，收率：67％)。LC-MS(ESI):m/z＝223.2[M+H]+。Step 2: Compound 104B (5.4 g, 28.24 mmol) was dissolved in tetrahydrofuran (60 mL), replaced with nitrogen three times, and then benzylmagnesium bromide (16.55 g, 84.72 mmol) was slowly added in batches at 0°C, and reacted at room temperature overnight. After the reaction was completed, it was diluted with water, extracted with ethyl acetate three times, and the organic phases were combined and concentrated. The residue was purified by silica gel column chromatography to obtain compound 104C (4.2 g, yield: 67%). LC-MS (ESI): m/z=223.2[M+H] + .

第三步：将化合物104C(4g，18.00mmol)、甲醛水溶液(2.16g，72mmol)、乙酸(0.22g，3.6mmol)和哌啶(0.15g，1.8mmol)溶于甲醇(60mL)中，然后80℃反应5小时。反应完成后，直接浓缩，所得残余物经硅胶柱层析纯化得到化合物104D(3.8g，收率：90％)。LC-MS(ESI):m/z＝235.2[M+H]+。Step 3: Compound 104C (4 g, 18.00 mmol), aqueous formaldehyde solution (2.16 g, 72 mmol), acetic acid (0.22 g, 3.6 mmol) and piperidine (0.15 g, 1.8 mmol) were dissolved in methanol (60 mL) and then reacted at 80° C. for 5 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104D (3.8 g, yield: 90%). LC-MS (ESI): m/z=235.2[M+H] + .

第四步：将化合物104D(3.6g，15.37mmol)溶于乙醇(35mL)，然后加入水合肼(6.16g，122.96mmol)，80℃反应4小时。反应完成后，直接浓缩，所得残余物经硅胶柱层析纯化得到化合物104E(2.8g，收率：73％)。LC-MS(ESI):m/z＝249.2[M+H]+。Step 4: Compound 104D (3.6 g, 15.37 mmol) was dissolved in ethanol (35 mL), and then hydrazine hydrate (6.16 g, 122.96 mmol) was added and reacted at 80°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104E (2.8 g, yield: 73%). LC-MS (ESI): m/z=249.2[M+H] + .

第五步：将化合物104E(2.8g，11.28mmol)和化合物100H(4.36g，14.66mmol)溶于甲苯(40mL)，然后120℃反应5小时。反应完成后，直接浓缩，所得残余物经硅胶柱层析纯化得到化合物104G(4.2g，收率：75％)。LC-MS(ESI):m/z＝500.1[M+H]+。Step 5: Compound 104E (2.8 g, 11.28 mmol) and compound 100H (4.36 g, 14.66 mmol) were dissolved in toluene (40 mL), and then reacted at 120° C. for 5 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104G (4.2 g, yield: 75%). LC-MS (ESI): m/z=500.1[M+H] + .

第六步：将化合物104G(4g，8.01mmol)和乙基二异丙胺(2.59g，20.02mmol)溶于甲苯(50mL)，然后缓慢加入三氯氧磷(1.84g，12.02mmol)，氮气保护下加热至100℃反应3小时。反应完成后，直接浓缩，所得残余物经硅胶柱层析纯化得到化合物104H(2.8g，收率：67％)。LC-MS(ESI):m/z＝518.1[M+H]+。Step 6: Compound 104G (4 g, 8.01 mmol) and ethyldiisopropylamine (2.59 g, 20.02 mmol) were dissolved in toluene (50 mL), and then phosphorus oxychloride (1.84 g, 12.02 mmol) was slowly added, and heated to 100° C. under nitrogen protection for 3 hours. After the reaction was completed, it was directly concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound 104H (2.8 g, yield: 67%). LC-MS (ESI): m/z=518.1[M+H] + .

第七步：将化合物104H(0.15g，0.29mmol)、化合物1C(0.059g，0.46mmol)和乙基二异丙胺(0.11g，0.87mmol)溶于N,N-二甲基甲酰胺(8mL)中，然后室温反应3小时。反应完成后，加水稀释，乙酸乙酯萃取3次，合并有机相浓缩，所得残余物经硅胶柱层析纯化得到化合物104I(0.13g，收率：73％)。LC-MS(ESI):m/z＝609.1[M+H]+。Step 7: Compound 104H (0.15 g, 0.29 mmol), compound 1C (0.059 g, 0.46 mmol) and ethyldiisopropylamine (0.11 g, 0.87 mmol) were dissolved in N,N-dimethylformamide (8 mL) and then reacted at room temperature for 3 hours. After the reaction was completed, water was added for dilution, ethyl acetate was extracted 3 times, the organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 104I (0.13 g, yield: 73%). LC-MS (ESI): m/z=609.1[M+H] + .

第八步：将化合物104I(130mg，0.21mmol)经手性SFC拆分得到化合物104(SFC分析保留时间：1.992min，58mg)和化合物105(SFC分析保留时间：2.349min，56mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:for甲醇；梯度:40％B梯度；洗脱流速:100mL/min；柱温:25℃；波长:220nm；循环时间:3.0min；样品制备:样品浓度5mg/mL，乙腈二氯甲烷混合溶液进样:每次3.0mL。Step 8: Compound 104I (130 mg, 0.21 mmol) was subjected to chiral SFC separation to obtain compound 104 (SFC analysis retention time: 1.992 min, 58 mg) and compound 105 (SFC analysis retention time: 2.349 min, 56 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35° C. wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: for methanol; gradient: 40% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 3.0 min; sample preparation: sample concentration 5 mg/mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

化合物104(SFC分析保留时间：1.992min)：1H NMR(400MHz,DMSO-d6)δ8.02(d,2H),7.81(d,2H),7.38(d,1H),7.33-7.17(m,6H),7.01(d,1H),5.05-4.96(m,1H),4.51-4.39(m,1H),3.90-3.80(m,1H),3.06(s,4H),1.99(s,1H),1.32-1.17(m,1H),0.99-0.79(m,4H)；LC-MS(ESI):m/z＝609.1[M+H]+。Compound 104 (SFC analysis retention time: 1.992 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d, 2H), 7.81 (d, 2H), 7.38 (d, 1H), 7.33-7.17 (m, 6H), 7.01 (d, 1H), 5.05-4.96 (m, 1H), 4.51-4.39 (m, 1H), 3.90-3.80 (m, 1H), 3.06 (s, 4H), 1.99 (s, 1H), 1.32-1.17 (m, 1H), 0.99-0.79 (m, 4H); LC-MS (ESI): m/z=609.1 [M+H] + .

化合物105(SFC分析保留时间：2.349min)：1H NMR(400MHz,DMSO-d6)δ8.02(d,2H),7.81(d,2H),7.38(d,1H),7.33-7.19(m,6H),7.01(d,1H),5.05-4.95(m,1H),4.52-4.38(m,1H),3.90-3.80(m,1H),3.06(s,4H),1.98(s,1H),1.31-1.18(m,1H),0.98-0.77(m,4H)；LC-MS(ESI):m/z＝609.1[M+H]+。Compound 105 (SFC analysis retention time: 2.349 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d, 2H), 7.81 (d, 2H), 7.38 (d, 1H), 7.33-7.19 (m, 6H), 7.01 (d, 1H), 5.05-4.95 (m, 1H), 4.52-4.38 (m, 1H), 3.90-3.80 (m, 1H), 3.06 (s, 4H), 1.98 (s, 1H), 1.31-1.18 (m, 1H), 0.98-0.77 (m, 4H); LC-MS (ESI): m/z=609.1 [M+H] + .

实施例106和实施例107
Example 106 and Example 107

第一步：将3-N-叔丁氧羰基胺基环丁胺(1g,5.81mmol)和三乙胺(1.76g,17.43mmol)溶于二氯甲烷(10mL)，再缓慢滴加化合物106A(0.90g,6.39mmol)，室温下反应2h。反应结束后浓缩，向体系中加入100mL乙酸乙酯，饱和食盐水洗涤(50mL×4)，收集有机相，无水硫酸钠干燥、浓缩，所得残余物经硅胶柱层析纯化得到化合物106B(1.2g，收率：74.78％)。Step 1: Dissolve 3-N-tert-butyloxycarbonylaminocyclobutylamine (1g, 5.81mmol) and triethylamine (1.76g, 17.43mmol) in dichloromethane (10mL), then slowly add compound 106A (0.90g, 6.39mmol) dropwise, and react at room temperature for 2h. After the reaction is completed, concentrate, add 100mL of ethyl acetate to the system, wash with saturated brine (50mL×4), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain compound 106B (1.2g, yield: 74.78%).

第二步：将化合物106B(0.3g,1.09mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(0.3mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物106C(0.2g粗品)，直接用于下一步反应。Step 2: Compound 106B (0.3 g, 1.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 106C (0.2 g crude product), which was directly used in the next step.

第三步：化合物106C(0.2g粗品)参照实施例18第一步操作得到化合物106D(0.25g，收率：65.85％)。LC-MS(ESI):m/z＝666.2[M+H]+。Step 3: Compound 106C (0.2 g crude product) was processed by referring to the first step of Example 18 to obtain Compound 106D (0.25 g, yield: 65.85%). LC-MS (ESI): m/z = 666.2 [M+H] + .

第四步：化合物106D经手性SFC拆分得到化合物106(SFC制备前出峰，80mg)和化合物107(SFC制备后出峰，85mg)。SFC制备方法:仪器:SFC Prep 150AP，柱:AS(19mm*250mm)；流动相:A:CO2,B:0.01％氨水的异丙醇；梯度:等梯度，50％B；流速:38mL/min柱温:35℃波长:220nm,循环时间:5.0min；样品制备:样品浓度3mg/mL，甲醇溶液进样:每次5mL。Step 4: Compound 106D was separated by chiral SFC to obtain compound 106 (SFC pre-preparation peak, 80 mg) and compound 107 (SFC post-preparation peak, 85 mg). SFC preparation method: instrument: SFC Prep 150AP, column: AS (19 mm*250 mm); mobile phase: A: CO 2 , B: 0.01% ammonia in isopropanol; gradient: isocratic, 50% B; flow rate: 38 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 5.0 min; sample preparation: sample concentration 3 mg/mL, methanol solution injection: 5 mL each time.

化合物106(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.62(d,1H),8.01(d,2H),7.87(d,2H),7.75(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.20(m,3H),5.10-5.05(m,1H),4.68-4.62(m,1H),4.54-4.49(m,H),4.08-3.92(m,5H),2.77-2.69(m,1H),1.07-0.96(m,2H),0.95-0.91(m,2H)；LC-MS(ESI):m/z＝666.2[M+H]+。Compound 106 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (d, 1H), 8.01 (d, 2H), 7.87 (d, 2H), 7.75 (d, 2H), 7.46 (d, 2H), 7.35-7.31 (m, 2H), 7.28-7.20 (m, 3H), 5.10-5.05 (m, 1H), 4.68-4.62 (m, 1H), 4.54-4.49 (m, H), 4.08-3.92 (m, 5H), 2.77-2.69 (m, 1H), 1.07-0.96 (m, 2H), 0.95-0.91 (m, 2H); LC-MS (ESI): m/z=666.2 [M+H] + .

化合物107(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ8.62(d,1H),8.01(d,2H),7.87(d,2H),7.75(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.20(m,3H),5.10-5.05(m,1H),4.68-4.62(m,1H),4.54-4.49(m,H),4.08-3.92(m,5H),2.77-2.69(m,1H),1.07-0.96(m,2H),0.95-0.91(m,2H)；LC-MS(ESI):m/z＝666.2[M+H]+。Compound 107 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (d, 1H), 8.01 (d, 2H), 7.87 (d, 2H), 7.75 (d, 2H), 7.46 (d, 2H), 7.35-7.31 (m, 2H), 7.28-7.20 (m, 3H), 5.10-5.05 (m, 1H), 4.68-4.62 (m, 1H), 4.54-4.49 (m, H), 4.08-3.92 (m, 5H), 2.77-2.69 (m, 1H), 1.07-0.96 (m, 2H), 0.95-0.91 (m, 2H); LC-MS (ESI): m/z=666.2 [M+H] + .

实施例108和实施例109
Example 108 and Example 109

第一步：将3-N-叔丁氧羰基胺基环丁胺(1g,5.81mmol)和三乙胺(1.76g,17.43mmol)溶于二氯甲烷(10mL)，再缓慢滴加化合物108A(1.01g,5.81mmol)，室温下反应2h。反应结束后浓缩，向体系中加入100mL乙酸乙酯，饱和食盐水洗涤(50mL×4)，收集有机相，无水硫酸钠干燥，浓缩所得残余物经硅胶柱层析纯化得到化合物108B(1.1g，收率：68.55％)。Step 1: Dissolve 3-N-tert-butyloxycarbonylaminocyclobutylamine (1g, 5.81mmol) and triethylamine (1.76g, 17.43mmol) in dichloromethane (10mL), then slowly add compound 108A (1.01g, 5.81mmol) dropwise, and react at room temperature for 2h. After the reaction is completed, concentrate, add 100mL of ethyl acetate to the system, wash with saturated brine (50mL×4), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate the residue to obtain compound 108B (1.1g, yield: 68.55%).

第二步：将化合物108B(0.2g,0.80mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(0.3mL)，在室温下搅拌过夜。将反应液减压浓缩得化合物108C(0.2g粗品)，直接用于下一步反应。Step 2: Compound 108B (0.2 g, 0.80 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 108C (0.2 g crude product), which was directly used in the next step.

第三步：化合物108C(0.2g)参照实施例18第一步操作得到化合物108D(0.27g，收率：74.01％)。LC-MS(ESI):m/z＝640.2[M+H]+。Step 3: Compound 108C (0.2 g) was treated with the same method as in the first step of Example 18 to obtain Compound 108D (0.27 g, yield: 74.01%). LC-MS (ESI): m/z = 640.2 [M+H] + .

第四步：化合物108D经手性SFC拆分得到化合物108(SFC制备前出峰，85mg)和化合物109(SFC制备后出峰，87mg)。SFC制备方法:仪器:SFC Prep 150AP，柱:AS(19mm*250mm)；流动相:A:CO2,B:0.01％氨水的异丙醇；梯度:等梯度，40％B；流速:40mL/min柱温:35℃波长:220nm,循环时间:5.0min；样品制备:样品浓度3mg/mL，甲醇溶液进样:每次5mL。Step 4: Compound 108D was separated by chiral SFC to obtain compound 108 (SFC pre-preparation peak, 85 mg) and compound 109 (SFC post-preparation peak, 87 mg). SFC preparation method: instrument: SFC Prep 150AP, column: AS (19 mm*250 mm); mobile phase: A: CO 2 , B: 0.01% ammonia in isopropanol; gradient: isocratic, 40% B; flow rate: 40 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 5.0 min; sample preparation: sample concentration 3 mg/mL, methanol solution injection: 5 mL each time.

化合物108(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.01(d,2H),7.86(d,2H),7.74(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.19(m,3H),5.10-5.05(m,1H),4.69-4.58(m,1H),4.53-4.47(m,1H),4.02-3.92(m,5H),3.03(s,3H)；LC-MS(ESI):m/z＝640.2[M+H]+。Compound 108 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, 1H), 8.01 (d, 2H), 7.86 (d, 2H), 7.74 (d, 2H), 7.46 (d, 2H), 7.35-7.31 (m, 2H), 7.28-7.19 (m, 3H), 5.10-5.05 (m, 1H), 4.69-4.58 (m, 1H), 4.53-4.47 (m, 1H), 4.02-3.92 (m, 5H), 3.03 (s, 3H); LC-MS (ESI): m/z=640.2 [M+H] + .

化合物109(SFC制备后出峰):1H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.01(d,2H),7.86(d,2H),7.74(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.19(m,3H),5.10-5.05(m,1H),4.69-4.58(m,1H),4.53-4.47(m,1H),4.02-3.92(m,5H),3.03(s,3H)；LC-MS(ESI):m/z＝640.2[M+H]+。Compound 109 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(d,1H),8.01(d,2H),7.86(d,2H),7.74(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.19(m,3H),5.10-5.05(m,1H),4.69-4.58(m,1H),4.53-4.47(m,1H),4.02-3.92(m,5H),3.03(s,3H); LC-MS(ESI):m/z＝640.2[M+H] + .

实施例110和实施例111
Example 110 and Example 111

第一步：将化合物110A(5.0g，26.45mmol)加入反应瓶，用乙腈(100mL)溶解，然后加入1,2-二溴乙烷-d4(5.08g，26.45mmol)，在85℃反应12小时。TLC监测反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化，得到化合物110B(4.4g，收率：75.92％)。1H NMR(400MHz,DMSO-d6)δ7.06-7.04(m,1H),6.99-6.95(m,1H),6.84-6.80(m,1H)。Step 1: Add compound 110A (5.0 g, 26.45 mmol) to a reaction bottle, dissolve it with acetonitrile (100 mL), then add 1,2-dibromoethane-d4 (5.08 g, 26.45 mmol), and react at 85°C for 12 hours. After the reaction is completed by TLC monitoring, cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound 110B (4.4 g, yield: 75.92%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.06-7.04 (m, 1H), 6.99-6.95 (m, 1H), 6.84-6.80 (m, 1H).

第二步：将化合物110B(4.4g，20.08mmol)、苄硫醇(4.99g，40.16mmol)、Pd(dppf)Cl2(1.46g，2.01mmol)、Xantphos(2.3g，4.02mmol)和DIPEA(10.5mL，60.24mmol)加入反应瓶，用甲苯(100mL)溶解，氮气置换三次，在100℃反应16小时。TLC监测反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110C(1.55g，收率：29.41％)。1H NMR(400MHz,DMSO-d6)δ7.30-7.19(m,5H),6.85-6.93(m,1H),6.80-6.77(m,2H),4.11(s,2H)。Step 2: Compound 110B (4.4 g, 20.08 mmol), benzyl mercaptan (4.99 g, 40.16 mmol), Pd(dppf)Cl 2 (1.46 g, 2.01 mmol), Xantphos (2.3 g, 4.02 mmol) and DIPEA (10.5 mL, 60.24 mmol) were added to a reaction bottle, dissolved with toluene (100 mL), replaced with nitrogen three times, and reacted at 100° C. for 16 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 110C (1.55 g, yield: 29.41%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.30-7.19 (m, 5H), 6.85-6.93 (m, 1H), 6.80-6.77 (m, 2H), 4.11 (s, 2H).

第三步：将化合物110C(1.5g，5.72mmol)加入反应瓶，用乙酸：水＝9:1(50mL)溶解，然后加入N-氯代丁二酰亚胺(3.1g，22.88mmol)，室温反应20min。反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110D(0.81g，收率：64.33％)。1H NMR(400MHz,DMSO-d6)δ14.61(s,1H),7.08-7.02(m,2H),6.79-6.76(m,1H)。Step 3: Add compound 110C (1.5 g, 5.72 mmol) to a reaction flask, dissolve it with acetic acid: water = 9:1 (50 mL), then add N-chlorosuccinimide (3.1 g, 22.88 mmol), and react at room temperature for 20 min. After the reaction is completed, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 110D (0.81 g, yield: 64.33%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.61 (s, 1H), 7.08-7.02 (m, 2H), 6.79-6.76 (m, 1H).

第四步：将化合物110D(0.80g，3.63mmol)加入反应瓶，用NH3的1,4二氧六环溶液(25mL)溶解，然后加入DIPEA(3mL)，室温反应16小时。反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110E(0.75g，收率：94.17％)。1H NMR(400MHz,DMSO-d6)δ7.30-7.26(m,2H),7.19(s,2H),7.02-6.99(m,1H)。Step 4: Compound 110D (0.80 g, 3.63 mmol) was added to a reaction flask, dissolved with NH 3 in 1,4-dioxane solution (25 mL), and then DIPEA (3 mL) was added and reacted at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 110E (0.75 g, yield: 94.17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.30-7.26 (m, 2H), 7.19 (s, 2H), 7.02-6.99 (m, 1H).

第五步：将化合物110E(0.61g，2.78mmol)、氯甲酸乙酯(0.60g，5.56mmol)和碳酸钾(1.15g，8.34mmol)加入反应瓶，用乙腈(30mL)溶解，在85℃反应3小时。反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110F(0.8g，收率：98.71％)。LC-MS(ESI):m/z＝292.1[M+H]+。Step 5: Compound 110E (0.61 g, 2.78 mmol), ethyl chloroformate (0.60 g, 5.56 mmol) and potassium carbonate (1.15 g, 8.34 mmol) were added to a reaction bottle, dissolved with acetonitrile (30 mL), and reacted at 85° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 110F (0.8 g, yield: 98.71%). LC-MS (ESI): m/z=292.1[M+H] + .

第六步：将化合物64C(0.11g，0.43mmol)和化合物110F(0.14g，0.47mmol)加入反应瓶，用甲苯(10mL)溶解，在120℃反应4小时。反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110G(0.2g，收率：92.99％)。LC-MS(ESI):m/z＝502.1[M+H]+。Step 6: Compound 64C (0.11 g, 0.43 mmol) and compound 110F (0.14 g, 0.47 mmol) were added to a reaction bottle, dissolved with toluene (10 mL), and reacted at 120° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 110G (0.2 g, yield: 92.99%). LC-MS (ESI): m/z=502.1[M+H] + .

第七步：将化合物110G(0.2g，0.40mmol)用甲苯(10mL)溶解，然后加入DIPEA(0.42mL，2.4mmol)和三氯氧磷(122mg，0.80mmol)，在100℃反应1小时。反应完成后，冷却到室温，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110H(0.15g，收率：72.34％)。LC-MS(ESI):m/z＝520.1[M+H]+。Step 7: Compound 110G (0.2 g, 0.40 mmol) was dissolved in toluene (10 mL), and then DIPEA (0.42 mL, 2.4 mmol) and phosphorus oxychloride (122 mg, 0.80 mmol) were added and reacted at 100°C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 110H (0.15 g, yield: 72.34%). LC-MS (ESI): m/z=520.1 [M+H] + .

第八步：将化合物110H(0.15g，0.29mmol)、化合物1C(0.15g，1.16mmol)和DIPEA(0.5mL，2.9mmol)加入反应瓶，用DCM(10mL)溶解，室温反应12小时。反应完成后，减压浓缩，所得残余物经硅胶柱层析纯化得到化合物110I(0.1g，收率：56.43％)。LC-MS(ESI):m/z＝611.3[M+H]+。Step 8: Compound 110H (0.15 g, 0.29 mmol), compound 1C (0.15 g, 1.16 mmol) and DIPEA (0.5 mL, 2.9 mmol) were added to a reaction bottle, dissolved with DCM (10 mL), and reacted at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 110I (0.1 g, yield: 56.43%). LC-MS (ESI): m/z=611.3 [M+H] + .

第九步：化合物110I经手性SFC拆分得到化合物110(SFC制备前出峰，30mg)和化合物111(SFC制备后出峰，27mg)。SFC制备方法：1.仪器：SFC prep 150AP，色谱柱：IK(19mm*250mm)，2.样品用甲醇溶解，用0.45μm滤头过滤，制成样品溶液。3.制备色谱条件：流动相A：CO2，流动相B：异丙醇，等梯度洗脱，流动相B含量60％，流量：38mL/min。Step 9: Compound 110I was subjected to chiral SFC separation to obtain compound 110 (SFC pre-preparation peak, 30 mg) and compound 111 (SFC post-preparation peak, 27 mg). SFC preparation method: 1. Instrument: SFC prep 150AP, chromatographic column: IK (19 mm*250 mm), 2. The sample was dissolved in methanol and filtered with a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatographic conditions: mobile phase A: CO 2 , mobile phase B: isopropanol, isocratic elution, mobile phase B content 60%, flow rate: 38 mL/min.

化合物110(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.55-7.49(m,2H),7.42-7.37(m,2H),7.35-7.19(m,8H),6.90-6.85(m,1H),5.04-4.97(m,1H),4.50-4.43(m,1H),3.87-3.79(m,1H),2.04-1.95(m,1H),0.92-0.82(m,4H)；LC-MS(ESI):m/z＝611.3[M+H]+。Compound 110 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 7.55-7.49 (m, 2H), 7.42-7.37 (m, 2H), 7.35-7.19 (m, 8H), 6.90-6.85 (m, 1H), 5.04-4.97 (m, 1H), 4.50-4.43 (m, 1H), 3.87-3.79 (m, 1H), 2.04-1.95 (m, 1H), 0.92-0.82 (m, 4H); LC-MS (ESI): m/z=611.3 [M+H] + .

化合物111(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.55-7.49(m,2H),7.42-7.37(m,2H),7.34-7.19(m,8H),6.90-6.86(m,1H),5.04-4.97(m,1H),4.50-4.41(m,1H),3.87-3.80(m,1H),2.05-1.94(m,1H),0.93-0.83(m,4H)；LC-MS(ESI):m/z＝611.3[M+H]+。Compound 111 (peak after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.55-7.49 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.19 (m, 8H), 6.90-6.86 (m, 1H), 5.04-4.97 (m, 1H), 4.50-4.41 (m, 1H), 3.87-3.80 (m, 1H), 2.05-1.94 (m, 1H), 0.93-0.83 (m, 4H); LC-MS (ESI): m/z=611.3 [M+H] + .

实施例112和实施例113
Example 112 and Example 113

第一步：将化合物112A(5g,28.54mmol)和三乙胺(8.66g,85.62mmol,)溶于二氯甲烷(60mL)中，然后冰水浴下加入氯甲酸乙酯(4.03g,37.10mmol)，室温反应过夜。反应完成后加入饱和碳酸氢钠溶液淬灭反应，然后加入稀盐酸调至酸性，二氯甲烷萃取3次，合并有机相浓缩得到化合物112B(7g粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝248.2[M+H]+。Step 1: Dissolve compound 112A (5 g, 28.54 mmol) and triethylamine (8.66 g, 85.62 mmol) in dichloromethane (60 mL), then add ethyl chloroformate (4.03 g, 37.10 mmol) under an ice-water bath, and react at room temperature overnight. After the reaction is completed, add saturated sodium bicarbonate solution to quench the reaction, then add dilute hydrochloric acid to adjust to acidity, extract with dichloromethane 3 times, combine the organic phases and concentrate to obtain compound 112B (7 g crude product), which is directly used in the next step. LC-MS (ESI): m/z=248.2[M+H] + .

第二步：将化合物112B(2g,8.09mmol)和化合物22D(2.70g,10.52mmol)溶于甲苯(25mL)中，然后120℃反应3小时。反应完成后冷却到室温，浓缩，所得残余物进行打浆操作得到化合物112C(3.6g，收率：97％)。LC-MS(ESI):m/z＝458.2[M+H]+。Step 2: Compound 112B (2 g, 8.09 mmol) and compound 22D (2.70 g, 10.52 mmol) were dissolved in toluene (25 mL) and then reacted at 120°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The residue was slurried to obtain compound 112C (3.6 g, yield: 97%). LC-MS (ESI): m/z = 458.2 [M+H] + .

第三步：将化合物112C(1g,2.18mmol)、DIPEA(0.70g,5.45mmol)溶于甲苯(15mL)中，然后缓慢加入三氯氧磷(0.50g,3.27mmol)，100℃反应2小时。反应完成后直接浓缩，所得残余物经硅胶柱层析纯化得到化合物112D(0.6g，收率：58％)。LC-MS(ESI):m/z＝476.3[M+H]+。Step 3: Compound 112C (1 g, 2.18 mmol) and DIPEA (0.70 g, 5.45 mmol) were dissolved in toluene (15 mL), and then phosphorus oxychloride (0.50 g, 3.27 mmol) was slowly added and reacted at 100°C for 2 hours. After the reaction was completed, the product was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 112D (0.6 g, yield: 58%). LC-MS (ESI): m/z = 476.3 [M+H] + .

第四步：将化合物112D(0.2g,0.42mmol)、化合物1C(0.080g,0.63mmol)和DIPEA(0.16g,1.26mmol)溶于DMF(10mL)中，室温反应2小时。反应完成后加水稀释,乙酸乙酯萃取3次，合并有机相浓缩，所得残余物经硅胶柱层析纯化得到化合物112E(0.13g，收率：55％)。LC-MS(ESI):m/z＝567.2[M+H]+。Step 4: Compound 112D (0.2 g, 0.42 mmol), compound 1C (0.080 g, 0.63 mmol) and DIPEA (0.16 g, 1.26 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate three times, the organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 112E (0.13 g, yield: 55%). LC-MS (ESI): m/z = 567.2 [M+H] + .

第五步：化合物112E经手性SFC拆分得到化合物112(SFC分析保留时间：2.100min，56mg)和化合物113(SFC分析保留时间：2.418min，56mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:254nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in甲醇；梯度:35％B梯度洗脱流速:120mL/min，柱温:25℃；波长:254nm；循环时间:6.5min；样品制备:样品浓度5mg/mL，甲醇和乙腈溶液进样:每次3mL。Step 5: Compound 112E was separated by chiral SFC to obtain compound 112 (SFC analysis retention time: 2.100 min, 56 mg) and compound 113 (SFC analysis retention time: 2.418 min, 56 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 254 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in methanol; gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C; wavelength: 254 nm; cycle time: 6.5 min; sample preparation: sample concentration 5 mg/mL, methanol and acetonitrile solution injection: 3 mL each time.

化合物112(SFC分析保留时间：2.100min)：1H NMR(400MHz,DMSO-d6)δ7.93-7.84(m,2H),7.52(d,2H),7.43-7.37(m,2H),7.35-7.20(m,7H),5.07-4.97(m,1H),4.54-4.41(m,1H),3.91-3.82(m,1H),2.01(d,1H),0.96-0.80(m,4H)；LC-MS(ESI):m/z＝567.2[M+H]+。Compound 112 (SFC analysis retention time: 2.100 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93-7.84 (m, 2H), 7.52 (d, 2H), 7.43-7.37 (m, 2H), 7.35-7.20 (m, 7H), 5.07-4.97 (m, 1H), 4.54-4.41 (m, 1H), 3.91-3.82 (m, 1H), 2.01 (d, 1H), 0.96-0.80 (m, 4H); LC-MS (ESI): m/z=567.2 [M+H] + .

化合物113(SFC分析保留时间：2.418min)：1H NMR(400MHz,DMSO-d6)δ7.93-7.84(m,2H),7.53(d,2H),7.44-7.36(m,2H),7.34-7.20(m,7H),5.06-4.98(m,1H),4.55-4.42(m,1H),3.93-3.80(m,1H),2.03(d,1H),0.95-0.77(m,4H)；LC-MS(ESI):m/z＝567.2[M+H]+。Compound 113 (SFC analysis retention time: 2.418 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93-7.84 (m, 2H), 7.53 (d, 2H), 7.44-7.36 (m, 2H), 7.34-7.20 (m, 7H), 5.06-4.98 (m, 1H), 4.55-4.42 (m, 1H), 3.93-3.80 (m, 1H), 2.03 (d, 1H), 0.95-0.77 (m, 4H); LC-MS (ESI): m/z=567.2 [M+H] + .

实施例114和实施例115
Example 114 and Example 115

第一步：将化合物114A(560mg，5mmol)溶于N,N-二甲基甲酰胺(20mL)，氮气氛围下加入NaH(200mg，5mmol)、继续搅拌30min后加入化合物1D(526mg,1mmol)。10min后，饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(50mL×2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，所得残余物经柱层析纯化得到目标化合物114B(562mg，收率：93.3％)。LC-MS(ESI):m/z＝602.2[M+H]+。Step 1: Compound 114A (560 mg, 5 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (200 mg, 5 mmol) was added under nitrogen atmosphere. After stirring for 30 min, compound 1D (526 mg, 1 mmol) was added. After 10 min, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain the target compound 114B (562 mg, yield: 93.3%). LC-MS (ESI): m/z=602.2[M+H] + .

第二步：将化合物144B(562mg,0.9mmol)溶于二氯甲烷(10mL)中，加入三乙胺(1mL)和环丙基甲酰氯(104mg,1mmol)，在室温下搅拌10min。浓缩反应液，所得残余物经硅胶柱层析分离后得到化合物114C(171mg，收率：28.3％)。LC-MS(ESI):m/z＝670.2[M+H]+。Step 2: Dissolve compound 144B (562 mg, 0.9 mmol) in dichloromethane (10 mL), add triethylamine (1 mL) and cyclopropylcarbonyl chloride (104 mg, 1 mmol), and stir at room temperature for 10 min. Concentrate the reaction solution, and the residue is separated by silica gel column chromatography to obtain compound 114C (171 mg, yield: 28.3%). LC-MS (ESI): m/z = 670.2 [M+H] + .

第三步：化合物114C经手性拆分得到化合物114(SFC分析保留时间：2.034min，5.6mg)和化合物115(SFC分析保留时间：2.266min，6.1mg)。SFC分析方法:仪器:SHIMADZU LC-30AD SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in MeOH；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in MeOH；梯度:35％B梯度洗脱流速:120mL/min，柱温:room temperature波长:220nm循环时间:5.0min；样品制备:样品浓度2mg/mL，甲醇溶液进样:每次2mL。Step 3: Compound 114C was subjected to chiral separation to obtain Compound 114 (SFC analysis retention time: 2.034 min, 5.6 mg) and Compound 115 (SFC analysis retention time: 2.266 min, 6.1 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.05% DEA in MeOH; Gradient: 5-40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in MeOH; Gradient: 35% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 5.0 min; Sample preparation: Sample concentration 2 mg/mL, Methanol solution injection: 2 mL each time.

化合物114(SFC分析保留时间：2.034min)：1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.15-7.02(m,13H),3.91(s,2H),3.07-2.78(m,1H),2.19-2.07(m,1H),1.10-0.69(m,4H)；LC-MS(ESI):m/z＝670.2[M+H]+。Compound 114 (SFC analysis retention time: 2.034 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.15-7.02 (m, 13H), 3.91 (s, 2H), 3.07-2.78 (m, 1H), 2.19-2.07 (m, 1H), 1.10-0.69 (m, 4H); LC-MS (ESI): m/z=670.2 [M+H] + .

化合物115(SFC分析保留时间：2.266min)：1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.15-7.02(m,13H),3.91(s,2H),3.07-2.78(m,1H),2.19-2.07(m,1H),1.10-0.69(m,4H)；LC-MS(ESI):m/z＝670.2[M+H]+。Compound 115 (SFC analysis retention time: 2.266 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.15-7.02 (m, 13H), 3.91 (s, 2H), 3.07-2.78 (m, 1H), 2.19-2.07 (m, 1H), 1.10-0.69 (m, 4H); LC-MS (ESI): m/z=670.2 [M+H] + .

实施例116、实施例117、实施例118和实施例119
Example 116, Example 117, Example 118 and Example 119

第一步：将对甲基苯磺酰胺(10g,58.4mmol)、过硫酸铵(66.63g,292mmol)和选择性氟试剂(82.76g,233.6mmol)溶于乙腈(100mL)和水(100mL)，在0℃下加入硝酸银(1.98g,11.68mmol)，然后氮气置换3次，最后升温至80℃反应5h。反应结束后，向体系中缓慢加入饱和碳酸氢钠溶液，直至没有气泡产生。然后用乙酸乙酯(100mL)萃取3次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物116B和化合物118B的混合物(5g)。Step 1: Dissolve p-toluenesulfonamide (10 g, 58.4 mmol), ammonium persulfate (66.63 g, 292 mmol) and selective fluorine reagent (82.76 g, 233.6 mmol) in acetonitrile (100 mL) and water (100 mL), add silver nitrate (1.98 g, 11.68 mmol) at 0°C, then replace with nitrogen 3 times, and finally heat to 80°C for 5 hours. After the reaction is completed, slowly add saturated sodium bicarbonate solution to the system until no bubbles are generated. Then extract with ethyl acetate (100 mL) 3 times, combine the organic phases, dry with anhydrous sodium sulfate and concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography to obtain a mixture of compound 116B and compound 118B (5 g).

化合物116B：LC-MS(ESI):m/z＝190[M+H]+。化合物118B：LC-MS(ESI):m/z＝206[M-H]-。Compound 116B: LC-MS (ESI): m/z = 190 [M+H] + . Compound 118B: LC-MS (ESI): m/z = 206 [MH] − .

第二步：将化合物116B和化合物118B的混合物(1.5g)和三乙胺(0.63g,2.15mmol)溶于二氯甲烷(30mL)，再缓慢滴加氯甲酸异丙酯(0.98g,7.96mmol)，室温下反应2h。反应结束后，向体系中加入水(100mL)，并用1M HCl调至pH＝3，然后用二氯甲烷(50mL)萃取3次，合并有机相，以无水硫酸钠干燥后减压浓缩，得到化合物116C和118C的混合物(1.6g)，直接用于下一步反应。Step 2: Dissolve the mixture of compound 116B and compound 118B (1.5 g) and triethylamine (0.63 g, 2.15 mmol) in dichloromethane (30 mL), then slowly add isopropyl chloroformate (0.98 g, 7.96 mmol) and react at room temperature for 2 h. After the reaction, add water (100 mL) to the system, adjust the pH to 3 with 1M HCl, and then extract with dichloromethane (50 mL) 3 times, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a mixture of compound 116C and 118C (1.6 g), which is directly used in the next step.

化合物116C：LC-MS(ESI):m/z＝274[M-H]-。化合物118C：LC-MS(ESI):m/z＝292[M-H]-。Compound 116C: LC-MS (ESI): m/z = 274 [MH] − . Compound 118C: LC-MS (ESI): m/z = 292 [MH] − .

第三步：将化合物116C和化合物118C的混合物(0.5g)和化合物22D(0.63g,2.15mmol)加入甲苯(30mL)中，氮气保护，加热至100℃搅拌过夜，然后冷却，浓缩，所得残余物通过硅胶柱层析纯化得到化合物116D和化合物118D的混合物(0.5g)。Step 3: Add a mixture of compound 116C and compound 118C (0.5 g) and compound 22D (0.63 g, 2.15 mmol) to toluene (30 mL), protect with nitrogen, heat to 100°C and stir overnight, then cool and concentrate. The residue is purified by silica gel column chromatography to obtain a mixture of compound 116D and compound 118D (0.5 g).

化合物116D：LC-MS(ESI):m/z＝470[M-H]-。化合物118D：LC-MS(ESI):m/z＝488[M-H]-。Compound 116D: LC-MS (ESI): m/z = 470 [MH] − . Compound 118D: LC-MS (ESI): m/z = 488 [MH] − .

第四步：将116D和化合物118D的混合物(0.5g)和DIPEA(2.64g，20.4mmol)溶于甲苯(10mL)，然后缓慢滴加入三氯氧磷(1.56g，10.2mmol)，加料完毕后体系氮气保护并100℃搅拌1h，反应液减压浓缩，所得残余物通过硅胶柱层析纯化得到化合物116E和化合物118E的混合物(0.4g)。Step 4: A mixture of 116D and compound 118D (0.5 g) and DIPEA (2.64 g, 20.4 mmol) were dissolved in toluene (10 mL), and then phosphorus oxychloride (1.56 g, 10.2 mmol) was slowly added dropwise. After the addition was completed, the system was protected by nitrogen and stirred at 100°C for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a mixture of compound 116E and compound 118E (0.4 g).

化合物116E:LC-MS(ESI):m/z＝488[M-H]-。化合物118E:LC-MS(ESI):m/z＝506[M-H]-。Compound 116E: LC-MS (ESI): m/z = 488 [MH] − . Compound 118E: LC-MS (ESI): m/z = 506 [MH] − .

第五步:将化合物116E和化合物118E的混合物(0.4g)和三乙胺(0.16mg，1.58mmol)溶于DMF(8mL)中，然后加入化合物1C(0.15g，1.19mmol)，加料完毕后室温搅拌过夜。反应完毕后向体系中加入水(50mL),然后用乙酸乙酯(50mL)萃取3次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物送制备HPLC纯化，得到化合物116F(80mg)和化合物118F(51mg)。Step 5: The mixture of compound 116E and compound 118E (0.4 g) and triethylamine (0.16 mg, 1.58 mmol) were dissolved in DMF (8 mL), and then compound 1C (0.15 g, 1.19 mmol) was added. After the addition was completed, the mixture was stirred at room temperature overnight. After the reaction was completed, water (50 mL) was added to the system, and then extracted with ethyl acetate (50 mL) 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 116F (80 mg) and compound 118F (51 mg).

化合物116F:LC-MS(ESI):m/z＝581[M+H]+。化合物118F:LC-MS(ESI):m/z＝599[M+H]+。Compound 116F: LC-MS (ESI): m/z = 581 [M+H] + . Compound 118F: LC-MS (ESI): m/z = 599 [M+H] + .

第六步：化合物116F经手性SFC拆分得到化合物116(SFC制备前出峰，22mg)和化合物117(SFC制备后出峰，29mg)。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK column；流动相:A:CO2,B:0.05％DEA in m乙醇；梯度:5-40％B in A；流速:120mL/min柱温:35℃波长:220nm,循环时间:6.8min；样品制备:样品浓度2mg/mL，甲醇溶液进样:每次2mL。Step 6: Compound 116F was separated by chiral SFC to obtain compound 116 (pre-SFC peak, 22 mg) and compound 117 (post-SFC peak, 29 mg). SFC preparation method: Instrument: Waters 150 Prep-SFC, column: Chiral IK column; Mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol; Gradient: 5-40% B in A; Flow rate: 120 mL/min Column temperature: 35°C Wavelength: 220 nm, Cycle time: 6.8 min; Sample preparation: Sample concentration 2 mg/mL, Methanol solution injection: 2 mL each time.

化合物118F经手性SFC拆分得到化合物118(SFC制备前出峰，16mg)和化合物119(SFC制备后出峰，16mg)。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IK column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:5-40％B in A；流速:100mL/min柱温:35℃波长:220nm,循环时间:3.6min；样品制备:样品浓度2mg/mL，乙醇溶液进样:每次2mL。Compound 118F was separated by chiral SFC to obtain compound 118 (pre-SFC preparation peak, 16 mg) and compound 119 (post-SFC preparation peak, 16 mg). SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK column; mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; gradient: 5-40% B in A; flow rate: 100 mL/min column temperature: 35°C wavelength: 220 nm, cycle time: 3.6 min; sample preparation: sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.

化合物116(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ7.90-7.84(m,2H),7.54-7.46(m,4H),7.42-7.36(m,2H),7.34-7.20(m,5H),5.48(d,2H),5.01-4.99(m,1H),4.50-4.44(m,1H),3.89-3.84(m,1H),2.00(s,1H),0.94-0.78(m,4H)；LC-MS(ESI):m/z＝581.1[M+H]+。Compound 116 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.90-7.84 (m, 2H), 7.54-7.46 (m, 4H), 7.42-7.36 (m, 2H), 7.34-7.20 (m, 5H), 5.48 (d, 2H), 5.01-4.99 (m, 1H), 4.50-4.44 (m, 1H), 3.89-3.84 (m, 1H), 2.00 (s, 1H), 0.94-0.78 (m, 4H); LC-MS (ESI): m/z=581.1 [M+H] + .

化合物117(SFC制备后出峰)：1H NMR(400MHz,DMSO-d6)δ7.89-7.84(m,2H),7.55-7.45(m,4H),7.42-7.37(m,2H),7.34-7.20(m,5H),5.48(d,2H),5.01-4.99(m,1H),4.50-4.44(m,1H),3.89-3.84(m,1H),2.00(s,1H),0.97-0.79(m,4H)；LC-MS(ESI):m/z＝581.1[M+H]+。Compound 117 (eluted after SFC preparation): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.89-7.84 (m, 2H), 7.55-7.45 (m, 4H), 7.42-7.37 (m, 2H), 7.34-7.20 (m, 5H), 5.48 (d, 2H), 5.01-4.99 (m, 1H), 4.50-4.44 (m, 1H), 3.89-3.84 (m, 1H), 2.00 (s, 1H), 0.97-0.79 (m, 4H); LC-MS (ESI): m/z=581.1 [M+H] + .

化合物118(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),7.96(d,2H),7.65(d,2H),7.55-7.46(m,2H),7.44-7.35(m,2H),7.34-7.22(m,5H),7.22-6.95(m,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.99(s,1H),0.95-0.81(m,4H)；LC-MS(ESI):m/z＝599.2[M+H]+。Compound 118 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 7.96 (d, 2H), 7.65 (d, 2H), 7.55-7.46 (m, 2H), 7.44-7.35 (m, 2H), 7.34-7.22 (m, 5H), 7.22-6.95 (m, 1H), 5.04-5.00 (m, 1H), 4.51-4.45 (m, 1H), 3.90-3.85 (m, 1H), 1.99 (s, 1H), 0.95-0.81 (m, 4H); LC-MS (ESI): m/z=599.2 [M+H] + .

化合物119(SFC制备前出峰)：1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),7.96(d,2H),7.65(d,2H),7.53-7.49(m,2H),7.41-7.37(m,2H),7.33-7.22(m,5H),7.22-6.95(m,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.99(s,1H),0.97-0.80(m,4H)；LC-MS(ESI):m/z＝599.2[M+H]+。Compound 119 (pre-SFC preparation peak): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 7.96 (d, 2H), 7.65 (d, 2H), 7.53-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.33-7.22 (m, 5H), 7.22-6.95 (m, 1H), 5.04-5.00 (m, 1H), 4.51-4.45 (m, 1H), 3.90-3.85 (m, 1H), 1.99 (s, 1H), 0.97-0.80 (m, 4H); LC-MS (ESI): m/z=599.2 [M+H] + .

实施例120和实施例121
Example 120 and Example 121

第一步：将化合物120A(2.00g,7.27mmol)、甲醛水溶液(0.87g,29.08mmol,37％含量)、哌啶(62mg,0.73mmol)和冰乙酸(87mg,1.45mmol)先后加入无水甲醇(50mL)中，然后加热至80℃搅拌4小时。冷却，浓缩，所得残余物通过硅胶柱层析纯化得到化合物120B(1.9g,收率：91％)。LC-MS(ESI):m/z＝287.0[M+H]+。Step 1: Compound 120A (2.00 g, 7.27 mmol), aqueous formaldehyde solution (0.87 g, 29.08 mmol, 37% content), piperidine (62 mg, 0.73 mmol) and glacial acetic acid (87 mg, 1.45 mmol) were added to anhydrous methanol (50 mL) successively, and then heated to 80° C. and stirred for 4 hours. After cooling and concentration, the residue was purified by silica gel column chromatography to obtain compound 120B (1.9 g, yield: 91%). LC-MS (ESI): m/z=287.0[M+H] + .

第二步：将化合物120B(1.9g,6.62mmol)和水合肼(3.31g,52.96mmol，80％含量)加入无水乙醇(50mL)中，氮气保护，加热至80℃搅拌4小时。冷却，过滤，滤饼用无水乙醇洗涤，烘干后得到化合物120C(1.5g,收率：76％)。LC-MS(ESI):m/z＝301.0[M+H]+。Step 2: Compound 120B (1.9 g, 6.62 mmol) and hydrazine hydrate (3.31 g, 52.96 mmol, 80% content) were added to anhydrous ethanol (50 mL), and heated to 80°C with nitrogen protection and stirred for 4 hours. The mixture was cooled, filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 120C (1.5 g, yield: 76%). LC-MS (ESI): m/z = 301.0 [M+H] + .

第三步：将化合物120C(1.5g,4.98mmol)和化合物120I(1.41g,4.98mmol)加入甲苯(30mL)中，加热至100℃搅拌2小时。冷却，浓缩，所得残余物通过硅胶柱层析纯化得到化合物120D(2.4g,收率：87％)。LC-MS(ESI):m/z＝552.1[M+H]+。Step 3: Compound 120C (1.5 g, 4.98 mmol) and compound 120I (1.41 g, 4.98 mmol) were added to toluene (30 mL), heated to 100°C and stirred for 2 hours. After cooling and concentration, the residue was purified by silica gel column chromatography to obtain compound 120D (2.4 g, yield: 87%). LC-MS (ESI): m/z = 552.1 [M+H] + .

第四步：将化合物120D(600mg，1.09mmol)和三异丙基硅基乙炔(800mg,4.36mmol)溶于四氢呋喃(25mL)中，依次加入Pd(PPh3)2Cl2(77mg,0.11mmol)、碘化亚铜(21mg，0.11mmol)和三乙胺(550mg，5.45mmol)，氮气置换三次后，氮气保护下于60℃反应16小时。反应结束后，加入饱和氯化铵水溶液(20mL)，以乙酸乙酯萃取两次，有机相合并浓缩，所得残余物经硅胶柱层析纯化得化合物120E(200mg,收率：28％)。LC-MS(ESI):m/z＝654.2[M+H]+。Step 4: Compound 120D (600 mg, 1.09 mmol) and triisopropylsilyl acetylene (800 mg, 4.36 mmol) were dissolved in tetrahydrofuran (25 mL), and Pd(PPh 3 ) 2 Cl 2 (77 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol) and triethylamine (550 mg, 5.45 mmol) were added in sequence. After nitrogen replacement three times, the mixture was reacted at 60° C. under nitrogen protection for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 120E (200 mg, yield: 28%). LC-MS (ESI): m/z=654.2[M+H] + .

第五步：向50mL的单口瓶中加入甲苯(20mL)，随后加入化合物120E(200mg，0.31mmol)和DIPEA(120mg，0.93mmol)，然后缓慢滴加入三氯氧磷(140mg，0.93mmol)，加料完毕后体系氮气保护并100℃搅拌2h。反应液冷却后减压浓缩，所得残余物经硅胶柱层析纯化得化合物120F(100mg,收率：49％)。LC-MS(ESI):m/z＝672.2[M+H]+。Step 5: Add toluene (20 mL) to a 50 mL single-mouth bottle, then add compound 120E (200 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol), then slowly add phosphorus oxychloride (140 mg, 0.93 mmol), after the addition is complete, the system is protected by nitrogen and stirred at 100 ° C for 2 h. After the reaction solution is cooled, it is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 120F (100 mg, yield: 49%). LC-MS (ESI): m/z=672.2[M+H] + .

第六步：向50mL的单口瓶中加入化合物120F(270mg，0.40mmol)和二氯甲烷(10mL)溶解，加入化合物1C(140mg，0.60mmol)，随后加入DIPEA(160mg，1.20mmol)，加料完毕后室温搅拌16h。减压浓缩，残余物中加入水(20mL)，搅拌5min,二氯甲烷萃取3次，分离出有机相，无水硫酸钠干燥，减压浓缩，粗品经硅胶柱层析纯化得到化合物120G(200mg,收率：65％)。LC-MS(ESI):m/z＝763.3[M+H]+。Step 6: Add compound 120F (270 mg, 0.40 mmol) and dichloromethane (10 mL) to a 50 mL single-mouth bottle to dissolve, add compound 1C (140 mg, 0.60 mmol), and then add DIPEA (160 mg, 1.20 mmol). After the addition is complete, stir at room temperature for 16 h. Concentrate under reduced pressure, add water (20 mL) to the residue, stir for 5 min, extract with dichloromethane 3 times, separate the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain compound 120G (200 mg, yield: 65%). LC-MS (ESI): m/z=763.3[M+H] + .

第七步：将化合物120G(200mg，0.26mmol)溶于5mL四氢呋喃中，加入四丁基氟化铵(0.52mL，0.52mmol，1M in THF)，室温下搅拌反应3小时。反应结束后，将反应液浓缩，残余物通过硅胶柱层析纯化得到化合物120H(120mg，收率：75％)。LC-MS(ESI):m/z＝607.2[M+H]+。Step 7: Compound 120G (200 mg, 0.26 mmol) was dissolved in 5 mL of tetrahydrofuran, tetrabutylammonium fluoride (0.52 mL, 0.52 mmol, 1 M in THF) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 120H (120 mg, yield: 75%). LC-MS (ESI): m/z=607.2 [M+H] + .

第八步：将化合物120H进一步经手性SFC拆分得到化合物120(SFC分析保留时间：1.957min，31mg)和化合物121(SFC分析保留时间：2.091min，20mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral Whelk Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral IC Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:40％B梯度洗脱流速:100mL/min，柱温:25℃波长:220nm循环时间:3.8min样品制备:样品浓度10mg/mL，甲醇溶液进样:每次2.0mL。Step 8: Compound 120H was further separated by chiral SFC to obtain compound 120 (SFC analysis retention time: 1.957 min, 31 mg) and compound 121 (SFC analysis retention time: 2.091 min, 20 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral Whelk Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 3.8 min Sample preparation: Sample concentration 10 mg/mL, methanol solution injection: 2.0 mL each time.

化合物120(SFC分析保留时间：1.957min)：1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.05-7.99(m,2H),7.85-7.78(m,2H),7.54-7.47(m,2H),7.44-7.37(m,2H),7.35-7.20(m,5H),5.10-4.97(m,1H),4.56-4.43(m,1H),4.29(s,1H),3.93-3.82(m,1H),2.04-1.92(m,1H),0.95-0.81(m,4H)；LC-MS(ESI):m/z＝607.3[M+H]+。Compound 120 (SFC analysis retention time: 1.957 min): 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.05-7.99 (m, 2H), 7.85-7.78 (m, 2H), 7.54-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.35-7.20 (m, 5H), 5.10-4.97 (m, 1H), 4.56-4.43 (m, 1H), 4.29 (s, 1H), 3.93-3.82 (m, 1H), 2.04-1.92 (m, 1H), 0.95-0.81 (m, 4H); LC-MS (ESI): m/z = 607.3 [M+H] + .

化合物121(SFC分析保留时间：2.091min)：1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.05-7.99(m,2H),7.85-7.78(m,2H),7.54-7.47(m,2H),7.44-7.37(m,2H),7.35-7.20(m,5H),5.10-4.97(m,1H),4.56-4.43(m,1H),4.29(s,1H),3.93-3.82(m,1H),2.04-1.92(m,1H),0.95-0.81(m,4H)；LC-MS(ESI):m/z＝607.3[M+H]+。Compound 121 (SFC analysis retention time: 2.091 min): 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.05-7.99 (m, 2H), 7.85-7.78 (m, 2H), 7.54-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.35-7.20 (m, 5H), 5.10-4.97 (m, 1H), 4.56-4.43 (m, 1H), 4.29 (s, 1H), 3.93-3.82 (m, 1H), 2.04-1.92 (m, 1H), 0.95-0.81 (m, 4H); LC-MS (ESI): m/z = 607.3 [M+H] + .

实施例122和实施例123
Example 122 and Example 123

第一步：将化合物122A(2g,17.69mmol)和BOC-胍(3.38g,21.23mmol)溶于四氢呋喃(40mL)中，加入三乙胺(5.36g,53.07mmol)，然后加入1-正丙基磷酸酐(16.88g,26.54mmol)，氮气保护中室温搅拌2h。加水(50mL)淬灭反应，并用乙酸乙酯(50mL)萃取两次，收集有机相，经饱和食盐水洗涤，无水硫酸钠干燥后浓缩，所得残余物经柱层析纯化得到化合物122B(1.6g,收率：36％)。LC-MS(ESI):m/z＝255.1[M+H]+。Step 1: Compound 122A (2 g, 17.69 mmol) and BOC-guanidine (3.38 g, 21.23 mmol) were dissolved in tetrahydrofuran (40 mL), triethylamine (5.36 g, 53.07 mmol) was added, and then 1-n-propylphosphoric anhydride (16.88 g, 26.54 mmol) was added, and stirred at room temperature for 2 h under nitrogen protection. Water (50 mL) was added to quench the reaction, and extracted twice with ethyl acetate (50 mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain compound 122B (1.6 g, yield: 36%). LC-MS (ESI): m/z=255.1[M+H] + .

第二步：将化合物122B(1.6g,6.30mmol)溶于二氯甲烷(35mL)中，加入三氟乙酸(10mL)，室温搅拌16h。加氢氧化钠溶液(50mL)淬灭反应，并用二氯甲烷(50mL)萃取两次，收集有机相，经饱和食盐水洗涤，无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物122C(459mg,收率：47％)。LC-MS(ESI):m/z＝155.1[M+H]+。Step 2: Compound 122B (1.6 g, 6.30 mmol) was dissolved in dichloromethane (35 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched with sodium hydroxide solution (50 mL), and extracted twice with dichloromethane (50 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 122C (459 mg, yield: 47%). LC-MS (ESI): m/z=155.1[M+H] + .

第三步：将化合物122C(200mg,1.30mmol)和化合物1D(666mg，1.30mmol)溶于DMF(10mL)中，加入甲醇钠(210mg,3.90mmol)，室温搅拌过夜。加水(40mL)淬灭反应，用二氯甲烷(50mL)萃取三次，收集有机相，经无水硫酸钠干燥后浓缩，所得残余物经硅胶柱层析纯化得到化合物122D(350mg,收率：42％)。LC-MS(ESI):m/z＝644.2[M+H]+。Step 3: Compound 122C (200 mg, 1.30 mmol) and compound 1D (666 mg, 1.30 mmol) were dissolved in DMF (10 mL), sodium methoxide (210 mg, 3.90 mmol) was added, and the mixture was stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 122D (350 mg, yield: 42%). LC-MS (ESI): m/z=644.2[M+H] + .

第四步：将化合物122D进一步经手性SFC拆分得到化合物122(SFC分析保留时间：0.831min，98.0mg)和化合物123(SFC分析保留时间：1.276min，96.9mg)。SFC分析方法:仪器:SHIMADZU LC-30AD SFC，柱:Chiral IX column；流动相:A:CO2,B:0.05％DEA in m乙醇；梯度:5％-40％B；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法：仪器:Waters 150 Prep-SFC，柱:Chiral IK column；流动相:A:CO2,B:甲醇；梯度:45％B梯度洗脱流速:120mL/min，柱温:室温波长:220nm循环时间:6.5min样品制备:样品浓度10mg/mL，乙醇溶液进样:每次2.0mL。Step 4: Compound 122D was further separated by chiral SFC to obtain compound 122 (SFC analysis retention time: 0.831 min, 98.0 mg) and compound 123 (SFC analysis retention time: 1.276 min, 96.9 mg). SFC analysis method: instrument: SHIMADZU LC-30AD SFC, column: Chiral IX column; mobile phase: A: CO 2 , B: 0.05% DEA in m ethanol; gradient: 5%-40% B; flow rate: 3 mL/min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO 2 , B: methanol; Gradient: 45% B gradient elution flow rate: 120 mL/min, Column temperature: room temperature Wavelength: 220 nm Cycle time: 6.5 min Sample preparation: Sample concentration 10 mg/mL, Ethanol solution injection: 2.0 mL each time.

化合物122(SFC分析保留时间：0.831min):1H NMR(400MHz,DMSO-d6))δ8.70(s,1H),8.25(s,1H),8.03(d,2H),7.88(s,1H),7.80(d,2H),7.53(d,2H),7.37(d,2H),7.34-7.17(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝644.0[M+H]+。Compound 122 (SFC analysis retention time: 0.831 min): 1 H NMR (400 MHz, DMSO-d 6 )) δ 8.70 (s, 1H), 8.25 (s, 1H), 8.03 (d, 2H), 7.88 (s, 1H), 7.80 (d, 2H), 7.53 (d, 2H), 7.37 (d, 2H), 7.34-7.17 (m, 5H), 5.06-5.02 (m, 1H), 4.54-4.48 (m, 1H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=644.0 [M+H] + .

化合物123(SFC分析保留时间：1.276min):1H NMR(400MHz,DMSO-d6))δ8.70(s,1H),8.25(s,1H),8.03(d,2H),7.88(s,1H),7.80(d,2H),7.53(d,2H),7.37(d,2H),7.34-7.17(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H)；LC-MS(ESI):m/z＝644.0[M+H]+。Compound 123 (SFC analysis retention time: 1.276 min): 1 H NMR (400 MHz, DMSO-d 6 )) δ 8.70 (s, 1H), 8.25 (s, 1H), 8.03 (d, 2H), 7.88 (s, 1H), 7.80 (d, 2H), 7.53 (d, 2H), 7.37 (d, 2H), 7.34-7.17 (m, 5H), 5.06-5.02 (m, 1H), 4.54-4.48 (m, 1H), 3.92-3.88 (m, 1H); LC-MS (ESI): m/z=644.0 [M+H] + .

实施例124和实施例125
Example 124 and Example 125

第一步：化合物124A(2g，12.69mmol)溶于二氯甲烷(50mL)中，冰水浴下缓慢加入HATU(5.79g，15.23mmol)，三乙胺(3.85g，38.07mmol)，然后加入N,O-二甲基羟胺盐酸盐(1.78g，18.3mmol)，室温反应2小时。加水(100mL)，二氯甲烷(50mL)萃取，无水硫酸钠干燥后减压浓缩，残余物经硅胶柱层析纯化得到化合物124B(2.2g，收率：86％)。LC-MS(ESI):m/z＝201.1[M+H]+。Step 1: Compound 124A (2 g, 12.69 mmol) was dissolved in dichloromethane (50 mL), HATU (5.79 g, 15.23 mmol), triethylamine (3.85 g, 38.07 mmol) were slowly added under ice-water bath, and then N, O-dimethylhydroxylamine hydrochloride (1.78 g, 18.3 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Water (100 mL) was added, and dichloromethane (50 mL) was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124B (2.2 g, yield: 86%). LC-MS (ESI): m/z=201.1[M+H] + .

第二步：将化合物124B(2.2g，10.97mmol)溶于四氢呋喃(60mL)中，氮气置换3次后，于0℃下分批缓慢加入苄基溴化镁(2.48g，14.46mmol)，室温反应过夜。反应完成后加水(80mL)稀释，乙酸乙酯(50mL)萃取，减压浓缩，残余物经硅胶柱层析纯化得到化合物124C(1.8g，收率：71％)。LC-MS(ESI):m/z＝232.2[M+H]+。Step 2: Compound 124B (2.2 g, 10.97 mmol) was dissolved in tetrahydrofuran (60 mL), replaced with nitrogen three times, and then benzylmagnesium bromide (2.48 g, 14.46 mmol) was slowly added in batches at 0°C, and reacted at room temperature overnight. After the reaction was completed, water (80 mL) was added for dilution, and ethyl acetate (50 mL) was extracted and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124C (1.8 g, yield: 71%). LC-MS (ESI): m/z=232.2[M+H] + .

第三步：将化合物124C(1.6g，6.91mmol)、甲醛水溶液(2.59g，34.55mmol)、乙酸(91mg，1.5mmol)和哌啶(88mg，1.1mmol)溶于甲醇(60mL)中，然后80℃反应5小时。反应完成后，加水(50mL)稀释，乙酸乙酯(30mL)萃取，减压浓缩，残余物经硅胶柱层析纯化得到化合物124D(1g，收率：59％)。LC-MS(ESI):m/z＝244.2[M+H]+。Step 3: Compound 124C (1.6 g, 6.91 mmol), aqueous formaldehyde solution (2.59 g, 34.55 mmol), acetic acid (91 mg, 1.5 mmol) and piperidine (88 mg, 1.1 mmol) were dissolved in methanol (60 mL) and then reacted at 80°C for 5 hours. After the reaction was completed, water (50 mL) was added for dilution, ethyl acetate (30 mL) was extracted, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124D (1 g, yield: 59%). LC-MS (ESI): m/z=244.2[M+H] + .

第四步：将化合物124D(1.0g，2.99mmol)溶于乙醇(35mL)，然后加入水合肼(0.94g，14.95mmol)，80℃反应4小时。反应完成后，直接浓缩，得到化合物124E(1.2g粗品)，直接用于下一步反应。Step 4: Compound 124D (1.0 g, 2.99 mmol) was dissolved in ethanol (35 mL), and then hydrazine hydrate (0.94 g, 14.95 mmol) was added and reacted at 80° C. for 4 hours. After the reaction was completed, it was directly concentrated to obtain compound 124E (1.2 g crude product), which was directly used in the next step.

LC-MS(ESI):m/z＝258.2[M+H]+。LC-MS (ESI): m/z=258.2[M+H] + .

第五步：将化合物124E(1.3g，5.04mmol)和化合物100H(1.43g，5.04mmol)溶于甲苯(40mL)，然后120℃反应5小时。反应完成后，直接浓缩，残余物经硅胶柱层析纯化得到化合物124F(0.60g，收率：23％)。LC-MS(ESI):m/z＝509.2[M+H]+。Step 5: Compound 124E (1.3 g, 5.04 mmol) and compound 100H (1.43 g, 5.04 mmol) were dissolved in toluene (40 mL), and then reacted at 120° C. for 5 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography to obtain compound 124F (0.60 g, yield: 23%). LC-MS (ESI): m/z=509.2[M+H] + .

第六步：将化合物124F(0.5g，0.98mmol)和DIPEA(0.32g，2.45mmol)溶于甲苯(20mL)，缓慢加入三氯氧磷(0.23g，1.47mmol)，氮气保护下加热至100℃反应1小时。反应完成后，加水(50mL)稀释，乙酸乙酯(30mL)萃取，减压浓缩，残余物经硅胶柱层析纯化得到化合物124G(0.23g，收率：44％)。LC-MS(ESI):m/z＝527.1[M+H]+。Step 6: Compound 124F (0.5 g, 0.98 mmol) and DIPEA (0.32 g, 2.45 mmol) were dissolved in toluene (20 mL), phosphorus oxychloride (0.23 g, 1.47 mmol) was slowly added, and the mixture was heated to 100° C. under nitrogen protection for 1 hour. After the reaction was completed, water (50 mL) was added for dilution, ethyl acetate (30 mL) was used for extraction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124G (0.23 g, yield: 44%). LC-MS (ESI): m/z=527.1[M+H] + .

第七步：将化合物124G(0.23g，0.44mmol)、化合物1C(0.11g，0.88mmol)和DIPEA(0.17g，1.32mmol)溶于二氯甲烷(10mL)中，室温反应3小时。反应完成后，加水(20mL)稀释，乙酸乙酯(20mL)萃取，减压浓缩，残余物经硅胶柱层析纯化得到化合物124H(0.08g，收率：29％)。LC-MS(ESI):m/z＝618.1[M+H]+。Step 7: Compound 124G (0.23 g, 0.44 mmol), compound 1C (0.11 g, 0.88 mmol) and DIPEA (0.17 g, 1.32 mmol) were dissolved in dichloromethane (10 mL) and reacted at room temperature for 3 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (20 mL) was extracted, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124H (0.08 g, yield: 29%). LC-MS (ESI): m/z=618.1[M+H] + .

第八步：将化合物124H(80mg)经手性SFC拆分得到化合物124(SFC分析保留时间：2.130min，20mg)和化合物125(SFC分析保留时间：2.628min，21mg)。SFC分析方法:仪器:SHIMADZU LC-30AD sf，柱:Chiral WHELK Column；流动相:A:CO2,B:0.05％DEA in甲醇；梯度:5-40％B in A；流速:3.0mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHELK Column；流动相:A:CO2,B:for乙醇；梯度:50％B梯度；洗脱流速:100mL/min；柱温:25℃；波长:220nm；循环时间:5.0min；样品制备:样品浓度4mg/mL，乙腈乙醇混合溶液进样:每次3.0mL。Step 8: Compound 124H (80 mg) was subjected to chiral SFC separation to obtain compound 124 (SFC analysis retention time: 2.130 min, 20 mg) and compound 125 (SFC analysis retention time: 2.628 min, 21 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: 0.05% DEA in methanol; gradient: 5-40% B in A; flow rate: 3.0 mL/min column temperature: 35° C. wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHELK Column; mobile phase: A: CO 2 , B: for ethanol; gradient: 50% B gradient; elution flow rate: 100 mL/min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.0 min; sample preparation: sample concentration 4 mg/mL, acetonitrile ethanol mixed solution injection: 3.0 mL each time.

化合物124(SFC分析保留时间：2.130min)：1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.45(d,1H),8.03(d,2H),7.90-7.87(m,1H),7.82(d,2H),7.51(d,1H),7.35-7.23(m,5H),5.12-5.05(m,1H),4.52(t,1H),3.93-3.89(m,1H),2.03-1.92(m,1H),0.97-0.76(m,4H)；LC-MS(ESI):m/z＝618.1[M+H]+。Compound 124 (SFC analysis retention time: 2.130 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.45 (d, 1H), 8.03 (d, 2H), 7.90-7.87 (m, 1H), 7.82 (d, 2H), 7.51 (d, 1H), 7.35-7.23 (m, 5H), 5.12-5.05 (m, 1H), 4.52 (t, 1H), 3.93-3.89 (m, 1H), 2.03-1.92 (m, 1H), 0.97-0.76 (m, 4H); LC-MS (ESI): m/z=618.1 [M+H] + .

化合物125(SFC分析保留时间：2.628min)：1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.45(d,1H),8.03(d,2H),7.91-7.88(m,1H),7.82(d,2H),7.51(d,1H),7.35-7.23(m,5H),5.11-5.07(m,1H),4.53(t,1H),3.93-3.89(m,1H),2.02-1.94(m,1H),0.99-0.80(m,4H)；LC-MS(ESI):m/z＝618.1[M+H]+。Compound 125 (SFC analysis retention time: 2.628 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.45 (d, 1H), 8.03 (d, 2H), 7.91-7.88 (m, 1H), 7.82 (d, 2H), 7.51 (d, 1H), 7.35-7.23 (m, 5H), 5.11-5.07 (m, 1H), 4.53 (t, 1H), 3.93-3.89 (m, 1H), 2.02-1.94 (m, 1H), 0.99-0.80 (m, 4H); LC-MS (ESI): m/z=618.1 [M+H] + .

实施例126、实施例127、实施例128和实施例129

Example 126, Example 127, Example 128 and Example 129

第一步：将化合物126A(2g,3.85mmol,根据文献Journal of Medicinal Chemistry,60(3),1126-1141合成)、乙烯基三氟硼酸钾(1.03g,7.71mmol)、Pd(PPh3)4(445mg,0.38mmol)和碳酸铯(3.76g,11.6mmol)溶于1,4-二氧六环和水的混合溶剂中(dioxane：H2O＝10:1,共计110mL)中，氮气置换三次后，于80℃下搅拌反应4h。反应结束后，加水(30mL)淬灭反应，用100mL二氯甲烷萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物126B(1.1g,收率：61％)。LC-MS(ESI):m/z＝464.3[M-H]-。Step 1: Compound 126A (2 g, 3.85 mmol, synthesized according to Journal of Medicinal Chemistry, 60 (3), 1126-1141), potassium vinyl trifluoroborate (1.03 g, 7.71 mmol), Pd(PPh 3 ) 4 (445 mg, 0.38 mmol) and cesium carbonate (3.76 g, 11.6 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (dioxane: H 2 O=10:1, 110 mL in total), replaced with nitrogen three times, and stirred at 80° C. for 4 h. After the reaction was completed, water (30 mL) was added to quench the reaction, and the mixture was extracted twice with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 126B (1.1 g, yield: 61%). LC-MS (ESI): m/z=464.3[MH] - .

第二步：将化合物126B(1.1g，2.36mmol)和NIS(586mg,2.60mmol)溶于20mL无水DCM中，氮气保护下于-10℃搅拌10min。随后-10℃下缓慢滴加氟化氢吡啶溶液(270mg，260mmol)，从-10℃缓慢恢复到室温继续反应1h。反应完全后，冰浴下缓慢滴加饱和碳酸氢钠水溶液20mL，分液，水相用20mL二氯甲烷萃取一次后，合并有机相干燥，浓缩所得残余物通过硅胶柱层析分离得到化合物126C(510mg，包含原料126B的混合物)。LC-MS(ESI):m/z＝609.9[M-H]-&464.3[M-H]-。Step 2: Compound 126B (1.1 g, 2.36 mmol) and NIS (586 mg, 2.60 mmol) were dissolved in 20 mL of anhydrous DCM and stirred at -10 °C for 10 min under nitrogen protection. Then, hydrogen fluoride pyridine solution (270 mg, 260 mmol) was slowly added dropwise at -10 °C, and the mixture was slowly restored from -10 °C to room temperature and continued to react for 1 h. After the reaction was complete, 20 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise under an ice bath, and the liquids were separated. The aqueous phase was extracted once with 20 mL of dichloromethane, and the organic phases were combined and dried. The residue obtained by concentration was separated by silica gel column chromatography to obtain compound 126C (510 mg, a mixture containing raw material 126B). LC-MS (ESI): m/z=609.9 [MH] - & 464.3 [MH] - .

第三步：将化合物126C和126B的混合物(510mg，按全为126C计算当量：0.83mmol)，溶于10mL DCM中，加入DBU(253mg，1.67mmol)，室温反应过夜。反应完全后，冰浴下缓慢滴加饱和碳酸氢钠水溶液10mL，分液，水相用10mL二氯甲烷萃取一次后，有机相合并干燥，浓缩即得化合物126D(320mg，包含126B的混合物)，直接用于下一步反应。LC-MS(ESI):m/z＝481.9[M-H]-&464.3[M-H]-。Step 3: The mixture of compound 126C and 126B (510 mg, equivalent weight calculated based on 126C: 0.83 mmol) was dissolved in 10 mL of DCM, and DBU (253 mg, 1.67 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was complete, 10 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise under an ice bath, and the liquids were separated. The aqueous phase was extracted once with 10 mL of dichloromethane, and the organic phases were combined, dried, and concentrated to obtain compound 126D (320 mg, a mixture containing 126B), which was directly used for the next step. LC-MS (ESI): m/z = 481.9 [MH] - & 464.3 [MH] - .

第四步：向25mL的单口瓶中加入甲苯(5mL)，随后加入化合物126D和126B的混合物(320mg，按全为126D计算当量：0.69mmol)和DIPEA(100mg，0.76mmol)，然后缓慢滴加入三氯氧磷(113mg，0.76mmol)，加料完毕后体系氮气保护下加热至100℃搅拌1h。原料消失后，反应液减压浓缩所得残余物通过硅胶柱层析纯化得到化合物126E和126F的混合物(120mg)。Step 4: Toluene (5 mL) was added to a 25 mL single-mouth bottle, followed by a mixture of compounds 126D and 126B (320 mg, equivalent weight calculated based on 126D: 0.69 mmol) and DIPEA (100 mg, 0.76 mmol), and then phosphorus oxychloride (113 mg, 0.76 mmol) was slowly added dropwise. After the addition was completed, the system was heated to 100 ° C and stirred for 1 h under nitrogen protection. After the raw materials disappeared, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a mixture of compounds 126E and 126F (120 mg).

第五步：将化合物1C(121mg，0.50mmol)溶于二氯甲烷(5mL)中，加入三乙胺(198mg,1.00mmol)搅拌半小时后，加入126E和126F的混合物(120mg,按全为126F计算当量：0.25mmol)，在室温下搅拌过夜。加水(5mL)淬灭反应，分液，以二氯甲烷(5mL)萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化后得化合物126G和126H的混合物(60mg)。Step 5: Compound 1C (121 mg, 0.50 mmol) was dissolved in dichloromethane (5 mL), triethylamine (198 mg, 1.00 mmol) was added and stirred for half an hour, then a mixture of 126E and 126F (120 mg, equivalent weight calculated based on 126F: 0.25 mmol) was added and stirred at room temperature overnight. Water (5 mL) was added to quench the reaction, the mixture was separated, and extracted twice with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a mixture of compounds 126G and 126H (60 mg).

LC-MS(ESI):m/z＝593.0[M+H]+&575.1[M+H]+。LC-MS (ESI): m/z=593.0[M+H] + &575.1[M+H] + .

第六步：将化合物126G和126H的混合物(60mg)经手性SFC拆分得到化合物126(SFC分析保留时间：0.959min,6.1mg)、化合物127(SFC分析保留时间：1.155min,14.2mg)、化合物128(SFC分析保留时间：1.392min,5.3mg)和化合物129(SFC分析保留时间：1.700min,13.6mg)。SFC分析方法：仪器:SHIMADZU LC-30AD sf，柱:Chiral IK Column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:40％B in A；流速:3mL/min；柱温:35℃；检测波长:220nm。SFC制备方法：仪器:Waters 150Prep-SFC，柱:Chiral IK Column；流动相:A:CO2,B:0.1％NH3·H2O in乙醇；梯度:40％B梯度洗脱流速:100mL/min，柱温:25℃波长:220nm循环时间:8.0min；样品制备:样品浓度2mg/mL，乙醇溶液进样:每次2mL。Step 6: The mixture of compounds 126G and 126H (60 mg) was subjected to chiral SFC separation to obtain compound 126 (SFC analysis retention time: 0.959 min, 6.1 mg), compound 127 (SFC analysis retention time: 1.155 min, 14.2 mg), compound 128 (SFC analysis retention time: 1.392 min, 5.3 mg) and compound 129 (SFC analysis retention time: 1.700 min, 13.6 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; gradient: 40% B in A; flow rate: 3 mL/min; column temperature: 35°C; detection wavelength: 220 nm. SFC preparation method: Instrument: Waters 150Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ·H 2 O in ethanol; Gradient: 40% B gradient elution flow rate: 100 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 8.0 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.

化合物126(SFC分析保留时间：0.959min)：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.87(d,2H),7.69(d,2H),7.52(d,2H),7.39(d,2H),7.34-7.21(m,5H),5.60-5.39(m,1H),5.16-4.94(m,2H),4.48(t,1H),3.91-3.82(m,1H),2.03-1.94(m,1H),0.95-0.82(m,4H)；19F NMR(377MHz,DMSO-d6)δ-106.35；LC-MS(ESI):m/z＝593.0[M+H]+。Compound 126 (SFC analysis retention time: 0.959 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.87 (d, 2H), 7.69 (d, 2H), 7.52 (d, 2H), 7.39 (d, 2H), 7.34-7.21 (m, 5H), 5.60-5.39 (m, 1H), 5.16-4.94 (m, 2H), 4.48 (t, 1H), 3.91-3.82 (m, 1H), 2.03-1.94 (m, 1H), 0.95-0.82 (m, 4H); 19 F NMR (377 MHz, DMSO-d 6 ) δ -106.35; LC-MS (ESI): m/z=593.0 [M+H] + .

化合物127(SFC分析保留时间：1.155min)：1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.83-7.76(d,2H),7.53(t,4H),7.39(d,2H),7.34-7.20(m,5H),6.83-6.74(m,1H),5.93(d,1H),5.38(d,1H),5.05-4.98(m,1H),4.47(t,1H),3.90-3.81(m,1H),2.05-1.95(m,1H),0.93-0.82(m,4H)；LC-MS(ESI):m/z＝575.1[M+H]+。Compound 127 (SFC analysis retention time: 1.155 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 7.83-7.76 (d, 2H), 7.53 (t, 4H), 7.39 (d, 2H), 7.34-7.20 (m, 5H), 6.83-6.74 (m, 1H), 5.93 (d, 1H), 5.38 (d, 1H), 5.05-4.98 (m, 1H), 4.47 (t, 1H), 3.90-3.81 (m, 1H), 2.05-1.95 (m, 1H), 0.93-0.82 (m, 4H); LC-MS (ESI): m/z=575.1 [M+H] + .

化合物128(SFC分析保留时间：1.392min)：1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.87(d,2H),7.69(d,2H),7.52(d,2H),7.39(d,2H),7.35-7.22(m,5H),5.59-5.38(m,1H),5.16-4.94(m,2H),4.48(t,1H),3.91-3.82(m,1H),2.03-1.94(m,1H),0.95-0.83(m,4H)；19F NMR(377MHz,DMSO-d6)δ-106.35；LC-MS(ESI):m/z＝593.0[M+H]+。Compound 128 (SFC analysis retention time: 1.392 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.87 (d, 2H), 7.69 (d, 2H), 7.52 (d, 2H), 7.39 (d, 2H), 7.35-7.22 (m, 5H), 5.59-5.38 (m, 1H), 5.16-4.94 (m, 2H), 4.48 (t, 1H), 3.91-3.82 (m, 1H), 2.03-1.94 (m, 1H), 0.95-0.83 (m, 4H); 19 F NMR (377 MHz, DMSO-d 6 ) δ -106.35; LC-MS (ESI): m/z=593.0 [M+H] + .

化合物129(SFC分析保留时间：1.700min)：1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.83-7.76(d,2H),7.53(t,4H),7.39(d,2H),7.35-7.21(m,5H),6.83-6.74(m,1H),5.93(d,1H),5.38(d,1H),5.05-4.98(m,1H),4.47(t,1H),3.90-3.81(m,1H),2.05-1.95(m,1H),0.93-0.82(m,4H)；LC-MS(ESI):m/z＝575.1[M+H]+。Compound 129 (SFC analysis retention time: 1.700 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 7.83-7.76 (d, 2H), 7.53 (t, 4H), 7.39 (d, 2H), 7.35-7.21 (m, 5H), 6.83-6.74 (m, 1H), 5.93 (d, 1H), 5.38 (d, 1H), 5.05-4.98 (m, 1H), 4.47 (t, 1H), 3.90-3.81 (m, 1H), 2.05-1.95 (m, 1H), 0.93-0.82 (m, 4H); LC-MS (ESI): m/z=575.1 [M+H] + .

实施例130
Embodiment 130

第一步：将化合物130A(3g,12.7mmol)、三异丙基硅基乙炔(6.95g,38.1mmol)、Pd(PPh3)2Cl2(892mg,1.27mmol)和碘化亚铜(242mg,1.27mmol)溶于1,4-二氧六环和三乙胺的混合溶剂中(v/v＝1:1,共100mL)中，氮气置换三次后，于100℃下搅拌反应16h。TLC监测反应结束后，浓缩反应液至原体积的1/3，加入100mL饱和氯化铵水溶液淬灭反应，用100mL乙酸乙酯萃取两次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经柱层析纯化得到化合物130B(3.5g,收率：81％)。LC-MS(ESI):m/z＝336.1[M-H]-。Step 1: Compound 130A (3 g, 12.7 mmol), triisopropylsilyl acetylene (6.95 g, 38.1 mmol), Pd(PPh 3 ) 2 Cl 2 (892 mg, 1.27 mmol) and cuprous iodide (242 mg, 1.27 mmol) were dissolved in a mixed solvent of 1,4-dioxane and triethylamine (v/v=1:1, 100 mL in total), replaced with nitrogen three times, and stirred at 100°C for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to 1/3 of the original volume, 100 mL of saturated ammonium chloride aqueous solution was added to quench the reaction, and extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 130B (3.5 g, yield: 81%). LC-MS (ESI): m/z=336.1[MH] - .

第二步：将化合物130B(400mg，1.18mmol)、三乙胺(359mg,3.54mmol)溶于10mL无水DCM中，室温搅拌下缓慢滴加氯甲酸异丙酯(217mg，1.77mmol)，继续反应1h。LCMS监测反应完全后，冰浴下加入10mL的0.5M的盐酸水溶液，分液，水相用20mL二氯甲烷萃取一次后，有机相合并干燥，浓缩后所得残余物通过硅胶柱层析纯化得到化合物130C(360mg,收率：72％)。LC-MS(ESI):m/z＝422.2[M-H]-。Step 2: Compound 130B (400 mg, 1.18 mmol) and triethylamine (359 mg, 3.54 mmol) were dissolved in 10 mL of anhydrous DCM, and isopropyl chloroformate (217 mg, 1.77 mmol) was slowly added dropwise under stirring at room temperature, and the reaction was continued for 1 h. After the reaction was complete as monitored by LCMS, 10 mL of 0.5 M aqueous hydrochloric acid solution was added under ice bath, and the liquids were separated. The aqueous phase was extracted once with 20 mL of dichloromethane, and the organic phases were combined and dried. The residue obtained after concentration was purified by silica gel column chromatography to obtain compound 130C (360 mg, yield: 72%). LC-MS (ESI): m/z = 422.2 [MH] - .

第三步：将化合物130C(360mg，0.85mmol)分散于10mL无水甲苯中，加入化合物22D(240mg,0.93mmol)，100℃下反应4h。反应结束后，浓缩，向所得残余物中加入石油醚和乙酸乙酯的混合溶液(v/v＝3:1,共10mL)，充分震荡后过滤，滤饼干燥后即得到化合物130D(250mg，收率：47％)。Step 3: Compound 130C (360 mg, 0.85 mmol) was dispersed in 10 mL of anhydrous toluene, and compound 22D (240 mg, 0.93 mmol) was added, and the mixture was reacted at 100°C for 4 h. After the reaction was completed, the mixture was concentrated, and a mixed solution of petroleum ether and ethyl acetate (v/v=3:1, 10 mL in total) was added to the residue, and the mixture was fully shaken and filtered. After the filter cake was dried, compound 130D (250 mg, yield: 47%) was obtained.

第四步：将化合物130D(250mg,0.40mmol)分散于无水甲苯中，加入三氯氧磷(122mg，0.8mmol)和DIPEA(155mg，1.2mmol)，100℃下反应1h。反应结束后，浓缩，所得残余物经硅胶柱层析纯化得到化合物130E(150mg，收率：58％)。Step 4: Disperse compound 130D (250 mg, 0.40 mmol) in anhydrous toluene, add phosphorus oxychloride (122 mg, 0.8 mmol) and DIPEA (155 mg, 1.2 mmol), and react at 100° C. for 1 h. After the reaction is completed, concentrate the residue, and purify it by silica gel column chromatography to obtain compound 130E (150 mg, yield: 58%).

第五步：将化合物1C(111mg，0.46mmol)溶于二氯甲烷(5mL)中，加入三乙胺(93mg,0.92mmol)搅拌半小时后，加入化合物130E(150mg,0.23mmol)，室温下搅拌过夜。加水(5mL)淬灭反应，分液，以二氯甲烷(5mL)萃取两次，合并有机相，无水硫酸钠干燥后减压浓缩。所得残余物溶解于10mL四氢呋喃中，加入TBAF(0.25mL,1M THF溶液),室温反应2h，加入20mL水和20mL二氯甲烷分液，收集有机相浓缩所得残余物经制备HPLC纯化后得化合物130(10mg，收率：7％)。Step 5: Dissolve compound 1C (111 mg, 0.46 mmol) in dichloromethane (5 mL), add triethylamine (93 mg, 0.92 mmol) and stir for half an hour, then add compound 130E (150 mg, 0.23 mmol) and stir at room temperature overnight. Add water (5 mL) to quench the reaction, separate the liquids, extract twice with dichloromethane (5 mL), combine the organic phases, dry over anhydrous sodium sulfate and concentrate under reduced pressure. The obtained residue was dissolved in 10 mL of tetrahydrofuran, TBAF (0.25 mL, 1M THF solution) was added, reacted at room temperature for 2 h, 20 mL of water and 20 mL of dichloromethane were added for separation, the organic phase was collected and concentrated, and the obtained residue was purified by preparative HPLC to obtain compound 130 (10 mg, yield: 7%).

1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.85-7.78(m,2H),7.57-7.48(m,4H),7.43-7.36(m,2H),7.35-7.19(m,5H),5.06-4.98(m,1H),4.48(t,1H),4.36(s,1H),3.90-3.82(m,1H),1.99(s,1H),0.98-0.82(m,4H)；LC-MS(ESI):m/z＝573.1[M+H]+。 1 H NMR (400MHz, DMSO-d 6 )δ10.80(s,1H),7.85-7.78(m,2H),7.57-7.48(m,4H),7.43-7.36(m,2H),7.35-7.19(m,5H),5.06-4.98(m,1H ),4.48(t,1H),4.36(s,1H),3.90-3.82(m,1H),1.99(s,1H),0.98-0.82(m,4H); LC-MS(ESI):m/z＝573.1[M+H] + .

实施例131和实施例132
Example 131 and Example 132

第一步：将化合物131A(1.00g,9.99mmol)溶于二氯甲烷(20mL)中，加入N,N'-二-BOC-1H-1-胍基吡唑(3.72g，11.99mmol)，加料完成后室温反应16h。加入水(30mL)，二氯甲烷(20mL)萃取，无水硫酸钠干燥后减压浓缩，残余物经硅胶柱层析纯化得到化合物131B(2.0g，收率：58.48％)。LC-MS(ESI):m/z＝343.1[M+H]+。Step 1: Dissolve compound 131A (1.00 g, 9.99 mmol) in dichloromethane (20 mL), add N,N'-di-BOC-1H-1-guanidinopyrazole (3.72 g, 11.99 mmol), and react at room temperature for 16 h. Add water (30 mL), extract with dichloromethane (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 131B (2.0 g, yield: 58.48%). LC-MS (ESI): m/z=343.1[M+H] + .

第二步：将化合物131B(1g,2.92mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(5mL)，在室温下搅拌16h，减压浓缩得化合物131C(600mg，粗品)，直接用于下一步反应。LC-MS(ESI):m/z＝143.1[M+H]+。Step 2: Compound 131B (1 g, 2.92 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 16 h, and concentrated under reduced pressure to obtain compound 131C (600 mg, crude product), which was directly used in the next step. LC-MS (ESI): m/z = 143.1 [M+H] + .

第三步：化合物131C(220mg,1.52mmol)参照实施例40第三步操作得到化合物131D(200mg)。LC-MS(ESI):m/z＝632.2[M+H]+。Step 3: Compound 131C (220 mg, 1.52 mmol) was processed according to the third step of Example 40 to obtain compound 131D (200 mg). LC-MS (ESI): m/z=632.2 [M+H] + .

第四步：化合物131D经手性SFC拆分得到化合物131(SFC分析保留时间：2.125min，8mg)和132(SFC分析保留时间：2.229min，5mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHELK column；流动相:A:CO2,B:0.05％DEA in乙醇；梯度:5-40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHELK column；流动相:A:CO2,B:乙醇；梯度:30％B梯度洗脱流速:120mL/min，柱温:25℃波长:254nm循环时间:8.1min；样品制备:样品浓度2mg/mL，乙醇溶液进样:每次2mL。Step 4: Compound 131D was separated by chiral SFC to obtain compounds 131 (SFC analysis retention time: 2.125min, 8mg) and 132 (SFC analysis retention time: 2.229min, 5mg). SFC analysis method: Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3mL/min Column temperature: 35℃ Wavelength: 220nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B: ethanol; Gradient: 30% B gradient elution flow rate: 120mL/min, Column temperature: 25℃ Wavelength: 254nm Cycle time: 8.1min; Sample preparation: Sample concentration 2mg/mL, ethanol solution injection: 2mL each time.

化合物131(SFC分析保留时间：2.125min)：1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.04(d,2H),7.82(d,2H),7.48-7.39(m,2H),7.31-7.20(m,8H),4.89-4.85(m,1H),4.41(t,1H),3.88-3.84(m,1H),1.62-1.56(m,1H),0.88-0.68(m,4H)；LC-MS(ESI):m/z＝632.2[M+H]+。Compound 131 (SFC analysis retention time: 2.125 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.04 (d, 2H), 7.82 (d, 2H), 7.48-7.39 (m, 2H), 7.31-7.20 (m, 8H), 4.89-4.85 (m, 1H), 4.41 (t, 1H), 3.88-3.84 (m, 1H), 1.62-1.56 (m, 1H), 0.88-0.68 (m, 4H); LC-MS (ESI): m/z=632.2 [M+H] + .

化合物132(SFC分析保留时间：2.229min)：1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.04(d,2H),7.82(d,2H),7.46-7.38(m,2H),7.31-7.21(m,8H),4.89-4.85(m,1H),4.40(t,1H),3.88-3.84(m,1H),1.60-1.55(m,1H),0.89-0.67(m,4H)；LC-MS(ESI):m/z＝632.2[M+H]+。Compound 132 (SFC analysis retention time: 2.229 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.04 (d, 2H), 7.82 (d, 2H), 7.46-7.38 (m, 2H), 7.31-7.21 (m, 8H), 4.89-4.85 (m, 1H), 4.40 (t, 1H), 3.88-3.84 (m, 1H), 1.60-1.55 (m, 1H), 0.89-0.67 (m, 4H); LC-MS (ESI): m/z=632.2 [M+H] + .

实施例133和实施例134
Example 133 and Example 134

第一步：将化合物133A(1.00g,6.51mmol)溶于1,4-二氧六环(10mL)中，加入苄胺(1.40g,13.02mmol)，Xphos Pd G2(0.51g,0.65mmol)和叔丁醇钾(1.10g,9.77mmol)，抽换氮气3次，升温至110℃反应过夜。反应完成后，加水(30mL)淬灭反应，用乙酸乙酯(50mL)萃取三次，合并有机相，以无水硫酸钠干燥后减压浓缩，所得残余物经硅胶柱层析纯化得到化合物133B(0.3g，收率：20％)。LC-MS(ESI):m/z＝225.1[M+H]+。Step 1: Compound 133A (1.00 g, 6.51 mmol) was dissolved in 1,4-dioxane (10 mL), benzylamine (1.40 g, 13.02 mmol), Xphos Pd G2 (0.51 g, 0.65 mmol) and potassium tert-butoxide (1.10 g, 9.77 mmol) were added, nitrogen was replaced 3 times, and the temperature was raised to 110°C for overnight reaction. After the reaction was completed, water (30 mL) was added to quench the reaction, and ethyl acetate (50 mL) was used for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 133B (0.3 g, yield: 20%). LC-MS (ESI): m/z=225.1[M+H] + .

第二步：将化合物133B(150mg,0.67mmol)溶于甲醇(5mL)中，加入10％钯碳(0.3g,2.82mmol)，置换氢气三次，在氢气氛围下室温搅拌24h。将反应液过滤后减压浓缩得化合物133C(40mg)，直接用于下一步反应。LC-MS(ESI):m/z＝135.1[M+H]+。Step 2: Compound 133B (150 mg, 0.67 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (0.3 g, 2.82 mmol) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 24 h under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 133C (40 mg), which was directly used in the next step. LC-MS (ESI): m/z = 135.1 [M+H] + .

第三步：将化合物1D(195mg，0.37mmol)溶于二氯甲烷(5mL)中，分别加入化合物133C(50mg,1.1mmol)和吡啶(60mg,0.74mmol)，在室温下搅拌过夜。加水(10mL)淬灭反应，以二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥后减压浓缩，所得残余物经反相柱层析纯化得到化合物133D(23mg，收率：10％)。LC-MS(ESI):m/z＝624.2[M+H]+。Step 3: Compound 1D (195 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and compound 133C (50 mg, 1.1 mmol) and pyridine (60 mg, 0.74 mmol) were added respectively, and stirred at room temperature overnight. Water (10 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography to obtain compound 133D (23 mg, yield: 10%). LC-MS (ESI): m/z=624.2[M+H] + .

第四步：化合物133D经手性SFC拆分得到化合物133(SFC分析保留时间：0.75min，3.19mg)和134(SFC分析保留时间：1.10min，2.2mg)。SFC分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral WHELK column；流动相:A:CO2,B for 0.05％DEA in异丙醇和乙腈；梯度:40％B in A；流速:3mL/min柱温:35℃波长:220nm。SFC制备方法:仪器:Waters 150 Prep-SFC，柱:Chiral WHELK column；流动相:A for CO2；B for 0.1％NH3·H2O in异丙醇和乙腈；梯度:35％B梯度洗脱流速:120mL/min，柱温:25℃波长:220nm循环时间:6.0min；样品制备:样品浓度2mg/mL，乙醇溶液进样:每次2mL。Step 4: Compound 133D was subjected to chiral SFC separation to obtain compounds 133 (SFC analysis retention time: 0.75 min, 3.19 mg) and 134 (SFC analysis retention time: 1.10 min, 2.2 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK column; Mobile phase: A: CO 2 , B for 0.05% DEA in isopropanol and acetonitrile; Gradient: 40% B in A; Flow rate: 3 mL/min Column temperature: 35°C Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK column; Mobile phase: A for CO 2 ; B for 0.1% NH 3 ·H 2 O in isopropanol and acetonitrile; Gradient: 35% B gradient elution flow rate: 120 mL/min, column temperature: 25°C Wavelength: 220 nm Cycle time: 6.0 min; Sample preparation: Sample concentration 2 mg/mL, ethanol solution injection: 2 mL each time.

化合物133(SFC分析保留时间：0.75min)：1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.92(d,2H),7.78(s,1H),7.67(d,2H),7.35-7.18(m,7H),7.09-7.02(m,2H),6.89-6.82(m,2H),6.36-6.34(m,1H),4.65-4.60(m,1H),4.35-4.28(m,1H),3.86-3.80(m,1H)；LC-MS(ESI):m/z＝624.2[M+H]+。Compound 133 (SFC analysis retention time: 0.75 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 7.92 (d, 2H), 7.78 (s, 1H), 7.67 (d, 2H), 7.35-7.18 (m, 7H), 7.09-7.02 (m, 2H), 6.89-6.82 (m, 2H), 6.36-6.34 (m, 1H), 4.65-4.60 (m, 1H), 4.35-4.28 (m, 1H), 3.86-3.80 (m, 1H); LC-MS (ESI): m/z=624.2 [M+H] + .

化合物134(SFC分析保留时间：1.10min)：1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.92(d,2H),7.78(s,1H),7.67(d,2H),7.34-7.17(m,7H),7.11-7.01(m,2H),6.91-6.82(m,2H),6.35-6.34(m,1H),4.65-4.59(m,1H),4.35-4.30(m,1H),3.85-3.80(m,1H)；LC-MS(ESI):m/z＝624.2[M+H]+。Compound 134 (SFC analysis retention time: 1.10 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 7.92 (d, 2H), 7.78 (s, 1H), 7.67 (d, 2H), 7.34-7.17 (m, 7H), 7.11-7.01 (m, 2H), 6.91-6.82 (m, 2H), 6.35-6.34 (m, 1H), 4.65-4.59 (m, 1H), 4.35-4.30 (m, 1H), 3.85-3.80 (m, 1H); LC-MS (ESI): m/z=624.2 [M+H] + .

其余实施例例如表一、二中的化合物的合成路线参考实施例1和2的合成路线。The synthetic routes of the compounds in other embodiments, such as Tables 1 and 2, refer to the synthetic routes of Examples 1 and 2.

生物测试Biological Testing

一、TR-FRET cAMP方法测定化合物对CB1受体的作用情况1. TR-FRET cAMP method to determine the effect of compounds on CB1 receptors

按照LANCE Ultra cAMP试剂盒说明书配制1×Stimulation Buffer待用。准备受试物10×工作液。细胞胰酶消化处理，离心后重悬于1×Stimulation Buffer中，经计数后接种于384孔板中。稀释好的化合物加入相应实验孔中，置于37℃孵育10分钟。然后加入Forskolin溶液于37℃孵育30分钟，诱导cAMP产生。用Detection buffer将Eu-cAMP稀释至4×工作浓度，然后加入相应实验孔中。用Detection buffer将ULight-anti-cAMP稀释至4×工作浓度，然后加入相应实验孔中，离心后置于室温孵育。孵育完成后，使用多功能酶标仪检测665nm和620nm读值。运用GraphPad Prism软件计算IC50值。Prepare 1×Stimulation Buffer according to the instructions of LANCE Ultra cAMP kit. Prepare 10× working solution of the test substance. Digest the cells with trypsin, resuspend in 1×Stimulation Buffer after centrifugation, and inoculate in 384-well plates after counting. Add the diluted compound to the corresponding experimental wells and incubate at 37℃ for 10 minutes. Then add Forskolin solution and incubate at 37℃ for 30 minutes to induce cAMP production. Dilute Eu-cAMP to 4× working concentration with detection buffer and add it to the corresponding experimental wells. Dilute ULight-anti-cAMP to 4× working concentration with detection buffer and add it to the corresponding experimental wells. Centrifuge and incubate at room temperature. After incubation, use a multifunctional microplate reader to detect the readings at 665nm and 620nm. Calculate the IC 50 value using GraphPad Prism software.

本发明化合物，例如实施例化合物对CB1受体下游cAMP信号通路具有小于1000nM的IC50值，一些优选化合物的IC50<100nM，一些更优选化合物的IC50<50nM，一些更优选的化合物的IC50<10nM，一些更优选的化合物的IC50<1nM。部分具体化合物的IC50值如表1所示，其中AA代表IC50<1nM，A代表1nM≤IC50<10nM，B代表10nM≤IC50<50nM，C代表50nM≤IC50<100nM，D代表100nM≤IC50<1000nM。The compounds of the present invention, such as the compounds of the examples, have an IC 50 value of less than 1000 nM for the cAMP signaling pathway downstream of the CB1 receptor, some preferred compounds have an IC 50 <100 nM, some more preferred compounds have an IC 50 <50 nM, some more preferred compounds have an IC 50 <10 nM, and some more preferred compounds have an IC 50 <1 nM. The IC 50 values of some specific compounds are shown in Table 1, wherein AA represents IC 50 <1 nM, A represents 1 nM≤IC 50 <10 nM, B represents 10 nM≤IC 50 <50 nM, C represents 50 nM≤IC 50 <100 nM, and D represents 100 nM≤IC 50 <1000 nM.

表1化合物对CB1受体下游cAMP信号通路的IC50值

Table 1 IC 50 values of compounds on cAMP signaling pathway downstream of CB1 receptor

结论：本发明化合物，例如实施例化合物对CB1受体下游cAMP信号通路有较强的拮抗作用，部分化合物的IC50小于1nM，例如化合物2的IC50为0.4744nM，化合物5的IC50为0.75nM，化合物9的IC50为0.6693nM，化合物14的IC50为0.46nM，化合物21的IC50为0.44nM，化合物23的IC50为0.38nM，化合物25的IC50为0.357nM，化合物27的IC50为0.46nM，化合物30的IC50为0.41nM，化合物31的IC50为0.389nM，化合物32的IC50为0.2196nM，化合物35的IC50为0.734nM，化合物43的IC50为0.5223nM，化合物46的IC50为0.6745nM，化合物47的IC50为0.4382nM，化合物51的IC50为0.5359nM，化合物53的IC50为0.834nM，化合物59的IC50为0.3883nM，化合物62的IC50为0.607nM，化合物63的IC50为0.8594nM，化合物64的IC50为0.8295nM，化合物73的IC50为0.8538nM，化合物74的IC50为0.7239nM，化合物77的IC50为0.4387nM，化合物79的IC50为0.5482nM，化合物81的IC50为0.6907nM，化合物83的IC50为0.6728nM，化合物84的IC50为0.9576nM，化合物86的IC50为0.2643nM，化合物88的IC50为0.4643nM，化合物91的IC50为0.6341nM，化合物94的IC50为0.2809nM，化合物95的IC50为0.2731nM，化合物97的IC50为0.8712nM，化合物99的IC50为0.6908nM，化合物101的IC50为0.8704nM，化合物109的IC50为0.4332nM，化合物113的IC50为0.4411nM，化合物117的IC50为0.8096nM，化合物119的IC50为0.5189nM，化合物121的IC50为0.4364nM，化合物123的IC50为0.4646nM，化合物124的IC50为0.8466nM，化合物128的IC50为0.5681nM，化合物129的IC50为0.6207nM，化合物131的IC50为0.3047nM，化合物134的IC50为0.5136nM。Conclusion: The compounds of the present invention, such as the compounds in the examples, have a strong antagonistic effect on the cAMP signaling pathway downstream of the CB1 receptor. The IC 50 of some compounds is less than 1 nM, for example, the IC 50 of compound 2 is 0.4744 nM, the IC 50 of compound 5 is 0.75 nM, the IC 50 of compound 9 is 0.6693 nM, the IC 50 of compound 14 is 0.46 nM, the IC 50 of compound 21 is 0.44 nM, the IC 50 of compound 23 is 0.38 nM, the IC 50 of compound 25 is 0.357 nM, the IC 50 of compound 27 is 0.46 nM, the IC 50 of compound 30 is 0.41 nM, the IC 50 of compound 31 is 0.389 nM, the IC 50 of compound 32 is 0.2196 nM, the IC 50 of compound 35 is 0.734 nM, and the IC 50 of compound 43 is 0. The IC 50 of compound 46 was 0.6745 nM, the IC 50 of compound 47 was 0.4382 nM, the IC 50 of compound 51 was 0.5359 nM, the IC 50 of compound 53 was 0.834 nM, the IC 50 of compound 59 was 0.3883 nM, the IC 50 of compound 62 was 0.607 nM, the IC 50 of compound 63 was 0.8594 nM, the IC 50 of compound 64 was 0.8295 nM, the IC 50 of compound 73 was 0.8538 nM, the IC 50 of compound 74 was 0.7239 nM, the IC 50 of compound 77 was 0.4387 nM, the IC 50 of compound 79 was 0.5482 nM, the IC 50 of compound 81 was The IC 50 of compound 83 was 0.6728 nM, the IC 50 of compound 84 was 0.9576 nM, the IC 50 of compound 86 was 0.2643 nM, the IC 50 of compound 88 was 0.4643 nM, the IC 50 of compound 91 was 0.6341 nM, the IC 50 of compound 94 was 0.2809 nM, the IC 50 of compound 95 was 0.2731 nM, the IC 50 of compound 97 was 0.8712 nM, the IC 50 of compound 99 was 0.6908 nM, the IC 50 of compound 101 was 0.8704 nM, the IC 50 of compound 109 was 0.4332 nM, the IC 50 of compound 113 was 0.4411 nM, the IC 50 of compound 117 was The IC 50 of compound 119 was 0.5189 nM, the IC 50 of compound 121 was 0.4364 nM, the IC 50 of compound 123 was 0.4646 nM, the IC 50 of compound 124 was 0.8466 nM, the IC 50 of compound 128 was 0.5681 nM, the IC 50 of compound 129 was 0.6207 nM, the IC 50 of compound 131 was 0.3047 nM, and the IC 50 of compound 134 was 0.5136 nM.

二、NanoBiT方法测定化合物对CB1募集arrestin2作用的影响2. NanoBiT method to determine the effect of compounds on CB1 recruitment of arrestin2

第一天，HEK293T细胞培养至80％融合度，胰酶消化处理收集细胞，经计数后接种于6孔板。第二天，细胞密度达到70％左右，通过Lipo3000共转受体与βarrestin2质粒。第三天，转染24h后，将细胞消化，重新铺入96孔板，过夜。第四天，准备受试物10×工作液，将检测底物和配制好的化合物加入。96孔板中进行孵育，用酶标仪读取Luminescence信号值。运用GraphPad Prism软件计算IC50值。部分具体化合物的IC50值如表2所示，其中AA代表IC50<1nM，A代表1nM≤IC50<10nM，B代表10nM≤IC50<50nM，C代表50nM≤IC50<100nM，D代表100nM≤IC50<1000nM。On the first day, HEK293T cells were cultured to 80% confluence, and the cells were collected by trypsin digestion and counted and inoculated into 6-well plates. On the second day, the cell density reached about 70%, and the receptor and βarrestin2 plasmids were co-transfected by Lipo3000. On the third day, 24 hours after transfection, the cells were digested and re-plated into 96-well plates overnight. On the fourth day, 10× working solution of the test substance was prepared, and the detection substrate and the prepared compound were added. Incubate in 96-well plates, and read the luminescence signal value with an enzyme reader. IC 50 value was calculated using GraphPad Prism software. The IC 50 values of some specific compounds are shown in Table 2, wherein AA represents IC 50 <1 nM, A represents 1 nM≤IC 50 <10 nM, B represents 10 nM≤IC 50 <50 nM, C represents 50 nM≤IC 50 <100 nM, and D represents 100 nM≤IC 50 <1000 nM.

表2化合物对CB1受体下游β-arrestin信号通路的IC50值
Table 2 IC 50 values of compounds on β-arrestin signaling pathway downstream of CB1 receptor

结论：本发明化合物，例如实施例化合物对CB1受体下游β-arrestin信号通路有较强的拮抗作用。Conclusion: The compounds of the present invention, such as the compounds in the examples, have a strong antagonistic effect on the β-arrestin signaling pathway downstream of the CB1 receptor.

三、TR-FRET cAMP方法测定化合物对CB2受体的作用情况3. TR-FRET cAMP method to determine the effect of compounds on CB2 receptors

使用稳定表达CB2受体的中国仓鼠卵巢(CHO)细胞系。在TR-FRET cAMP实验中，首先将阳性化合物和待测物进行梯度稀释，之后将处理好的细胞计数后接种于384-well板中。接下来，取稀释好的化合物加入至相应实验孔中，放置于37℃孵育10分钟。孵育结束后，取4μL激动剂溶液加入相应实验孔中孵育30分钟，诱导cAMP产生。孵育结束后，加入提前配制的Eu-cAMP和ULightTM-anti-cAMP至所有实验孔中，离心后于室温孵育1小时，利用酶标仪检测波长330nm激发下，665nm和620nm读值。运用GraphPad Prism软件计算IC50值。部分具体化合物对CB2的IC50值如表3所示，A代表10nM≤IC50<50nM，B代表50nM≤IC50<100nM，C代表100nM≤IC50<500nM，D代表≥500nM。A Chinese hamster ovary (CHO) cell line that stably expresses CB2 receptors was used. In the TR-FRET cAMP experiment, the positive compound and the test substance were first diluted in series, and then the treated cells were counted and inoculated in a 384-well plate. Next, the diluted compound was added to the corresponding experimental wells and incubated at 37°C for 10 minutes. After the incubation, 4 μL of agonist solution was added to the corresponding experimental wells and incubated for 30 minutes to induce cAMP production. After the incubation, Eu-cAMP and ULight TM -anti-cAMP prepared in advance were added to all experimental wells, centrifuged and incubated at room temperature for 1 hour, and the readings at 665nm and 620nm were detected using an enzyme reader under excitation at a wavelength of 330nm. The IC 50 value was calculated using GraphPad Prism software. The IC 50 values of some specific compounds for CB 2 are shown in Table 3, where A represents 10 nM ≤ IC 50 <50 nM, B represents 50 nM ≤ IC 50 <100 nM, C represents 100 nM ≤ IC 50 <500 nM, and D represents ≥500 nM.

表3化合物对CB2受体下游cAMP信号通路的IC50值
Table 3 IC 50 values of compounds on CB2 receptor downstream cAMP signaling pathway

结论：本发明化合物，例如实施例化合物对CB2受体下游cAMP信号通路拮抗作用较弱。Conclusion: The compounds of the present invention, such as the compounds in the examples, have a weak antagonistic effect on the cAMP signaling pathway downstream of the CB2 receptor.

四、小鼠药代动力学测试4. Pharmacokinetics test in mice

1、试验动物：雄性C57小鼠，18～25g。购于北京华阜康生物科技股份有限公司。1. Experimental animals: Male C57 mice, 18-25 g, purchased from Beijing Huafukang Biotechnology Co., Ltd.

2、试验设计：试验当天，C57小鼠按体重随机分组，分为IV、PO两组。给药前1天禁食不禁水12～14h，给药后4h喂食。2. Experimental design: On the day of the experiment, C57 mice were randomly divided into two groups according to body weight, namely, IV and PO. The mice were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

表4.1给药信息
Table 4.1 Dosage information

注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCNote: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

(DMA：N,N-二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline:生理盐水；MC：甲基纤维素)(DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

于给药前及给药后经眼眶取全血0.03mL，置于EDTA-K2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点：0,5,15,30min,1,2,4,7h,24h，且灌胃组分别于给药后1,4,24h采集脑组织和腹部脂肪组织，以观察药物在小鼠脑和脂肪组织的分布情况。脑组织用冷生理盐水冲净表面残留血液，吸干水分后，进行称重和匀浆处理；脂肪组织用冷生理盐水冲净表面残留血液及毛发，吸干水分后，进行称重和匀浆处理。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 0.03 mL of whole blood was collected from the eye sockets, placed in an EDTA-K 2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 7 h, and 24 h in the intravenous group and the gavage group, and brain tissue and abdominal adipose tissue were collected at 1, 4, and 24 h after administration in the gavage group to observe the distribution of the drug in the brain and adipose tissue of mice. The brain tissue was rinsed with cold saline to remove residual blood on the surface, and after absorbing the water, it was weighed and homogenized; the adipose tissue was rinsed with cold saline to remove residual blood and hair on the surface, and after absorbing the water, it was weighed and homogenized. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS/MS.

表4.2测试化合物在小鼠血浆中的药代动力学参数
Table 4.2 Pharmacokinetic parameters of test compounds in mouse plasma

表4.3测试化合物在小鼠血浆、脑和脂肪组织中的药代动力学参数
Table 4.3 Pharmacokinetic parameters of test compounds in mouse plasma, brain and adipose tissue

表4.4测试化合物在小鼠血浆、脑和脂肪组织中的暴露比
Table 4.4 Exposure ratios of test compounds in mouse plasma, brain and adipose tissue

*：以1h，4h，24h计算参数*: Parameters are calculated in 1h, 4h, 24h

结论：本发明化合物，例如实施例化合物在小鼠中具有良好的药代动力学特征。而且，实施例化合物在小鼠脑组织暴露少，具有较低的脑/血浆比值；在脂肪组织暴露高，具有很高的脂肪/血浆比值。Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic characteristics in mice. Moreover, the example compounds have low exposure in the brain tissue of mice, with a lower brain/plasma ratio, and high exposure in the adipose tissue, with a very high fat/plasma ratio.

五、大鼠药代动力学测试5. Pharmacokinetics test in rats

1、试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。1. Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

2、试验设计：试验当天，SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。2. Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

于给药前及给药后异氟烷麻醉经眼眶取血0.15mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after drug administration, 0.15 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在大鼠中具有良好的药代动力学特征。Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in rats.

六、比格犬药代动力学测试6. Beagle dog pharmacokinetic test

1、试验动物：雄性比格犬，8～11kg左右，6只/化合物，购于北京玛斯生物技术有限公司。1. Experimental animals: Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

2、试验方法：试验当天，比格犬按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。2. Test method: On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

于给药前及给药后通过颈静脉或四肢静脉取血1mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 mL of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. All samples were stored at -80°C before analysis and testing, and the samples were quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在比格犬中具有良好的药代动力学特征。Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

七、猴药代动力学测试7. Monkey Pharmacokinetic Test

1、试验动物：雄性食蟹猴，3～5kg，3～6年龄，4只/化合物。购于苏州西山生物技术有限公司。1. Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

2、试验方法：试验当天，猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。2. Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted but not watered for 14-18 hours one day before administration and fed 4 hours after administration.

于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. All samples were stored at -80°C before analysis and testing, and the samples were quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在猴中具有良好的药代动力学特征。Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

八、hERG钾离子通道作用测试8. hERG potassium channel action test

1、实验平台：电生理手动膜片钳系统1. Experimental platform: electrophysiological manual patch clamp system

2、细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系2. Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

3、实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(IhERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。3. Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode liquid was about 2-5MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10kHz and a filter frequency of 2kHz. After obtaining the whole-cell recording, the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s. This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute). Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n≥2) were tested at each concentration.

4、数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：Inhibition％＝[1-(I/Io)]×100％。其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。4. Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I/Io)] × 100%. Wherein, Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively. Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)). Wherein, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

结论：本发明化合物，例如实施例化合物对hERG钾通道电流没有抑制。Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibition on the hERG potassium channel current.

九、CYP450酶抑制测试9. CYP450 enzyme inhibition test

本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC 50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.

表9.1化合物对对各CYP酶亚型的抑制潜能
Table 9.1 Inhibitory potential of compounds on various CYP enzyme subtypes

结论：本发明化合物，例如实施例化合物对人肝微粒体细胞色素P450(CYP)的5种同工酶没有抑制，尤其是化合物2对1A2，2C19，2D6，3A4只有很弱的抑制。Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibition on the five isozymes of human liver microsomal cytochrome P450 (CYP), especially compound 2 has only weak inhibition on 1A2, 2C19, 2D6, and 3A4.

十、肝微粒体稳定性测试10. Liver microsome stability test

本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。In this study, liver microsomes from five species, including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) were further calculated.

结论：本发明化合物，例如实施例化合物在肝微粒体稳定性测试中表现出良好的代谢稳定性。Conclusion: The compounds of the present invention, such as the compounds in the examples, showed good metabolic stability in the liver microsome stability test.

十一、Caco-2渗透性测试11. Caco-2 permeability test

试验使用单层Caco-2细胞，在96孔Transwell板中采用三平行孵育。将含有本发明化合物(2μM)或对照化合物地高辛(10μM)、纳多洛尔(2μM)和美托洛尔(2μM)的转运缓冲溶液(HBSS，10mM HEPES，pH 7.4±0.05)加入顶端侧或基底侧的给药端孔中。对应接收端孔中加入含DMSO的转运缓冲溶液。在37±1℃条件下孵育2小时后，取出细胞板并从顶端和底端各取出适量样品至新的96孔板中。随后加入含内标的乙腈沉淀蛋白。使用LC MS/MS分析样品并测定本发明化合物和对照化合物的浓度。浓度数据用于计算从单层细胞顶端侧向基底侧、以及基底侧向顶端转运的表观渗透系数，从而计算外排率。用荧光黄的渗漏评价孵育2小时后单层细胞的完整性。The experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (2μM) or the control compounds digoxin (10μM), nadolol (2μM) and metoprolol (2μM) was added to the dosing port well on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

结论：本发明化合物，例如实施例化合物在Caco-2渗透性测试中表现出良好的渗透性。Conclusion: The compounds of the present invention, such as the compounds of the examples, showed good permeability in the Caco-2 permeability test.

十二、化合物在饮食诱导肥胖模型中的减重药效试验12. Weight loss efficacy test of compounds in diet-induced obesity model

饮食诱导肥胖模型使用8-10周龄的雄性C57BL/6J进行。模型诱导期间，小鼠使用高脂肪饲料进行喂养，饲料采购自Research Diets，货号D12492，60％热量为脂肪。连续诱导14周后，诱导得到肥胖小鼠，小鼠体重约50克。诱导完成后开始进行化合物给药，3mg/kg QD连续给药20天，每天测量体重1次。The diet-induced obesity model was performed using male C57BL/6J mice aged 8-10 weeks. During the model induction, mice were fed a high-fat diet purchased from Research Diets, catalog number D12492, with 60% of calories being fat. After 14 weeks of continuous induction, obese mice were induced, weighing approximately 50 grams. After the induction was completed, compound administration began, 3 mg/kg QD for 20 consecutive days, and body weight was measured once a day.

结果如图1所示，表明化合物2及化合物5均能显著降低饮食诱导肥胖小鼠的体重，且降低体重的药效强于INV-202和利莫那班；The results are shown in Figure 1, indicating that both Compound 2 and Compound 5 can significantly reduce the body weight of diet-induced obese mice, and the efficacy of reducing body weight is stronger than INV-202 and rimonabant;

注：INV-202为专利US20180273485A1中的表格化合物72。Note: INV-202 is Table Compound 72 in patent US20180273485A1.

Claims (12)

一种式(I)、式(IV)、式(IV-a)、式(IV-b)所示的化合物，其立体异构体、药学上可接受的盐，
A compound represented by formula (I), formula (IV), formula (IV-a), or formula (IV-b), or a stereoisomer or a pharmaceutically acceptable salt thereof,
其中，R1、R2、R3各自独立地选自氢、氘、卤素、羟基、氰基、氨基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、-SF5、-SCF3、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-O-C3-8环烷基或-O-(3-8元杂环烷基)，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -SF 5 , -SCF 3 , 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 3-8 cycloalkyl, or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-5 Ra; RA选自-L1-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -L1- W1 - L2 - W2- RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ; L1、L2各自独立地选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted with 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH 2 ; W1、W2各自独立地选自键、-O-、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-C(＝O)O-、-OC(＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(＝O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -O-, -NRW1-, -NRW1- NRw1 (C=O)-, -(C=O) NRW1- , -NRW1 (C=O)-, -C (=O)O-, -OC(=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(=O)(=NH)-, -N=C( NH2 )-, -N=S( = O)( C1-6alkyl )-, -N=C( CH3 )-; 条件是，L1、L2、W1、W2不同时为键；Provided that L 1 , L 2 , W 1 , and W 2 are not bonds at the same time; RA1选自氘、卤素、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; RW1选自H、C1-4烷基、卤素、氰基；R W1 is selected from H, C 1-4 alkyl, halogen, cyano; Ra选自氘、卤素、羟基、氰基、氨基、硝基、氧代基、C1-6烷基、C1-6烷基亚基、C1-6卤代烷基亚基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-10元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-8环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-8环烷基、-S(O)2C3-8环烷基或-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 alkyl, C 1-6 alkylene group, C 1-6 haloalkylene group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-8 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-8 cycloalkyl, -S(O) 2 C 3-8 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy; RA2选自C3-8环烷基、3-8元杂环烷基、5-10元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-6烷氧基的基团所取代；R A2 is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-6 alkoxy; X1、X2、X3、X4选自CH或N；X 1 , X 2 , X 3 , X 4 are selected from CH or N; 作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-8环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, a C 2-6 alkynyl, or a C 3-8 cycloalkyl; 作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-8环烷基、3-8元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基或氘代C1-6烷氧基的基团所取代；Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy or deuterated C 1-6 alkoxy; n选自0、1、2、3、4或5；n is selected from 0, 1, 2, 3, 4 or 5; m选自1、2、3、4或5；m is selected from 1, 2, 3, 4 or 5; k选自1、2、3、4或5；k is selected from 1, 2, 3, 4 or 5; 并且式(I)化合物满足如下条件：And the compound of formula (I) satisfies the following conditions: (1)RA不为 (1) R A does not (2)RA选自时，R3不为C2-6炔基和C1-6氘代烷基；(2) R A is selected from When R 3 is not C 2-6 alkynyl or C 1-6 deuterated alkyl; (3)当m、k同时选自1时，R1、R3不同时选自卤素。(3) When m and k are both selected from 1, R 1 and R 3 are not simultaneously selected from halogen. 根据权利要求1所述的式(I)、式(IV)、式(IV-a)、式(IV-b)化合物，其立体异构体、药学上可接受的盐，其中The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein R1、R2、R3各自独立地选自氢、氘、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、-SF5、-SCF3、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-O-C3-6环烷基或-O-(3-6元杂环烷基)，其中所述的烷基、烯基、炔基任选进一步被1-5个Ra取代；R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -SF 5 , -SCF 3 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, and alkynyl are optionally further substituted with 1-5 Ra; n选自0、1、2或3；n is selected from 0, 1, 2 or 3; m选自1、2或3；m is selected from 1, 2 or 3; k选自1、2或3。k is selected from 1, 2 or 3. 根据权利要求1-2任意一项所述的式(I)、式(IV)、式(IV-a)、式(IV-b)化合物，其立体异构体、药学上可接受的盐，其中，The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to any one of claims 1 to 2, and its stereoisomers and pharmaceutically acceptable salts, wherein: RA选自-W1-L2-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1； RA is selected from -W1 - L2 - W2 - RA1, -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 ; L2选自键、C1-4亚烷基、C2-4亚烯基，所述的亚烷基、亚烯基任选进一步被1-4个RL1取代；RL1各自独立的选自卤素、＝O、C1-4烷基、3-6元环烷基，所述的烷基、环烷基任选进一步被1-4个选自卤素的取代基取代； L2 is selected from a bond, C1-4 alkylene, C2-4 alkenylene, and the alkylene and alkenylene are optionally further substituted by 1-4 R L1 ; R L1 are each independently selected from halogen, =O, C1-4 alkyl, 3-6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally further substituted by 1-4 substituents selected from halogen; W1、W2各自独立地选自键、-NRW1-、-(C＝O)NRW1-、-NRW1(C＝O)-、-NRW1-NRw1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1- , -(C=O) NRW1- , -NRW1(C=O)-, -NRW1 - NRw1 (C=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(O)(=NH)-, -N = C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-; 条件是，L2、W1、W2不同时为键；The condition is that L 2 , W 1 , and W 2 are not bonds at the same time; RA1选自氘、卤素、羟基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-4烷氧基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-10元杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; RW1选自H、C1-2烷基、卤素、氰基；R W1 is selected from H, C 1-2 alkyl, halogen, cyano; Ra选自氘、卤素、羟基、氰基、氧代基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4氘代烷基、C1-4卤代烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C3-6环烷基、3-6元杂环烷基、C6-8芳基、5-6元杂芳基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-6环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-6环烷基、-S(O)2C3-6环烷基、-S(O)2C1-4烷基，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxyl, cyano, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 deuterated alkyl, C1-4 haloalkyl, C1-3 alkyl substituent, C1-3 haloalkyl substituent, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-8 aryl, 5-6 membered heteroaryl, -C(O) C1-4 alkyl, -C(O) C1-4 deuterated alkyl, -NRW1C (O) C1-4 alkyl, -NRW1C (O) C1-4 deuterated alkyl, -S(O) 2NH2 , -S(O )2NHC1-4 alkyl , -C(O) C3-6 cycloalkyl , -C(O) NRW1C1-4 alkyl , -NRW1C ( O )C C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy; RA2选自C3-6环烷基、3-6元杂环烷基、5-6元杂芳基，所述的环烷基、杂芳基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；R A2 is selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent or deuterated C 1-4 alkoxy; 作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C2-6炔基、C3-6环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl; 作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C3-6环烷基、3-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy. 根据权利要求3所述的式(I)、式(IV)、式(IV-a)、式(IV-b)化合物，其立体异构体、药学上可接受的盐，其中，The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 3, its stereoisomers, and pharmaceutically acceptable salts, wherein: RA选自-W1-W2-RA1、-C3-6环烷基-RA1或-3-6元杂环烷基-RA1,优选RA选自-N＝C(NH2)-NRW1C(O)-RA1、-N＝C(NH2)-NRW1RA1、-N＝C(NH2)-RA1、-NRW1-RA1、-N＝S(＝O)(C1-6烷基)-RA1、-NRW1S(O)2-NRW1C(O)-RA1、-NRW1-S(O)(＝NH)-RA1、-N＝C(CH3)-NRW1RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1、-C3-6环烷基-RA1、-3-6元杂环烷基-RA1； RA is selected from -W1 - W2 - RA1 , -C3-6cycloalkyl - RA1 or -3-6memberedheterocycloalkyl- RA1 . Preferably RA is selected from -N＝C( NH2 )-NRW1C(O) -RA1 , -N＝C( NH2 ) -NRW1RA1 , -N＝C( NH2 ) -RA1 , -NRW1 -RA1 , -N＝S(＝O)( C1-6alkyl ) -RA1 , -NRW1S(O) 2- NRW1C (O )-RA1 , -NRW1 - S (O)(＝NH) -RA1 , -N＝C( CH3 ) -NRW1RA1 , -N＝C( NH2 ) -NRW1 - NRW1C (O) -RA1 , -C3-6cycloalkyl - RA1 , -3-6 membered heterocycloalkyl-R A1 ; W1、W2各自独立地选自键、-NRW1-、-NRW1-NRw1(C＝O)-、-(C＝O)NRW1-、-NRW1(C＝O)-、-S(O)2-、-S(O)2NRW1-、-NRW1S(O)2-、-S(O)(＝NH)-、-N＝C(NH2)-、-N＝S(＝O)(C1-6烷基)-、-N＝C(CH3)-； W1 and W2 are each independently selected from a bond, -NRW1-, -NRW1 - NRw1 (C=O)-, -(C=O) NRW1- , -NRW1 ( C=O)-, -S(O) 2- , -S(O) 2NRW1- , -NRW1S (O) 2- , -S(O)(=NH)-, -N = C( NH2 )-, -N=S(=O)( C1-6alkyl )-, -N=C( CH3 )-; 条件是，W1、W2不同时为键；The condition is that W 1 and W 2 are not bonds at the same time; RA1选自氘、卤素、氰基、C1-4烷基、C2-4烯基、C1-4氘代烷基、C1-4卤代烷基、C3-6环烷基、3-6元杂环烷基、C6-8芳基或5-6元杂芳基，其中所述的烷基、烯基、环烷基、杂环烷基、芳基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; RW1选自H、C1-2烷基、氰基；R W1 is selected from H, C 1-2 alkyl, cyano; Ra选自氘、卤素、羟基、氧代基、C1-4烷基、C1-3烷基亚基、C1-3卤代烷基亚基、C1-4氘代烷基、C1-4卤代烷基、-C(O)C1-4烷基、-C(O)C1-4氘代烷基、-NRW1C(O)C1-4烷基、-NRW1C(O)C1-4氘代烷基、-S(O)2NH2、-S(O)2NHC1-4烷基、-C(O)C3-6环烷基、-C(O)NRW1C1-4烷基、-NRW1C(O)C3-6环烷基、-S(O)2C3-6环烷基或-S(O)2C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代；Ra is selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-3 alkyl substituent, C 1-3 haloalkyl substituent, C 1-4 deuterated alkyl, C 1-4 haloalkyl, -C(O)C 1-4 alkyl, -C(O)C 1-4 deuterated alkyl, -NR W1 C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 deuterated alkyl, -S(O) 2 NH 2 , -S(O) 2 NHC 1-4 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)NR W1 C 1-4 alkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 3-6 cycloalkyl or -S(O) 2 C 1-4 alkyl, wherein the alkyl or cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy; RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-3烷基亚基、C1-3卤代烷基亚基或氘代C1-4烷氧基的基团所取代；R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-3 alkyl substituent, C 1-3 halogenated alkyl substituent or deuterated C 1-4 alkoxy; 作为选择，同一个碳原子上的两个Ra与其相连的碳原子一起形成C2-6烯基、C3-6环烷基；Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl or a C 3-6 cycloalkyl; 作为选择，不同碳原子上的两个R1或者两个R3与其相连的碳原子一起形成C4-6环烷基、4-6元杂环烷基，所述的环烷基或杂环烷基任选进一步被1-5个选自氘、卤素、羟基、氰基、氨基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。Alternatively, two R 1 or two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy or deuterated C 1-4 alkoxy. 根据权利要求1所述的式(I)、式(IV)、式(IV-a)、式(IV-b)的化合物，其立体异构体、药学上可接受的盐，其中，The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein: R1选自卤素、C1-4烷基、C2-4炔基；R 1 is selected from halogen, C 1-4 alkyl, C 2-4 alkynyl; R2选自氢； R2 is selected from hydrogen; R3选自氘、卤素、C1-4卤代烷基、-SF5、C2-4烯基、C2-4炔基，其中所述的烯基、炔基任选进一步被1-3个Ra取代；R 3 is selected from deuterium, halogen, C 1-4 haloalkyl, -SF 5 , C 2-4 alkenyl, C 2-4 alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra; 作为选择，不同碳原子两个R3与其相连的碳原子一起形成C4-6环烷基，所述的环烷基任选进一步被1-5个选自氘、卤素、C1-4烷基的基团所取代；Alternatively, two R 3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1-5 groups selected from deuterium, halogen, and C 1-4 alkyl; X1、X2、X3、X4选自CH或N；X 1 , X 2 , X 3 , X 4 are selected from CH or N; RA选自-N＝C(NH2)-NRW1C(O)-RA1、-NRW1-RA1、-N＝C(NH2)-NRW1-NRW1C(O)-RA1； RA is selected from -N=C( NH2 ) -NRW1C (O) -RA1 , -NRW1 - RA1 , -N=C(NH2)-NRW1 - NRW1C (O) -RA1 ; RA1选自C1-4烷基、C3-6环烷基、3-6元杂环烷基或5-6元杂芳基，其中所述的烷基、环烷基、杂环烷基或杂芳基任选进一步被1-5个Ra取代；R A1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra; RW1选自H、C1-2烷基；R W1 is selected from H, C 1-2 alkyl; Ra选自氘、卤素、氧代基、C1-4烷基、-C(O)C1-4烷基、-NRW1C(O)C1-4烷基、-S(O)2NH2、-C(O)C3-6环烷基、-NRW1C(O)C3-6环烷基、-S(O)2C1-4烷基、-S(＝O)(＝NH)-C1-4烷基，其中所述的烷基、环烷基任选进一步被1-5个选自卤素、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基的基团所取代；Ra is selected from deuterium, halogen, oxo, C 1-4 alkyl, -C(O)C 1-4 alkyl, -NR W1 C(O)C 1-4 alkyl, -S(O) 2 NH 2 , -C(O)C 3-6 cycloalkyl, -NR W1 C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-4 alkyl, -S(＝O)(＝NH)-C 1-4 alkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-5 groups selected from halogen, C 1-4 alkyl, halogenated C 1-4 alkyl and deuterated C 1-4 alkyl; RA2选自C3-6环烷基、5-6元杂芳基，所述的环烷基、杂芳基任选进一步被1-5个选自氘、卤素、羟基、氧代基、C1-4烷基、卤代C1-4烷基、氘代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基或氘代C1-4烷氧基的基团所取代。R A2 is selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl, and the cycloalkyl, heteroaryl is optionally further substituted with 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy. 根据权利要求1所述的式(I)、式(IV)、式(IV-a)、式(IV-b)的化合物，其立体异构体、药学上可接受的盐，其中，The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein: RA选自: R A is selected from: RA2选自环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基，所述的环丙基、环丁基、环戊基、环己基、5元杂芳基、6元杂芳基、6元杂环烷基、5元杂环烷基、4元杂环烷基任选进一步被1-5个选自氘、羟基、氰基、氨基、甲基、乙基、异丙基、甲氧基、乙氧基、F、Cl、氧代基、甲亚基、乙亚基、1-甲基乙亚基、氟甲亚基、二氟甲亚基、-CH2D、-CHD2、-CD3、-CH2CH2D、-CH2CHD2、-CH2CD3、-CHDCH2D、-CHDCHD2、-CHDCD3、-CD2CH2D、-CD2CHD2、-CD2CD3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CHFCH2F、-CHFCHF2、-CHFCF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-OCHF2、-OCH2F、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCHFCH2F、-OCHFCHF2、-OCHFCF3、-OCF2CH2F、-OCF2CHF2、-OCF2CF3、-OCHD2、-OCH2D、-OCD3、-OCH2CH2D、-OCH2CHD2、-OCH2CD3、-OCHDCH2D、-OCHDCHD2、-OCHDCD3、-OCD2CH2D、-OCD2CHD2、-OCD2CD3的基团所取代。R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 4-membered heterocycloalkyl are optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy , F, Cl, oxo, methylidene, ethylidene, 1 - methylethylidene, fluoromethylidene, difluoromethylidene , -CH2D , -CHD2 , -CD3 , -CH2CH2D , -CH2CHHD2 , -CH2CD3 , -CHDCH2D , -CHDCHD2 , -CHDCD3 , -CD2CH2D , -CD 2 CHD 2 , -CD 2 CD 3 , -CH 2 F , -CHF 2 , -CF 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 2 F , -CHFCHF 2 , -CHFCF 3 , -CF 2 CH 2 F , -CF 2 CHF 2 , -CF 2 CF 3 , -OCHF 2 , -OCH 2 F , -OCF 3 , -OCH 2 CH 2 F , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 2 F , -OCHFCHF 2 , -OCHFCF 3 , -OCF 2 CH 2 F , -OCF 2 CHF 2 , -OCF 2 CF 3 , -OCHD 2 , -OCH 2 D, -OCD 3 , -OCH 2 CH 2 D, -OCH 2 CHD 2 , -OCH 2 CD 3 , -OCHDCH 2 D, -OCHDCHD 2 , -OCHDCD 3 , -OCD 2 CH 2 D, -OCD 2 CHD 2 , -OCD 2 CD 3 . 根据权利要求1所述的式(I)、式(IV)、式(IV-a)、式(IV-b)的化合物，其立体异构体、药学上可接受的盐，其中所述化合物选自表一或表二中结构之一。The compound of formula (I), formula (IV), formula (IV-a), and formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table 1 or Table 2. 一种药物组合物，其中，含有权利要求1-7任意一项所述的化合物、其立体异构体、药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its stereoisomers, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and/or excipients. 权利要求1-7任意一项所述的化合物、其立体异构体、药学上可接受的盐或者权利要求8所述的组合物在制备治疗CB1介导的疾病的药物中的应用。Use of the compound according to any one of claims 1 to 7, its stereoisomer, pharmaceutically acceptable salt or the composition according to claim 8 in the preparation of a medicament for treating CB1-mediated diseases. 根据权利要求9所述的应用，其中，所述CB1介导的疾病为肥胖症、糖尿病、非酒精性和酒精性脂肪肝疾病、糖尿病性肾病、代谢综合征、高血脂或痛风。The use according to claim 9, wherein the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout. 一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含1-1000mg的选自权利要求1-7任意一项所述的化合物或者其立体异构体或药学上可接受的盐和载体和/或辅料。A pharmaceutical composition or pharmaceutical preparation comprising 1-1000 mg of a compound selected from any one of claims 1-7 or a stereoisomer or a pharmaceutically acceptable salt thereof and a carrier and/or an excipient. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-7任意一项所述的化合物或者其立体异构体或药学上可接受的盐，治疗有效量优选1-1000mg，所述的疾病优选肥胖症、糖尿病、非酒精性和酒精性脂肪肝疾病、糖尿病性肾病、代谢综合征、高血脂或痛风。A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer or a pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1 to 1000 mg, the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.
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