A class of cyclopentane compounds and their preparation and application

Abstract

The present invention belongs to the field of medical technology and relates to a class of cyclopentadiene compounds as shown in formula (I') and their preparation and application. The test results show that the compounds of the present invention can significantly inhibit the activity of ATM kinase and have good selectivity for ATM targets, and have medical uses for treating cancer.

Description

[0001] Citation of Related Applications

[0002] This invention claims priority to the invention patent application entitled “A class of cyclopentadiene compounds and their preparation and application” filed in China on September 28, 2020, with application number 202011044828.9 and the invention patent application entitled “A class of cyclopentadiene compounds and their preparation and application” filed in China on August 5, 2021, with application number 202110905531.5. The entire contents of the patent applications are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of medical technology, and in particular relates to a new compound having ATM protein kinase inhibitory activity and the use of the compound or pharmaceutical composition in preparing medicines. Background Art

[0004] Hereditary ataxia-telangiectasia (AT) is an autosomal recessive genetic disorder characterized by progressive cerebellar ataxia, facial telangiectasia, increased sensitivity to radiation, and a significant increased predisposition to tumors (Taylor AM, Harnden DG, Arlett CF, et al. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature, 1975, 258:427-429). AT is currently known to be caused by mutations in the ataxia telangiectasia mutated gene (ATM). The ATM gene is located on chromosome 11q22-23, is 150 kb long, and has 66 exons, making it one of the human genes with the most exons discovered to date (Savitsky K, Bar Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science, 1995, 268(5218):1749-1753).

[0005] ATM protein kinase is the encoded product of the ATM gene, a serine / threonine protein kinase containing 3056 amino acids and a relative molecular mass of approximately 350 kDa (CHEN G, LEE E. The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem, 1996, 271(52): 33693-33697). It is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family (Watters D, Khanna KK, Beamish H, et al. Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms. Oncogene, 1997, 14: 1911-1921). It is distributed in the nucleus and cytoplasm, is ubiquitous in the tissue cells of higher eukaryotic organisms, and is highly expressed in some tissue cells such as the testis, spleen, and thymus.ATM participates in the regulation of cell cycle and the recognition and repair of DNA damage through its C-terminal functional domain. Its functions in cell signal transduction pathways include activating cell cycle checkpoints (Canman CE, Lim DS, Cimprich KA et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 1998, 281: 1677-1679), regulating the repair of DNA damage (matsuoka S, huang M, elledge SJ. linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998; 282: 1893-1897), and regulating telomeres (Kishi S, Lu KP. A critical role for Pin2 / TRF1 in ATM-dependent regulation. Inhibition of Pin2 / TRF1 function complements telomere shortening, radio sensitivity, and the G(2) / M checkpoint defect of ataxia-telangiectasia cells. Journal Bio Chem. 2002, 277(9): 7420-7429), and regulation of cell apoptosis (Lee Y, Barnes DE, Lindahl T, et al. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 2000, 14: 2576-2580).

[0006] ATM protein kinase mainly acts on the repair of DNA double-strand breaks, maintaining the stability of DNA by guiding the phosphorylation of downstream effectors. When cells are damaged by double-strand DNA damage caused by ionization or ultraviolet radiation, DNA double-strand breaks (DSBs) occur. The MRE11-RAD50-NBS1 (MRN) complex senses DSBs and initiates DNA repair, thereby recruiting ATM protein kinase. ATM protein kinase is the main sensor in the DSB repair process, recruiting and interacting with other proteins. At the DSB site, ATM homodimers separate into active monomers and are catalytically activated by autophosphorylation and acetylation. Coordination with other proteins promotes the repair of broken DNA (Lee JH, Paull TT, Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007, 26 (56): 7741-7748).

[0007] ATM can also regulate the cell cycle through the Chk2-p53 / AKT pathway, thereby affecting the proliferation and apoptosis of tumor cells (Lazzaro F, Giannattasio M, Puddu F, et al. Checkpoint mechanisms at the intersection between DNA damage and repair. DNA Repair, 2009, 8 (9): 1055-1067). At the same time, activated ATM can also affect the occurrence, migration and invasion of tumors through the ATM-Akt-GSK-3β pathway, transcriptional regulatory factors NF-κB and interleukin IL-8, and participate in DNA damage response through different mechanisms, thereby increasing the resistance and resistance of tumor cells to radiotherapy and chemotherapy (Bo Peng, Janice Ortega, et al. Phosphorylation of proliferating cell nuclear antigen promotes cancer progression by activating the ATM / AKT / GSK3β / Snail signaling pathway. JBC, 2019 (295) 9767).

[0008] Currently, ATM inhibitors are being studied clinically in combination with radiation therapy and chemotherapy. Other candidates under clinical development include AstraZeneca's AZD-1390 and Merck's M-3541.

[0009] ATM kinase inhibitors can treat solid tumors or hematological tumors.

[0010] Summary of the Invention

[0011] [Annular compounds]

[0012] The present invention provides a class of compounds with novel structures as ATM kinase inhibitors.

[0013] Specifically, the present invention provides a compound as shown in formula (I') or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, which has the following structure:

[0014]

[0015] in,

[0016] Y is

[0017] X1 is selected from the group consisting of a bond, hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R 1x )C(O)-、-C(O)N(R 1x )-or-N(R 1x )-;R 1x is selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 The oxo group is substituted by a substituent of an aryl group or a 5-12 membered heteroaryl group; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0018] When X1 is hydrogen, deuterium, halogen, hydroxy, amino, nitro or cyano, R1, X2, R2 and R3 are absent;

[0019] R1 is selected from absence, a bond, hydrogen, deuterium or an optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 1a Replaced by; R 1a Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 1b 、-OR 1b 、-SR 1b 、-S(O)R 1b 、-SO2(R 1b ),-C(O)R 1b 、-C(O)OR 1b 、-OC(O)R 1b 、-NH(R 1b )、-N(R 1b )(R 1c )、-C(O)NH(R 1b )、-C(O)N(R 1b )(R 1c )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-S(O)N(R 1b )(R 1c )、-SO2NH(R 1b )、-SO2N(R 1b )(R 1c )、-NHS(O)(R 1b )、-N(R 1b )S(O)(R 1c )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c );R 1b 、R 1c Each occurrence is independently selected from hydrogen, deuterium or optionally deuterated, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c and the nitrogen atom to which it is attached together to form an optionally substituted deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0020] When R1 is hydrogen or deuterium, X2, R2 and R3 do not exist;

[0021] X2 is selected from the group consisting of absence, a bond, hydrogen, deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, -O-, -S-, -P-, -C(O)-, -C(S)-, -C(=NR 2x )-, -CH=N-, -C(O)O-, -C(O)C(O)-, -OC(O)-, -OC(S)-, -O-SO2-, -OP(O)-, -N=CH-, -C(O)N(R 2x )-、-N(R 2x )C(O)-、-N(R 2x )-, -S(O)-, -SO2-, -S(O)N(R 2x )-、-SO2N(R 2x )-or-P(O)-;R 2x is selected from hydrogen, deuterium or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14Aryl or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 The oxo group is substituted by a substituent of an aryl group or a 5-12 membered heteroaryl group; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0022] When X2 is hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto or cyano, R2 and R3 are absent;

[0023] R2 is selected from absence, a bond, hydrogen, deuterium or an optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 2a Replaced by; R 2a Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 2b 、-OR 2b 、-SR 2b 、-S(O)(R 2b )、-SO2(R 2b ),-C(O)R 2b 、-C(O)OR 2b 、-OC(O)R 2b 、-NH(R 2b )、-N(R 2b )(R 2c )、-C(O)NH(R 2b )、-C(O)N(R 2b )(R 2c )、-NHC(O)(R 2b )、-N(R 2b )C(O)(R 2c )、-S(O)NH(R 2b )、-S(O)N(R 2b)(R 2c )、-SO2NH(R 2b )、-SO2N(R 2b )(R 2c )、-NHS(O)(R 2b )、-N(R 2b )S(O)(R 2c )、-NHSO2(R 2b ) or -N(R 2b )SO2(R 2c );R 2b 、R 2c Each occurrence is independently selected from optionally deuterated, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 2b and R 2c When connected to the same nitrogen atom, R 2b and R 2c and the nitrogen atom to which it is attached together to form an optionally substituted deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0024] When R2 is hydrogen or deuterium, R3 is absent;

[0025] R3 is selected from the group consisting of absent, hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 3b 、-OR 3b 、-SR 3b 、-S(O)(R 3b )、-SO2(R 3b ),-C(O)R 3b、-C(O)OR 3b 、-OC(O)R 3b 、-NH(R 3b )、-N(R 3b )(R 3c )、-C(O)NH(R 3b )、-C(O)N(R 3b )(R 3c )、-NHC(O)(R 3b )、-N(R 3b )C(O)(R 3c )、-S(O)NH(R 3b )、-S(O)N(R 3b )(R 3c )、-SO2NH(R 3b )、-SO2N(R 3b )(R 3c )、-NHS(O)(R 3b )、-N(R 3b )S(O)(R 3c )、-NHSO2(R 3b ) or -N(R 3b )SO2(R 3c );R 3b 、R 3c Each occurrence is independently selected from hydrogen, deuterium or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 3-20 membered heterocyclic group or a 5-12 membered heteroaryl group; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 3d Replaced by; R 3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 3e 、-OR 3e 、-SR 3e 、-S(O)(R 3e )、-SO2(R 3e ),-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R3e 、-NH(R 3e )、-N(R 3e )(R 3f )、-C(O)NH(R 3e )、-C(O)N(R 3e )(R 3f )、-NHC(O)(R 3e )、-N(R 3e )C(O)(R 3f )、-S(O)NH(R 3e )、-S(O)N(R 3e )(R 3f )、-SO2NH(R 3e )、-SO2N(R 3e )(R 3f )、-NHS(O)(R 3e )、-N(R 3e )S(O)(R 3f )、-NHSO2(R 3e ) or -N(R 3e )SO2(R 3f );R 3e 、R 3f Each occurrence is independently selected from hydrogen, deuterium or optionally substituted with halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3e and R 3f When connected to the same nitrogen atom, R 3e and R 3f and the nitrogen atom to which it is attached together to form an optionally substituted deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0026] R4 is independently selected at each occurrence from hydrogen, deuterium, halogen, nitro, amino, cyano, hydroxy, carboxyl, thiol or C optionally substituted with one or more deuterium, halogen, hydroxy or amino groups. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio;

[0027] h is 1 or 2;

[0028] R5 is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl or C optionally substituted with one or more deuterium, halogen, hydroxyl, amino or cyano groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl;

[0029] L is C(R L ) or N;

[0030] R L Each occurrence is independently selected from hydrogen, deuterium, halogen, nitro, amino, cyano, hydroxyl, carboxyl, thiol, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio;

[0031] A is

[0032] in, represents a single bond or a double bond; Q1 is connected to W;

[0033] t1, t2, t3, t4, t5, and t6 are independently 0 or 1;

[0034] n1 and n2 are independently 0, 1 or 2, and n1 and n2 are not 0 at the same time, wherein n1 represents n1 Q1s connected in sequence, and n2 represents n2 Q2s connected in sequence; two adjacent Q1s are connected by a single bond or a double bond; two adjacent Q2s are connected by a single bond or a double bond;

[0035] W, Q1, Q2 are independently selected from C, O, N or S;

[0036] Q3 is C; when the bond connecting one side of Q3 is a double bond, R 10 or R 11 does not exist;

[0037] R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, nitro, -R 6a 、-OR 6a 、-SR 6a 、-S(O)(R 6a )、-SO2(R 6a ),-C(O)R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-NH(R 6a )、-N(R 6a )(R 6b )、-C(O)NH(R 6a )、-C(O)N(R 6a )(R 6b )、-NHC(O)(R 6a )、-N(R 6a )C(O)(R 6b )、-S(O)NH(R 6a )、-S(O)N(R 6a )(R 6b )、-SO2NH(R 6a )、-SO2N(R 6a )(R 6b )、-NHS(O)(R 6a )、-N(R 6a )S(O)(R 6b )、-NHSO2(R 6a ) or -N(R 6a )SO2(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two substituents attached to the same atom together form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, monospirocyclic group or heteromonospirocyclic group;

[0038] R 6a 、R 6b Each occurrence is independently selected from hydrogen, deuterium or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; or when R 6a and R 6b When connected to the same nitrogen atom, R 6a and R 6b and the nitrogen atom to which it is attached together form an optionally R 6c substituted 3-10 membered heterocyclyl or 5-12 membered heteroaryl;

[0039] R 6c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, nitro, azido, oxo, -R 6d 、-OR 6d 、-N(R 6d )R 6e 、-C(O)R 6d 、-C(O)N(R 6d )R 6e 、-N(R 6d )C(O)R 6e 、-C(O)OR 6d 、-OC(O)R 6d 、-S(O)N(R 6d )(R 6e )、-SO2N(R 6d )(R 6e )、-N(R 6d )S(O)(R 6e )、-N(R 6d )SO2(R 6e ), =NR 6dor =CH-R 6d ; The oxo group refers to two H groups at the same substitution site being replaced by the same O to form a double bond; the =NR 6d It means that two H at the same substitution site are replaced by the same N to form a double bond, and N is replaced by R 6d Substitution; said =CH-R 6d It means that two H at the same substitution site are replaced by the same C to form a double bond, and C is replaced by R 6d replace;

[0040] R 6d 、R 6e Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano or optionally substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, monospirocyclic group, heteromonospirocyclic group, fused ring group or heterofused ring group; or when R 6d and R 6e When connected to the same nitrogen atom, R 6d and R 6e and the nitrogen atom to which it is attached form an optionally substituted 3-10 membered heterocyclic group or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 6f Replaced by; R 6f Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the oxo group means that two H at the same substitution site are replaced by the same O to form a double bond;

[0041] When a heterocycloalkyl group, a heteroaryl group, a heterocyclic group, a heteromonospirocyclic group, a heterofused cyclic group and / or a heterobridged cyclic group is present, the heteroatoms therein are independently selected from O, N or S, and the number of the heteroatoms is 1, 2, 3 or 4.

[0042] The present invention also provides a compound as shown in formula (I) or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, which has the following structure:

[0043]

[0044] in,

[0045] Y is

[0046] X1 is selected from the group consisting of a bond, hydrogen, halogen, hydroxy, amino, nitro, cyano, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R 1x )C(O)-、-C(O)N(R 1x )-or-N(R 1x )-;R 1x is selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 The oxo group refers to a group in which two H atoms at the same substitution site are replaced by the same O atoms to form a double bond.

[0047] When X1 is hydrogen, halogen, hydroxy, amino, nitro or cyano, R1, X2, R2 and R3 are absent;

[0048] R1 is selected from absence, a bond, hydrogen or an optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 1a Replaced by; R 1a Each occurrence is independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 1b 、-OR 1b 、-SR 1b 、-S(O)R 1b 、-SO2(R 1b ),-C(O)R 1b 、-C(O)OR 1b 、-OC(O)R 1b 、-NH(R 1b )、-N(R 1b )(R 1c )、-C(O)NH(R 1b )、-C(O)N(R 1b )(R 1c )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-S(O)N(R 1b )(R 1c )、-SO2NH(R 1b )、-SO2N(R 1b )(R 1c )、-NHS(O)(R 1b )、-N(R 1b )S(O)(R 1c )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c );R 1b 、R 1c Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c and the nitrogen atom to which it is attached together to form a group optionally substituted by halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0049] When R1 is hydrogen, X2, R2 and R3 are absent;

[0050] X2 is selected from the group consisting of absence, a bond, hydrogen, halogen, hydroxy, amino, nitro, mercapto, cyano, -O-, -S-, -P-, -C(O)-, -C(S)-, -C(=NR 2x )-, -CH=N-, -C(O)O-, -C(O)C(O)-, -OC(O)-, -OC(S)-, -O-SO2-, -OP(O)-, -N=CH-, -C(O)N(R 2x )-、-N(R 2x )C(O)-、-N(R 2x )-, -S(O)-, -SO2-, -S(O)N(R 2x )-、-SO2N(R 2x )-or-P(O)-;R 2x is selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 The oxo group is substituted by a substituent of an aryl group or a 5-12 membered heteroaryl group; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0051] When X2 is hydrogen, halogen, hydroxy, amino, nitro, mercapto or cyano, R2 and R3 are absent;

[0052] R2 is selected from absent, a bond, hydrogen or an optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 2a Replaced by; R 2a Each occurrence is independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 2b 、-OR 2b 、-SR 2b 、-S(O)(R 2b )、-SO2(R 2b ),-C(O)R 2b 、-C(O)OR 2b 、-OC(O)R 2b 、-NH(R 2b )、-N(R 2b )(R 2c )、-C(O)NH(R 2b )、-C(O)N(R 2b )(R 2c )、-NHC(O)(R 2b )、-N(R 2b )C(O)(R 2c )、-S(O)NH(R 2b )、-S(O)N(R 2b )(R 2c )、-SO2NH(R 2b )、-SO2N(R 2b )(R 2c )、-NHS(O)(R 2b )、-N(R 2b )S(O)(R 2c )、-NHSO2(R 2b ) or -N(R2b )SO2(R 2c );R 2b 、R 2c Each occurrence is independently selected from optionally substituted halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 2b and R 2c When connected to the same nitrogen atom, R 2b and R 2c and the nitrogen atom to which it is attached together to form a group optionally substituted by halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0053] When R2 is hydrogen, R3 is absent;

[0054] R3 is selected from the group consisting of absent, hydrogen, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 3b 、-OR 3b 、-SR 3b 、-S(O)(R 3b )、-SO2(R 3b ),-C(O)R 3b 、-C(O)OR 3b 、-OC(O)R 3b 、-NH(R 3b )、-N(R 3b )(R 3c )、-C(O)NH(R 3b )、-C(O)N(R 3b )(R 3c )、-NHC(O)(R3b )、-N(R 3b )C(O)(R 3c )、-S(O)NH(R 3b )、-S(O)N(R 3b )(R 3c )、-SO2NH(R 3b )、-SO2N(R 3b )(R 3c )、-NHS(O)(R 3b )、-N(R 3b )S(O)(R 3c )、-NHSO2(R 3b ) or -N(R 3b )SO2(R 3c );R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 3d Replaced by; R 3d Each occurrence is independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R 3e 、-OR 3e 、-SR 3e 、-S(O)(R 3e )、-SO2(R 3e ),-C(O)R 3e 、-C(O)OR 3e 、-OC(O)R 3e 、-NH(R 3e )、-N(R 3e )(R 3f )、-C(O)NH(R 3e )、-C(O)N(R 3e )(R 3f )、-NHC(O)(R 3e )、-N(R 3e)C(O)(R 3f )、-S(O)NH(R 3e )、-S(O)N(R 3e )(R 3f )、-SO2NH(R 3e )、-SO2N(R 3e )(R 3f )、-NHS(O)(R 3e )、-N(R 3e )S(O)(R 3f )、-NHSO2(R 3e ) or -N(R 3e )SO2(R 3f );R 3e 、R 3f Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3e and R 3f When connected to the same nitrogen atom, R 3e and R 3f and the nitrogen atom to which it is attached together to form a group optionally substituted by halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond;

[0055] R4 is selected from hydrogen, halogen, nitro, amino, cyano, hydroxy, carboxyl, mercapto or C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio;

[0056] R5 is selected from hydrogen, halogen, hydroxy or C optionally substituted by one or more halogen, hydroxy, amino or cyano groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl, and 5-12 membered heteroaryl;

[0057] L is C(R L ) or N;

[0058] R L Selected from hydrogen, halogen, nitro, amino, cyano, hydroxyl, carboxyl, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio;

[0059] A is

[0060] in, represents a single bond or a double bond; Q1 is connected to W;

[0061] t1, t2, t3, t4, t5, and t6 are independently 0 or 1;

[0062] n1 and n2 are independently 0, 1 or 2, and n1 and n2 are not 0 at the same time, wherein n1 represents n1 Q1s connected in sequence, and n2 represents n2 Q2s connected in sequence; two adjacent Q1s are connected by a single bond or a double bond; two adjacent Q2s are connected by a single bond or a double bond;

[0063] W, Q1, Q2 are independently selected from C, O, N or S;

[0064] Q3 is C; when the bond connecting one side of Q3 is a double bond, R 10 or R 11 does not exist;

[0065] R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, -R 6a 、-OR 6a 、-SR 6a 、-S(O)(R 6a )、-SO2(R 6a ),-C(O)R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-NH(R 6a)、-N(R 6a )(R 6b )、-C(O)NH(R 6a )、-C(O)N(R 6a )(R 6b )、-NHC(O)(R 6a )、-N(R 6a )C(O)(R 6b )、-S(O)NH(R 6a )、-S(O)N(R 6a )(R 6b )、-SO2NH(R 6a )、-SO2N(R 6a )(R 6b )、-NHS(O)(R 6a )、-N(R 6a )S(O)(R 6b )、-NHSO2(R 6a ) or -N(R 6a )SO2(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two substituents attached to the same atom together form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, monospirocyclic group or heteromonospirocyclic group;

[0066] R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring group, 4-12 membered heterobridged ring group, monospiro ring group, heteromonospiro ring group, fused ring group or heterofused ring group; or when R 6a and R 6b When connected to the same nitrogen atom, R 6a and R 6b and the nitrogen atom to which it is attached together form an optionally R 6c substituted 3-10 membered heterocyclyl or 5-12 membered heteroaryl;

[0067] R 6c Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, azido, oxo, -R 6d 、-OR 6d 、-N(R 6d )R 6e 、-C(O)R 6d 、-C(O)N(R 6d )R 6e 、-N(R 6d )C(O)R 6e 、-C(O)OR 6d 、-OC(O)R 6d 、-S(O)N(R 6d )(R 6e )、-SO2N(R 6d )(R 6e )、-N(R 6d )S(O)(R 6e )、-N(R 6d )SO2(R 6e ), =NR 6d or =CH-R 6d ; The oxo group refers to two H groups at the same substitution site being replaced by the same O to form a double bond; the =NR 6d It means that two H at the same substitution site are replaced by the same N to form a double bond, and N is replaced by R 6d Substitution; said =CH-R 6d It means that two H at the same substitution site are replaced by the same C to form a double bond, and C is replaced by R 6d replace;

[0068] R 6d 、R 6e Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano or optionally substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, monospirocyclic group, heteromonospirocyclic group, fused ring group or heterofused ring group; or when R 6d and R 6e When connected to the same nitrogen atom, R 6d and R 6e and the nitrogen atom to which it is attached form an optionally substituted 3-10 membered heterocyclic group or 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 6f Replaced by; R 6f Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the oxo group means that two H at the same substitution site are replaced by the same O to form a double bond;

[0069] When a heterocycloalkyl group, a heteroaryl group, a heterocyclic group, a heteromonospirocyclic group, a heterofused cyclic group and / or a heterobridged cyclic group is present, the heteroatoms therein are independently selected from O, N or S, and the number of the heteroatoms is 1, 2, 3 or 4.

[0070] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (Ia):

[0071]

[0072] wherein each substituent is as defined in formula (I') or the compound of formula (I).

[0073] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (Ib):

[0074]

[0075] wherein each substituent is as defined in formula (I') or the compound of formula (I).

[0076] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (Ic):

[0077]

[0078] wherein each substituent is as defined in formula (I') or the compound of formula (I).

[0079] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X1 is selected from a bond, hydrogen, halogen, hydroxyl, amino, nitro, cyano, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R 1x )C(O)-、-C(O)N(R 1x )-or-N(R 1x )-;R 1x Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-12 membered heteroaryl.

[0080] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X1 is selected from a bond, hydrogen, halogen, hydroxyl, amino, nitro, cyano, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R 1x )C(O)-、-C(O)N(R 1x )-or-N(R 1x )-;R 1x Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0081] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X1 is selected from a bond, hydrogen, halogen, hydroxyl, amino, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NH- or -N(CH3)-.

[0082] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X1 is selected from a bond, hydrogen, -S-, -NHC(O)- or -C(O)NH-.

[0083] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X1 is selected from a bond.

[0084] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from an optionally substituted 3-10 membered heterocyclic group; the optional substitution refers to the optional substitution of R 1a replaced.

[0085] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from an optionally substituted 5-8 membered heterocyclic group, wherein the heteroatom is N and the number of heteroatoms is 1 or 2; the optional substitution refers to the optional substitution of R 1a replaced.

[0086] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted dihydropyridyl; the optional substitution refers to optionally replaced by R 1a replaced.

[0087] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from absence, bond, hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14Aryl or 5-12 membered heteroaryl; the optional substitution means optionally replaced by R 1a replaced.

[0088] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-14 Aryl or 5-12 membered heteroaryl; the optional substitution means optionally replaced by R 1a replaced.

[0089] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 6-14 Aryl or 5-12 membered heteroaryl; the optional substitution means optionally replaced by R 1a replaced.

[0090] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted C 2-6 Alkynyl or 5-12 membered heteroaryl; the optional substitution means optionally replaced by R 1a replaced.

[0091] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted C 2-6 Alkynyl or 5-8 membered heteroaryl, wherein the heteroatom is N, and the number of heteroatoms is 1, 2 or 3; the optional substitution refers to the optional substitution of R 1a replaced.

[0092] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted C 2-6 Alkynyl; the optional substitution refers to optionally R 1a replaced.

[0093] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from an optionally substituted 5-12 membered heteroaryl group; the optional substitution refers to the optional substitution of R 1a replaced.

[0094] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from an optionally substituted 5-8 membered heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 1, 2 or 3; the optional substitution refers to the optional substitution of R 1a replaced.

[0095] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from an optionally substituted 5-6 membered heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 1 or 2; the optional substitution refers to the optional substitution of R 1a replaced.

[0096] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted ethynyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl; the optional substitution means that R 1a replaced.

[0097] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R1 is selected from ethynyl.

[0098] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyridyl, pyrimidinyl, pyrazinyl or pyrazolyl; the optional substitution means that R 1a replaced.

[0099] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyridyl; the optional substitution means that R 1a replaced.

[0100] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Each occurrence is independently selected from halogen, hydroxy, amino, oxo, -R 1b 、-OR 1b 、-SR 1b 、-S(O)R 1b 、-SO2(R 1b ),-C(O)R 1b 、-C(O)OR 1b 、-OC(O)R 1b 、-NH(R 1b )、-N(R 1b )(R 1c )、-C(O)NH(R 1b )、-C(O)N(R 1b )(R 1c )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-S(O)N(R 1b )(R 1c )、-SO2NH(R 1b )、-SO2N(R 1b )(R 1c )、-NHS(O)(R 1b )、-N(R 1b )S(O)(R 1c )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0101] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Each occurrence is independently selected from halogen, hydroxy, amino, oxo, -R 1b 、-OR 1b 、-SO2(R 1b ),-C(O)R 1b 、-C(O)OR 1b 、-OC(O)R 1b 、-N(R 1b )(R 1c )、-C(O)N(R1b )(R 1c )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-S(O)N(R 1b )(R 1c )、-SO2NH(R 1b )、-SO2N(R 1b )(R 1c )、-NHS(O)(R 1b )、-N(R 1b )S(O)(R 1c )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0102] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Each occurrence is independently selected from halogen, hydroxy, amino, oxo, -R 1b 、-C(O)NH(R 1c )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-SO2NH(R 1b )、-NHS(O)(R 1b )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0103] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Each occurrence is independently selected from halogen, amino, oxo, -R 1b 、-NHC(O)(R 1b ) or -NHSO2(R 1b ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0104] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Each occurrence is independently selected from -NHC(O)(R 1b ) or -NHSO2(R 1b ).

[0105] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c and the nitrogen atom to which it is attached together to form an optionally substituted halogen, hydroxyl, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 One or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl groups among aryl or 5-8 membered heteroaryl groups; the oxo group means that two H groups at the same substitution site are replaced by the same O group to form a double bond.

[0106] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14Aryl or 5-12 membered heteroaryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a 3-10 membered heterocycloalkyl.

[0107] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-6 Alkyl, 3-8 membered heterocycloalkyl or C 6-8 Aryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocycloalkyl group.

[0108] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or C 6-8 Aryl; or when R 1b and R 1c When connected to the same nitrogen atom, R 1b and R 1c Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocycloalkyl group.

[0109] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-8 Aryl.

[0110] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C6 aryl (i.e. phenyl).

[0111] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0112] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from C 1-4 Alkyl or C 3-4 Cycloalkyl.

[0113] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from methyl, ethyl, cyclopropanyl, phenyl or tetrahydropyranyl.

[0114] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1b 、R 1c Each occurrence is independently selected from methyl or cyclopropane.

[0115] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyrazolyl; the optional substitution means that R 1a Replaced by; R 1a Independently selected from C 1-6 Alkyl or 3-8 membered heterocycloalkyl.

[0116] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyrazolyl; the optional substitution means that R 1a Replaced by; R 1a Independently selected from C 1-4 Alkyl or 6-membered heterocycloalkyl.

[0117] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyrazolyl; the optional substitution means that R 1a Replaced by; R 1a Independently selected from methyl, ethyl or tetrahydropyranyl.

[0118] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyridyl; the optional substitution refers to optionally replaced by R 1a Replaced by; R 1a independently selected from amino, -NHC(O)(R 1b ) or -NHSO2(R 1b );R 1b Each occurrence is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl or phenyl.

[0119] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted pyridyl; the optional substitution means that R 1a Replaced by; R 1a independently selected from amino, -NHC(O)(R 1b ) or -NHSO2(R 1b );R 1b Each occurrence is independently selected from C 1-4 Alkyl, C 3-4 cycloalkyl or phenyl.

[0120] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following optionally substituted groups:

[0121]

[0122] Wherein, the "*" end is one end connected to X1, and the other end is one end connected to X2; the optional substitution means that R 1a replaced.

[0123] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from optionally substituted

[0124] Wherein, the "*" end is one end connected to X1, and the other end is one end connected to X2; the optional substitution means that R 1a replaced.

[0125] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0126]

[0127] Among them, the "*" end is connected to X1, and the other end is connected to X2.

[0128] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0129]

[0130]

[0131] Among them, the "*" end is connected to X1, and the other end is connected to X2.

[0132] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0133]

[0134] Among them, the "*" end is connected to X1, and the other end is connected to X2.

[0135] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0136] Among them, the "*" end is connected to X1, and the other end is connected to X2.

[0137] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0138]

[0139] Among them, the "*" end is connected to X1, and the other end is connected to X2.

[0140] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R1 is selected from the following groups:

[0141] The "*" end is the end connected to X1.

[0142] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from the group consisting of absence, bond, hydrogen, halogen, hydroxyl, amino, -O-, -S-, -C(O)O-, -OC(O)-, -C(O)N(R 2x )-、-N(R 2x )C(O)-or-N(R 2x )-;R 2x is selected from hydrogen or C optionally substituted by halogen, hydroxy or amino 1-6 alkyl.

[0143] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from absence, bond, hydrogen, halogen, hydroxyl, amino, -O-, -S-, -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)-, -NH-, -N(CH3)- or -N(CH2CH3)-.

[0144] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from absence, a bond, -O-, -NH- or -N(CH3)-.

[0145] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from absence, a bond, -O- or -N(CH3)-.

[0146] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from a bond, -O- or -NH-.

[0147] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from absence, a bond or -O-.

[0148] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, X2 is selected from -O-.

[0149] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R2 is selected from absence, bond, hydrogen or optionally replaced by halogen, hydroxyl, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl.

[0150] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R2 is selected from the group consisting of absence, hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 aryl, 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl.

[0151] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R2 is selected from the group consisting of: 1-6 Alkyl, C 2-4 Alkynyl or 5-6 membered heterocycloalkyl, wherein the heteroatom is N or O, and the number of heteroatoms is 1 or 2.

[0152] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R2 is selected from absent, methyl, ethyl, propyl (n-propyl, isopropyl), butyl (n-butyl, isobutyl, sec-butyl, tert-butyl), ethynyl, piperidinyl, tetrahydropyrrolyl or tetrahydropyranyl.

[0153] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R2 is selected from n-propyl.

[0154] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the group consisting of absence, hydrogen, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, -R 3b 、-OR 3b 、-SR 3b 、-C(O)R 3b 、-C(O)OR 3b 、-OC(O)R 3b 、-N(R 3b )(R 3c )、-C(O)N(R 3b )(R 3c )、-C(O)NH(R 3b )、-NHC(O)(R 3b )、-N(R 3b )C(O)(R 3c )、-S(O)N(R 3b )(R 3c )、-SO2N(R 3b )(R 3c )、-N(R 3b )S(O)(R 3c ) or -N(R 3b )SO2(R 3c ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0155] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the group consisting of absence, hydrogen, halogen, hydroxyl, amino, oxo, -R 3b 、-OR 3b 、-SR 3b 、-C(O)R 3b 、-C(O)OR 3b、-OC(O)R 3b 、-N(R 3b )(R 3c )、-C(O)N(R 3b )(R 3c )、-C(O)NH(R 3b ) or -NHC(O)(R 3b ); The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0156] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the group consisting of: absent, -R 3b 、-OR 3b or -N(R 3b )(R 3c ).

[0157] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from -N(R 3b )(R 3c ).

[0158] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl, a 4-12 membered bicyclic heterocyclyl or a 5-12 membered heteroaryl; the optional substitution refers to an optionally substituted R 3d replaced.

[0159] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl; the optional substitution refers to an optionally substituted R 3d replaced.

[0160] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy or 3-10 membered heterocycloalkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0161] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the group consisting of: 1-6 Alkyl, C 1-6 Alkoxy or -N(R 3b )(R 3c );R 3b 、R 3c Independently selected from optionally substituted C 1-6 Alkyl, or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0162] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C1-6 Alkoxy or 3-10 membered heterocycloalkyl; the optional substitution means optionally replaced by R 3d replaced.

[0163] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from hydrogen or optionally substituted C 1-6 Alkyl; the optional substitution refers to optionally R 3d replaced.

[0164] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0165] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution refers to the optional substitution of R 3d replaced.

[0166] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-6 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl or 4-12 membered bicyclic heterocyclyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0167] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-6 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 4-8 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0168] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution refers to the optional substitution of R 3d replaced.

[0169] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3cand the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 3-membered heteromonospirocyclic radical, a 3-membered / 5-membered heteromonospirocyclic radical, a 5-membered / 3-membered heteromonospirocyclic radical, a 3-membered / 6-membered heteromonospirocyclic radical, a 6-membered / 3-membered heteromonospirocyclic radical, a 4-membered / 5-membered heteromonospirocyclic radical, a 5-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 6-membered heteromonospirocyclic radical, a 6-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 4-membered heteromonospirocyclic radical heteromonospirocyclic group, 5-membered / 5-membered heteromonospirocyclic group, 5-membered / 6-membered heteromonospirocyclic group, 6-membered / 5-membered heteromonospirocyclic group, 3-membered / 5-membered heterocyclic group, 5-membered / 3-membered heterocyclic group, 3-membered / 6-membered heterocyclic group, 6-membered / 3-membered heterocyclic group, 5-membered / 6-membered heterocyclic group or 6-membered / 5-membered heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution refers to optionally being replaced by R 3d replaced.

[0170] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 6-membered heteromonospirocyclic group, a 6-membered / 3-membered heteromonospirocyclic group, a 4-membered / 6-membered heteromonospirocyclic group, a 6-membered / 4-membered heteromonospirocyclic group or a 4-membered / 4-membered heteromonospirocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1 or 2; the optional substitution refers to optionally being replaced by R 3d replaced.

[0171] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted methyl, or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted piperidinyl; the optionally substituted refers to optionally being replaced by R 3d replaced.

[0172] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-N(R 3e )(R 3f ) or -C(O)NH(R 3e );R 3e 、R 3f Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3e and R 3f When connected to the same nitrogen atom, R 3e and R 3f and the nitrogen atom to which it is attached together to form an optionally halogenated, hydroxyl, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-12 membered heteroaryl, and one or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl.

[0173] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-N(R 3e )(R 3f ) or -C(O)NH(R 3e );R 3e 、R 3f Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 3-6 One or more substituted C6 alkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl 1-6 Alkyl, C 1-6 Alkoxy, C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl.

[0174] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -CHO, -CO(C 1-6 alkyl), -COOH, -COO(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy or 3-6 membered heterocycloalkyl.

[0175] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, hydroxyl, amino, -CHO, -CO(C 1-6 alkyl), -COOH, -COO(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy or 5-6 membered heterocycloalkyl.

[0176] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, fluorine, hydroxy, amino, cyano, -CHO, -COCH3, -COOH, -COOCH3, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, piperidinyl, piperazinyl or tetrahydropyrrolyl.

[0177] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, fluorine, amino, cyano, -C(O)NH2, -CH3 or piperidinyl.

[0178] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from halogen, hydroxy, amino, -R 3e or -N(R 3e )(R 3f );R 3e 、R 3f Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 One or more optionally substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 3e and R 3f When connected to the same nitrogen atom, R 3e and R 3f and the nitrogen atom to which it is attached together to form an optionally halogenated, hydroxyl, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-12 membered heteroaryl, and one or more arbitrarily substituted 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl.

[0179] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from -R 3e or -N(R 3e )(R 3f );R 3e 、R 3f Each occurrence is independently selected from C 1-6 Alkyl or 3-8 membered heterocycloalkyl, or when R 3e and R 3f When connected to the same nitrogen atom, R 3e and R 3f Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocycloalkyl group.

[0180] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3dis selected from methyl, -N(methyl)(methyl) (ie dimethylamino) or piperidinyl.

[0181] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the following optionally substituted groups:

[0182]

[0183] The optional substitution refers to optionally being replaced by R 3d replaced.

[0184] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the following groups:

[0185]

[0186]

[0187] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R3 is selected from the following groups:

[0188]

[0189] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-a):

[0190]

[0191] Among them, m 1-1 Selected from 0, 1 or 2, R 1a-1 For example, in the compound of formula (I') or formula (I), R 1a As defined, X 2-1 As defined in formula (I') or X2 in the compound of formula (I), R 2-1 As defined for R2 in formula (I') or compounds of formula (I), R 3-1 As defined in formula (I') or R3 in the compound of formula (I), R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0192] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-a1):

[0193]

[0194] wherein R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0195] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-a2):

[0196]

[0197] Among them, R 3b-1 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-1 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0198] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-b):

[0199]

[0200] Among them, m 1-2 Selected from 0, 1, 2 or 3, R 1a-2 For example, in the compound of formula (I') or formula (I), R 1a As defined, X 2-2 As defined in formula (I') or X2 in the compound of formula (I), R 2-2 As defined for R2 in formula (I') or compounds of formula (I), R 3-2 As defined in formula (I') or R3 in the compound of formula (I), R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0201] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-b1):

[0202]

[0203] Among them, m 1-3 Selected from 0, 1, 2 or 3, R 1a -3 For example, R in the compound of formula (I') or formula (I) 1a R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0204] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-c):

[0205]

[0206] Among them, m 1-4 Selected from 0, 1, 2 or 3, R 1a-4 For example, in the compound of formula (I') or formula (I), R 1a As defined, X 2-3 As defined in formula (I') or X2 in the compound of formula (I), R 2-3 As defined for R2 in formula (I') or compounds of formula (I), R 3-3 As defined in formula (I') or R3 in the compound of formula (I), R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0207] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-c1):

[0208]

[0209] Among them, m 1-5 Selected from 0, 1, 2 or 3, R 1a-5 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-2 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-2 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0210] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d):

[0211]

[0212] Wherein, E1, E2, E3, E4, E5, E6 are independently selected from C or N, m 1-6 Selected from 0, 1, 2, 3 or 4, R 1a-6 For example, in the compound of formula (I') or formula (I), R 1a As defined, X 2-4 As defined in formula (I') or X2 in the compound of formula (I), R 2-4 As defined in formula (I') or R2 in the compound of formula (I), R 3-4 As defined in formula (I') or R3 in the compound of formula (I), R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0213] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d1):

[0214]

[0215] Among them, m 1-7 Selected from 0, 1, 2 or 3, R 1a-7 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-3 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-3 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0216] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d2):

[0217]

[0218] Among them, m 1-8 Selected from 0, 1 or 2, R 1a-8 For example, in the compound of formula (I') or formula (I), R1a As defined, R 3b-4 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-4 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0219] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d3):

[0220]

[0221] Among them, m 1-9 Selected from 0, 1 or 2, R 1a-9 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-5 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-5 As R in right 1 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0222] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d4):

[0223]

[0224] Among them, m 1-10 Selected from 0, 1, 2 or 3, R 1a-10 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3e-1 For example, in the compound of formula (I') or formula (I), R 3e As defined, R 3f-1 For example, in the compound of formula (I') or formula (I), R 3f R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0225] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d5):

[0226]

[0227] Among them, m 1-11 Selected from 0, 1, 2 or 3, R 1a-11 For example, in the compound of formula (I') or formula (I), R 1a R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0228] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-d6):

[0229]

[0230] Among them, m 1-12 Selected from 0, 1, 2 or 3, R 1a-12 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-6 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-6 For example, in the compound of formula (I') or formula (I), R 3c As defined, R 2x-1 For example, in the compound of formula (I') or formula (I), R 2x R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0231] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-e):

[0232]

[0233] Among them, E7, E8, E9, E 10 、E 11 、E 12 Independently selected from C or N, m 1-13 Selected from 0, 1, 2 or 3, m 2-1 Selected from 0, 1, 2, 3 or 4, R 1a-13 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 2a-1 For example, in the compound of formula (I') or formula (I), R 2a As defined, R 3-5As defined in formula (I') or R3 in the compound of formula (I), R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0234] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-e1):

[0235]

[0236] Among them, m 1-14 Selected from 0, 1, 2 or 3; m 2-2 Selected from 0, 1, 2, 3 or 4, R 1a-14 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 2a-2 For example, in the compound of formula (I') or formula (I), R 2a As defined, R 3b-7 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-7 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0237] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-f):

[0238]

[0239] Among them, m 1-15 Selected from 0, 1, 2 or 3, R 1a-15 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3e-2 For example, in the compound of formula (I') or formula (I), R 3e As defined, R 3f-2 For example, in the compound of formula (I') or formula (I), R 3f R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0240] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (II-g):

[0241]

[0242] Among them, R 3b-8 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-8 For example, in the compound of formula (I') or formula (I), R 3c R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or the compound of formula (I).

[0243] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Independently selected from -H, -F, -Cl, -NH2, oxo, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -NHC(O)CH3, -C(O)NHCH3, The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0244] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1a Independently selected from -H, -NH2, oxo, -CH3, -CH2CH3, -NHC(O)CH3, The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

[0245] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, Y is selected from the following groups:

[0246]

[0247] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, Y is selected from the following groups:

[0248]

[0249] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R4 is selected from hydrogen, halogen, amino or C 1-6 Alkoxy.

[0250] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R4 is selected from hydrogen, halogen or C 1-3 Alkoxy.

[0251] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R4 is selected from hydrogen, fluorine or methoxy.

[0252] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R4 is selected from hydrogen or fluorine.

[0253] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R4 is selected from methoxy.

[0254] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R5 is selected from hydrogen, deuterium or C optionally substituted by one or more deuteriums. 1-6 alkyl.

[0255] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R5 is C 1-6 alkyl.

[0256] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R5 is C 1-3 alkyl.

[0257] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R5 is methyl.

[0258] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, L is C(R L ) or N, R L Selected from hydrogen, halogen, amino, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy.

[0259] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, L is C(R L ), R L is selected from hydrogen, halogen, amino, methyl or methoxy.

[0260] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, L is CH.

[0261] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, L is N.

[0262] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, Q1, Q2 are independently selected from O, C, S or N; Q3 is C; wherein Q1 is connected to W.

[0263] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, Q1, Q2 are independently selected from O, C or S; Q3 is C; wherein Q1 is connected to W.

[0264] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W is selected from O or N; Q1 is C; Q2 is C; Q3 is C; wherein Q1 is connected to W.

[0265] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, -R 6a 、-OR 6a 、-SO2(R 6a ),-C(O)R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-NH(R 6a )、-N(R6a )(R 6b )、-C(O)NH(R 6a )、-C(O)N(R 6a )(R 6b )、-NHC(O)(R 6a )、-N(R 6a )C(O)(R 6b )、-SO2NH(R 6a )、-SO2N(R 6a )(R 6b )、-NHSO2(R 6a ) or -N(R 6a )SO2(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, monospirocyclic group or heteromonospirocyclic group.

[0266] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, -R 6a 、-OR 6a 、-SO2(R 6a ),-C(O)R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-NH(R 6a )、-N(R 6a )(R6b )、-C(O)NH(R 6a )、-C(O)N(R 6a )(R 6b )、-NHC(O)(R 6a )、-N(R 6a )C(O)(R 6b )、-SO2NH(R 6a )、-SO2N(R 6a )(R 6b )、-NHSO2(R 6a ) or -N(R 6a )SO2(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, monospirocyclic group or heteromonospirocyclic group.

[0267] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, -R 6a 、-OR 6a 、-C(O)R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-NH(R 6a )、-N(R 6a )(R 6b )、-C(O)NH(R 6a)、-C(O)N(R 6a )(R 6b )、-NHC(O)(R 6a ) or -N(R 6a )C(O)(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl or 5-12 membered heteroaryl.

[0268] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, -R 6a 、-NH(R 6a ) or -N(R 6a )(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl or 5-12 membered heteroaryl.

[0269] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, -R 6a 、-NH(R 6a ) or -N(R 6a )(R 6b ); or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 carbocyclic group or 3-10 membered heterocyclic group.

[0270] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, -R 6a 、-NH(R 6a ) or -N(R 6a )(R 6b ); or R6, R7, R8, R9, R 10、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, fused cyclic group or heterofused cyclic group; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereof together form an optionally substituted R 6c Substituted C 3-10 carbocyclic group or 3-10 membered heterocyclic group.

[0271] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, halogen or -R 6a ; or R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups connected to the same atom form =O, =NR 6a or =CH-R 6a or W, each occurrence of Q1, each occurrence of Q2 and Q3 any two adjacent atoms and the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-12 membered heteroaryl; or W, each occurrence of Q1, each occurrence of Q2 and Q3 and any one of the substituents thereto together form an optionally substituted R 6c Substituted C 3-10 carbocyclic group or 3-10 membered heterocyclic group.

[0272] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3, and any two adjacent atoms and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-10Carbocyclic group, 3-10 membered heterocyclic alkyl group, C 6-8 aryl or 5-10 membered heteroaryl.

[0273] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3, any two adjacent atoms and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 aryl or 5-8 membered heteroaryl.

[0274] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3, any two adjacent atoms and the substituents connected thereto together form an optionally substituted R 6c Substituted C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, wherein the heteroatom is selected from O or N, and the number of heteroatoms is 1 or 2.

[0275] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3 and the substituents attached thereto together form an optionally substituted R 6c Substituted C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl.

[0276] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3 and the substituents attached thereto together form an optionally substituted R 6c Substituted C 3-6 Cycloalkyl or 3-7 membered heterocycloalkyl.

[0277] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3 and the substituents attached thereto together form an optionally substituted R 6c Substituted C 3-4 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the heteroatom is selected from O or N, and the number of heteroatoms is 1 or 2.

[0278] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3 and the substituents attached thereto together form an optionally substituted R 6c Substituted C 3-4 Cycloalkyl.

[0279] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or when R 6a and R 6b When connected to the same nitrogen atom, R 6a and R 6b and the nitrogen atom to which it is attached together form an optionally R 6c substituted 3- to 10-membered heterocyclyl or 5- to 12-membered heteroaryl.

[0280] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 aryl or 5-10 membered heteroaryl.

[0281] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen, deuterium or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl.

[0282] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl or C 1-6 Alkoxy.

[0283] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-3 Alkyl or C 1-3 Alkoxy.

[0284] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c substituted methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

[0285] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6a 、R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c substituted methyl or ethyl.

[0286] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -R 6d 、-OR 6d 、-N(R 6d )R 6e 、-C(O)R 6d 、-C(O)N(R 6d )R 6e 、-N(R 6d )C(O)R6e or-C(O)OR 6d .

[0287] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, -R 6d 、-OR 6d 、-N(R 6d )R 6e 、-C(O)R 6d 、-C(O)N(R 6d )R 6e 、-N(R 6d )C(O)R 6e or-C(O)OR 6d .

[0288] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6d 、R 6e Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano or optionally substituted by halogen, hydroxy, amino or C 1-6 Alkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or when R 6d and R 6e When connected to the same nitrogen atom, R 6d and R 6e and the nitrogen atom to which it is attached together form an optionally substituted halogen, hydroxyl, amino or C 1-6 3-10 membered heterocyclic group or 5-12 membered heteroaryl group substituted by an alkyl group.

[0289] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6d 、R 6e Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group; or when R 6d and R 6e When connected to the same nitrogen atom, R 6d and R 6e and the nitrogen atom to which it is attached together form a 3-10 membered heterocyclic group or a 5-12 membered heteroaryl group.

[0290] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6d 、R 6e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, fused cyclic group or heterofused cyclic group.

[0291] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6d 、R 6e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 aryl or 5-10 membered heteroaryl.

[0292] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 aryl, 5-10 membered heteroaryl, fused cyclic group or heterofused cyclic group.

[0293] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 aryl or 5-10 membered heteroaryl.

[0294] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-10 membered heteroaryl, wherein the heteroatom is selected from N or S, and the number of heteroatoms is 1, 2 or 3.

[0295] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the heteroatom is selected from N or S, and the number of heteroatoms is 1, 2 or 3.

[0296] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0297] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

[0298] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen, deuterium or optionally deuterated, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 C substituted with cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl.

[0299] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 C substituted by cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl.

[0300] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl) or -NHC(O)(C 1-6 Alkyl) substituted C 1-6 Alkyl or C 1-6 Alkoxy.

[0301] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl or C 1-6Alkoxy.

[0302] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-3 Alkyl or C 1-3 Alkoxy-substituted C 1-3 Alkyl or C 1-3 Alkoxy.

[0303] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from the group consisting of: -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)CH3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH(CH3)CH2OCH3, -NHCH3, -N(CH3)CH3, -CH2N(CH3)CH3,

[0304]

[0305] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13Each occurrence is independently selected from the group consisting of: -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)CH3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -NHCH3, -N(CH3)CH3, -CH2N(CH3)CH3,

[0306]

[0307] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Each occurrence is independently selected from the group consisting of -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, or -CH(CH3)CH2OCH3.

[0308] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotope derivative or pharmaceutically acceptable salt, R6, R7, R8, R9, R 10 、R 11 、R 12 and R 13 Any two groups attached to the same atom form =O or =CH2.

[0309] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and Q3, any two adjacent atoms and the substituents attached thereto together form the following group:

[0310]

[0311] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and any one of Q3 and the substituents attached thereto together form the following group:

[0312]

[0313] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and any one of Q3 and the substituents attached thereto together form the following group:

[0314]

[0315] Further preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, W, each occurrence of Q1, each occurrence of Q2 and any one of Q3 and the substituents attached thereto together form the following group:

[0316]

[0317] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (III-a):

[0318]

[0319] Among them, m 1-16 Selected from 0, 1, 2 or 3, R 1a-16 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-9 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-9 For example, in the compound of formula (I') or formula (I), R 3c As defined, R4, R5, R6, R7, R8, R9, R 10 、R 11 , W, L, t1, t2 are as defined in formula (I') or the compound of formula (I).

[0320] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (III-a1):

[0321]

[0322] Among them, m 1-17 Selected from 0, 1, 2 or 3, R 1a-17 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-10 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-10 For example, in the compound of formula (I') or formula (I), R 3c As defined, R4, R5, R8, R9, R 10 、R 11 , L are as defined in formula (I') or the compound of formula (I).

[0323] Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (III-a2):

[0324]

[0325] Among them, m 1-18 Selected from 0, 1, 2 or 3, R 1a-18 For example, in the compound of formula (I') or formula (I), R 1a As defined, R 3b-11 For example, in the compound of formula (I') or formula (I), R 3b As defined, R 3c-11 For example, in the compound of formula (I') or formula (I), R 3c As defined, R4, R5, R7, R8, R9, R 10 、R 11 , L are as defined in formula (I') or the compound of formula (I).

[0326] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-6 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 3-10 membered heterocycloalkyl; the optional substitution refers to optionally being replaced by R 3d replaced.

[0327] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2 or 3; the optional substitution refers to the optional substitution of R 3d replaced.

[0328] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 6-membered heteromonospirocyclic group, a 4-membered / 6-membered heteromonospirocyclic group or a 3-membered / 5-membered heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2 or 3; the optional substitution refers to optionally being replaced by R 3d replaced.

[0329] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b 、R 3c Each occurrence is independently selected from optionally substituted methyl, or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, 2-oxa-7-azaspiro[3.5]nonyl (e.g., 2-oxa-7-azaspiro[3.5]non-7-yl), 3-azabicyclo[3.1.0]hexyl (e.g., 3-azabicyclo[3.1.0]hex-3-yl) or 6-azaspiro[2.5]octyl (e.g., 6-azaspiro[2.5]oct-6-yl); the optionally substituted refers to optionally replaced by R 3d replaced.

[0330] Preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, fluorine, hydroxy, amino, cyano, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3 or -CH2CH2CH3.

[0331] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3d Each occurrence is independently selected from deuterium, fluorine, cyano, -C(O)NH2 or -CH3.

[0332] More preferably, in the compound provided by the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 3b and R 3c and the nitrogen atom to which it is connected together form a group selected from the following groups:

[0333]

[0334] Preferably, the present invention provides the following compounds or their prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts.

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344] [Synthetic intermediates and preparation methods]

[0345] With respect to the above-mentioned compound, the present invention also provides an intermediate for preparing the compound of formula (I') or formula (I), which has a structure as shown in formula (M-1):

[0346]

[0347] Among them, R x1 is selected from halogen or hydrogen; R4, R6, R7, A, W, L, t1, t2, h are as defined in formula (I') or the compound of formula (I).

[0348] Regarding the above-mentioned compound, the present invention also provides an intermediate for preparing the compound of formula (I') or formula (I), which has a structure as shown in formula (M-2):

[0349]

[0350] Among them, R x1 is selected from halogen or hydrogen; R4, R6, R7, A, W, L, t1, t2, h are as defined in formula (I') or the compound of formula (I).

[0351] Regarding the above-mentioned compound, the present invention also provides an intermediate for preparing a compound of formula (I') or formula (I), which has a structure as shown in formula (M-3):

[0352]

[0353] Among them, R x1 is selected from halogen or hydrogen, and R4, R6, R7, A, W, L, t1, t2, and h are as defined in formula (I') or the compound of formula (I).

[0354] With respect to the above-mentioned compound, the present invention also provides an intermediate for preparing a compound of formula (I') or formula (I), which has a structure as shown in formula (M-4):

[0355]

[0356] Among them, R x2 is selected from halogen or hydrogen, and R4, R6, R7, A, W, L, t1, t2, and h are as defined in formula (I') or the compound of formula (I).

[0357] Regarding the above-mentioned compound, the present invention also provides an intermediate for preparing the compound of formula (I') or formula (I), which has a structure as shown in formula (M-5):

[0358]

[0359] Among them, R x3is selected from halogen or hydrogen, and R4, R5, R6, R7, A, W, L, t1, t2, and h are as defined in formula (I') or the compound of formula (I).

[0360] With respect to the above-mentioned compound, the present invention also provides an intermediate for preparing the compound of formula (I') or formula (I), which has a structure as shown in formula (M-6):

[0361]

[0362] Among them, R x4 is selected from halogen or hydrogen, and R4, R5, R6, R7, A, W, L, t1, t2, and h are as defined in formula (I') or the compound of formula (I).

[0363] Preferably, the present invention provides the following synthetic intermediates for preparing the target compounds.

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] The present invention also provides a method for preparing the compound of formula (I') or formula (I), which can be prepared using the method shown in the following synthesis schemes 1, 2 or 3.

[0372] Synthesis Scheme 1:

[0373]

[0374] i) Compound I-a1 undergoes chemical transformation (e.g., substitution reaction) to obtain Compound I-a2;

[0375] For example, compound I-a1 and thionyl chloride are used as basic raw materials to obtain compound I-a2;

[0376] ii) Compound I-a2 undergoes chemical transformation (such as substitution reaction and optional ring closure reaction) to obtain compound I-a4;

[0377] For example, using compounds I-a2 and I-a3 as basic raw materials, reacting under alkaline conditions to obtain an unclosed or closed ring compound I-a4; iii) compound I-a4 undergoes chemical conversion (such as hydrolysis) to obtain compound I-a5;

[0378] For example, compound I-a4 is reacted under alkaline conditions to obtain compound I-a5;

[0379] iv) Compound I-a5 undergoes chemical transformation (e.g., ring closure reaction) to obtain compound I-a6;

[0380] For example, compound I-a5 and diphenylphosphoryl azide are reacted under alkaline conditions to obtain compound I-a6; v) compound I-a6 undergoes chemical transformation (such as alkylation reaction) to obtain compound I-a7;

[0381] For example, compound I-a6 and a halide (such as iodomethane) are used as basic raw materials and reacted under alkaline conditions to obtain compound I-a7;

[0382] vi) Compound I-a7 undergoes chemical transformation (e.g., coupling reaction) to obtain compound I-a8;

[0383] For example, compound I-a7 and a boronic acid derivative are used as basic raw materials, and a coupling reaction occurs to obtain compound I-a8;

[0384] vii) Compound I-a8 undergoes chemical transformation (e.g., substitution reaction) to obtain Compound I;

[0385] For example, compound I-a8 is used as a basic raw material and reacted under alkaline conditions to obtain compound I of the general formula.

[0386] Synthesis Scheme 2:

[0387]

[0388] i) Compound I-b1 and thionyl chloride are used as basic raw materials to obtain compound I-b2;

[0389] ii) using compounds I-b2 and I-b3 as basic raw materials, reacting under alkaline conditions to obtain compound I-b4;

[0390] iii) Compound I-b4 reacts under alkaline conditions to obtain compound I-b5;

[0391] iv) Compound I-b5 and a suitable reducing agent (such as iron powder, zinc powder, etc.), ammonium chloride, etc. are used as basic raw materials to obtain compound I-b6;

[0392] v) Compound I-b7 is obtained using compound I-b6 and N,N-carbonyldiimidazole (CDI) as basic raw materials;

[0393] vi) using compound I-b7 and a halide (such as iodomethane) as basic raw materials, reacting under alkaline conditions to obtain compound I-b8;

[0394] vii) using compound I-b8 and a boronic acid derivative as basic raw materials, undergoing a coupling reaction to obtain compound I-b9;

[0395] viii) Compound I-b9 and amines or alcohols are reacted under alkaline conditions to obtain compound I of the general formula.

[0396] Synthesis Scheme 3:

[0397]

[0398] i) Compound I-b1 and thionyl chloride are used as basic raw materials to obtain compound I-b2;

[0399] ii) using compounds I-b2 and I-b3 as basic raw materials, reacting under alkaline conditions to obtain compound I-b5;

[0400] iii) Compound I-b5, a suitable reducing agent (such as iron powder, zinc powder, etc.), ammonium chloride, etc. are used as basic raw materials to obtain compound I-b6;

[0401] iv) Compound I-b7 is obtained using compound I-b6 and N,N-carbonyldiimidazole (CDI) as basic raw materials;

[0402] v) Compound I-b7 and a halide (such as iodomethane) are reacted under alkaline conditions to obtain compound I-b8;

[0403] vi) using compound I-b8 and a boronic acid derivative as basic raw materials, undergoing a coupling reaction to obtain compound I-b9;

[0404] vii) Compound I-b9 and amines or alcohols are reacted under alkaline conditions to obtain compound I of the general formula.

[0405] Preferably, in the preparation method of the present invention, R x1 is selected from halogen or hydrogen, and X1, R4, R5, R6, R7, A, W, L, t1, and t2 are as defined in formula (I') or formula (I).

[0406] Preferably, in the preparation method of the present invention, the reaction is carried out in an organic solvent.

[0407] Further preferably, in the preparation method of the present invention, the organic solvent is selected from ethers, halogenated hydrocarbons, alcohols, alkanes, aromatic hydrocarbons, esters, acetonitrile, N,N-dimethylformamide and mixtures thereof; preferably, the ethers are selected from tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and mixtures thereof, the halogenated hydrocarbons are selected from dichloromethane, chloroform, dichloroethane, tetrachloromethane and mixtures thereof, the alcohols are selected from methanol, ethanol, n-propanol, isopropanol and mixtures thereof, the alkanes are selected from petroleum ether, n-hexane and mixtures thereof, the aromatic hydrocarbons are selected from benzene, toluene, xylene and mixtures thereof, and the esters are selected from ethyl acetate, etc.

[0408] Further preferably, in the preparation method of the present invention, the organic solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, halogenated hydrocarbon, ether and ethyl acetate; preferably, the halogenated hydrocarbon is dichloroethane.

[0409] Preferably, in the preparation method of the present invention, the base is selected from one or more of potassium carbonate, sodium carbonate, magnesium carbonate, sodium bicarbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydroxide, magnesium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, piperidine, pyrrole, pyridine, lutidine and dimethylaminopyridine.

[0410] [Pharmaceutical composition]

[0411] With respect to the above-mentioned compound, the present invention further provides a pharmaceutical composition comprising the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt.

[0412] Preferably, the pharmaceutical composition of the present invention comprises the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

[0413] [Medical use]

[0414] The present invention also provides a compound of the present invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, which is used as an ATM kinase inhibitor.

[0415] The present invention also provides a compound of the present invention, or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in preventing and / or treating a disease and / or condition mediated at least in part by ATM kinase. Preferably, the disease and / or condition mediated at least in part by ATM kinase is cancer.

[0416] Furthermore, the present invention also provides a compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt or pharmaceutical composition of the present invention, which is used to prevent and / or treat cancer. Further, the cancer includes solid tumors and hematological tumors. Preferably, the cancer includes breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, glioblastoma.

[0417] The present invention also provides use of the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention in the preparation of an ATM kinase inhibitor.

[0418] The present invention also provides the use of a compound of the present invention, or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing and / or treating a disease and / or condition mediated at least in part by ATM kinase. Preferably, the disease and / or condition mediated at least in part by ATM kinase is cancer.

[0419] Furthermore, the present invention also provides the use of the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating cancer. Furthermore, the cancer includes solid tumors and hematological tumors. More preferably, the cancer includes breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, glioblastoma.

[0420] The present application also provides a method for preventing and / or treating a disease and / or condition mediated at least in part by ATM kinase, comprising administering to a subject in need thereof a preventatively and / or therapeutically effective amount of a compound of the present invention, or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention; preferably, the disease and / or condition mediated at least in part by ATM kinase is cancer; more preferably, the cancer includes solid tumors and hematological tumors. More preferably, the cancer includes breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma.

[0421] Furthermore, the present application also provides a method for preventing and / or treating cancer, comprising administering to an individual in need thereof a preventive and / or therapeutically effective amount of a compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, or a pharmaceutical composition of the present invention; preferably, the cancer includes solid tumors and hematological tumors. More preferably, the cancer includes breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, and glioblastoma.

[0422] Furthermore, the present invention provides a use or method, wherein the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention is used in combination with at least one additional anti-tumor agent or treatment method (such as radiotherapy); preferably, the anti-tumor agent is selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775 and AZD6738.

[0423] Furthermore, the present invention provides a use or method, wherein the compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention is administered simultaneously, separately or sequentially with radiotherapy.

[0424] The present invention also provides a drug combination (or drug combination composition, pharmaceutical compound composition), which comprises a compound of the present invention or its prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt or pharmaceutical composition of the present invention, and at least one additional anti-tumor agent or treatment. Preferably, the anti-tumor agent is selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775 and AZD6738. Preferably, the treatment is radiotherapy.

[0425] [Definition of terms]

[0426] The terms "optional," "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0427] Accordingly, the term "optionally substituted" means that a group may be unsubstituted or substituted at its substitutable positions with one or more independently existing substituents. When the group is substituted, the hydrogen at one or more substitutable positions of the substituted group is independently replaced by a substituent, which may be independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-12 membered heteroaryl; the oxo group means that two H at the same substitution site are replaced by the same O to form a double bond.

[0428] Unless otherwise specified, the term "bond" refers to a chemical bond, including (but not limited to) a covalent bond (e.g., a carbon-carbon single bond, a carbon-nitrogen single bond, a carbon-oxygen single bond, a carbon-sulfur single bond, a carbon-carbon double bond, a carbon-nitrogen double bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-carbon triple bond, a carbon-nitrogen triple bond, etc.), an ionic bond, a coordination bond, etc.; in the compounds of the present invention, the bond between the parent nucleus and the substituent or between different substituents is essentially a covalent bond.

[0429] Unless otherwise specified, the term "carboxy" refers to a "-C(O)OH" group.

[0430] Unless otherwise specified, the term "hydroxy" refers to a "-OH" group.

[0431] Unless otherwise specified, the term "mercapto" refers to a "-SH" group.

[0432] Unless otherwise specified, the term "amino" refers to a "-NH2" group. In some embodiments, amino groups also include groups in which one or two hydrogen atoms are replaced by alkyl groups (e.g., -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, etc.).

[0433] Unless otherwise specified, the term "nitro" refers to a "-NO2" group.

[0434] Unless otherwise specified, the term "cyano" refers to a "-CN" group.

[0435] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond (ie, "=O").

[0436] Unless otherwise specified, the term "alkyl" refers to a straight or branched, saturated, monovalent aliphatic hydrocarbon group, which may contain 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkyl). For example, “C 1-6 The term "alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6). Illustrative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0437] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above and may contain 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, further preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkoxy). For example, "C 1-6 The term "alkoxy" means that the group is an alkoxy group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5 or 6). Illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0438] Unless otherwise specified, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0439] Unless otherwise specified, the term "haloalkyl" refers to a group in which one, two, more or all of the hydrogen atoms in an alkyl group as defined above are replaced by halogen. Illustrative examples of haloalkyl include, but are not limited to, -CCl , -CF , -CHCl , -CH Cl , -CH Br , -CH I , -CH CF , -CF CF , etc.

[0440] Unless otherwise specified, the term "alkenyl" refers to a linear or branched, monovalent aliphatic hydrocarbon group containing one or more (e.g., 1, 2, 3, or 4) carbon-carbon double bonds, which may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, further preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms (i.e., C 2-6 For example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically, 2, 3, 4, 5 or 6). Illustrative examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, n-butenyl, n-pentenyl, and the like.

[0441] Unless otherwise specified, the term "alkynyl" refers to a linear or branched monovalent aliphatic hydrocarbon group containing one or more (e.g., 1, 2, 3, or 4) carbon-carbon triple bonds, which may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, further preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms (i.e., C 2-6 For example, "C 2-6"Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Illustrative examples of alkenyl include (but are not limited to) ethynyl, n-propynyl, n-butynyl, n-pentynyl, etc.

[0442] Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a monocyclic or polycyclic, saturated or partially unsaturated, monovalent non-aromatic hydrocarbon radical which may contain 3 to 14 ring carbon atoms (i.e., C 3-14 Carbocyclic), preferably containing 3-12 ring carbon atoms (ie, C 3-12 Carbocyclic group), further preferably contains 4-12 ring carbon atoms (ie C 4-12 Carbocyclic) or 3-10 ring carbon atoms (ie C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 Carbocyclyl”). Exemplary C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclic groups include (but are not limited to) the aforementioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. The carbocyclyl group can be a monocyclic (monocyclic carbocyclyl) ring system, a fused (fused cyclyl), a bridged (bridged cyclyl) or a spiro-connected (spirocyclyl) ring system, such as a bicyclic system (bicyclic carbocyclyl), and can be saturated or partially unsaturated. In some embodiments, the carbocyclyl group also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl / heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring; or, in some embodiments, a ring system in which the carbocyclyl group as defined above is fused to one or more carbocyclyl groups as defined above, wherein the point of attachment is on any carbocyclyl ring. In the above case, the number of atoms of the carbocyclyl ring system is the number of ring carbon atoms of the ring system after fusion. In some embodiments, the carbocyclyl group is optionally substituted, for example, unsubstituted (unsubstituted carbocyclyl) or substituted by one or more substituents (substituted carbocyclyl). In some embodiments, the carbocyclyl group is unsubstituted C 3-10 In some embodiments, the carbocyclyl is a substituted C 3-10 Carbocyclic group.

[0443] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic, saturated, monovalent aliphatic hydrocarbon group which may contain 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl), preferably containing 3 to 10 carbon atoms (ie, C 3-10 cycloalkyl), further preferably containing 3-7 carbon atoms (i.e. C 3-7 Cycloalkyl), 4-6 carbon atoms (ie C 4-6 Cycloalkyl) or 5-6 carbon atoms (ie C 5-6 Cycloalkyl). For example, "C 3-10 "Cycloalkyl" means that the group is a cycloalkyl group, and the number of carbon atoms in the carbon ring is between 3 and 10 (specifically 3, 4, 5, 6, 7, 8, 9 or 10). Illustrative examples of cycloalkyl include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, dimethylcyclobutyl, and the like.

[0444] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a monocyclic or polycyclic, saturated or partially unsaturated, monovalent non-aromatic group having ring carbon atoms and 1 to 4 ring heteroatoms, which may contain 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, preferably containing 3-12 ring atoms (i.e., 3-12-membered heterocyclyl), further preferably containing 3-10 ring atoms (i.e., 3-10-membered heterocyclyl), 3-8 ring atoms (i.e., 3-8-membered heterocyclyl), 3-6 ring atoms (i.e., 3-6-membered heterocyclyl), 4-6 ring atoms (i.e., 4-6-membered heterocyclyl) or 5-6 ring atoms (i.e., 5-6-membered heterocyclyl), and the number of heteroatoms is 1-4, preferably 1-3 (i.e., 1, 2 or 3). Illustrative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyls include paracyclic, spirocyclic, fused, and bridged heterocyclyls. The heterocyclyl group can be a monocyclic (monocyclic heterocyclyl) ring system, or a fused (fused heterocyclyl or heterofused heterocyclyl), paracyclic (heteroparacyclic or paracyclic heterocyclyl), bridged (heterobridged or bridged heterocyclyl), or spiro (heterospiro or spiroheterocyclyl) ring system, such as a bicyclic system (bicyclic heterocyclyl), and can be saturated or partially unsaturated. The bicyclic heterocyclyl group can contain one or more heteroatoms in one or both rings. In some embodiments, heterocyclyl also includes ring systems in which a heterocyclyl as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or, in some embodiments, heterocyclyl also includes ring systems in which a heterocyclyl as defined above is fused to one or more aryl / heteroaryl groups, wherein the point of attachment is on the aryl / heteroaryl or heterocyclyl ring; or, in some embodiments, a heterocyclyl as defined above is fused to one or more heterocyclyl groups as defined above, wherein the point of attachment is on either heterocyclyl ring. In these cases, the number of members of the heterocyclyl ring system is the number of ring atoms in the ring system after fusion. In some embodiments, heterocyclyl is optionally substituted, e.g., unsubstituted (unsubstituted heterocyclyl) or substituted with one or more substituents (substituted heterocyclyl). Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and 2,5-dioxopyrrolidinyl.Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and 2-oxoxazolidinyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiopyranyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazinanyl, oxadiazinanyl, thiadiazinanyl, oxathiazinanyl, and dioxazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0445] Unless otherwise specified, "heterocycloalkyl" refers to a monocyclic, saturated, "heterocyclyl" or "heterocycle" as defined above, which may contain 3-20 ring atoms (i.e., 3-20-membered heterocycloalkyl), wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, preferably contains 3-12 ring atoms (i.e., 3-12-membered heterocycloalkyl), further preferably contains 3-10 ring atoms (i.e., 3-10-membered heterocycloalkyl), 3-8 ring atoms (i.e., 3-8-membered heterocycloalkyl), 4-7 ring atoms (i.e., 4-7-membered heterocycloalkyl), 5-10 ring atoms (i.e., 5-10-membered heterocycloalkyl) or 5-6 ring atoms (i.e., 5-6-membered heterocycloalkyl), and the number of heteroatoms is 1-4, preferably 1-3 (1, 2 or 3). In some embodiments, heterocycloalkyl is optionally substituted, for example, unsubstituted (unsubstituted heterocycloalkyl) or substituted with one or more substituents (substituted heterocycloalkyl). Some exemplary heterocycloalkyl groups are given above in the "heterocyclyl" or "heterocycle" section, and also include (but are not limited to) aziridine, oxirane, thiirane, azetidinyl, oxetane, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, oxazolidinyl, dioxanyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.

[0446] Unless otherwise specified, the term "paracyclic" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, including paracarbocyclic and paraheterocyclic groups, wherein the ring atoms of the paraheterocyclic group contain one or more heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0447] Unless otherwise specified, the term "monospirocyclic group" refers to a saturated, monovalent aliphatic hydrocarbon group containing only one spiro carbon atom, which may contain 6-14 ring carbon atoms, preferably 7-10 ring carbon atoms. Monospirocyclic groups include 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered and 5-membered / 6-membered monospirocyclic groups, wherein the spiro atom is counted as the number of members of each ring. Illustrative examples of monospirocyclic groups include (but are not limited to) wait.

[0448] Unless otherwise specified, the term "heteromonospirocyclic group" refers to a saturated, monovalent aliphatic group containing only one spiro carbon atom, which may contain 6-14 ring atoms, preferably 7-10 ring atoms, including 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O, and S. Heteromonospirocyclic groups include 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, and 5-membered / 6-membered heteromonospirocyclic groups, wherein the spiro atom is counted in the number of members of each ring. Illustrative examples of heteromonospirocyclic groups include (but are not limited to) wait.

[0449] Unless otherwise specified, the term "bridged ring group" refers to a polycyclic, monovalent aliphatic hydrocarbon group in which any two rings share two ring carbon atoms that are not directly connected, which may contain 5-20 ring carbon atoms, preferably 6-14 ring carbon atoms, more preferably 7-10 ring carbon atoms, and may contain one or more double bonds, but no ring has a completely conjugated π electron system. Bridged ring groups include bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic bridged ring groups, more preferably bicyclic or tricyclic bridged ring groups. Illustrative examples of bridged ring groups include (but are not limited to)

[0450]

[0451] Unless otherwise specified, the term "heterobridged cyclic group" refers to a polycyclic, monovalent aliphatic group in which any two rings share two ring atoms that are not directly connected, which may contain 5-14 ring atoms, preferably 6-14 ring atoms, more preferably 7-10 ring atoms, wherein 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S, and may contain one or more double bonds, but no ring has a completely conjugated π electron system. Heterobridged cyclic groups include bicyclic, tricyclic, tetracyclic or polycyclic heterobridged cyclic groups, preferably bicyclic, tricyclic or tetracyclic heterobridged cyclic groups, more preferably bicyclic or tricyclic heterobridged cyclic groups. Illustrative examples of heterobridged cyclic groups include (but are not limited to)

[0452]

[0453] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic or polycyclic, monovalent aromatic hydrocarbon group that may contain 6 to 16 ring carbon atoms (i.e., C 6-16 Aryl), 6-14 ring carbon atoms (ie C 6-14 Aryl), 6-12 ring carbon atoms (ie C 6-12 Aryl) or 6-10 ring carbon atoms (ie C 6-10In some embodiments, the term "aryl" can be used interchangeably with the term "aromatic ring". Illustrative examples of aryl include (but are not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, etc.

[0454] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" refers to a monocyclic or polycyclic, monovalent aromatic group that may contain 5-14 ring atoms (i.e., 5-14 membered heteroaryl), 5-10 ring atoms (i.e., 5-10 membered heteroaryl), 5-8 ring atoms (i.e., 5-8 membered heteroaryl), or 5-6 ring atoms (i.e., 5-6 membered heteroaryl), wherein 1, 2, 3 or more ring atoms are heteroatoms independently selected from O, N or S, and the remaining ring atoms are C. In some embodiments, the term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring". Illustrative examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, Benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0455] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with mammalian (particularly human) tissues without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of sound medical judgment, such as pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0456] Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the atom with the greatest natural abundance. Isotopes may be radioactive or non-radioactive. Isotopes commonly used as isotopic labels include, but are not limited to, hydrogen isotopes: 2 H and 3 H; Carbon isotope: 13C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O. 17 O and 18 O; and sulfur isotopes: 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 2 H and 13 C, because they are easy to label and convenient to detect, they are more widely used.

[0457] Unless otherwise specified, the term "solvate" or "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution-phase and isolatable solvates. Illustrative examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0458] Unless otherwise specified, the term "optical isomers" refers to isomers that have similar physical and chemical properties, the same atomic bonding sequence in the molecules, but different optical rotations.

[0459] Unless otherwise specified, the term "geometric isomer" (particularly "cis / trans isomers") refers to isomers containing carbon-carbon or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond, and the order can be determined using the Cahn-Ingold-Prelog priority rules. The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers.

[0460] Unless otherwise specified, the term "tautomer" refers to isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include tautomers that interconvert via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include tautomers that interconvert via reorganization of bonding electrons.

[0461] Unless otherwise specified, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers (e.g., conformational isomers), tautomers, etc.). For example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, geometric isomers (e.g., conformational isomers), or tautomers are all within the scope of the present invention.

[0462] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which themselves may be related to physicochemical properties. For example, they may be bioavailable orally, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An illustrative example (but not limited to) of a prodrug is any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then hydrolyzed to the carboxylic acid, the active entity. Another illustrative example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0463] [Beneficial Effects]

[0464] The present invention provides a novel ATM kinase inhibitor, its preparation method, and its application in medicine. In particular, the compounds of the present invention are useful in treating cancer. Enzymatic assay results demonstrate that the compounds of the present invention exhibit good selectivity for the ATM target and significantly inhibit ATM kinase activity. Furthermore, the present invention utilizes a specific synthesis method that is simple, easy to operate, and amenable to large-scale industrial production and application. DETAILED DESCRIPTION

[0465] The present invention will be further described below with reference to specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0466] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0467] Unless otherwise specified, the technical terms and scientific terms used in the following examples have the meanings familiar to professionals in the field. The abbreviations used in the preparation examples, examples and other contexts have the following meanings:

[0468] DCM dichloromethane

[0469] TEA triethylamine

[0470] DIEA / DIPEA N,N-Diisopropylethylamine

[0471] DMF N,N-dimethylformamide

[0472] EtOAc

[0473] h hour

[0474] mL milliliters

[0475] HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0476] MeOH methanol

[0477] TFA trifluoroacetic acid

[0478] DMSO-d6 deuterated dimethyl sulfoxide

[0479] [Intermediate Preparation Example]

[0480] Intermediate Preparation Example 1: Preparation of (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-1)

[0481]

[0482] Step 1: Synthesis of diethyl 2-((4-bromo-3,5-difluorophenyl)amino)methylene)malonate

[0483] 4-Bromo-3,5-difluoroaniline (5.00 g, 24 mmol), diethyl 2-ethoxymethylenemalonate (7.80 g, 36 mmol), and anhydrous ethanol (50 mL) were added to a 250 mL reaction flask. The reaction solution was refluxed for 8 h. After completion of the reaction, the reaction solution was cooled to 10°C, and a white solid precipitated. The solid was collected by filtration, rinsed with n-hexane, and dried to obtain diethyl 2-((4-bromo-3,5-difluorophenyl)amino)methylene)malonate (7.3 g, 80.3% yield). ESI-MS (m / z): 378.01 / 380.01 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.236-1.269(m,6H),4.137(q,2H),4.216(q,2H),7.483-7.506(t,2H),8.308(d,1H),10.613(d,1H).

[0484] Step 2: Synthesis of ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate

[0485] Diphenyl ether (80 mL) was added to a 250 mL reaction flask, the temperature was raised to 240°C, and then diethyl 2-((4-bromo-3,5-difluorophenyl)amino)methylene)malonate (7.30 g, 19.3 mmol) was added portionwise. The reaction solution was reacted at 240°C for 1 h. After TLC monitoring, the reaction solution was cooled to 25°C to precipitate a crystalline solid. The mixture was diluted with diethyl ether (80 mL), and the solid was collected by filtration. The solid was rinsed with diethyl ether and dried to obtain ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate (5.50 g, yield 85.8%). ESI-MS (m / z): 331.97 / 333.96 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 1.271 (t, 3H), 4.208 (q, 2H), 7.402 (d, 1H), 8.528 (s, 1H), 12.404 (s, 1H).

[0486] Step 3: Synthesis of ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate

[0487] Thionyl chloride (20 mL) and ethyl 6-bromo-5,7-difluoro-4-hydroxyquinoline-3-carboxylate (1.40 g, 4.2 mmol) were added to a 100 mL reaction flask. The reaction mixture was allowed to react at 80°C for 3 h. After completion of the reaction, the reaction mixture was cooled and concentrated to dryness to obtain crude ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate (1.48 g, 100% yield). ESI-MS (m / z): 351.93 [M+H] + .

[0488] Step 4: Synthesis of (S)-ethyl 6-bromo-5,7-difluoro-4-((1-hydroxypropan-2-yl)amino)quinoline-3-carboxylate

[0489] To a 100 mL reaction flask, DMF (20 mL), ethyl 6-bromo-4-chloro-5,7-difluoroquinoline-3-carboxylate (1.48 g, 4.2 mmol), L-aminopropanol (0.47 g, 6.3 mmol), and DIEA (1.09 g, 8.4 mmol) were added sequentially. The temperature was raised to 90°C and the reaction was allowed to react for 3 h. TLC monitored the reaction completion. The reaction solution was cooled to room temperature and water was added to precipitate a solid, which was collected by filtration, rinsed with water, and dried to afford (S)-ethyl 6-bromo-5,7-difluoro-4-((1-hydroxypropyl-2-yl)amino)quinoline-3-carboxylate (1.2 g, 73.4% yield). ESI-MS (m / z): 389.02 / 391.02 [M+H] + ; 1 H NMR(600MHz, CDCl3)δ:1.429(t,3H),1.555(d,3H),4.292-4.356(m,2H),4.420(q,2H),4.638(d,1H),8.010(s,1H),9.048(s,1H),11.557(s,1H).

[0490] Step 5: (S)-10-Bromo-9-fluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepine Synthesis of 5-[5,6,7-de]quinoline-5-carboxylic acid

[0491] To a 100 mL reaction flask, THF (10 mL), ethyl (S)-6-bromo-5,7-difluoro-4-((1-hydroxypropyl-2-yl)amino)quinoline-3-carboxylate (1.20 g, 3.08 mmol), water (5 mL), and sodium hydroxide (0.37 g, 9.24 mmol) were added sequentially. The temperature was raised to 60°C and the reaction was allowed to proceed for 3 h. The reaction was monitored by TLC. The reaction solution was cooled to room temperature and the pH was adjusted to 5 with 1N hydrochloric acid to precipitate a solid. The solid was collected by filtration, rinsed with water, and dried to obtain (S)-10-bromo-9-fluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepine. [5,6,7-de]quinoline-5-carboxylic acid (0.8 g, yield 76.1%). ESI-MS (m / z): 340.99 / 342.98 [M+H] + .

[0492] Step 6: Synthesis of (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0493] In a 100 mL reaction flask, DMF (15 mL), (S)-10-bromo-9-fluoro-3-methyl-3,4-dihydro-2H-[1,4]oxazepine were added in sequence. [5,6,7-de]quinoline-5-carboxylic acid (0.8 g, 2.35 mmol), DIEA (0.46 g, 3.53 mmol), and diphenylphosphoryl azide (0.78 g, 2.82 mmol) were heated to 60°C for 3 h. After completion of the reaction, the solution was cooled to room temperature and water was added to precipitate a solid, which was collected by filtration, rinsed with water, and dried to afford (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (0.7 g, 88.1% yield). ESI-MS (m / z): 337.99 / 339.98 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.443(d,3H),4.593-4.616(m,2H),4.803-4.829(m,1H),7.594(d,1H),8.678(s,1H),11.681(s,1H).

[0494] Step 7: Synthesis of (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-1)

[0495] In a 100 mL reaction bottle, DMF (15 mL) and (S)-7-bromo-6-fluoro-10-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.7 g, 2.07 mmol) were added in sequence. After cooling to 0°C, NaH (0.124 g, 3.11 mmol) was added and the reaction was carried out at this temperature for 0.5 h. Then, iodomethane (0.441 g, 3.11 mmol) was added and the reaction was carried out at room temperature overnight. The reaction was monitored by TLC. Water was added to the reaction solution to precipitate a solid, which was collected by filtration, rinsed with water, and dried to obtain (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.62 g, yield 85.1%). ESI-MS (m / z): 352.00 / 354.00 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.451(d,3H),3.536(s,3H),4.590-4.612(m,1H),4.651-4.665(m,1H),4.814-4.841(m,1H),7.635(d,1H),8.925(s,1H).

[0496] Intermediate Preparation Example 2: Preparation of (R)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-2)

[0497]

[0498] The synthesis method was the same as that of Preparation Example 1, except that D-aminopropanol was used instead of L-aminopropanol to obtain (R)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 75.4%. ESI-MS (m / z): 352.20 / 354.19 [M+H] + .

[0499] Intermediate Preparation Example 3: Preparation of 7-bromo-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-3)

[0500]

[0501] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-1-(4-fluorophenyl)ethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 82.4%. ESI-MS (m / z): 432.01 / 434.01 [M+H] + .

[0502] Intermediate Preparation Example 4: Preparation of 7-bromo-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-4)

[0503]

[0504] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-2-methyl-propanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in 82.4% yield. ESI-MS (m / z): 366.01 / 368.01 [M+H] + .

[0505] Intermediate Preparation Example 5: Preparation of 7-bromo-6-fluoro-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-5)

[0506]

[0507] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-1-(pyridin-2-yl)ethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one. ESI-MS (m / z): 415.01 / 417.01 [M+H] + .

[0508] Intermediate Preparation Example 6: Preparation of (R)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-6)

[0509]

[0510] The synthesis method was the same as that of Preparation Example 1, except that D-leucinol was used instead of L-aminopropanol to obtain (R)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 30.9%. ESI-MS (m / z): 394.05 / 396.05 [M+H] + .

[0511] Intermediate Preparation Example 7: Preparation of (S)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxo-2,4,10a-triazaanthraquinone[2,1,8-cde]azulen-1(2H)-one (M-7)

[0512]

[0513] The synthesis method was the same as that of Preparation Example 1, except that L-leucinol was used instead of L-aminopropanol to obtain (S)-7-bromo-6-fluoro-10-isobutyl-2-methyl-9,10-dihydro-8-oxo-2,4,10a-triazaanthraquinone[2,1,8-cde]azulene-1(2H)-one in a yield of 51.0%. ESI-MS (m / z): 393.92 / 395.87 [M+H] + .

[0514] Intermediate Preparation Example 8: Preparation of 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-8)

[0515]

[0516] The synthesis method was the same as that of Preparation Example 1, except that mercaptoethylamine was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in an 82.1% yield. ESI-MS (m / z): 353.96 / 355.97 [M+H] + .

[0517] Intermediate Preparation Example 9: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropane]-1-one (M-9)

[0518]

[0519] The synthesis method was the same as that of Preparation Example 1, except that 1-aminocyclopropylmethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropane]-1-one in a yield of 43.7%. ESI-MS (m / z): 364.01 / 366.01 [M+H] + .

[0520] Intermediate Preparation Example 10: Preparation of 7-bromo-9-(ethoxymethyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazaanthraquinone[2,1,8-cde]azulen-1(2H)-one (M-10)

[0521]

[0522] The synthesis method was the same as that of Preparation Example 1, except that 1-amino-3-ethoxy-2-propanol was used instead of L-aminopropanol to obtain 7-bromo-9-(ethoxymethyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazaanthraquinone[2,1,8-cde]azulen-1(2H)-one in a yield of 49.3%. ESI-MS (m / z): 396.03 / 398.03 [M+H] + .

[0523] Intermediate Preparation Example 11: Preparation of (S)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-11)

[0524]

[0525] The synthesis method was the same as that of Preparation Example 1, except that (S)-2-amino-3-phenylpropan-1-ol was used instead of L-aminopropanol to obtain (S)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxo-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 53.2%. ESI-MS (m / z): 428.03 / 430.03 [M+H] + .

[0526] Intermediate Preparation Example 12: Preparation of (R)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-12)

[0527]

[0528] The synthesis method was the same as that of Preparation Example 1, except that (R)-2-amino-3-phenylpropan-1-ol was used instead of L-aminopropanol to obtain (R)-10-benzyl-7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 32.6%. ESI-MS (m / z): 428.03 / 430.03 [M+H] + .

[0529] Intermediate Preparation Example 13: Preparation of 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-13)

[0530]

[0531] The synthesis method was the same as that of Preparation Example 1, except that 2-aminoethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 40.7%. ESI-MS (m / z): 337.99 / 339.99 [M+H] + .

[0532] Intermediate Preparation Example 14: Preparation of (S)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-14)

[0533]

[0534] The synthesis method was the same as that of Preparation Example 1, except that L-valinol was used instead of L-aminopropanol to obtain (S)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 52.3%. ESI-MS (m / z): 380.03 / 382.03 [M+H] + .

[0535] Intermediate Preparation Example 15: Preparation of (R)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-15)

[0536]

[0537] The synthesis method was the same as that of Preparation Example 1, except that D-valinol was used instead of L-aminopropanol to obtain (R)-7-bromo-6-fluoro-10-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 59.3%. ESI-MS (m / z): 380.03 / 382.03 [M+H] + .

[0538] Intermediate Preparation Example 16: Preparation of 7-bromo-6-fluoro-9-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-16)

[0539]

[0540] The synthesis method was the same as that of Preparation Example 1, except that 1-amino-3-methyl-butan-2-ol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-9-isopropyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 30.6%. ESI-MS (m / z): 380.03 / 382.03 [M+H]+.

[0541] Intermediate Preparation Example 17: Preparation of (S)-7-bromo-9-((dimethylamino)methyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-17)

[0542]

[0543] The synthesis method was the same as that of Preparation Example 1, except that (R)-1-amino-3-(dimethylamino)propan-2-ol was used instead of L-aminopropanol to obtain (S)-7-bromo-9-((dimethylamino)methyl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 75.5%. ESI-MS (m / z): 395.04 / 397.04 [M+H] + .

[0544] Intermediate Preparation Example 18: Preparation of (S)-7-bromo-6-fluoro-2-methyl-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-18)

[0545]

[0546] The synthesis method was the same as that of Preparation Example 1, except that (R)-1-amino-3-(piperidin-1-yl)propan-2-ol was used instead of L-aminopropanol to obtain (S)-7-bromo-6-fluoro-2-methyl-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 72.1%. ESI-MS (m / z): 435.08 / 437.08 [M+H] + .

[0547] Intermediate Preparation Example 19: Preparation of 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (M-19)

[0548]

[0549] The synthesis method was the same as that of Preparation Example 1, except that 2-aminocyclohexanol was used instead of L-aminopropanol to obtain 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one in a yield of 68.5%. ESI-MS (m / z): 392.03 / 394.03 [M+H] + .

[0550] Intermediate Preparation Example 20: Preparation of (R)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-20)

[0551]

[0552] The synthesis method was the same as that of Preparation Example 1, except that (R)-2-amino-1-butanol was used instead of L-aminopropanol to obtain (R)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 71.5%. ESI-MS (m / z): 366.02 / 368.02 [M+H] + .

[0553] Intermediate Preparation Example 21: Preparation of (S)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-21)

[0554]

[0555] The synthesis method was the same as that of Preparation Example 1, except that (S)-2-amino-1-butanol was used instead of L-aminopropanol to obtain (S)-7-bromo-10-ethyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 68.5%. ESI-MS (m / z): 366.02 / 368.02 [M+H] + .

[0556] Intermediate Preparation Example 22: Preparation of 7-bromo-6-fluoro-2,9-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-22)

[0557]

[0558] The synthesis method was the same as that of Preparation Example 1, except that 1-amino-2-propanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2,9-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in 82.4% yield. ESI-MS (m / z): 352.00 / 354.00 [M+H] + .

[0559] Intermediate Preparation Example 23: Preparation of 7-bromo-6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-23)

[0560]

[0561] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-1-(2-fluoro-pyridin-4-yl)ethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 32.5%. ESI-MS (m / z): 433.00 / 435.00 [M+H] + .

[0562] Intermediate Preparation Example 24: Preparation of 7-bromo-10-cyclopropyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-24)

[0563]

[0564] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-2-cyclopropylethanol was used instead of L-aminopropanol to obtain 7-bromo-10-cyclopropyl-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 28.4%. ESI-MS (m / z): 378.02 / 380.02 [M+H] + .

[0565] Intermediate Preparation Example 25: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one (M-25)

[0566]

[0567] The synthesis method was the same as that of Preparation Example 1, except that (1-aminocyclobutyl)methanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one in a yield of 37.5%. ESI-MS (m / z): 377.93 / 379.95 [M+H] + .

[0568] Intermediate Preparation Example 26: Preparation of (6aR,10aS)-5-bromo-4-fluoro-12-methyl-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylic acid ethyl ester (M-26)

[0569]

[0570] The synthesis method was the same as that of Preparation Example 1, except that (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid ethyl ester was used instead of L-aminopropanol to obtain (6aR,10aS)-5-bromo-4-fluoro-12-methyl-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylic acid ethyl ester in a yield of 37.5%. ESI-MS (m / z): 464.93 / 466.95 [M+H] + .

[0571] Intermediate Preparation Example 27: Preparation of 7-bromo-6-fluoro-10-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-27)

[0572]

[0573] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-2-(4-fluorophenyl)ethanol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-10-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (100 mg, 32% yield). ESI-MS (m / z): 432.21 / 434.25 [M+H] + .

[0574] Intermediate Preparation Example 28: Preparation of 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-28)

[0575]

[0576] Step 1: Synthesis of 4-bromo-3-fluoro-5-methoxyaniline

[0577] To a 250 mL reaction flask, 3-fluoro-5-methoxyaniline (4.1 g, 29.1 mmol) and DMF (50 mL) were added sequentially. NBS (5.2 g, 29.1 mmol) was then added portionwise at room temperature. The mixture was allowed to react for 1 h. After cooling, 100 mL of water and 100 mL of ethyl acetate were added. The organic phase was separated and extracted, concentrated to dryness, and purified by column chromatography (PE:EA = 10:1 to 2:1) to obtain 4.90 g of 4-bromo-3-fluoro-5-methoxyaniline. ESI-MS (m / z): 219.98 / 222.01 [M+H] + .

[0578] Step 2: Synthesis of diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate

[0579] To a 250 mL reaction flask, 4-bromo-3-fluoro-5-methoxyaniline (4.8 g, 21.8 mmol), diethyl 2-(ethoxymethylene)malonate (7.0 g, 32.4 mmol), and 50 mL of anhydrous ethanol were added sequentially. The reaction mixture was heated to reflux and reacted for 6 h. The mixture was then cooled to room temperature. 100 mL of n-hexane was added at room temperature and filtered to obtain 5.9 g of diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate. ESI-MS (m / z): 390.20 / 392.18 [M+H] + .

[0580] Step 3: Synthesis of ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinoline-3-carboxylate

[0581] To a 250 mL reaction flask, add 40 mL of diphenyl ether, raise the temperature to 240°C, and add diethyl 2-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)malonate (5.9 g, 15.1 mmol) in portions. Maintain the temperature for 1 hour, then cool to room temperature. Add 100 mL of n-hexane at room temperature and filter to obtain 4.6 g of ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinoline-3-carboxylate. ESI-MS (m / z): 344.14 / 346.18 [M+H] + .

[0582] Step 4: Synthesis of ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate

[0583] To a 100 mL reaction flask, ethyl 6-bromo-5-fluoro-4-hydroxy-7-methoxyquinoline-3-carboxylate (800 mg, 2.32 mmol) and 10 mL of thionyl chloride were added dropwise. Two drops of DMF were added dropwise and the mixture was refluxed for 4 h. After completion of the reaction, the mixture was evaporated to dryness under reduced pressure to give 840 mg of ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate. ESI-MS (m / z): 361.91 / 363.99 [M+H] + .

[0584] Step 5: Synthesis of ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate

[0585] To a 100 mL reaction flask were added ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (840 mg, 2.32 mmol), 10 mL of DMF, DIPEA (1500 mg, 11.6 mmol), and 2-amino-2-(pyridin-2-yl)ethanol (600 mg, 2.84 mmol). The reaction mixture was heated to 90°C for 2 h. Following completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was filtered. The filter cake was dried to yield 1.1 g of ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate. ESI-MS (m / z): 464.29 / 466.30 [M+H]. + .

[0586] Step 6: Synthesis of 10-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxaza[5,6,7-de]quinoline-5-carboxylic acid

[0587] To a 100 mL reaction flask, ethyl 6-bromo-5-fluoro-4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-7-methoxyquinoline-3-carboxylate (1100 mg, 2.37 mmol), 10 mL of THF, 5 mL of water, and sodium hydroxide (520 mg, 13.0 mmol) were added. The reaction mixture was heated to 60°C for 8 h. After completion of the reaction, THF was removed under reduced pressure, and the pH was adjusted to 3 with 6N hydrochloric acid. Filtration afforded 0.3 g of 110-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxaza[5,6,7-de]quinoline-5-carboxylic acid. ESI-MS (m / z): 416.19 / 418.20 [M+H] + .

[0588] Step 7: Synthesis of 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0589] To a 100 mL reaction flask were added 10-bromo-9-methoxy-3-(pyridin-2-yl)-3,4-dihydro-2H-[1,4]oxazepine[5,6,7-de]quinoline-5-carboxylic acid (300 mg, 0.72 mmol), 10 mL of DMF, triethylamine (150 mg, 1.48 mmol), and DPPA (300 mg, 1.09 mmol) in sequence. The reaction mixture was heated to 90°C for 2 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and water was added to precipitate a solid. Filtering afforded 0.3 g of 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one. ESI-MS(m / z):412.19 / 414.23[M+H] + .

[0590] Step 8: Synthesis of 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0591] To a reaction flask were added 7-bromo-6-methoxy-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (300 mg, 0.72 mmol), cesium carbonate (474 ​​mg, 1.45 mmol), and 10 mL of DMF. Methyl iodide (155 mg, 1.10 mmol) was added at room temperature and allowed to react for 1.5 h. The reaction was monitored by TLC. The reaction solution was cooled to room temperature and water was added to precipitate a solid. Filtering afforded 0.2 g of 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one in a yield of 64.5%. ESI-MS(m / z):427.03 / 429.03[M+H] + .

[0592] Intermediate Preparation Example 29: Preparation of (S)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-29)

[0593]

[0594] The synthesis method was the same as that of Preparation Example 1, except that 4-bromo-3-fluoro-5-methoxyaniline was used instead of 4-bromo-3,5-difluoroaniline to obtain (S)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 82.4%. ESI-MS (m / z): 364.02 / 366.02 [M+H] + .

[0595] Intermediate Preparation Example 30: Preparation of (R)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-30)

[0596]

[0597] The synthesis method was the same as that of Preparation Example 1, except that 4-bromo-3-fluoro-5-methoxyaniline was used instead of 4-bromo-3,5-difluoroaniline, and (R)-2-amino-1-propanol was used instead of (S)-2-amino-1-propanol to obtain (R)-7-bromo-6-methoxy-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in 82.4% yield. ESI-MS (m / z): 364.02 / 366.02 [M+H] + .

[0598] Intermediate Preparation Example 31: Preparation of 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (M-31)

[0599]

[0600] Step 1: Synthesis of ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate

[0601] To a 100 mL reaction flask, ethyl 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (840 mg, 2.32 mmol), 2-aminophenol (280 mg, 2.57 mmol), and 10 mL of glacial acetic acid were added sequentially. The reaction mixture was heated to 60°C for 1 h. Following completion of the reaction, the reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The layers were separated, and the organic phase was washed twice with saturated sodium bicarbonate and concentrated to dryness under reduced pressure to yield 1.0 g of ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate.

[0602] Step 2: Synthesis of 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid

[0603] To a 100 mL reaction flask, add ethyl 6-bromo-5-fluoro-4-((2-hydroxyphenyl)amino)-7-methoxyquinoline-3-carboxylate (1000 mg, 2.30 mmol), 10 mL of THF, 5 mL of water, and sodium hydroxide (460 mg, 11.5 mmol). The reaction mixture was heated to 60°C and reacted for 8 h. After completion of the reaction, THF was removed under reduced pressure, the pH was adjusted to 3 with 6N hydrochloric acid, and filtration was performed to obtain 0.86 g of 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid.

[0604] Step 3: Synthesis of 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one

[0605] To a 100 mL reaction flask, 6-bromo-5-methoxy-12H-benzo[2,3][1,4]oxazepine[5,6,7-de]quinoline-1-carboxylic acid (860 mg, 2.22 mmol), 10 mL of DMF, triethylamine (450 mg, 4.45 mmol), and DPPA (917 mg, 3.33 mmol) were added sequentially. The reaction mixture was heated to 90°C for 2 h. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and water was added. Solids precipitated, which were filtered to obtain 0.84 g of 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one.

[0606] Step 4: Synthesis of 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one

[0607] To a reaction flask, 5-bromo-4-methoxy-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one (840 mg, 2.19 mmol), cesium carbonate (1420 mg, 4.36 mmol), and 10 mL of DMF were added sequentially. Methyl iodide (466 mg, 3.28 mmol) was added dropwise at room temperature. The mixture was allowed to react for 1.5 h. The reaction was monitored by TLC. Water was added to the reaction solution, and solids precipitated. Filtration afforded 0.76 g of 5-bromo-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one, a yield of 87.3%. ESI-MS (m / z): 398.01 / 400.01 [M+H]. + .

[0608] Intermediate Preparation Example 32: Preparation of 5-bromo-4-methoxy-12-methyl-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pyroxene-11(12H)-one (M-32)

[0609]

[0610] The synthesis method was the same as that of Preparation Example 31, except that 3-amino-4-hydroxypyridine was used instead of 2-aminophenol to obtain 5-bromo-4-methoxy-12-methyl-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pyroxene-11(12H)-one in a yield of 27.3%. ESI-MS (m / z): 398.99 / 400.96 [M+H] + .

[0611] Intermediate Preparation Example 33: Preparation of (6aS,9aR)-5-(6-bromopyridin-3-yl)-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopentadien[h]naphtho[2,1,8-cde]azulene-10(11H)-one (M-33)

[0612]

[0613] The synthesis method was the same as that of Preparation Example 1, except that (3S,4R)-4-aminotetrahydrofuran-3-ol was used instead of L-aminopropanol to obtain (6aS,9aR)-5-bromo-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulen-10(11H)-one in a yield of 60.3%. ESI-MS (m / z): 379.94 / 381.95 [M+H] + .

[0614] Intermediate Preparation Example 34: Preparation of (6aR,9aS)-5-bromo-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulene-10(11H)-one (M-34)

[0615]

[0616] The synthesis method was the same as that of Preparation Example 1, except that (3R,4S)-4-aminotetrahydrofuran-3-ol was used instead of L-aminopropanol to obtain (6aR,9aS)-5-bromo-4-fluoro-11-methyl-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulene-10(11H)-one in a yield of 82.4%. ESI-MS (m / z): 380.00 / 382.00 [M+H] + .

[0617] Intermediate Preparation Example 35: Preparation of 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3'-oxetanyl]-1-one (M-35)

[0618]

[0619] The synthesis method was the same as that of Preparation Example 1, except that 3-amino-3-hydroxymethyloxetane was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3'-oxetanyl]-1-one in a yield of 32.1%. ESI-MS (m / z): 380.00 / 381.99 [M+H] + .

[0620] Intermediate Preparation Example 36: Preparation of 7-bromo-6-methoxy-10-hydroxymethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-36)

[0621]

[0622] The synthesis method was the same as that of Preparation Example 31, except that 2-amino-1,3-propanediol was used instead of 2-aminophenol to obtain 7-bromo-6-methoxy-10-hydroxymethyl-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 28.0%. ESI-MS (m / z): 380.02 / 382.02 [M+H] + .

[0623] Intermediate Preparation Example 37: Preparation of 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-37)

[0624]

[0625] The synthesis method was the same as that of Preparation Example 1, except that 2-amino-1,3-propanediol was used instead of L-aminopropanol to obtain 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 74.2%. ESI-MS (m / z): 367.96 / 370.02 [M+H] + .

[0626] Intermediate Preparation Example 38: Preparation of 5-bromo-8-fluoro-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (M-38)

[0627]

[0628] The synthesis method was the same as that of Preparation Example 31, except that 2-amino-5-fluorophenol was used instead of 2-aminophenol to obtain 5-bromo-8-fluoro-4-methoxy-12-methyl-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one in a yield of 74.5%. ESI-MS (m / z): 416.20 / 418.20 [M+H] + .

[0629] Intermediate Preparation Example 39: Preparation of 7-bromo-6-methoxy-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-39)

[0630]

[0631] The synthesis method was the same as that of Preparation Example 28, except that 2-amino-1-(pyridin-2-yl)ethanol was used instead of 2-amino-2-(pyridin-2-yl)ethanol to obtain 7-bromo-6-methoxy-2-methyl-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 63.8%. ESI-MS (m / z): 427.03 / 429.03 [M+H] + .

[0632] Intermediate Preparation Example 40: Preparation of (R)-7-bromo-6-methoxy-2-methyl-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (M-40)

[0633]

[0634] The synthesis method was the same as that of Preparation Example 28, except that (R)-2-amino-2-phenylethanol was used instead of 2-amino-2-(pyridin-2-yl)ethanol to obtain (R)-7-bromo-6-methoxy-2-methyl-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one in a yield of 67.2%. ESI-MS (m / z): 426.04 / 428.04 [M+H] + .

[0635] Intermediate Preparation Example 41: Preparation of ethyl 5-fluoro-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-41)

[0636]

[0637] To a 100 mL round-bottom flask, ethyl 4-chloro-5,7-difluoroquinoline-3-carboxylate (0.20 mmol), o-aminophenol (0.24 mmol), DIPEA (0.4 mmol) and DMF (20 mL) were added in sequence, and the reaction system was stirred at 90°C for 2.0 h. After TLC monitoring showed that no starting material remained, heating was stopped and the reaction mixture was cooled to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic phase was extracted. The organic phase was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain ethyl 5-fluoro-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate in a yield of 83.7%. 1 H NMR (600MHz, CDCl3) δ11.590(s,1H),9.130(s,1H),7.388(d,J=10.2Hz,1H),7.238-7.250(m,1 H),7.105-7.126(m,2H),7.025-7.061(m,2H),4.470(q,J=6.6Hz,2H),1.470(t,J=6.6Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.78, 165.44, 163.76, 156.80 (d, J = 13.5 Hz), 153.05 (d, J = 13.5 Hz), 152.54, 151.39, 148.82, 133.76, 125.85, 125.54, 121.70, 110.35 (d, J = 19.5 Hz), 107.28 (d, J = 27 Hz), 102.71, 61.51, 14.39; HR-MS (ESI) calculated value C 18H 14 FN2O3[M+H] + :325.1734, measured value 325.1732.

[0638] Intermediate Preparation Example 42: Preparation of ethyl 5-fluoro-12H-benzo[2,3][1,4]thiazino[5,6,7-de]quinoline-1-carboxylate (M-42)

[0639]

[0640] The synthesis method was the same as that in Preparation Example 41 to obtain ethyl 5-fluoro-12H-benzo[2,3][1,4]thiazino[5,6,7-de]quinoline-1-carboxylate in a yield of 81.6%. 1 H NMR (600MHz, CDCl3) δ11.885(s,1H),9.181(s,1H),7.549(d,J=7.2Hz,1H),7.500(d,J=7.8Hz,1H),7.429 -7.442(m,1H),7.295-7.320(m,1H),7.134-7.167(m,2H),4.495(q,J=7.2Hz,2H),1.484(t,J=6.6Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.99, 164.33, 162.63, 154.39, 154.00 (d, J = 13.5 Hz), 152.55, 144.81, 135.75 (d, J = 9.0 Hz), 131.88, 129.85, 128.59, 126.04, 123.62, 119.35 (d, J = 24 Hz), 113.95 (d, J = 21 Hz), 104.93, 61.71, 14.41; HR-MS (ESI) calculated value C 18 H 14 FN2O2S[M+H] + :341.0957, measured value 341.0959.

[0641] Intermediate Preparation Example 43: Preparation of ethyl 5-fluoro-7,12-dihydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate (M-43)

[0642]

[0643] The synthesis method was the same as that in Preparation Example 41 to obtain ethyl 5-fluoro-7,12-dihydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate in a yield of 86.4%. 1H NMR(600MHz,CD3OD+CF3COOH)δ9.040(s,1H),7.021-7.035(m,1H),6.958-6.976(m,1H),6.875-6.90 0(m,1H),6.793-6.806(m,2H),6.757-6.778(m,1H),4.496(q,J=7.2Hz,2H),1.474(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CD3OD+CF3COOH) δ 168.10, 156.01, 145.60, 135.97, 124.63, 123.84, 120.84, 118.89, 117.00, 115.12, 113.23, 106.01 (d, J = 25.5 Hz), 104.73, 102.73, 99.08 (d, J = 25.5 Hz), 64.20, 55.61, 14.30; HR-MS (ESI) calculated value C 18 H 15 FN3O2[M+H] + :324.1171, measured value 324.1173.

[0644] Intermediate Preparation Example 44: Preparation of ethyl 5,9-difluoro-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-44)

[0645]

[0646] The synthesis method was the same as that in Preparation Example 41 to obtain ethyl 5,9-difluoro-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate in a yield of 80.3%. 1 H NMR (600MHz, CDCl3) δ11.585 (s, 1H), 9.161 (s, 1H), 7.439 (d, J = 8.4Hz, 1H), 7.022- 7.060(m,3H),6.888-6.899(m,1H),4.476(q,J=7.2Hz,2H),1.475(t,J=7.2Hz,3H); 13CNMR (150 MHz, CDCl3) δ 168.84, 165.48, 163.67, 160.62, 158.98, 156.30 (d, J = 15 Hz), 156.05, 152.63, 151.25, 130.27, 122.36 (d, J = 9 Hz), 112.90 (d, J = 25.5 Hz), 110.76 (d, J = 19.5 Hz), 109.35 (d, J = 24 Hz), 107.48 (d, J = 25.5 Hz), 102.77, 61.65, 14.43; HR-MS (ESI) calculated value C 18 H 13 F2N2O3[M+H] + :343.2013, measured value 343.2011.

[0647] Intermediate Preparation Example 45: Preparation of ethyl 5-fluoro-10-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-45)

[0648]

[0649] The synthesis method was the same as that in Preparation Example 41 to obtain 5-fluoro-10-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 85.6%. 1 H NMR (600MHz, CDCl3) δ11.542(s,1H),9.124(s,1H),7.370-7.390(m,1H),7.136(d,J=9.0Hz,1H),6.987-7.0 06(m,1H),6.215-6.634(m,1H),6.536(m,1H),4.462(q,J=7.2Hz,2H),3.768(s,3H),1.467(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.82, 165.52, 163.84, 157.39, 157.20 (d, J = 13.5 Hz), 152.50 (d, J = 13.5 Hz), 152.42, 151.62, 142.84, 134.35, 122.24, 111.14, 110.51 (d, J = 3 Hz), 110.14 (d, J = 21 Hz), 107.10 (d, J = 25.5 Hz), 106.39, 102.70, 61.56, 55.93, 14.40; HR-MS (ESI) calculated value C 19 H 16 FN2O4[M+H]+ :355.0978, measured value 355.0980.

[0650] Intermediate Preparation Example 46: Preparation of ethyl 5-fluoro-12H-pyrido[3',4':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-46)

[0651]

[0652] The synthesis method was the same as that of Preparation Example 41 to obtain ethyl 5-fluoro-12H-pyrido[3',4':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate in a yield of 95.8%. 1 H NMR (600MHz, CD3OD) δ9.425 (s, 1H), 8.932 (s, 1H), 8.585 (d, J = 4.8Hz, 1H), 7.636-7.736 (m, 3H), 4.619 (q, J = 6.6Hz, 2H), 1.528 (t, J = 6.6Hz, 3H); 13 C NMR (150 MHz, CD3OD+CF3COOH) δ 168.23, 166.68, 156.40 (d, J = 15 Hz), 152.15, 150.11, 145.83 (d, J = 18 Hz), 142.15, 139.35, 119.32, 117.80, 116.99, 115.89, 111.65 (d, J = 28.5 Hz), 110.61, 106.95, 64.53, 14.31; HR-MS (ESI) calculated value C 17 H 13 FN3O3[M+H] + :326.0832, measured value 326.0830.

[0653] Intermediate Preparation Example 47: Preparation of ethyl 5-fluoro-12H-pyrido[4',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-47)

[0654]

[0655] The synthesis method was the same as that of Preparation Example 41 to obtain ethyl 5-fluoro-12H-pyrido[4',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate in a yield of 94.5%. 1H NMR (600MHz, CF3COOH+CDCl3) δ13.144(s,1H),9.406(s,1H),8.799(s,1H),8.588(d,J=4.2Hz,1H),7.927(d, J=7.8Hz,1H),7.584(d,J=5.4Hz,1H),7.422(d,J=7.8Hz,1H),4.571(q,J=7.2Hz,2H),1.485(t,J=7.2Hz,3H); 13 CNMR (150 MHz, CF3COOH+CDCl3) δ 167.84, 166.63, 166.09, 156.08, 154.78 (d, J = 13.5 Hz), 153.43, 146.80, 144.71, 140.78, 129.00, 118.64, 116.56, 117.69 (d, J = 27 Hz), 107.99, 106.15 (d, J = 24 Hz), 104.00, 64.24, 13.93; HR-MS (ESI) calculated value C 17 H 13 FN3O3[M+H] + :326.1438, measured value 326.1440.

[0656] Intermediate Preparation Example 48: Preparation of ethyl 5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-48)

[0657]

[0658] Step 1: Synthesis of diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate

[0659] 3-Fluoro-5-methoxyaniline (1.41 g, 0.01 mol), diethyl 2-(ethoxymethylene)malonate (2.16 g, 0.01 mol), and 25 mL of anhydrous ethanol were added sequentially to a 100 mL reaction flask. The reaction solution was heated to reflux and reacted for 6 h. After cooling to room temperature, the solvent was removed by rotary evaporation to obtain 2.76 g of diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate as a colorless, transparent liquid with a yield of 88.7%. HR-MS (ESI) calculated value: C 15 H 19 FNO5[M+H] + 312.0755, measured value 312.0756; 1H NMR(600MHz, CDCl3)δ:10.841~10.862(m,1H),8.322~8.344(m,1H),6.304-6 .395(m,3H),4.165~4.239(m,4H),3.716~3.726(m,3H),1.243~1.316(m,6H).

[0660] Step 2: Synthesis of ethyl 5-fluoro-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0661] 40 mL of diphenyl ether was added to a 100 mL reaction flask, the temperature was raised to 240°C, and diethyl 2-(((3-fluoro-5-methoxyphenyl)amino)methylene)malonate (3.11 g, 0.01 mol) was added. The temperature was maintained for 1 h, and the mixture was cooled to room temperature. 100 mL of n-hexane was added at room temperature and filtered to obtain 2.24 g of ethyl 5-fluoro-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate as a white solid with a yield of 84.4%. The theoretical value of HR-MS (ESI) was C 13 H 12 FNO4[M+H] + 266.1326, measured value 266.1328; 1 HNMR(600MHz,DMSO-d6)δ:12.071(s,1H),8.396(s,1H),6.833-6.844(m,1H), 6.758~6.780(m,1H), 4.155~4.201(m,2H), 3.853(s,3H), 1.244~1.286(m,3H).

[0662] Step 3: Synthesis of ethyl 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate

[0663] In a 50 mL reaction flask, 5-fluoro-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (1.30 g, 4.90 mmol) and 10 mL of thionyl chloride were added dropwise, and two drops of DMF were added dropwise. The mixture was refluxed for 4 h. After completion of the reaction, the mixture was evaporated to dryness under reduced pressure to obtain 1.21 g of 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylic acid ethyl ester as a yellow solid with a yield of 87.1%. HR-MS (ESI) theoretical value C 13 H 12 ClFNO3[M+H] + 283.1184, measured value 283.1186; 1H NMR (600MHz, CDCl3) δ: 9.152 (s, 1H), 7.785 (m, 1H), 6.955-6.976 (m, 1H), 4.522 (q, J = 7.2Hz, 2H), 4.025 (s, 3H), 1.444 (t, J = 7.2Hz, 3H).

[0664] Step 4: Synthesis of ethyl 5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate

[0665] To a 100 mL round-bottom flask, ethyl 4-chloro-5-fluoro-7-methoxyquinoline-3-carboxylate (0.20 mmol), o-aminophenol (0.24 mmol), DIPEA (0.4 mmol), and DMF (20 mL) were added sequentially. The reaction system was stirred at 90°C for 2.0 h. TLC monitoring confirmed the absence of residual starting material. Heating was discontinued, and the mixture was cooled to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic phase was extracted and concentrated under reduced pressure. The crude product was separated by column chromatography to obtain ethyl 5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate in a yield of 75.0%. 1 H NMR (600MHz, CDCl3) δ11.535(s,1H),9.122(s,1H),7.276-7.290(m,1H),7.081-7.169(m ,4H),6.937-6.941(m,1H),4.483(q,J=7.2Hz,2H),3.959(s,3H),1.494(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.99, 163.05, 156.11, 153.64, 152.18, 151.32, 149.00, 134.20, 125.58, 125.24, 121.79, 121.61, 108.68, 107.97, 105.52, 101.94, 61.27, 55.91, 14.46; HR-MS (ESI) calculated value C 19 H 14 N2O4[M+H] + :337.1074, measured value 337.1076.

[0666] Intermediate Preparation Example 49: Preparation of ethyl 5-methoxy-12H-benzo[2,3][1,4]thiazino[5,6,7-de]quinoline-1-carboxylate (M-49)

[0667]

[0668] The synthesis method was the same as that of Preparation Example 48 to obtain 5-methoxy-12H-benzo[2,3][1,4]thiazino[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 64.0%. 1 H NMR (600MHz, DMSO-d6) δ11.565(s,1H),9.051(s,1H),7.611(d,J=7.2Hz,1H),7.399-7.422(m,1H),7.338(d,J=3.0 Hz,2H),7.279(d,J=3.0Hz,1H),7.197-7.242(m,2H),4.454(q,J=7.2Hz,2H),3.909(s,3H),1.417(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 169.10, 161.96, 154.33, 154.13, 151.90, 145.07, 134.17, 131.88, 129.59, 128.77, 125.74, 123.49, 121.56, 116.46, 108.45, 104.12, 61.50, 55.87, 14.45; HR-MS (ESI) calculated value C 19 H 17 N2O3S[M+H] + :353.1283, measured value 353.1284.

[0669] Intermediate Preparation Example 50: Preparation of ethyl 5-methoxy-7,12-dihydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate (M-50)

[0670]

[0671] The synthesis method was the same as that of Preparation Example 48 to obtain 5-methoxy-7,12-dihydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 79.0%. 1 H NMR(600MHz, CDCl3)δ11.641(s,1H),9.109(s,1H),6.899-6.963(m,4H),6.772-6.785(m,1H),6 .406-6.409(m,1H),6.085(s,1H),4.431(q,J=7.2Hz,2H),3.878(s,3H),1.452(t,J=7.2Hz,3H); 13C NMR (150 MHz, CDCl3) δ 169.20, 162.68, 153.63, 152.28, 151.58, 144.79, 135.46, 131.39, 124.64, 122.84, 121.62, 119.15, 105.33, 104.62, 102.77, 101.68, 61.20, 55.61, 14.41; HR-MS (ESI) calculated value C 19 H 18 N3O3[M+H] + :336.0512, measured value 336.0513.

[0672] Intermediate Preparation Example 51: Preparation of ethyl 9-fluoro-5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-51)

[0673]

[0674] The synthesis method was the same as that of Preparation Example 48 to obtain 9-fluoro-5-methoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 56.3%. 1 H NMR(600MHz, CDCl3)δ11.481(s,1H),9.102(s,1H),7.169-7.173(m,1H),7.002-7.035(m,2H),6.90 2-6.906(m,1H),6.839-6.871(m,1H),4.458(q,J=6.6Hz,2H),3.942(s,3H),1.468(t,J=6.6Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.99, 163.07, 160.43, 158.80, 155.60, 152.13, 151.12, 149.48 (d, J = 10.5 Hz), 130.61, 122.18 (d, J = 10.5 Hz), 112.53 (d, J = 22.5 Hz), 109.34 (d, J = 24 Hz), 108.85, 107.73, 105.75, 101.97, 61.38, 56.00, 14.43; HR-MS (ESI) calculated value C 19 H 16 FN2O4[M+H] + :355.1337, measured value 355.1338.

[0675] Intermediate Preparation Example 52: Preparation of ethyl 5,10-dimethoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-52)

[0676]

[0677] The synthesis method was the same as that of Preparation Example 48 to obtain 5,10-dimethoxy-12H-benzo[2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 59.4%. 1 H NMR(600MHz,DMSO-d6)δ10.955(s,1H),9.766(s,1H),8.894(s,1H),8.582(s,1H),8.321(s,1H),7.165( m,1H),6.194-6.199(m,1H),4.435(q,J=7.2Hz,2H),3.939(s,3H),3.737(s,3H),1.408(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 168.98, 163.32, 157.24, 156.53, 153.29, 151.88, 151.63, 143.03, 134.70, 122.35, 111.01, 108.57, 108.09, 106.30, 105.11, 101.93, 61.38, 55.96, 14.46; HR-MS (ESI) calculated value C 20 H 18 N2O5[M+H] + :367.1534, measured value 367.1535.

[0678] Intermediate Preparation Example 53: Preparation of ethyl 5-methoxy-12H-pyrido[4',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-53)

[0679]

[0680] The synthesis method was the same as that of Preparation Example 48 to obtain 5-methoxy-12H-pyrido[4',3':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 81.2%. 1H NMR (600MHz, DMSO-d6) δ11.456(s,1H),9.058(s,1H),8.493(s,1H),8.350(d,J=5.4Hz,1H),7.442(d,J=5.4Hz,1 H),7.265(d,J=2.4Hz,1H),7.161(d,J=2.4Hz,1H),4.464(q,J=7.2Hz,2H),3.962(s,3H),1.427(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 175.53, 158.63, 163.25, 153.84, 152.10, 151.08, 150.34, 145.88, 142.68, 130.14, 116.44, 109.87, 106.14, 105.17, 102.37, 61.81, 56.12, 14.34; HR-MS (ESI) calculated value C 18 H 16 N3O4[M+H] + :338.1382, measured value 338.1382.

[0681] Intermediate Preparation Example 54: Preparation of ethyl 5-methoxy-12H-pyrido[3',4':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylate (M-54)

[0682]

[0683] The synthesis method was the same as that of Preparation Example 48 to obtain 5-methoxy-12H-pyrido[3',4':2,3][1,4]oxaza[5,6,7-de]quinoline-1-carboxylic acid ethyl ester in a yield of 89.4%. 1 H NMR (600MHz, CDCl3) δ11.831(s,1H),9.145(s,1H),8.508(s,1H),8.273(s,1H),7.182(m ,1H),6.948-6.988(m,2H),4.471(q,J=7.2Hz,2H),3.946(s,3H),1.473(t,J=7.2Hz,3H); 13C NMR (150 MHz, CDCl3) δ 168.99, 163.10, 154.94, 153.65, 151.98, 149.68, 146.62, 144.38, 143.81, 140.10, 115.09, 109.56, 107.02, 106.06, 102.75, 61.74, 56.02, 14.40; HR-MS (ESI) calculated value C 18 H 16 N3O4[M+H] + :338.1438, measured value 338.1440.

[0684] Intermediate Preparation Example 55: Preparation of ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate (M-55)

[0685]

[0686] The synthesis method was the same as that in Preparation Example 41 to obtain ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate in a yield of 95.7%. 1 H NMR (600MHz, CDCl3) δ10.086(s,1H),8.911(s,1H),6.860-6.880(m,1H),6.215-6.236(m,1H),4.485(s,1H),4.422(q,J=7.2Hz,2H ),3.228-3.267(m,1H),3.099-3.139(m,1H),2.189-2.212(m,1H),2.036-2.057(m,1H),1.807-1.814(m,2H),1.296-1.528(m,7H); 13 C NMR (150 MHz, CDCl3) δ 169.38, 165.53, 163.38, 156.22, 154.47 (d, J = 15 Hz), 152.68, 149.54 (d, J = 13.5 Hz), 105.52, 103.58 (d, J = 21 Hz), 99.35, 99.20, 99.03, 60.50 (d, J = 15 Hz), 59.35, 32.89, 32.39, 23.79 (d, J = 6 Hz), 14.47; HR-MS (ESI) calculated value C 18 H 20 FN3O2[M+H] +:330.1237, measured value 330.1238.

[0687] Intermediate Preparation Example 56: Preparation of ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate (M-56)

[0688]

[0689] The synthesis method was the same as that in Preparation Example 41 to obtain ethyl 5-fluoro-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate in a yield of 96.4%. 1 H NMR (600MHz, CDCl3) δ10.637(s,1H),8.923(s,1H),6.909-6.928(m,1H),6.300-6.321(m,1H),5.38 3(s,1H),4.349(q,J=6.6Hz,2H),3.708-3.722(m,2H),3.584-3.596(m,2H),1.401(t,J=6.6Hz,3H); 13 C NMR (150 MHz, CDCl3) δ 169.81, 169.25, 165.82, 164.05, 157.74, 151.56, 104.78, 102.76, 99.41 (d, J = 21 Hz), 99.17, 60.95, 47.47, 46.83, 14.47; HR-MS (ESI) calculated value C 14 H 15 FN3O2[M+H] + :276.0974, measured value 276.0973.

[0690] Intermediate Preparation Example 57: Preparation of ethyl 5-methoxy-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate (M-57)

[0691]

[0692] The synthesis method was the same as that of Preparation Example 48 to obtain ethyl 5-methoxy-7,7a,8,9,10,11,11a,12-octahydrobenzo[2,3][1,4]diaza[5,6,7-de]quinoline-1-carboxylate in a yield of 95.4%. 1H NMR (600MHz, CDCl3) δ10.333(s,1H),8.825(s,1H),6.827-6.830(m,1H),6.209-6.212(m,1H),4.782(s,1H),4.321(q,J=7.2Hz,2H),3.81 6(s,3H),3.294-3.335(m,1H),3.287-3.127(m,1H),2.211-2.234(m, 1H),2.139-2.160(m,1H),1.821-1.836(m,2H),1.315-1.528(m,7H); 13 C NMR (150 MHz, CDCl3) δ 168.69, 163.32, 156.43, 149.30, 149.02, 102.72, 100.86, 98.63, 97.86, 61.10, 61.05, 58.72, 55.68, 32.70, 32.40, 29.83, 23.82, 23.73, 14.46; HR-MS (ESI) calculated value C 19 H 24 N3O3[M+H] + :342.2013, measured value 342.2011.

[0693] Intermediate Preparation Example 58: Preparation of ethyl 9-methoxy-4,5,6,7-tetrahydro-[1,4]diaza[5,6,7-de]quinoline-3-carboxylate (M-58)

[0694]

[0695] The synthesis method was the same as that of Preparation Example 48 to obtain 9-methoxy-4,5,6,7-tetrahydro-[1,4]diaza[5,6,7-de]quinoline-3-carboxylic acid ethyl ester in a yield of 97.1%. 1 H NMR(600MHz,DMSO-d6)δ10.219(s,1H),8.664(s,1H),7.182(s,1H),6.487-6.492(m,1H),6.261-6.265(m,1 H),4.461(q,J=7.2Hz,2H),3.771(s,3H),3.610-3.627(m,2H),3.374-3.390(m,2H),1.314(t,J=7.2Hz,3H); 13C NMR (150 MHz, DMSO-d6) δ 168.38, 161.84, 156.80, 154.00, 151.06, 150.82, 101.75, 99.14, 98.06, 97.11, 59.93, 54.97, 47.07, 45.79, 14.31; HR-MS (ESI) calculated value C 15 H 18 N3O3[M+H] + :288.0876, measured value 276.0878.

[0696] [Example]

[0697] Example 1: (S)-6-Fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-1)

[0698]

[0699] Step 1: Synthesis of (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0700] To a 100 mL reaction flask, 1,4-dioxane (15 mL), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (0.62 g, 1.76 mmol), 6-fluoropyridine-3-boronic acid (0.315 g, 2.11 mmol), potassium carbonate (0.607 g, 4.4 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.203 g, 0.18 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 2.5 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 60:1) to obtain (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.43 g, yield 66.3%). ESI-MS (m / z): 369.11 [M+H] + ; 1H NMR(600MHz,CD3OD)δ:1.541(d,3H),3.632(s,3H),4.525-4.660(m,2H),4.707-4.739 (m,1H),7.213-7.231(m,1H),7.565(d,1H),8.105(t,1H),8.343(s,1H),8.837(s,1H).

[0701] Step 2: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0702] In a 100 mL reaction flask, THF (4 mL) and 1-piperidinepropanol (115 mg, 0.8 mmol) were added in sequence. The temperature was lowered to 0°C and NaH (56 mg, 1.4 mmol) was added. The reaction was carried out at this temperature for 0.5 h. Then, (S)-6-fluoro-7-(6-fluoropyridin-3-yl)-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (147 mg, 0.4 mmol) was added and the reaction was carried out at room temperature overnight. The reaction was monitored by TLC for completion. The reaction solution was quenched with water and then concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 15:1) to obtain (S)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, 32% yield). ESI-MS (m / z): 492.23 [M+H]. + ; 1 H NMR(600MHz,CD3OD)δ:1.495-1.533(m,5H),1.620-1.657(m,4H),2.027-2.053(m,2H),2.507-2.577(m,6H),3.610(s,3H),4.373(t,J=6.0Hz,2H) ,4.467-4.612(m,2H),4.630-4.701(m,1H),6.899(d,J=8.4Hz,1H),7.48 0(d,J=10.8Hz,1H),7.794(d,J=8.4Hz,1H),8.209(s,1H),8.767(s,1H).

[0703] Example 2: (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-2)

[0704]

[0705] The synthesis method was the same as in Example 1, except that 3-dimethylaminopropanol was used instead of 1-piperidinylpropanol to obtain (S)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, 32.0% yield). ESI-MS (m / z): 452.20 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:1.526(d,J=7.2Hz,3H),2.040-2.066(m,2H),2.390(s,6H),2.662(t,J=7.8Hz,2H),3.610(s,3H),4.398(t,J=6.0Hz,2H), 4.467-4.632(m,2H),4.689-4.702(m,1H),6.912(d,J=8.4Hz,1H),7.47 6(d,J=11.4Hz,1H),7.800(d,J=9.0Hz,1H),8.215(s,1H),8.765(s,1H).

[0706] Example 3: (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-3)

[0707]

[0708] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, yield 27.1%). ESI-MS (m / z): 452.20 [M+H] + ; 1H NMR(600MHz,CD3OD)δ:1.536(d,J=7.2Hz,3H),2.001-2.048(m,2H),2.310(s,6H),2.565(t,J=7.8Hz,2H),3.620(s,3H),4.388(t,J=6.0Hz,2H) ,4.484-4.641(m,2H),4.698-4.712(m,1H),6.915(d,J=9.0Hz,1H),7.5 09(d,J=11.4Hz,1H),7.803-7.818(m,1H),8.226(s,1H),8.792(s,1H).

[0709] Example 4: (R)-6-Fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-4)

[0710]

[0711] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, 32% yield). ESI-MS (m / z): 492.20 [M+H] + ; 1 H NMR(600MHz, CDCl3)δ:1.577-1.588(m,4H),1.590-2.100(m,6H),2.211-3.199(m,7H),3.629(s,3H),4.366-4.388(m,1H),4.465(t,J=6.0Hz,2H ),4.582-4.608(m,1H),4.735-4.749(m,1H),6.848(d,J=8.4Hz,1H),7. 607(d,J=10.8Hz,1H),7.732-7.746(m,1H),8.291(s,1H),8.691(s,1H).

[0712] Example 5: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-5)

[0713]

[0714] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-9-(4-fluorophenyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (15 mg, yield 13.0%). ESI-MS (m / z): 532.21 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.230-1.236(m,2H),1.937(t,J=6.6Hz,2H),2.349(s,6H),2.610-2.618(m,2H),3.533(s,3H),4.220-4.242(m,1H) ,4.315(t,J=6.0Hz,2H),6.864(d,J=8.4Hz,1H),6.871-7.180(m,3H), 7.501-7.522(m,2H),7.800-7.814(m,1H),8.234(s,1H),8.788(s,1H).

[0715] Example 6: 6-Fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-6)

[0716]

[0717] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (70 mg, yield 33.2%). ESI-MS (m / z): 506.25 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:1.383(s,2H),1.482-1.518(m,4H),1.639(s,6H),1.883-1.928(m,2H),2.348-2.405(m,4H),2.498-2.510(m,2H),3.50 3(s,3H),4.335(t,J=6.6Hz,2H),4.441(s,2H),6.937-6.952(m,1H),7. 560(d,J=10.8Hz,1H),7.824-7.844(m,1H),8.276(s,1H),8.899(s,1H).

[0718] Example 7: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-7)

[0719]

[0720] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (63 mg, yield 32.0%). ESI-MS (m / z): 555.2 [M+H] + ; 1 H NMR(600MHz,DMSO)δ:1.439(brs,2H),1.382-1.579(m,4H),1.970-1.997(m,2H),2.487-2.500(m,2H),2.520-2. 750(m,4H),3.581(s,3H),4.228-4.239(m,1H),4.332(d,J=6.6Hz,2H),4.887(d,J=13.8Hz,1H),5.858(d,J=9.6 Hz,1H),6.855(d,J=9.0Hz,1H),7.177(d,J=8.4Hz,1H),7.370-7.391(m,1H),7.663(d,J=10.8Hz,1H),7.733(d, J=7.2Hz,1H),7.711-7.752(m,1H),7.818(d,J=8.4Hz,1H),8.242(s,1H),8.600(d,J=4.2Hz,1H),8.963(s,1H).

[0721] Example 8: (R)-6-Fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-8)

[0722]

[0723] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (53 mg, yield 45.3%). ESI-MS (m / z): 534.28 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:0.980(s,3H),1.239(s,3H),1.395(s,2H),1.515(s,4H),1.567-1. 616(m,1H),1.695-1.762(m,2H),1.921(s,2H),2.287-2.492(m,6H),3.550(s,3H),4.344(t, J=6.6Hz,2H),4.516(d,J=13.2Hz,1H),4.595-4.701(m,1H),4.722(d,J=3.0Hz,1H),6.948(d ,J=8.4Hz,1H),7.594(d,J=10.8Hz,1H),7.837(d,J=8.4Hz,1H),8.278(s,1H),8.913(s,1H).

[0724] Example 9: (S)-6-Fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-9)

[0725]

[0726] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-6-fluoro-10-isobutyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, yield 46.0%). ESI-MS (m / z): 534.28 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 0.920-0.930 (d, J=6.0Hz, 3H), 0.970-0.980 (d, J=6.0Hz, 3H), 1.400-1.402 (m, 2H), 1.51 8-1.600(m,6H),1.706-1.741(m,1H),1.918-1.924(m,2H),2.345-2.392(m,6H),3.550(s,3H),4.334-4.356(t,J= 6.6Hz, J=6.6Hz, 2H), 4.505-4.527 (d, J=13.2Hz, 1H), 4.606-4.615 (d, J=5.4Hz, 1H), 4.697-4.724 (m, 1H), 6.941-6 .956(d,J=9.0Hz,1H),7.586-7.604(d,J=10.8Hz,1H),7.830-7.845(d,J=9.0Hz,1H),8.279(s,1H),8.914(s,1H).

[0727] Example 10: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-10)

[0728]

[0729] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (90 mg, yield 45.2%). ESI-MS (m / z): 494.12 [M+H] + ; 1H NMR(600MHz, DMSO-d6)δ:1.424-1.425(m,3H),1.560-1.562(m,5H),1.910-1.980(m,2H),2.420-2.421(m,2H),2.631-2.632(m,2H),3.350-3.3 53(m,2H),3.565(s,3H),4.297-4.366(m,4H),6.952-6.966(d,J=8.4Hz ,1H),7.719-7.774(m,2H),8.126-8.130(d,J=8.4Hz,1H),8.996(s,1H).

[0730] Example 11: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropane]-1-one (A-11)

[0731]

[0732] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1-cyclopropane]-1-one (50 mg, yield 21.2%). ESI-MS (m / z): 504.23 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.062-1.064(m,2H),1.425-1.557(m,2H),1.557-1.574(m,4H),1.915-2.207(m,4H),2.508-2.587(m ,5H),3.90-3.475(m,4H),4.33-4.354(t,J=6.6Hz,2H),4.464(s,2H),6.939(d,J=8.4Hz,1H),7.594(d,J=10.8Hz,1H),7.812(m 1H),8.254(s,1H),8.896(s,1H).

[0733] Example 12: 9-(Ethoxymethyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxy-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-12)

[0734]

[0735] The synthesis method was the same as in Example 1 except that the starting materials were changed to obtain (9-(ethoxymethyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (86 mg, yield 51.0%). ESI-MS (m / z): 536.26 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:1.110-1.134(m,3H),1.594(s,2H),1.744-1.762(m,4H) ,2.145-1.172(m,2H),2.870-2.918(m,6H),3.423-3.489(m,2H),3.612-3.720( m,5H),3.987-4.026(m,1H),4.419-4.439(m,2H),4.545(d,J=13.8Hz,1H),4.65 7(d,J=9.6Hz,1H),6.921(d,J=8.4Hz,1H),7.513(d,J=10.8Hz,1H),7.884(dd,J 1＝ 1.2Hz, J2=8.4Hz, 1H), 8.285 (s, 1H), 8.788 (s, 1H).

[0736] Example 13: (S)-10-Benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxy-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-13)

[0737]

[0738] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, yield 20.2%). ESI-MS (m / z): 568.26 [M+H] + ; 1H NMR(600MHz, DMSO-d6)δ:1.463-1.624(m,6H),2.055-2.103(m,2H),2.69 5-2.713(m,4H),3.104-3.190(m,4H),3.569(s,3H),4.297-4.440(m,4H) ,4.692-4.714(m,1H),6.985(d,J=8.4Hz,1H),7.246-7.349(m,5H),7.62 6(d,J=11.4Hz,1H),7.928(d,J=8.4Hz,1H),8.343(s,1H),8.952(s,1H).

[0739] Example 14: (R)-10-Benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-14)

[0740]

[0741] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-10-benzyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (53 mg, yield 41.5%). ESI-MS (m / z): 568.26 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.463-1.624(m,6H),2.055-2.103(m,2H),2.695-2. 713(m,4H),3.104-3.190(m,4H),3.569(s,3H),4.297-4.440(m,4H),4.692-4. 714(m,1H),6.976-6.990(d,J=8.4Hz,1H),7.246-7.349(m,5H),7.616-7.635 (d, J = 11.4Hz, 1H), 7.921-7.935 (d, J = 8.4Hz, 1H), 8.343 (s, 1H), 8.952 (s, 1H).

[0742] Example 15: 7-(6-(3-Dimethylamino-propyloxy)-pyridin-3-yl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-15)

[0743]

[0744] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 7-(6-(3-dimethylamino-propyloxy)-pyridin-3-yl)-6-fluoro-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (15 mg, yield 48.2%). ESI-MS (m / z): 438.42 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:2.076-2.102(m,2H),2.467(s,6H),2.747-2.773(m,2H),3.624(s,3H),4.325-4.330(m,2H),4.407-4.427( m,2H),4.608-4.620(m,2H),6.939(d,J=8.4Hz,1H),7.534(d,J=16.8Hz,1H),7.832(d,J=14.4Hz,1H),8.236(s,1H),8.807(s,1H).

[0745] Example 16: (S)-6-Fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-16)

[0746]

[0747] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 24% yield). ESI-MS (m / z): 520.26 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:0.933(d,J=7.2Hz,3H),1.013(d,J=6.6Hz,3H),1.400-1.5 37(m,6H),1.922-1.954(m,2H),2.221-2.258(m,1H),2.433-2.514(m,6H),3.558(s, 3H),4.282-4.351(m,3H),4.445-4.468(m,1H),4.828-4.856(m,1H),6.935(d,J=8. 4Hz, 1H), 7.566 (d, J = 10.8Hz, 1H), 7.828-7.813 (m, 1H), 8.260 (s, 1H), 8.909 (s, 1H).

[0748] Example 17: (R)-6-Fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-17)

[0749]

[0750] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-6-fluoro-10-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (45 mg, 24% yield). ESI-MS (m / z): 520.26 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:0.947(d,J=6.6Hz,3H),1.022(d,J=6.6Hz,3H),1.415-1.5 44(m,6H),1.933-1.963(m,2H),2.240-2.261(m,1H),2.449-2.529(m,6H),3.560(s, 3H),4.296-4.365(m,3H),4.459-4.482(m,1H),4.839-4.867(m,1H),6.949(d,J=8. 4Hz, 1H), 7.579 (d, J = 10.8Hz, 1H), 7.840-7.825 (m, 1H), 8.271 (s, 1H), 8.920 (s, 1H).

[0751] Example 18: 6-Fluoro-9-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-18)

[0752]

[0753] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-9-isopropyl-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (58 mg, 44.3% yield). ESI-MS (m / z): 519.26 [M+H] + ; 1 H NMR(600MHz,DMSO)δ:0.635(d,J=7.2Hz,3H),0.798(d,J=6.6Hz,3H),1.305-1.892 (m,6H),1.909-1.962(m,1H),2.012-2.198(m,2H),2.753-2.965(m,2H),3.137-3.3 26(m,4H),3.547(s,3H),3.994-4.032(m,1H),4.290-4.378(m,4H),6.961(d,J=8.4 Hz, 1H), 7.590 (d, J = 10.8Hz, 1H), 7.852-7.840 (m, 1H), 8.267 (s, 1H), 8.921 (s, 1H).

[0754] Example 19: (S)-9-((dimethylamino)methyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-19)

[0755]

[0756] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-9-((dimethylamino)methyl)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (100 mg, yield 55.0%). ESI-MS (m / z): 535.28 [M+H] +; 1 H NMR(600MHz,DMSO-d6)δ:1.600(s,2H),1.746-1.763(m,4H),2.149-2.193(m, 8H),2.650-2.671(m,2H),2.813-2.864(m,6H),3.648(s,3H),4.016-4.055(q ,1H),4.448(t,J=6.0Hz,2H),4.660(d,J=13.2Hz,2H),6.960(d,J=9.0Hz,1H) ,7.550(d,J=10.8Hz,1H),7.797(d,J=8.4Hz,1H),8.290(s,1H),8.833(s,1H).

[0757] Example 20: (S)-6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-20)

[0758]

[0759] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9-(piperidin-1-ylmethyl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (150 mg, yield 29.6%). ESI-MS (m / z): 575.31 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.396(s,2H),1.478-1.515(m,4H),1.550(s,2H),1.678- 1.716(m,4H),2.092-2.119(m,2H),2.329(s,4H),2.607-2.700(m,8H),3.627(s,3H ),3.973-4.013(m,1H),4.415-4.587(m,2H),4.611-4.915(m,2H),6.942(d,J=9.0 Hz, 1H), 7.521 (d, J = 10.8Hz, 1H), 7.902-7.921 (m, 1H), 8.318 (s, 1H), 8.785 (s, 1H).

[0760] Example 21: 4-Fluoro-12-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[GH]pyroxene-11(12H)-one (A-21)

[0761]

[0762] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 4-fluoro-12-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one (200 mg, 38.5% yield). ESI-MS (m / z): 532.26 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.635-1.693(m,4H),1.788-1.830(m,7H),2.120(d,J =12.0Hz,1H),2.179-2.225(m,2H),2.954-2.999(m,7H),3.593(s,3H),3.691(d ,J=13.2Hz,1H),4.305-4.339(m,2H),4.456-4.476(m,2H),6.961(d,J=8.4Hz, 1H), 7.517 (d, J = 10.8Hz, 1H), 7.852-7.869 (m, 1H), 8.271 (s, 1H), 8.794 (s, 1H).

[0763] Example 22: (R)-10-Ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-22)

[0764]

[0765] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (150 mg, yield 14.3%). ESI-MS (m / z): 506.25 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:1.099-1.111(m,3H),1.560(s,2H),1.693-1.730(m,4H) ,1.942-1.979(m,2H),2.091-2.138(m,2H),2.682-2.749(m,6H),3.640(s,3H),4. 410-4.460(m,3H),4.510-4.525(m,1H),4.815-4.842(m,1H),6.938(d,J=8.4Hz, 1H), 7.505 (d, J = 10.8Hz, 1H), 7.825 (d, J = 8.4Hz, 1H), 8.238 (s, 1H), 8.802 (s, 1H).

[0766] Example 23: (S)-10-Ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-23)

[0767]

[0768] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-10-ethyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (180 mg, yield 42.6%). ESI-MS (m / z): 506.25 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.099-1.111(m,3H),1.533(s,2H),1.663-1.701(m,4H),1.93 2-1.969(m,2H),2.065-2.112(m,2H),2.643-2.712(m,6H),3.625(s,3H),4.390-4.441 (m,2H),4.442(d,J=13.2Hz,1H),4.484-4.512(m,1H),4.798-4.825(m,1H),6.922(d,J =8.4Hz,1H),7.512(d,J=10.8Hz,1H),7.807-7.824(m,1H),8.229(s,1H),8.802(s,1H).

[0769] Example 24: 6-Fluoro-2,9-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-24)

[0770]

[0771] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2,9-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, yield 33.2%). ESI-MS (m / z): 491.23 [M+H] + ; 1 H NMR (600MHz, CD3OD) δ: 1.448 (d, J = 5.4Hz, 3H), 1.537 (m, 2H), 1.663-1.701 (m, 4H), 2.067-2.114 (m, 2H), 2.579-2.654 (m, 6H), 3.620 (s, 3H) ,3.932-3.971(m,1H),4.405-4.432(m,3H),4.677-4.702(m,1H),6.942(d,J=8.4Hz,1H),7.504(d,J=10.8Hz,1H),7.831-7.849(m,1H),8. 245(s,1H),8.777(s,1H),1.448(d,3H),1.537(m,2H),1.663-1.701( m,4H),2.067-2.114(m,2H),2.579-2.654(m,6H),3.620(s,3H),3.93 2-3.971(m,1H),4.405-4.432(m,3H),4.677-4.702(m,1H),6.942(d, 1H),7.504(d,1H),7.831-7.849(m,1H),8.245(s,1H),8.777(s,1H).

[0772] Example 25: 6-Fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-25)

[0773]

[0774] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-9-(2-fluoropyridin-4-yl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (85 mg, yield 26.8%). ESI-MS (m / z): 573.23 [M+H] + ; 1 H NMR(600MHz,MeOD)δ1.530-1.687(m,6H),2.025-2.089(m,2H),2.649-2.675(m,6H) ,3.645(s,3H),4.187-4.227(m,1H),4.365(t,J=6.6Hz,2H),4.646-4.669(m,1H),5 .808-5.824(m,1H),6.781(d,J=7.8Hz,1H),6.974(s,1H),7.305(d,J=4.8Hz,1H),7 .597(d,J=10.8Hz,1H),7.751(d,J=8.4Hz,1H),8.161-8.199(m,2H),8.860(s,1H).

[0775] Example 26: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-26)

[0776]

[0777] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 19% yield). ESI-MS (m / z): 478.22 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:1.356-1.450(m,2H),1.514-1.532(m,4H),1.916-1. 939(m,2H),2.406-2.461(m,6H),3.540(s,3H),4.204-4.212(m,2H),4.331-4 .353(t,J=6.6Hz,2H),4.607-4.619(t,J=3.6Hz,2H),6.943(d,J=8.4Hz,1H), 7.585(d,J=10.8Hz,1H), 7.821(d,J=8.4Hz,1H), 8.257(s,1H), 8.903(s,1H).

[0778] Example 27: 10-Cyclopropyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-27)

[0779]

[0780] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 10-cyclopropyl-6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (40 mg, yield 39.0%). ESI-MS (m / z): 518.25 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ0.495-0.535(m,3H),0.863-0.901(m,1H),1.281-1.358(m,1H),1.388-1.4 90(m,2H),1.501-1.592(m,4H),1.901-1.992(m,2H),2.385-2.502(m,6H),3.550(s,3H),3.924-3.9 43(m,1H),4.336-4.358(t,J=6.6Hz,2H),4.535-4.557(d,J=13.2Hz,1H),4.698-4.725(m,1H),6.9 45-6.960(m,1H),7.586-7.605(d,J=11.4Hz,1H),7.838-7.854(m,1H),8.285(s,1H),8.913(s,1H).

[0781] Example 28: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one (A-28)

[0782]

[0783] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one (70 mg, yield 44.2%). ESI-MS (m / z): 518.25 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.410-1.541(m,8H),1.910-1.964(m,6H),2.466-2.508(m,6H),3.524(s,3H),4.344-4.365(t,J=6.6Hz,2H),4 .647(m,2H),6.953-6.967(d,J=8.4Hz,1H),7.577-7.595(d,J=10.8Hz,1H),7.839-7.853(d,J=8.4Hz,1H),8.286(s,1H),8.900(s,1H).

[0784] Example 29: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclopropane]-1-one (A-29)

[0785]

[0786] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclopropane]-1-one (47 mg, yield 39.1%). ESI-MS (m / z): 464.20 [M+H] + ; 1H NMR(600MHz, DMSO-d6)δ:1.058-1.061(m,2H),1.962-2.194(m,4H),2.383(s,6H),2.660-2.663(m,2H),3.478(s,3H),4.338-4.359(t,J=6.6Hz ,2H),4.468(m,2H),6.927-6.941(d,J=8.4Hz,1H),7.599-7.618(d,J=1 1.4Hz, 1H), 7.817-7.832 (d, J = 9.0Hz, 1H), 8.256 (s, 1H), 8.916 (s, 1H).

[0787] Example 30: 6-Methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-30)

[0788]

[0789] In a 100 mL reaction bottle, 7-bromo-6-methoxy-2-methyl-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (200 mg, 0.47 mmol), cesium carbonate (382 mg, 1.17 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (90 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.05 mmol) and 20 mL of dioxane were added in sequence under N2 protection. The reaction solution was heated to 120 ° C for 4 h. The reaction mixture was cooled to room temperature, concentrated to dryness, and purified by column chromatography (DCM:MeOH = 40:1-30:1) to obtain 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (80 mg, 40.1% yield). ESI-MS (m / z): 429.16 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:3.525(s,3H),3.943-3.967(m,6H),4.867-4.916(m,2H),5.206(m,1H),7.039(s,1H),7.233-7.2 55(m,1H),7.533(d,J=8.4Hz,1H),7.755-7.783(m,1H),8.234(s,1H),8.274(d,J=3.6Hz,1H),8.372(s,1H),8.669(s,1H).

[0790] Example 31: (S)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-31)

[0791]

[0792] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (S)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, yield 33.2%). ESI-MS (m / z): 504.25 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:1.543(d,J=6.6Hz,3H),1.573-1.626(m,2H),1.781(m, 4H),2.170-2.196(m,2H),2.945(brs,6H),3.637(s,3H),3.925(s,3H),4.436 (t,J=6.0Hz,2H),4.465-4.571(m,2H),4.685-4.699(m,1H),6.916(d,J=9.0H z,1H),7.308(s,1H),7.749-7.767(m,1H),8.152-8.156(m,1H),8.743(s,1H).

[0793] Example 32: (R)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-32)

[0794]

[0795] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (R)-6-methoxy-2,10-dimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (68 mg, yield 33.2%). ESI-MS (m / z): 504.25 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:1.509(d,J=6.6Hz,3H),1.597(brs,2H),1.739-1.776(m ,4H),2.134-2.181(m,2H),2.881-2.938(m,6H),3.604(s,3H),3.893(s,3H),4 .407(t,J=6.0Hz,2H),4.426-4.538(m,2H),4.651-4.665(m,1H),6.878-6.893 (m,1H),7.268(s,1H),7.717-7.735(m,1H),8.119-8.123(m,1H),8.703(s,1H).

[0796] Example 33: 4-Methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (A-33)

[0797]

[0798] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one (120 mg, yield 31.5%). ESI-MS (m / z): 400.41 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.585(s,3H),3.970-3.998(m,6H),7.192-7.208(m,1H),7.271-7.29 9(m,1H),7.316-7.344(m,2H),8.005(s,1H),8.251(s,1H),8.414-8.431(m,1H),8.866(s,1H).

[0799] Example 34: (S)-9-(Dimethylamino)methyl)-6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-34)

[0800]

[0801] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain (S)-9-(dimethylamino)methyl)-6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, 50% yield). ESI-MS (m / z): 397.17 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:2.235(s,6H),2.729-2.801(m,2H),3.533(s,3H),3.935(s,4H),4.523-4.546(m, 1H), 4.779-4.787 (m, 1H), 7.555 (d, J = 13.2Hz, 1H), 7.996 (d, J = 2.4Hz, 1H), 8.488 (s, 1H), 8.851 (s, 1H).

[0802] Example 35: 6-Fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-35)

[0803]

[0804] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.15 g, 50% yield). ESI-MS (m / z): 356.23 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.362(t,J=4.8Hz,2H),3.561(s,3H),3.954(s,3H),4.347( t,J=4.8Hz,2H),7.589(s,1H),7.708(d,J=10.2Hz,1H),7.948(s,1H),8.952(s,1H).

[0805] Example 36: 6-Fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8-oxide (A-36)

[0806]

[0807] Dissolve 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (0.05 g, 0.14 mmol) in 20 mL of dichloromethane. Add m-chloroperbenzoic acid (0.03 g, 0.17 mmol) under ice-cooling. Stir the mixture under ice-cooling for 1 hour. A small amount of starting material remains, as monitored by TLC. The reaction solution was washed with a saturated aqueous sodium thiosulfate solution (10 mL × 2), then with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The product was separated and purified by column chromatography (DCM:MeOH = 50:1-25:1) to give the final product, 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one 8-oxide (0.04 g, yield 77%). ESI-MS (m / z): 372.23 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.651(m,3H),3.842-3.793(m,1H),3.994(s,3H),4.053-4.022(m,1H),4.541- 4.530(m,1H),4.567-4.552(m,1H),7.751(s,1H),8.104(d,J=10.8Hz,1H),8.153(s,1H),9.048(s,1H).

[0808] Example 37: 6-Fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one 8,8-dioxide (A-37)

[0809]

[0810] Dissolve 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (0.05 g, 0.14 mmol) in 20 mL of dichloromethane. Add m-chloroperbenzoic acid (0.05 g, 0.28 mmol) under ice-cooling. Stir the mixture at room temperature for 24 h. TLC monitoring revealed no residual starting material. The reaction solution was washed with a saturated aqueous sodium thiosulfate solution (10 mL × 2), then with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The product was separated and purified by column chromatography (DCM:MeOH = 50:1-30:1) to obtain 6-fluoro-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-thia-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one 8,8-dioxide (0.015 g, yield 27.3%). ESI-MS (m / z): 388.34 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 3.590 (s, 3H), 3.941 (s, 3H), 4.202 (t, J = 4.8Hz, 2H), 4.423 ( t,J=4.8Hz,2H),7.634(s,1H),7.974(s,1H),8.193(d,J=10.2Hz,1H),9.112(s,1H).

[0811] Example 38: (6aR, 10aS)-4-fluoro-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylic acid ethyl ester (A-38)

[0812]

[0813] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain (6aR,10aS)-4-fluoro-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6a,7,10,10a,11,12-hexahydro-6-oxa-2,8,10b,12-tetraazacyclopentadiene-8(9H)-carboxylic acid ethyl ester (0.10 g, yield 59%). ESI-MS (m / z): 467.2 [M+H] + .

[0814] Example 39: 6-Fluoro-10-(4-fluorophenyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-39)

[0815]

[0816] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 6-fluoro-10-(4-fluorophenyl)-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.05 g, 50% yield). ESI-MS (m / z): 434.2 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:3.561(s,3H),3.882(s,3H),4.833(d,J=13.2Hz,1H),5.134(d,J=13.2Hz,1H),5.820(s,1 H),7.171-7.141(m,2H),7.282-7.262(m,2H),7.603(d,J=12.6Hz,1H),7.774(s,1H),8.070(s,1H),8.941(s,1H).

[0817] Example 40: 4-Methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pyroxene-11(12H)-one (A-40)

[0818]

[0819] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,9,10b,12-tetraazacyclopenta[gh]pyroxene-11(12H)-one (12 mg, 30% yield). ESI-MS (m / z): 401.11 [M+H] + ; 1H NMR (600MHz, CD3OD) δ: 3.597 (s, 3H), 3.973 (s, 3H), 4.001 (s, 3H), 7.261 (d, J = 5.4Hz, 1H), 7. 399(s,1H),7.953(s,1H),8.230(s,1H),8.455(d,J=5.4Hz,1H),8.923(s,1H),9.714(s,1H).

[0820] Example 41: (6aS,9aR)-4-Fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopentadienyl[h]naphtho[2,1,8-cde]azulene-10(11H)-one (A-41)

[0821]

[0822] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (6aS,9aR)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulene-10(11H)-one (40 mg, 33.6%). ESI-MS (m / z): 520.19 [M+H] + ; 1 HNMR(600MHz,DMSO-d6)δ:1.590(s,2H),1.749(t,J=10.8Hz,4H),2.136-2.172(m,2H),2.855-2.91 3(m,6H),3.563(s,3H),3.791(t,J=16.8Hz,1H),4.144(t,J=19.8Hz,1H),4.209(t,J=16.8Hz,1H),4 .420(t,J=12.0Hz,2H),4.628-4.671(m,1H),4.879(s,1H),5.194(dd,J1=8.4Hz,J2=16.2Hz,1H),6 .915(d,J=8.4Hz,1H),7.545(d,J=10.8Hz,1H),7.804(d,J=7.8Hz,1H),8.210(s,1H),8.791(s,1H).

[0823] Example 42: (6aR,9aS)-4-Fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulene-10(11H)-one (A-42)

[0824]

[0825] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain (6aR,9aS)-4-fluoro-11-methyl-5-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-6a,7,9,9a-tetrahydro-6,8-dioxa-2,9b,11-triazacyclopenta[h]naphtho[2,1,8-cde]azulene-10(11H)-one. ESI-MS (m / z): 520.23 [M+H]. + ; 1 H NMR(600MHz,CD3OD)δ:1.550(brs,2H),1.674-1.711(m,4H),2.071-2.118(m,2H),2.679-2.74 3(m,6H),3.581(s,3H),3.807(t,J=8.4Hz,1H),4.148-4.180(m,1H),4.218(t,J=8.4Hz,1H),4. 397(t,J=6.0Hz,2H),4.678-4.722(m,1H),4.910-4.937(m,1H),5.230(q,J=8.4Hz,1H),6.908 (d, J=8.4Hz, 1H), 7.572 (d, J=13.2Hz, 1H), 7.801 (d, J=8.4Hz, 1H), 8.206 (s, 1H), 8.824 (s, 1H).

[0826] Example 43: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3'-oxetan-1-one (A-43)

[0827]

[0828] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,3'-oxetan-1-one (74 mg, 40.4% yield). ESI-MS (m / z): 520.23 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.380-1.405(m,2H),1.500-1.589(m,4H),1.947-1.956(m,2 H),2.465-2.737(m,6H),3.557(s,3H),4.348-4.370(t,J=6.6Hz,2H),4.348-4.500(m ,2H),4.875-4.960(m,2H),5.424-5.592(m,2H),6.958-6.972(d,J=8.4Hz,1H),7.621 -7.639(d,J=10.8Hz,1H),7.860-7.874(d,J=8.4Hz,1H),8.298(s,1H),8.952(s,1H).

[0829] Example 44: 6-Methoxy-10-hydroxymethyl-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-44)

[0830]

[0831] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 6-methoxy-10-hydroxymethyl-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (180 mg, yield 90.2%). ESI-MS (m / z): 370.1 [M+H] + ; 1H NMR(600MHz,DMSO)δ:3.332(s,3H),3.718-3.740(m,2H),3.916(s,3H),3.945(s,3H),4.373-4.415(m,1 H),4.993-5.019(m,1H),5.326-5.345(m,1H),7.229(s,1H),7.924(s,1H),8.125(s,1H),8.729(s,1H).

[0832] Example 45: 6-Methoxy-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-45)

[0833]

[0834] In a 100 mL reaction flask, DMF (10 mL) and methanol (8 mg, 0.24 mmol) were added in sequence. The temperature was lowered to 0°C and NaH (60%, 15 mg, 0.36 mmol) was added. The reaction was carried out at this temperature for 0.5 h. Then, 6-fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (60 mg, 0.12 mmol) was added and the reaction was carried out at 65°C for 24 h. The reaction was monitored by TLC for completion. The reaction solution was quenched with water and then concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1-15:1) to obtain 6-methoxy-2,10,10-trimethyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (36 mg, yield 58.2%). ESI-MS (m / z): 518.27 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:1.370-1.405(m,2H),1.490-1.520(m,4H),1.609(s,6H),1.862-1.910(m,2H),2.356-2.410(m,6H),3.474(s,3 H),3.383(s,3H),4.300-4.339(m,4H),6.871(d,J=8.4Hz,1H),7.269(s,1H),7.688-7.706(m,1H),8.138(d,J=1.8Hz,1H),8.784(s,1H).

[0835] Example 46: 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-46)

[0836]

[0837] The synthesis method was the same as in Example 1, except that 3-dimethylaminopropanol was used instead of 1-piperidinylpropanol to obtain 7-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-6-fluoro-2,10,10-trimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (40 mg, 41.5% yield). ESI-MS (m / z): 466.22 [M+H] + ; 1 H NMR(600MHz, DMSO-d6)δ:1.639(s,6H),1.874-1.898(m,2H),2.156(s,6H),2.366(t,J=7.2Hz,2H),3.504(s,3H),4.340(t,J= 6.6Hz, 2H), 4.443 (s, 2H), 6.948 (d, J = 8.4Hz, 1H), 7.598 (d, J = 11.4Hz, 1H), 7.827-7.843 (m, 1H), 8.276 (s, 1H), 8.901 (s, 1H).

[0838] Example 47: 6-Fluoro-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclopropane]-1-one (A-47)

[0839]

[0840] The synthesis method was the same as in Example 45, except that the starting materials were changed, to obtain 6-methoxy-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclopropane]-1-one (25 mg, 49.2% yield). ESI-MS (m / z): 504.22 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:0.999-1.050(m,2H),1.130-1.283(m,2H),1.400- 1.596(m,2H),1.604-1.710(m,4H),2.067-2.174(m,4H),2.508-2.873(m,4 H),3.451(s,3H),3.836(s,3H),4.327-4.348(m,4H),6.860(d,J=8.4Hz,1H ),7.294(s,1H),7.680-7.697(m,1H),8.115(d,J=1.8Hz,1H),8.803(s,1H).

[0841] Example 48: 6-Fluoro-10-(hydroxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-48)

[0842]

[0843] The synthesis method was the same as in Example 1, except that the starting materials were changed, to obtain 6-fluoro-10-(hydroxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxyl-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.10 g, yield 48.3%). ESI-MS (m / z): 508.21 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:1.427-1.568(m,6H),1.984-1.985(m,2H),2.500-2.506(m,6H),3.5 47(s,3H),3.630-3.721(m,2H),4.350-4.371(t,J=6.6Hz,2H),4.438-4.444(m,1H),4.505-4. 527(m,1H),4.820-4.846(m,1H),5.268-5.287(t,J=11.4Hz,1H),6.947-6.962(d,J=9.0Hz,1H ),7.590-7.609(d,J=11.4Hz,1H),7.844-7.858(d,J=8.4Hz,1H),8.288(s,1H),8.918(s,1H).

[0844] Example 49: 6-Fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-49)

[0845]

[0846] Step 1: Synthesis of 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0847] In a 100 mL reaction bottle, THF (10 mL) and 7-bromo-6-fluoro-10-(hydroxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.10 g, 0.27 mmol) were added in sequence. After cooling to 0°C, NaH (0.03 g, 0.82 mmol) was added and the reaction was carried out at this temperature for 0.5 h. Then, iodomethane (0.08 g, 0.54 mmol) was added and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC for completion. The reaction solution was quenched with water and then concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 50:1-25:1) to obtain 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (30 mg, yield 29.4%). ESI-M (m / z): 381.95 [M+H] + .

[0848] Step 2: Synthesis of 6-fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0849] To a 100 mL reaction flask, 1,4-dioxane (15 mL), 7-bromo-6-fluoro-10-(methoxymethyl)-2-methyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (0.03 g, 0.08 mmol), (6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)boronic acid (0.03 g, 0.12 mmol), cesium carbonate (0.05 g, 0.16 mmol), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 2.5 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 50:1-10:1) to obtain 6-fluoro-10-(methoxymethyl)-2-methyl-7-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (0.16 g, yield 39.2%). ESI-MS (m / z): 522.15 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.400-1.528(m,6H),1.926-1.947(m,2H),2.434-2.497(m,6H), 3.307(s,3H),3.570(s,3H),3.578-3.713(m,2H),4.330-4.351(t,J=6.6Hz,2H),4.526-4 .548(m,1H),4.647-4.734(m,1H),4.752-4.757(m,1H),6.939-6.953(d,J=8.4Hz,1H),7. 593-7.612(d,J=11.4Hz,1H),7.826-7.840(d,J=8.4Hz,1H),8.272(s,1H),8.920(s,1H).

[0850] Example 50: 6-Methoxy-10-methoxymethyl-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-50)

[0851]

[0852] To a 50 mL reaction flask, anhydrous tetrahydrofuran (10 mL) and 10-hydroxymethyl-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (50 mg, 0.13 mmol) were added sequentially. Sodium hydride (25 mg, 0.65 mmol) was added under ice-cooling. After stirring under ice-cooling for 30 min, iodomethane (22 mg, 0.15 mmol) was added. The reaction was allowed to react at room temperature for 2 h under nitrogen protection. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 30:1) to obtain 6-methoxy-10-methoxymethyl-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (20 mg, yield 40.4%). ESI-MS (m / z): 396.16 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.336(s,3H),3.501(s,3H),3.608-3.633(m,1H),3.733-3.764(m,1H),3.915(s,3H),3.941(s,3H) ),4.409-4.431(m,1H),4.614-4.636(m,1H),4.904-4.926(m,1H),7.233(s,1H),7.780(s,1H),8.089(s,1H),8.734(s,1H).

[0853] Example 51: 6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-10-methylene-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-51)

[0854]

[0855] To a 50 mL reaction flask, anhydrous tetrahydrofuran (2 mL) and 10-hydroxymethyl-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (20 mg, 0.05 mmol) were added sequentially. DMF (1 mL) was then added, and sodium hydride (25 mg, 0.65 mmol) was added under ice-cooling. After stirring under ice-cooling for 30 min, p-toluenesulfonyl chloride (15 mg, 0.08 mmol) was added. The reaction was allowed to react at room temperature for 2 h under nitrogen protection. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 30:1) to obtain 6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-10-methylene-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (10 mg, yield 48.2%). ESI-MS (m / z): 364.13 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.352(s,3H),3.915(s,3H),3.962(s,3H),4.954(s,2H),5 .396(s,1H),6.182(s,1H),7.283(s,1H),7.925(s,1H),8.157(s,1H),8.835(s,1H).

[0856] Example 52: 10-((Dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-52)

[0857]

[0858] Step 1: Synthesis of 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one

[0859] In a 50 mL reaction bottle, anhydrous N,N-dimethylformamide (2 mL), 6-methoxy-10-hydroxymethyl-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (50 mg, 0.13 mmol), triphenylphosphine (138 mg, 0.524 mmol), and phthalamide (29 mg, 0.19 mmol) were added in sequence, and diisopropyl azodicarboxylate (106 mg, 0.524 mmol) was added under nitrogen protection, and the reaction was carried out at room temperature under nitrogen protection for 2 h. The reaction was monitored for completion by TLC. The reaction mixture was added with 50 mL of water and extracted four times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. The next step was carried out directly. Methanol (15 mL) and hydrazine hydrate (2 mL) were added, and the mixture was reacted at room temperature under nitrogen for 2 h. The reaction was monitored for completion by TLC. The methanol was removed under reduced pressure, extracted four times with 30 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 20:1) to obtain 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (29 mg, 58.1% yield). ESI-MS (m / z): 381.16 [M+H] + .

[0860] Step 2: Synthesis of 10-((dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0861] To a 50 mL reaction flask, anhydrous methanol (6 mL) was added, followed by 10-(aminomethyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (29 mg, 0.08 mmol), aqueous formaldehyde solution (2 mL), and acetic acid (10 μL). The mixture was stirred at room temperature for 30 min, followed by the addition of sodium triacetoxyborohydride (49 mg, 0.23 mmol). The reaction was allowed to proceed at room temperature for 12 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 15:1) to obtain 10-((dimethylamino)methyl)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrrol-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (7 mg, yield 27.3%). ESI-MS (m / z): 409.19 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 2.503 (s, 6H), 2.694-2.712 (d, J = 10.8Hz, 1H), 3.121 (s, 1H), 3.594 (s, 3H), 4.007 (s, 3H), 4.019 (s, 3H), 4.269-4.290 (d,J=12.6Hz,1H),4.646-4.659(d,J=7.8Hz,1H),5.166-5.187(d,J=12.6Hz,1H),7.265(s,1H),7.310(s,1H),8.102(s,1H),8.555(s,1H).

[0862] Example 53: 8-Fluoro-4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triaza[gh]pyroxene-11(12H)-one (A-53)

[0863]

[0864] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 8-fluoro-4-methoxy-12-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxa-2,10b,12-triaza[gh]pyroxene-11(12H)-one (200 mg, yield 66.6%). ESI-MS (m / z): 418.12 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ:3.577(s,3H),3.967-3.998(m,6H),6.934-6.943(m,1H),7 .253(s,1H),7.349(s,1H),7.972(s,1H),8.235(s,1H),8.475(s,1H),8.872(s,1H).

[0865] Example 54: 6-Methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-54)

[0866]

[0867] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain 6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-(pyridin-2-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (230 mg, yield 63.9%). ESI-MS (m / z); 429.16 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.523(s,3H),3.773(s,3H),3.937(s,3H),4.369-4.406(m,1H),4.674-4.698(m,1H),5.734 (d,J=9.0Hz,1H),7.259(s,1H),7.435-7.446(m,2H),7.662(s,1H),7.849-7.906(m,2H),8.653(s,1H),8.763(s,1H).

[0868] Example 55: (R)-6-Methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (A-55)

[0869]

[0870] The synthesis method was the same as in Example 30, except that the starting materials were changed, to obtain (R)-6-methoxy-2-methyl-7-(1-methyl-1H-pyrazol-4-yl)-10-phenyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (130 mg, yield 43.3%). ESI-MS (m / z); 428.16 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:3.522(s,3H),3.830(s,3H),3.939(s,3H),4.747-4.769(m,1H),5.008-5.034(m,1H),5.74 6(s,1H),7.174-7.187(m,2H),7.261-7.275(m,2H),7.296-7.321(m,2H),7.689(s,1H),7.945(s,1H),8.821(s,1H).

[0871] Example 56: (S)-6-Fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-56)

[0872]

[0873] Step 1: Synthesis of (6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)boronic acid

[0874] To a 50 mL reaction flask, acetonitrile (20 mL), 1-(but-3-yn-1-yl)piperidine (1.37 g, 10.0 mmol), 2-bromopyridine-5-boronic acid (2.01 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.40 g, 0.35 mmol), cuprous iodide (0.07 g, 0.35 mmol), and triethylamine (2 mL) were added sequentially. The mixture was reacted at room temperature under nitrogen for 6 h. The reaction was monitored by TLC. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography (DCM:MeOH = 30:1) to obtain (6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)boronic acid (1.26 g, 61.1% yield). ESI-MS (m / z): 259.15 [M+H] + .

[0875] Step 2: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0876] To a 50 mL reaction flask, 1,4-dioxane (10 mL), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (170 mg, 0.48 mmol), (6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)boronic acid, potassium carbonate (132 mg, 0.96 mmol), water (1 mL), and tetrakis(triphenylphosphine)palladium (55 mg, 0.048 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 3 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1-10:1) to obtain (S)-6-fluoro-2,10-dimethyl-7-(6-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (35 mg, 15% yield). ESI-MS (m / z): 486.22 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:1.532-1.543(m,6H),1.722(s,4H),2.775(s,2H),2.812-2.836(m,2H),2.931(s,2H),3.632(s,4H),4.531-4.553(m,1H), 4.639-4.661(m,1H),4.722-4.731(m,1H),7.569(d,J=11.4Hz,1H),7.6 30(d,J=8.4Hz,1H),7.981(d,J=7.8Hz,1H),8.622(s,1H),8.842(s,1H).

[0877] Example 57: 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (A-57)

[0878]

[0879] Step 1: Synthesis of 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadien[gh]azulen-11(12H)-one

[0880] In a 100 mL reaction flask, 1,4-dioxane (15 mL), 5-bromo-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyrolein-11(12H)-one (0.69 g, 1.76 mmol), 6-fluoropyridine-3-boronic acid (0.315 g, 2.23 mmol), potassium carbonate (0.607 g, 4.4 mmol), water (1.5 mL) and tetrakis(triphenylphosphine)palladium (0.203 g, 0.18 mmol) were added in sequence, and the temperature was raised to 90 ° C under nitrogen protection and the reaction was carried out for 2.5 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 60:1) to obtain 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadien[gh]azulene-11(12H)-one (0.35 g, yield 48.7%). ESI-MS (m / z): 409.31 [M+H] + .

[0881] Step 2: Synthesis of 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadien[gh]pyroxene-11(12H)-one (A-57)

[0882] In a 100 mL reaction bottle, 10 ml of DMSO, 3 ml of DIPEA, 170 mg of 4-fluoro-5-(6-fluoropyridin-3-yl)-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]azulen-11(12H)-one and 167 mg of N,N-dimethylpiperidin-4-amine hydrochloride were added in sequence. The temperature was raised to 150 ° C. and the reaction was carried out for 12 h. The reaction solution was cooled to room temperature and the reaction solution was washed with ethyl acetate and The reaction mixture was washed 2-3 times with saturated brine, and the organic phase was dried and concentrated to give a crude product, which was then purified by column chromatography (DCM:MeOH = 30:1 to 6:1) to give 5-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-4-fluoro-12-methyl-6a,7,8,9,10,10a-hexahydro-6-oxa-2,10b,12-triazacyclopentadienyl[gh]pyroxene-11(12H)-one (30 mg, yield 13.9%). ESI-MS (m / z): 517.24 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ:1.280-1.353(m,2H),1.412-1.466(m,2H),1.533-1.641(m,1H),1.656-1.6 67(m,1H),1.713-1.728(m,1H),1.915(d,2H),2.098(d,1H),2.357(s,6H),2.615-2.636(m,1H),2.8 60(t,J=12.6Hz,2H),3.491(s,3H),3.554-3.576(m,2H),4.218-4.259(m,1H),4.373-4.391(m,3H), 6.973(d,J=9.0Hz,1H),7.543(d,J=10.8Hz,1H),7.647(d,J=8.4Hz,1H),8.197(s,1H),8.856(s,1H).

[0883] Example 58: (S)-6-Fluoro-2,10-dimethyl-7-(2-oxo-1-(3-piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-146)

[0884]

[0885] Step 1: Synthesis of 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one

[0886] To a 100 mL reaction flask, acetonitrile (30 mL), 1-(3-bromopropyl)piperidine hydrobromide (1.81 g, 6.32 mmol), 4-bromo-2-hydroxypyridine (1.0 g, 5.75 mmol), and potassium carbonate (1.98 g, 14.37 mmol) were added sequentially and refluxed for 5 h. The reaction was monitored by TLC. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1-15:1) to obtain 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one (1.24 g, 72.0% yield). ESI-M (m / z): 299.07 / 301.07 [M+H] + .

[0887] Step 2: Synthesis of 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridin-2(1H)-one

[0888] To a 100 mL reaction flask, 1,4-dioxane (25 mL), 4-bromo-1-(3-(piperidin-1-yl)propyl)pyridin-2(1H)-one (1.24 g, 4.14 mmol), pinacol diboron (2.10 g, 8.28 mmol), potassium acetate (1.22 g, 12.42 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.30 g, 0.41 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 3 h. The reaction was completed by TLC monitoring, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH=20:1-15:1) to give 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridin-2(1H)-one (1.13 g, yield 79%).

[0889] Step 3: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(2-oxo-1-(3-piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0890] To a 50 mL reaction flask, 1,4-dioxane (5 mL), 1-(3-(piperidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridin-2(1H)-one (156 mg, 0.45 mmol), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (106 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), water (0.5 mL), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were added in sequence. The mixture was heated to 90°C under nitrogen and reacted for 3 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1-10:1) to obtain (S)-6-fluoro-2,10-dimethyl-7-(2-oxo-1-(3-piperidin-1-yl)propyl)-1,2-dihydropyridin-4-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, yield 17%). ESI-M (m / z): 492.23 [M+H] + ; 1 H NMR(600MHz, CD3OD)δ:1.561-1.572(m,5H),1.707-1.726(m,4H),2.100-2.1 48(m,2H),2.665(brs,6H),3.657(s,3H),4.146(t,J=7.2Hz,2H),4.559-4.58 0(m,1H),4.689-4.715(m,1H),4.745-4.779(m,1H),6.582(d,J=6.6Hz,1H), 6.727(s,1H),7.560(d,J=11.4Hz,1H),7.795(d,J=6.6Hz,1H),8.868(s,1H).

[0891] Example 59: (S)-6-Fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-148)

[0892]

[0893] Step 1: Synthesis of 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine

[0894] To a 100 mL reaction flask, THF (30 mL) and N-hydroxyethylpiperidine (1.0 g, 7.74 mmol) were added sequentially. The temperature was lowered to 0°C, and NaH (0.62 g, 15.48 mmol) was added. The reaction was allowed to react at this temperature for 0.5 h. Then, 5-bromo-2-(bromomethyl)pyridine (1.94 g, 7.74 mmol) was added and allowed to react at room temperature for 5 h. The reaction was monitored by TLC. The reaction solution was quenched with water and then concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1 to 15:1) to give 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine (1.97 g, 85.0% yield). ESI-MS (m / z): 299.07 / 301.07 [M+H] + .

[0895] Step 2: Synthesis of 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxan-2-yl)pyridine

[0896] To a 100 mL reaction flask, 1,4-dioxane (25 mL), 5-bromo-2-((2-(piperidin-1-yl)ethoxy)methyl)pyridine (1.97 g, 6.58 mmol), pinacol diboron (3.34 g, 13.16 mmol), potassium acetate (1.61 g, 16.45 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.48 g, 0.66 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 3 h. The reaction was monitored by TLC. The reaction solution was concentrated to dryness to obtain crude 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxan-2-yl)pyridine, which was used directly in the next step.

[0897] Step 3: Synthesis of (S)-6-fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one

[0898] To a 50 mL reaction flask, 1,4-dioxane (5 mL), 2-((2-(piperidin-1-yl)ethoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxan-2-yl)pyridine (156 mg, 0.45 mmol), (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (106 mg, 0.3 mmol), potassium carbonate (83 mg, 0.6 mmol), water (0.5 mL), and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were added sequentially. The mixture was heated to 90°C under nitrogen and reacted for 3 h. The reaction was monitored by TLC, and the reaction solution was concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH = 20:1-10:1) to obtain (S)-6-fluoro-2,10-dimethyl-7-(6-((2-(piperidin-1-yl)ethoxy)methyl)pyridin-3-yl)-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (25 mg, 17% yield). ESI-MS (m / z): 492.23 [M+H] + ; 1 H NMR(600MHz, CD3OD)δ:1.463-1.624(m,5H),1.693-1.711(m,4H),2.748(br s,4H),2.881(brs,2H),3.622(s,3H),3.835(t,J=5.4Hz,2H),4.520-4.542( m,1H),4.613-4.634(m,1H),4.711-4.726(m,3H),7.533(d,J=11.4Hz,1H), 7.676(d,J=8.4Hz,1H), 8.004(d,J=8.4Hz,1H), 8.630(s,1H), 8.811(s,1H).

[0899] Example 60: N-(2-(3-(Dimethylamino)propoxy)-5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)pyridin-3-yl)cyclopropanecarboxamide (A-155)

[0900]

[0901] Step 1: Synthesis of 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine

[0902] To a 250 mL reaction flask, add anhydrous THF (4 mL) and 3-(dimethylamino)propan-1-ol (1.7 g, 16.4 mmol) sequentially. Cool to 0°C, then add NaH (0.66 g, 16.4 mmol). Return to room temperature and stir for 0.5 h. Under nitrogen protection, cool to -5°C, and slowly add a solution of 5-bromo-2-chloro-3-nitropyridine (3 g, 12.6 mmol) in THF (30 mL) dropwise. After the addition is complete, return to room temperature and react for 3 h. LC-MS showed the reaction was complete. After post-treatment, saturated ammonium chloride solution was added to quench the reaction, which was then diluted with water. Ethyl acetate was added, stirred, and the layers separated. The organic phase was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 40:1 to 10:1) to obtain 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (2.1 g, yield 54.5%). ESI-MS (m / z): 304.02 / 306.02 [M+H] + .

[0903] Step 2: Synthesis of 5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-amine

[0904] To a 250 mL reaction flask, AcOH (50 mL), 3-((5-bromo-3-nitropyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (2.1 g, 6.9 mmol), and Fe powder (2.0 g, 35.7 mmol) were added sequentially and allowed to react at room temperature for 2 h. LC-MS indicated the reaction was complete. After post-treatment, THF (50 mL) and DCM (100 mL) were added, followed by filtration. The filter cake was washed with DCM, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 80:1 to 5:1) to afford 5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-amine (1.4 g, 73.7% yield). ESI-MS (m / z): 274.05 / 276.02 [M+H] + .

[0905] Step 3: Synthesis of N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide

[0906] To a 100 mL reaction flask, DCM (20 mL), 5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-amine (0.50 g, 1.8 mmol), and TEA (0.46 g, 4.5 mmol) were added sequentially. The temperature was lowered, and cyclopropanoyl chloride (0.25 g, 2.4 mol) was added dropwise at 0°C. The reaction was allowed to react for 2 h at room temperature. LC-MS indicated the reaction was complete. After post-treatment, water was added to quench the reaction, the layers were separated, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 30:1 to 10:1) to afford N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide (0.5 g, 80.6% yield). ESI-MS (m / z): 342.07 / 344.07 [M+H]. + .

[0907] Step 4: Synthesis of N-(2-(3-(dimethylamino)propoxy)-5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)pyridin-3-yl)cyclopropanecarboxamide

[0908] In a 100 mL reaction bottle, DMF (20 mL), N-(5-bromo-2-(3-(dimethylamino)propoxy)pyridin-3-yl)cyclopropanecarboxamide (0.5 g, 1.5 mmol), diboronic acid pinacol ester (0.76 g, 3.0 mmol), PdCl2(dppf) (0.11 g, 0.15 mmol), and potassium acetate (0.37 g, 3.8 mmol) were added in sequence, and the mixture was reacted at 90 °C for 4 h under nitrogen protection. The temperature was lowered, and 7-bromo-6-fluoro-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one (0.57 g, 1.5 mmol), potassium carbonate (0.62 g, 4.5 mmol), water (1 mL), and tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol) were added. The mixture was heated to 90°C under nitrogen protection and reacted for 4 h. After post-treatment, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography (DCM:MeOH = 20:1-5:1) to obtain N-(2-(3-(dimethylamino)propoxy)-5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)pyridin-3-yl)cyclopropanecarboxamide (35 mg, yield 4.3%). ESI-MS (m / z): 561.25 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:0.907-0.987(m,6H),1.318-1.329(m,5H),1.942-1.957(m,1H),1.995-2.009(m,1H),2.102-2.137(m,3H),2.36 7(s,6H),2.626-2.651(m,2H),3.589(s,3H),4.540-4.561(m,2H),7.491(d,J=10.8Hz,1H),7.973(s,1H),8.484(s,1H),8.769(s,1H).

[0909] Example 61: N-(5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)-2-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)cyclopropanecarboxamide (A-156)

[0910]

[0911] Except for the change in starting materials, the synthesis method was the same as in Example 60 to obtain N-(5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)-2-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)cyclopropanecarboxamide (40 mg, yield 35.5%). ESI-MS (m / z): 601.29 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:0.897-0.985(m,6H),1.273-1.295(m,5H),1.629-1.639(m,2H) ),1.648-1.666(m,1H),1.891-1.995(m,1H),2.000-2.007(m,1H),2.014-2.139(m,4H ),2.533-2.579(m,4H),2.592-2.604(m,2H),3.582(s,3H),4.518-4.528(m,2H),4.5 39-4.604(m,2H),7.468(d,J=10.8Hz,1H),7.958(s,1H),8.487(s,1H),8.749(s,1H).

[0912] Example 62: N-(2-(3-(Dimethylamino)propoxy)-5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)pyridin-3-yl)methanesulfonamide (A-157)

[0913]

[0914] Except for the change in starting materials, the synthesis method was the same as in Example 60 to obtain N-(2-(3-(dimethylamino)propoxy)-5-(6'-fluoro-2'-methyl-1'-oxo-1',2'-dihydro-9'H-8'-oxa-2',4',10a'-triazaspiro[cyclobutane-1,10'-naphtho[2,1,8-cde]azulene]-2a',3',4a',4a1'(7a'),6'-pentan-7'-yl)pyridin-3-yl)methanesulfonamide (28 mg, yield 25.2%). ESI-MS (m / z): 571.21 [M+H] + ; 1 H NMR(600MHz,CD3OD)δ:0.885-0.908(m,2H),1.284(s,3H),1.912-1.930( m,1H),2.069-2.087(m,1H),2.132-2.154(m,2H),2.542(s,6H),2.831-2 .854(m,2H),3.020(s,3H),3.585(s,3H),4.502-4.522(m,2H),4.462(s, 2H), 7.496 (d, J = 10.8Hz, 1H), 7.870 (s, 1H), 7.946 (s, 1H), 8.764 (s, 1H).

[0915] Example 63: (S)-7-(6-((3-(dimethylamino)propyl)amino)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-158)

[0916]

[0917] The synthesis method was the same as that in Example 57, except that the starting material in step 1 was changed to (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one, and N,N-dimethyl-1,3-diaminopropane was used instead of N,N-dimethylpiperidin-4-amine hydrochloride in step 2 to obtain (S)-7-(6-((3-(dimethylamino)propyl)amino)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (88 mg, yield 47.5%). ESI-MS (m / z): 451.22 [M+H] + ; 1H NMR (600MHz, CD3OD) δ: 1.549 (d, J = 6.6Hz, 3H), 2.004 (m, 2H), 2.777 (s, 6H), 3.028 (t, J = 6.6Hz, 2H), 3.488 (t, J = 6.0Hz, 2H), 3.627 (s, 3H), 4.501 (d ,J=13.2Hz,1H),4.641(m,1H),4.717(m,2H),6.700(d,J=8.4Hz,1H),7.5 15(d,J=11.4Hz,1H),7.617(d,J=9.0Hz,1H),8.143(s,1H),8.802(s,1H).

[0918] Example 64: (S)-7-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-1(2H)-one (A-159)

[0919]

[0920] The synthesis method was the same as that in Example 57, except that the starting material in Step 1 was replaced with (S)-7-bromo-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one to obtain (S)-7-(6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)-6-fluoro-2,10-dimethyl-9,10-dihydro-8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulen-1(2H)-one (31 mg, 16.7% yield). ESI-MS (m / z): 477.23 [M+H]. + ; 1 H NMR(600MHz,CD3OD)δ:1.538(d,J=6.6Hz,3H),1.619-1.666(m,2H),2.091( d,J=12.6H,2H),2.609(s,6H),2.966(m,3H),3.616(s,3H),4.465-4.532(m, 3H),4.611-4.637(m,1H),4.699(d,J=5.4Hz,1H),6.977(d,J=9.0Hz,1H),7 .484(d,J=11.4Hz,1H),7.697(d,J=9.0Hz,1H),8.216(s,1H),8.771(s,1H).

[0921] Example 65: (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1′-cyclobutane]-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-3-carbonitrile (A-160)

[0922]

[0923] Step 1: Synthesis of (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile

[0924] To a 100 mL reaction flask, (S)-3-cyanopyrrolidine hydrochloride (0.95 g, 7.13 mmol), acetonitrile (20 mL), potassium carbonate (3.94 g, 28.54 mmol), and 3-bromo-1-propanol (1.19 g, 8.56 mmol) were added. The reaction was heated to 80°C for 5 h. The reaction was monitored for completion by TLC. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness and purified by column chromatography (DCM:MeOH = 50:1 to 20:1) to afford (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile (0.62 g, 56.4% yield). ESI-MS (m / z): 155.11 [M+H] + .

[0925] Step 2: Synthesis of (S)-1-(3-((5-(6-fluoro-2-methyl-1-oxo-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-7-yl)pyridin-2-yl)oxy)propyl)pyrrolidine-3-carbonitrile

[0926] To a 50 mL reaction flask, add anhydrous THF (4 mL) and (S)-1-(3-hydroxypropyl)pyrrolidine-3-carbonitrile (78 mg, 0.51 mmol). After cooling to 0°C, add NaH (35 mg, 0.89 mmol) in portions. After reacting at room temperature for 0.5 h, add 6-fluoro-7-(6-fluoropyridin-3-yl)-2-methyl-2,9-dihydro-1H-spiro[8-oxa-2,4,10a-triazanaphtho[2,1,8-cde]azulene-10,1'-cyclobutane]-1-one (100 mg, 0.25 mmol) and re...

Claims

1. A compound as represented by formula (I') or its optical isomer, deuterated compound or pharmaceutically acceptable salt, which has the following structure: in, Y is X1 is selected from a bond or halogen; when X1 is halogen, R1, X2, R2 and R3 are absent; R1 is selected from absent or optionally substituted C 2-6 Alkynyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the heteroatom is selected from N, and the number of the heteroatom is 1 or 2; the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 1a replaced by; R 1a Each occurrence is independently selected from halogen, hydroxy, amino, oxo, -R 1b 、-C(O)NH(R 1b )、-NHC(O)(R 1b )、-N(R 1b )C(O)(R 1c )、-S(O)NH(R 1b )、-SO2NH(R 1b )、-NHS(O)(R 1b )、-NHSO2(R 1b ) or -N(R 1b )SO2(R 1c ); The oxo group refers to two H groups at the same substitution site being replaced by the same O to form a double bond; R 1b , R 1c Each occurrence is independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl or phenyl; X2 is selected from absence, a bond, halogen, -O-, -NH- or -N(CH3)-; When X2 is a halogen, R2 and R3 do not exist; R2 is selected from the group consisting of not present, C 1-6 Alkyl, C 2-4 Alkynyl or 5-6 membered heterocycloalkyl, wherein the heteroatom is selected from N or O, and the number of the heteroatom is 1 or 2; R3 is selected from the group consisting of: absent, -R 3b 、-OR 3b or -N(R 3b )(R 3c ); R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-6 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 3-10 membered heterocycloalkyl or 4-12 membered bicyclic heterocyclyl; the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by R 3d replaced by; R 3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -R 3e 、-C(O)R 3e 、-C(O)OR 3e 、-N(R 3e )(R 3f ) or -C(O)NH(R 3e ); R 3e , R 3f Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 3-6 One or more of cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; R4 is independently selected at each occurrence from hydrogen, halogen, nitro, amino, cyano, hydroxyl or C optionally substituted with one or more halogen, hydroxyl or amino. 1-6 Alkyl or C 1-6 Alkoxy; h is 1; R5 at each occurrence is independently selected from hydrogen or C 1-6 alkyl; L is CH or N; A is in, represents a single bond or a double bond; Q1 is connected to W; t1, t2, t3, t4, t5, t6 are independently 0 or 1; n1 and n2 are independently 0 or 1, and n1 and n2 are not 0 at the same time; W is selected from C, O, N or S; Q1 is C; Q2 is C; Q3 is C; when the bond connecting one side of Q3 is a double bond, R 10 or R 11 does not exist; R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -R 6a 、-NH(R 6a ) or -N(R 6a )(R 6b ); or R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Any two substituents attached to the same atom together form =O, =NR 6a or =CH-R 6a ; or any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents to which they are connected together form a group optionally replaced by R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-12 membered heteroaryl; or any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-10 Carbocyclic group or 3-10 membered heterocyclic group; R 6a , R 6b Each occurrence is independently selected from hydrogen, deuterium or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-12 membered heteroaryl; or when R 6a and R 6b When connected to the same nitrogen atom, R 6a and R 6b and the nitrogen atom to which it is attached together form an optionally R 6c substituted 3-10 membered heterocyclyl or 5-12 membered heteroaryl; R 6c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -R 6d 、-OR 6d 、-N(R 6d )R 6e 、-C(O)R 6d 、-C(O)N(R 6d )R 6e 、-N(R 6d )C(O)R 6e or-C(O)OR 6d ; R 6d , R 6e Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-12 membered heteroaryl.

2. The compound according to claim 1 or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: The compound has a structure as shown in formula (Ia), formula (Ib) or (Ic): wherein each substituent is as defined in claim 1.

3. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from an optionally substituted 5-6 membered heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 1 or 2; the optional substitution refers to the optional substitution of R 1a replaced.

4. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from optionally substituted ethynyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl; the optional substitution means that R 1a replaced.

5. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl or pyrrolyl; the optional substitution means that R 1a replaced.

6. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from the group consisting of optionally substituted pyridyl, pyrimidinyl, pyrazinyl and pyrazolyl; the optional substitution means that R 1a replaced.

7. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from optionally substituted dihydropyridinyl; the optional substitution means optionally replaced by R 1a replaced.

8. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from ethynyl.

9. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from optionally substituted pyridyl; the optional substitution means optionally replaced by R 1a replaced.

10. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1a Each occurrence is independently selected from halogen, amino, oxo, -R 1b 、-NHC(O)(R 1b ) or -NHSO2(R 1b ); the oxo group refers to two H groups at the same substitution site being replaced by the same O to form a double bond.

11. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1a Each occurrence is independently selected from -NHC(O)(R 1b ) or -NHSO2(R 1b ).

12. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1a Each occurrence is independently selected from -F, -Cl, -NH2, oxo, -CH3, -CH2CH3, -NHC(O)CH3, -C(O)NHCH3, The oxo group refers to two H groups at the same substitution site being replaced by the same O group to form a double bond.

13. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1b , R 1c Each occurrence is independently selected from C 1-6 Alkyl or C 3-6 Cycloalkyl.

14. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1b , R 1c Each occurrence is independently selected from C 1-4 Alkyl or C 3-4 Cycloalkyl.

15. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1b , R 1c Each occurrence is independently selected from methyl, ethyl, cyclopropanyl, phenyl or tetrahydropyranyl.

16. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1b , R 1c Each occurrence is independently selected from methyl or cyclopropane.

17. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following optionally substituted groups: Wherein, the "*" end is one end connected to X1, and the other end is one end connected to X2; the optional substitution means that R 1a replaced.

18. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from optionally substituted Wherein, the "*" end is one end connected to X1, and the other end is one end connected to X2; the optional substitution means that R 1a replaced.

19. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following groups: Among them, the "*" end is the end connected to X1, and the other end is the end connected to X2.

20. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R2 is selected from absent, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, piperidinyl, tetrahydropyrrolyl or tetrahydropyranyl.

21. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R2 is selected from n-propyl.

22. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R3 is selected from -N(R 3b )(R 3c ).

23. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-6 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted 4-8 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclyl; the optional substitution refers to optionally being replaced by R 3d replaced.

24. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl or 6-10 membered bicyclic heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution refers to optionally being replaced by R 3d replaced.

25. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 3-membered heteromonospirocyclic radical, a 3-membered / 5-membered heteromonospirocyclic radical, a 5-membered / 3-membered heteromonospirocyclic radical, a 3-membered / 6-membered heteromonospirocyclic radical, a 6-membered / 3-membered heteromonospirocyclic radical, a 4-membered / 5-membered heteromonospirocyclic radical, a 5-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 6-membered heteromonospirocyclic radical, a 6-membered / 4-membered heteromonospirocyclic radical, a 4-membered / 4-membered heteromonospirocyclic radical, heteromonospirocyclic group, 5-membered / 5-membered heteromonospirocyclic group, 5-membered / 6-membered heteromonospirocyclic group, 6-membered / 5-membered heteromonospirocyclic group, 3-membered / 5-membered heterocyclic group, 5-membered / 3-membered heterocyclic group, 3-membered / 6-membered heterocyclic group, 6-membered / 3-membered heterocyclic group, 5-membered / 6-membered heterocyclic group or 6-membered / 5-membered heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution refers to the optional substitution of R 3d replaced.

26. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 6-membered heteromonospirocyclic group, a 6-membered / 3-membered heteromonospirocyclic group, a 4-membered / 6-membered heteromonospirocyclic group, a 6-membered / 4-membered heteromonospirocyclic group or a 4-membered / 4-membered heteromonospirocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1 or 2; the optional substitution refers to optionally being replaced by R 3d replaced.

27. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted C 1-4 Alkyl; or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached form an optionally substituted 5-6 membered heterocycloalkyl, a 3-membered / 6-membered heteromonospirocyclic group, a 4-membered / 6-membered heteromonospirocyclic group or a 3-membered / 5-membered heterocyclic group, wherein the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1, 2 or 3; the optional substitution refers to the optional substitution of R 3d replaced.

28. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted methyl, or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, 2-oxa-7-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl or 6-azaspiro[2.5]octyl; the optional substitution means that R 3d replaced.

29. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b , R 3c Each occurrence is independently selected from optionally substituted methyl, or when R 3b and R 3c When connected to the same nitrogen atom, R 3b and R 3c and the nitrogen atom to which it is attached together form an optionally substituted piperidinyl; the optional substitution refers to optionally being replaced by R 3d replaced.

30. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3b and R 3c and the nitrogen atom to which it is connected together form a group selected from the following groups:

31. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -CHO, -CO(C 1-6 alkyl), -COOH, -COO(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy or 3-6 membered heterocycloalkyl.

32. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from deuterium, hydroxyl, amino, -CHO, -CO(C 1-6 alkyl), -COOH, -COO(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy or 5-6 membered heterocycloalkyl.

33. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from deuterium, fluorine, hydroxy, amino, cyano, -CHO, -COCH3, -COOH, -COOCH3, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, piperidinyl, piperazinyl or tetrahydropyrrolyl.

34. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from deuterium, fluorine, hydroxy, amino, cyano, -NH(CH3), -N(CH3)(CH3), -C(O)NH2, -CH3, -CH2CH3 or -CH2CH2CH3.

35. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from deuterium, fluorine, amino, cyano, -C(O)NH2, -CH3 or piperidinyl.

36. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 3d Each occurrence is independently selected from methyl, -N(methyl)(methyl) or piperidinyl.

37. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R3 is selected from the following groups:

38. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R3 is selected from the following groups:

39. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Y is selected from the following groups:

40. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Y is selected from the following groups:

41. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R4 is selected from hydrogen, halogen, amino or C 1-6 Alkoxy.

42. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R4 is selected from hydrogen, fluorine or methoxy.

43. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R5 is methyl.

44. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-10 membered heteroaryl.

45. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen, deuterium or optionally replaced by R 6c Substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl.

46. ​​The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-6 Alkyl or C 1-6 Alkoxy.

47. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted C 1-3 Alkyl or C 1-3 Alkoxy.

48. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

49. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6a , R 6b Each occurrence is independently selected from hydrogen or optionally replaced by R 6c Substituted methyl or ethyl.

50. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxyl, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-10 membered heteroaryl.

51. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxyl, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-10 membered heteroaryl, wherein the heteroatom is selected from N or S, and the number of heteroatoms is 1, 2 or 3.

52. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxyl, amino, -NH(C 1-6 alkyl), -N(CH3)(C 1-6 alkyl), -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the heteroatom is selected from N or S, and the number of heteroatoms is 1, 2 or 3.

53. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

54. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 6c Each occurrence is independently selected from hydrogen, fluorine, chlorine, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

55. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen, deuterium or optionally deuterated, halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 C substituted with cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered bicyclic heteroaryl.

56. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 Alkyl), -NHC(O)(C 1-6 alkyl), -C(O)O(C 1-6 Alkyl), C 3-6 C substituted with cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl.

57. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl) or -NHC(O)(C 1-6 Alkyl) substituted C 1-6 Alkyl or C 1-6 Alkoxy.

58. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted C 1-6 Alkyl or C 1-6 Alkoxy.

59. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from hydrogen or optionally substituted by halogen, hydroxy, amino, C 1-3 Alkyl or C 1-3 Alkoxy substituted C 1-3 Alkyl or C 1-3 Alkoxy.

60. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from the following groups: -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)CH3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH(CH3)CH2OCH3, -NHCH3, -N(CH3)CH3, -CH2N(CH3)CH3, 61. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from the following groups: -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)CH3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -NHCH3, -N(CH3)CH3, -CH2N(CH3)CH3, 62. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each occurrence is independently selected from the following groups: -H, -F, -Cl, -OH, -NH2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3 or -CH(CH3)CH2OCH3.

63. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Any two groups attached to the same atom form =O or =CH2.

64. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-8 Aryl or 5-12 membered heteroaryl.

65. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally R 6c Substituted C 3-10 Carbocyclic group, 3-10 membered heterocyclic alkyl group, C 6-8 Aryl or 5-10 membered heteroaryl.

66. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally R 6c Substituted C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl or 5-8 membered heteroaryl.

67. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally R 6c Substituted C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl, wherein the heteroatom is selected from O or N, and the number of heteroatoms is 1 or 2.

68. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any two adjacent atoms in W, Q1, Q2 and Q3 and the substituents connected thereto together form the following group:

69. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl.

70. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-6 Cycloalkyl or 3-7 membered heterocycloalkyl.

71. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-4 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the heteroatom is selected from O or N, and the number of the heteroatoms is 1 or 2.

72. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form an optionally substituted R 6c Substituted C 3-4 Cycloalkyl.

73. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form the following group:

74. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form the following group:

75. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: Any one of W, Q1, Q2 and Q3 and the substituents connected thereto together form the following group:

76. The compound according to claim 1 or 2, or its optical isomer, deuterated compound or pharmaceutically acceptable salt, characterized in that: The compound has a structure as shown in formula (II-a): Among them, m 1-1 Select from 0 or 1, R 1a-1 As claimed in claim 1 or 2, R 1a Defined by X 2-1 As defined in X2 of claim 1 or 2, R 2-1 As defined in R2 of claim 1 or 2, R 3-1 R3 is as defined in claim 1 or 2, and R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-a1): Wherein, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-a2): Among them, R 3b-1 As claimed in claim 1 or 2, R 3b As defined, R 3c-1 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-b): Among them, m 1-2 Select from 0 or 1, R 1a-2 As claimed in claim 1 or 2, R 1a Defined by X 2-2 As defined in X2 of claim 1 or 2, R 2-2 As defined in R2 of claim 1 or 2, R 3-2 R3 is as defined in claim 1 or 2, and R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-b1): Among them, m 1-3 Select from 0 or 1, R 1a-3 As claimed in claim 1 or 2, R 1a As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-c): Among them, m 1-4 Select from 0 or 1, R 1a-4 As claimed in claim 1 or 2, R 1a Defined by X 2-3 As defined in X2 of claim 1 or 2, R 2-3 As defined in R2 of claim 1 or 2, R 3-3 R3 is as defined in claim 1 or 2, and R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-c1): Among them, m 1-5 Select from 0 or 1, R 1a-5 As claimed in claim 1 or 2, R 1a As defined, R 3b-2 As claimed in claim 1 or 2, R 3b As defined, R 3c-2 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d): Wherein, E1, E2, E3, E4, E5, E6 are independently selected from C or N, m 1-6 Select from 0 or 1, R 1a-6 As claimed in claim 1 or 2, R 1a Defined by X 2-4 As defined in X2 of claim 1 or 2, R 2-4 As defined in R2 of claim 1 or 2, R 3-4 R3 is as defined in claim 1 or 2, and R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d1): Among them, m 1-7 Select from 0 or 1, R 1a-7 As claimed in claim 1 or 2, R 1a As defined, R 3b-3 As claimed in claim 1 or 2, R 3b As defined, R 3c-3 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d2): Among them, m 1-8 Select from 0 or 1, R 1a-8 As claimed in claim 1 or 2, R 1a As defined, R 3b-4 As claimed in claim 1 or 2, R 3b As defined, R 3c-4 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d3): Among them, m 1-9 Select from 0 or 1, R 1a-9 As claimed in claim 1 or 2, R 1a As defined, R 3b-5 As claimed in claim 1 or 2, R 3b As defined, R 3c-5 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d4): Among them, m 1-10 Select from 0 or 1, R 1a-10 As claimed in claim 1 or 2, R 1a As defined, R 3e-1 As claimed in claim 1 or 2, R 3e As defined, R 3f-1 As claimed in claim 1 or 2, R 3f As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d5): Among them, m 1-11 Select from 0 or 1, R 1a-11 As claimed in claim 1 or 2, R 1a As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-d6): Among them, m 1-12 Select from 0 or 1, R 1a-12 As claimed in claim 1 or 2, R 1a As defined, R 3b-6 As claimed in claim 1 or 2, R 3b As defined, R 3c-6 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-e): Among them, E7, E8, E9, E 10 、E 11 、E 12 are independently selected from C or N, m 1-13 Select from 0 or 1, m 2-1 is selected from 0, 1, 2, 3 or 4, R 1a-13 As claimed in claim 1 or 2, R 1a As defined, R 2a-1 As claimed in claim 1 or 2, R 2a As defined, R 3-5 R3 is as defined in claim 1 or 2, and R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-e1): Among them, m 1-14 Select from 0 or 1; m 2-2 is selected from 0, 1, 2, 3 or 4, R 1a-14 As claimed in claim 1 or 2, R 1a As defined, R 2a-2 As claimed in claim 1 or 2, R 2a As defined, R 3b-7 As claimed in claim 1 or 2, R 3b As defined, R 3c-7 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-f): Among them, m 1-15 Select from 0 or 1, R 1a-15 As claimed in claim 1 or 2, R 1a As defined, R 3e-2 As claimed in claim 1 or 2, R 3e As defined, R 3f-2 As claimed in claim 1 or 2, R 3f As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (II-g): Among them, R 3b-8 As claimed in claim 1 or 2, R 3b As defined, R 3c-8 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1 or 2; Or the compound has a structure as shown in formula (III-a): Among them, m 1-16 Select from 0 or 1, R 1a-16 As claimed in claim 1 or 2, R 1a As defined, R 3b-9 As claimed in claim 1 or 2, R 3b As defined, R 3c-9 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R6, R7, R8, R9, R 10 , R 11 , W, L, t1, t2 as defined in claim 1 or 2; Or the compound has a structure as shown in formula (III-a1): Among them, m 1-17 Select from 0 or 1, R 1a-17 As claimed in claim 1 or 2, R 1a As defined, R 3b-10 As claimed in claim 1 or 2, R 3b As defined, R 3c-10 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R8, R9, R 10 , R 11 , L as defined in claim 1 or 2; Or the compound has a structure as shown in formula (III-a2): Among them, m 1-18 Select from 0 or 1, R 1a-18 As claimed in claim 1 or 2, R 1a As defined, R 3b-11 As claimed in claim 1 or 2, R 3b As defined, R 3c-11 As claimed in claim 1 or 2, R 3c As defined, R4, R5, R7, R8, R9, R 10 , R 11 , L as defined in claim 1 or 2.

77. The following compound or its optical isomer, deuterated compound or pharmaceutically acceptable salt:

78. A pharmaceutical composition comprising the compound according to any one of claims 1-77 or its optical isomer, deuterated compound or pharmaceutically acceptable salt.

79. Use of the compound according to any one of claims 1 to 77 or its optical isomer, deuterated compound or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 78 in the preparation of an ATM kinase inhibitor.

80. Use of a compound according to any one of claims 1 to 77 or an optical isomer, deuterated compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 78, in the preparation of a medicament for preventing and / or treating a disease and / or condition mediated at least in part by ATM kinase.

81. The use according to claim 80, characterized in that The disease and / or condition mediated at least in part by ATM kinase is cancer.

82. The use according to claim 81, characterized in that The cancer is selected from a solid tumor or a hematological tumor.

83. The use according to claim 81, characterized in that The cancer is selected from breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma or small cell lung cancer.

84. The use according to claim 83, characterized in that The malignant glioma is glioblastoma.

85. Use of a compound according to any one of claims 1 to 77 or its optical isomer, deuterated compound or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 78 in the preparation of a medicament for preventing and / or treating cancer.

86. The use according to claim 85, characterized in that The cancer is selected from a solid tumor or a hematological tumor.

87. The use according to claim 85, characterized in that The cancer is selected from breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma or small cell lung cancer.

88. The use according to claim 87, characterized in that The malignant glioma is glioblastoma.

89. A pharmaceutical combination composition or a pharmaceutical compound composition comprising a compound according to any one of claims 1 to 77 or an optical isomer, a deuterated compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 78 and at least one additional anti-tumor agent.

90. The pharmaceutical combination composition or pharmaceutical compound composition according to claim 89, characterized in that: The anti-tumor agent is selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775 or AZD6738.

91. Use of a compound according to any one of claims 1 to 77 or an optical isomer, deuterated compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 78 in the preparation of a medicament for preventing and / or treating cancer in combination with at least one additional anti-tumor agent.

92. The use according to claim 91, characterized in that The anti-tumor agent is selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin, epirubicin, olaparib, MEDI4736, AZD1775 or AZD6738.

93. Use of a compound according to any one of claims 1 to 77 or its optical isomer, deuterated compound or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 78 in the preparation of a medicament for preventing and / or treating cancer in combination with radiotherapy.

94. The use according to claim 93, characterized in that The cancer is selected from a solid tumor or a hematological tumor.

95. The use according to claim 93, characterized in that The cancer is selected from breast cancer, non-small cell lung cancer, glioma, colon cancer, rectal cancer, malignant glioma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma or small cell lung cancer.

96. The use according to claim 95, characterized in that The malignant glioma is glioblastoma.

97. An intermediate for preparing a compound according to any one of claims 1 to 77, having a structure as shown in formula (M-1), formula (M-2) or formula (M-3): in, R x1 is selected from halogen or hydrogen, R4, R6, R7, A, W, L, t1, t2, h are as defined in claim 1; or, It has a structure as shown in formula (M-4): Among them, R x2 is selected from halogen or hydrogen, R4, R6, R7, A, W, L, t1, t2, h are as defined in claim 1; or, It has a structure as shown in formula (M-5): Among them, R x3 is selected from halogen or hydrogen, R4, R5, R6, R7, A, W, L, t1, t2, h are as defined in claim 1; or It has a structure as shown in formula (M-6): Among them, R x4 is selected from halogen or hydrogen, and R4, R5, R6, R7, A, W, L, t1, t2, h are as defined in claim 1.

98. Prepare the following intermediates for the compounds according to any one of claims 1-77:

99. A method for preparing the compound according to claim 1, which is selected from any one of the following synthesis schemes: Synthesis Scheme 1: i) Compound I-a1 undergoes chemical conversion to obtain compound I-a2; ii) Compound I-a2 undergoes chemical conversion to obtain compound I-a4; iii) Compound I-a4 undergoes chemical transformation to obtain Compound I-a5; iv) Compound I-a5 undergoes chemical transformation to obtain Compound I-a6; v) Compound I-a6 undergoes chemical transformation to obtain compound I-a7; vi) Compound I-a7 is chemically transformed to obtain compound I-a8; vii) Compound I-a8 is chemically transformed to obtain a compound of formula I; Synthesis Scheme 2: i) using compound I-b1 as the basic raw material to obtain compound I-b2; ii) using compounds I-b2 and I-b3 as basic raw materials to obtain compound I-b4; iii) using compound I-b4 as a basic raw material to obtain compound I-b5; iv) using compound I-b5 as the basic raw material to obtain compound I-b6; v) using compound I-b6 as the basic raw material to obtain compound I-b7; vi) using compound I-b7 as the basic raw material to obtain compound I-b8; vii) using compound I-b8 as a basic raw material to obtain compound I-b9; viii) using compound I-b9 as a basic raw material to obtain a compound of formula I; Synthesis Scheme 3: i) using compound I-b1 as the basic raw material to obtain compound I-b2; ii) using compounds I-b2 and I-b3 as basic raw materials to obtain compound I-b5; iii) using compound I-b5 as a basic raw material to obtain compound I-b6; iv) using compound I-b6 as the basic raw material to obtain compound I-b7; v) using compound I-b7 as the basic raw material to obtain compound I-b8; vi) using compound I-b8 as the basic raw material to obtain compound I-b9; vii) using compound I-b9 as a basic raw material to obtain a compound of formula I; Among them, R x1 is selected from halogen or hydrogen, and X1, R4, R5, R6, R7, A, W, L, t1, t2 are as defined in claim 1.

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