Aromatic amide derivative as well as preparation method and medical application thereof

Abstract

The invention relates to an aromatic amide derivative, a preparation method of the aromatic amide derivative and application of a pharmaceutical composition containing the aromatic amide derivative in medicine. Specifically, the present invention relates to an aromatic amide derivative represented by general formula (I), a preparation method and a pharmaceutically acceptable salt thereof, and uses of the aromatic amide derivative and the pharmaceutically acceptable salt thereof as a therapeutic agent, especially a KIF18A inhibitor, in which the definition of each substituent in the general formula (I) is the same as the definition in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a KIF18A inhibitor. Background Art

[0002] Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes. Various microtubule-associated proteins (MAPs) of the kinesin-8 family regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules. KIF18A is a member of the kinesin-8 family. It can move toward the positive pole using microtubules as tracks and tends to bind to longer microtubules. Its activity is length-dependent and affects the length of the spindle, which can ensure the timely and smooth completion of the alignment of sister chromosomes. Its functions in different species are very similar and conservative.

[0003] KIF18A is a molecular motor protein that moves toward the positive end of microtubules using microtubules as tracks. It regulates the midplate assembly of chromosomes by affecting the dynamic instability of the microtubule ends and functions during mitosis. In the late stage of mitosis, the protein is ubiquitinated and degraded to ensure the precise separation of chromosomes during mitosis and promote the smooth completion of mitosis and cytokinesis. In the early stage of mitosis, the localization of KIF18A at the positive end of microtubules close to the kinetochore is a necessary condition for its function. The localization depends not only on the motor activity of its N-terminus, but also on the tail domain with microtubule binding ability. KIF18A is also subject to reversible protein phosphorylation / dephosphorylation modification, but there is still a lack of systematic research on how the post-translational modification of this protein regulates the function of KIF18A. Estrogen receptor ERɑ can bind to KIF18A and promote its transcription, but it is still unclear whether KIF18A is also regulated by other transcription factors. Therefore, the research on the gene transcription regulation mechanism of KIF18A needs to be deepened. During meiosis, cells lacking KIF18A will be unable to complete meiosis, which will lead to sperm formation disorders and testicular dysplasia in male animals.

[0004] Studies have found that KIF18A protein is highly expressed in a variety of cancers, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, etc., which indicates that KIF18A is closely related to the occurrence and development of tumors and can become a target for molecular diagnosis and treatment of a variety of tumors. The expression of KIF18A is related to the development of clinical colorectal cancer. Studies have found that KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice can significantly promote cell apoptosis. It is speculated that KIF18A can promote the occurrence and development of colorectal cancer by activating the PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is related to the grade, migration and prognosis of breast tumors. Studies on breast cancer cells have found that overexpression of KIF18A can lead to the production of multinucleated cells, while low expression can significantly reduce the ability of cell proliferation both in vivo and in vitro. This is due to the inactivation of the PI3K-Akt signal transduction pathway by KIF18A to stabilize microtubules at the ends of microtubules and induce cell apoptosis. In addition, KIF18A is upregulated at both the transcriptional and translational levels in lung adenocarcinoma, and abnormal expression of KIF18A is associated with clinical pathological malignancy. KIF18 gene mutations can be observed in lung adenocarcinoma, and its expression is also regulated by DNA copy number. KIF18A gene knockout can inhibit the proliferation of lung adenocarcinoma cells in vivo and in vitro, and induce cell apoptosis and G2 / M phase arrest. Genes that are highly expressed at the same time as KIF18A are concentrated in the cell cycle signaling pathway, so in-depth research on the mechanism of action of KIF18A in tumors is of great clinical significance.

[0005] There are no new drugs targeting KIF18A on the market, and currently only one compound, AMG-650 from Amgen, has entered Phase I clinical trials. As a relatively cutting-edge research direction, there is still a huge space for exploration in the research of KIF18A targets, and it is necessary to continue to study its mechanism of action and develop new inhibitors. Summary of the invention

[0006] In view of the above technical problems, the present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] Select from single or double bonds as required so that each atom thereof assumes a normal valence state;

[0010] Y1, Y2, Y3 are each independently selected from C, N or CR d, and at most two atoms among Y1, Y2, and Y3 are N atoms at the same time;

[0011] R d is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl;

[0012] Ring A is selected from 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl, 6-membered aryl or 5- to 7-membered heterocyclyl;

[0013] R c are the same or different and are independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0014] Ring B is selected from a 4- to 8-membered monocyclic heterocyclic group, wherein the heterocyclic group contains at least one nitrogen atom;

[0015] R a Does not exist; or two R a Together with the same or different atoms to which it is connected, it forms a 3-6-membered cycloalkyl or 3-6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more R A replace;

[0016] R A are the same or different and are independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl; or, two R A It forms a -C(=O) with the same carbon atom to which it is attached;

[0017] R bare the same or different and are each independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or =O;

[0018] Or, two R b The same carbon atom to which it is attached forms a -C(=O) or -C=CR g R h ; R g , R h are each independently selected from a hydrogen atom, a deuterium atom, a halogen or an alkyl group;

[0019] X1 and X2 are each independently selected from CR e or N atoms;

[0020] R e Selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl, alkoxy, -C(=O)NH2, -N(CH3)2 or acetyl; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, -N(CH3)2 or alkoxy;

[0021] R 2 , R 3 Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group, a cycloalkyl group or an alkoxy group; wherein the alkyl group, the cycloalkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group;

[0022] Or, R 2 and R 3 The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace;

[0023] R 4 is selected from cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(=O)R 5 、-C(=O)OR 5 、-NHC(=O)R 5 、-NHC(=O)OR 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-CH2NHC(=O)OR5 、-CH2NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0024] Or, when X2 is CR e When R 3 or R 4 and R e The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace;

[0025] Or, when X1 is CR e When R 4 and R e The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace;

[0026] R D Each is independently selected from halogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, heterocyclic, -OR 11 or =0, wherein the alkyl, cycloalkyl, alkoxy or heterocyclic group may be further substituted by halogen, hydroxyl, cyano, alkyl, cycloalkyl or alkoxy substituents;

[0027] R 11 Each is independently selected from cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, alkyl, alkoxy, haloalkyl;

[0028] L1 is selected from a bond, -C1-6 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-SC 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-OC 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)2NR f -C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )C(=O)NR f -C 0-4 Alkylene-, -C 0-4 Alkylene-C(=O)N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )C(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-PC 0-4 Alkylene-, -C 0-4 Alkylene-P(=O)2-C 0-4 Alkylene, -C 0-4 Alkylene-C(=O)-C 0-4 Alkylene- or -C 0-4 Alkylene-C(=N(OH))-C 0-4 Alkylene-, wherein the -C 1-6 Alkylene- or -C 0-4Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cycloalkyl or alkoxy;

[0029] R f are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group;

[0030] R 1 is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0031] L2 is selected from or a 5-6 membered heteroaryl;

[0032] R B Each is independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy. Preferably, R B is a hydrogen atom;

[0033] R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10substituted by a substituent;

[0034] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0035] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(=O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0036] R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0037] n is 0, 1, 2, 3 or 4;

[0038] m is 0, 1, 2, 3 or 4;

[0039] r is independently 0, 1 or 2.

[0040] A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound of general formula (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0041]

[0042] Among them, ring A, ring B, X1, X2, Y1, Y2, Y3, R 1 ~R 4 , R a , R b , R c , L1, m or n are as defined in the general formula (I).

[0043] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Each is independently selected from the following groups:

[0044] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein is a double bond, and Y1 and Y2 are C atoms.

[0045] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Each independently selected from:

[0046]

[0047]

[0048] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0049] L1 is selected from a bond, -N(R f )-C 0-4 Alkylene-, -N(R f )S(=O)2-C 0-4 Alkylene-, -S(=O)2N(Rf )-C 0-4 Alkylene-, -N(R f )S(=O)2N(R f )-、-S(=O)(=NH)-、-N(R f )S(=O)(=NH)-、-C 1-4 Alkylene-, -S(=O)-, -O-, -C(=O)-, -C(=O)N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2-C 0-4 Alkylene- or -N(R f )-C(=O)-, wherein the -C 0-4 Alkylene- or -C 1-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cyclopropyl or methoxy;

[0050] R f Each is independently selected from a hydrogen atom or a methyl group.

[0051] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0052] L1 is selected from a bond, -NHCH2CH2-, -NHS(=O)2-, -NHS(=O)2CH2-, -NHS(=O)2CH2CH2-, -S(=O)2NH-, -S(=O)2NHCH2CH2-, -NHS(=O)2NH-, -NHS(=O)2N(CH3)-, -S(=O)2-, -CH2S(=O)2-, -S(=O)2(= NH)-, -NHC(CH3)2CH2-, -C(=O)NHCH2CH2-, -C(=O)NHC(CH3)2CH2-, -C(=O)N(CH3)CH2CH 2-, -NHS(=O)2CH(CH3)CH2-, -S(=O)2NHC(CH3)2CH2-, -C(=O)NH- or -CH2S(=O)2CH2CH2-.

[0053] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.

[0054] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein for

[0055] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently selected from CR e or N atoms;

[0056] R e is selected from a hydrogen atom or an alkoxy group; preferably, the alkoxy group is a methoxy group.

[0057] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 2 , R 3 are each independently selected from a hydrogen atom.

[0058] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 4 Each is independently selected from a 3- to 10-membered heterocyclyl or a 3- to 10-membered cycloalkyl, wherein the heterocyclyl or cycloalkyl is optionally further substituted by one or more alkyl or halogen.

[0059] A preferred embodiment of the present invention is a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 4 for

[0060] In a preferred embodiment of the present invention, the compound described by general formula (I), (II-1) or (II-2) is selected from:

[0061]

[0062] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0063] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0064] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0065] The present invention provides a use of a compound of general formula (I), (II-1) or (II-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.

[0066] The present invention also provides a use of a compound of formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer; wherein the disease mediated by KIF18A is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer or lung adenocarcinoma.

[0067] The present invention further provides a use of a compound of general formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0068] The present invention provides a compound described in general formula (I), (II-1) or (II-2) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a drug for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer or lung adenocarcinoma.

[0069] Detailed description of the invention

[0070] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows: "alkyl" when used as a group or a part of a group refers to a C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0071] “C α-β "Alkylene" refers to an aliphatic hydrocarbon group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, wherein α and β represent integers, the designation of C0 alkylene represents a direct bond, and C 1-6 Examples of alkylene include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like. α-β The alkylene group may be substituted or unsubstituted.

[0072] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring are carbon atoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0073] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0074] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.

[0075] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

[0076] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a non-aromatic heterocyclic group in which one or more of the atoms forming the ring is selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings. Preferably, there are 5 to 7-membered monocyclic or 7 to 10-membered bicyclic or tricyclic rings, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclic radicals" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,

[0077]

[0078] The heterocyclic group may be substituted or unsubstituted.

[0079] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 7 to 14 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group. Monospiro heterocyclic group is preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group, and bispiro heterocyclic group is preferably 3 yuan / 4 yuan / 6 yuan, 3 yuan / 4 yuan / 4 yuan or 3 yuan / 4 yuan / 5 yuan bispiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0080]

[0081] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(=O) t (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin (dioxine).

[0082] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered, polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(=O) t(wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0083] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, the aromatic group is C6-C 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[0084] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 -triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolyl, quinazolinyl, 2H-isoindolyl, furano[3,2-b]pyridinyl, furano[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0085] A heteroaryl group can be substituted or unsubstituted.

[0086] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0087] "Nitro" refers to a -NO2 group.

[0088] "Hydroxy" refers to an -OH group.

[0089] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0090] "Amino" refers to -NH2.

[0091] "Cyano" refers to -CN.

[0092] "Benzyl" refers to -CH2-phenyl.

[0093] "Carboxy" refers to -C(=O)OH.

[0094] The "carboxylate group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein the alkyl group and the cycloalkyl group are as defined above.

[0095] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group wherein alkyl is as defined above.

[0096] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0097] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0098] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0099] "DMSO" refers to dimethyl sulfoxide.

[0100] "BOC" refers to tert-butoxycarbonyl.

[0101] "THP" refers to 2-tetrahydropyranyl.

[0102] "TFA" refers to trifluoroacetic acid.

[0103] "Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

[0104] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0105] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR 5 、-C(=O)R 5 、-C(=O)OR 5 、-NHC(=O)R 5 、-NHC(=O)OR 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-CH2NHC(=O)OR 5 、-CH2NR 6 R 7 or -S(=O) r R 5 substituted by a substituent;

[0106] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0107] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C=(O)R 10 substituted by a substituent;

[0108] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(=O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent;

[0109] R 8 , R 9 and R 10 Each is independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate; r is selected from 0, 1 or 2;

[0110] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0111] Unless otherwise indicated, structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.

[0112] "Pharmaceutically acceptable salts" refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0113] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0114] Synthesis method of the compound of the present invention

[0115] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:

[0116] Method 1:

[0117]

[0118] Compound (IA) and compound (IB) undergo condensation reaction to obtain compound of general formula (IC). Compound (IC) and compound (ID) may further undergo substitution and deprotection reaction to produce compound (II-1).

[0119] in:

[0120] X represents hydroxyl or chlorine;

[0121] W 1 represents fluorine, chlorine, bromine or iodine;

[0122] Ring A, Ring B, X1, X2, Y1, Y2, Y3, R 1 ~R 4 , R a , R b , R c , L1, m or n are as defined in the general formula (II-1).

[0123] Method 2:

[0124]

[0125] Compound (IIA) and compound (IIB) undergo condensation reaction to obtain compound of general formula (IIC), and compound (IIC) and compound (ID) are optionally further subjected to substitution and deprotection reaction to produce compound (II-2).

[0126] in:

[0127] X represents hydroxyl or chlorine;

[0128] W 1 represents fluorine, chlorine, bromine or iodine;

[0129] Ring A, Ring B, X1, X2, Y1, Y2, Y3, R 1 ~R 4 , R a , R b , R c , L1, m or n are as defined in the general formula (II-1). DETAILED DESCRIPTION

[0130] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0131] Example

[0132] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0133] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0134] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0135] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0136] In the following examples, unless otherwise indicated, all temperatures are degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0137] CD3OD: deuterated methanol.

[0138] CDCl3: deuterated chloroform.

[0139] DMSO-d6: deuterated dimethyl sulfoxide.

[0140] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0141] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0142] The compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.

[0143] Example 1

[0144] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4-(ethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0145] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4-(ethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0146]

[0147] first step

[0148] 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine

[0149] 4,4-Difluoro-1-(2-methoxy-5-nitrophenyl)piperidine

[0150] 2-Bromo-1-methoxy-4-nitrobenzene 1i-1 (2.0 g, 8.62 mmol) was dissolved in toluene (20 mL), and 4,4-difluoropiperidine 1i-2 (1.25 g, 10.34 mmol), tris(dibenzyl-BASE acetone)dipalladium (395 mg, 0.43 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (537 mg, 0.86 mmol) and sodium tert-butoxide (1.66 g, 17.24 mmol) were added in sequence, and the temperature was raised to 110 °C under a nitrogen atmosphere for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine 1i-3 (1.25 g) with a yield of 53%.

[0151] MS m / z(ESI):273.1[M+H] +

[0152] Step 2

[0153] 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline

[0154] 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline

[0155] 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine 1i-3 (1.2 g, 4.41 mmol) was dissolved in methanol (10 mL), 10% palladium carbon (120 mg) was added, and the mixture was reacted at room temperature for 8 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline 1i (934 mg), with a yield of 87%.

[0156] MS m / z(ESI):243.1[M+H] +

[0157] Step 3

[0158] 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile

[0159] 4-Bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile

[0160] 4-Bromo-2,6-difluorobenzonitrile 1a (20 g, 91.74 mmol) was dissolved in dimethyl sulfoxide (200 mL), N,N-diisopropylethylamine (23.71 g, 183.49 mmol) was added, the temperature was lowered to 0°C, 6-azaspiro[2.5]octane hydrochloride 1b (10.84 g, 58.86 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed overnight. The reaction solution was diluted with ethyl acetate (200 mL), washed with water (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile 1c (26 g), yield: 82%.

[0161] 1H NMR (400MHz, CDCl3) δ6.92-6.89(m,1H),6.85(dd,J=8.1,1.6Hz,1H),3.37-3.26(m,4H),1.58(t,J=2.7Hz,4H),0.38(s,4H).

[0162] Step 4

[0163] 4-bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile

[0164] 4-Bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile

[0165] 4-Bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile 1c (13 g, 42.05 mmol) was dissolved in tetrahydrofuran (141.21 mL), cooled to -40°C, and 2M lithium diisopropylamide (31.54 mL) was slowly added. After reacting for 30 minutes, ethylene oxide (18.52 g, 420.47 mmol) was added, and the temperature was slowly raised to room temperature. The reaction mixture was reacted overnight. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (100 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile 1d (16 g), with a yield of 100%.

[0166] MS m / z(ESI):353.1[M+H] +

[0167] Step 5

[0168] 4-bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0169] 4-Bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide

[0170] 4-Bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile 1d (11 g, 31.14 mmol) was dissolved in water (40 mL) and ethanol (40 mL), and (dimethylphosphonic acid) platinum (II) hydrogen complex (404 mg, 0.93 mmol, commercially available) was added, and the mixture was reacted overnight at 80° C. The reaction solution was filtered and the filtrate was concentrated to obtain 4-bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide 1e (9 g), with a yield of 81%.

[0171] MS m / z(ESI):371.0[M+H] +

[0172] Step 6

[0173] 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0174] 4-Bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0175] 4-Bromo-2-fluoro-3-(2-hydroxyethyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide 1e (9 g, 24.24 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (970 mg, 24.24 mmol, 60% purity) was added under nitrogen atmosphere, and the mixture was reacted at 90°C for 16 hours. Ice water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: System A) to obtain the product 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 1f (6 g) with a yield of 70%.

[0176] MS m / z(ESI):351.0[M+H] +

[0177] Step 7

[0178] tert-butyl(4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carbonyl)(tert-

[0179] butoxycarbonyl)carbamate

[0180] tert-Butyl (4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carbonyl)(tert-butoxycarbonyl)carbamate

[0181] 4-Bromo-6-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 1f (6 g, 17.08 mmol) was dissolved in dichloromethane (60 mL), and then di-tert-butyl dicarbonate (7.46 g, 34.16 mmol), 4,4-dimethylaminopyridine (2.30 g, 18.79 mmol) and triethylamine (7.12 mL, 51.25 mmol) were added in sequence, and the reaction was carried out at room temperature for 16 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl (4-bromo-6-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydrobenzofuran-7-carbonyl)(tert-butoxycarbonyl)carbamate 1 g (5.6 g), with a yield of 59%.

[0182] MS m / z(ESI):551.1[M+H] +

[0183] Step 8

[0184] 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxylic acid

[0185] 4-Bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxylic acid

[0186] 1 g (5.6 g, 10.15 mmol) of tert-butyl (4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carbonyl)(tert-butoxycarbonyl)carbamate was dissolved in a mixed solvent of water (15 mL), methanol (15 mL) and tetrahydrofuran (15 mL). Sodium hydroxide (4.06 g, 101.55 mmol) was slowly added to the above reaction system and reacted at 50 °C overnight. The reaction solution was concentrated, diluted with water (15 mL), washed once with ethyl acetate (30 mL), 1 M aqueous hydrochloric acid solution was slowly added to the aqueous phase to adjust the pH to 5-6, and then extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column chromatography (eluent: D system) to give 4-bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxylic acid 1h (840 mg) with a yield of 23%.

[0187] MS m / z(ESI):352.1[M+H] +

[0188] Step 9

[0189] 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-

[0190] dihydrobenzofuran-7-carboxamide

[0191] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-

[0192] 7-Formamide

[0193] 4-Bromo-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxylic acid 1h (202 mg, 0.57 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (260 mg, 0.68 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline 1i (138 mg, 0.57 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with water (15 mL) and saturated brine (15 mL) in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 1j (245 mg), yield: 74%. MS m / z (ESI): 576.2 [M+H] +

[0194] Step 10

[0195] tert-butyl(7-((3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)carbamoyl)-6-(6-

[0196] azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-4-yl)carbamate

[0197] tert-Butyl (7-((3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-4-yl)carbamate

[0198] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 1j (155 mg, 0.27 mmol) was dissolved in toluene (5 mL), and tert-butyl carbamate (316 mg, 2.7 mmol), tris(dibenzyl-BASE acetone) dipalladium (49 mg, 0.054 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (26 mg, 0.054 mmol) and potassium tert-butoxide (151 mg, 1.35 mmol) were added in sequence, and the reaction was carried out at 100 ° C for 8 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (7-((3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-4-yl)carbamate 1k (155 mg), yield: 94%.

[0199] MS m / z(ESI):613.4[M+H] +

[0200] Step 11

[0201] 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-

[0202] dihydrobenzofuran-7-carboxamide

[0203] 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0204] Tert-butyl (7-((3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-4-yl)carbamate 1k (155 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (15 mL), and saturated sodium bicarbonate solution was added to adjust the pH to 7. The mixture was washed with water (10 mL) and saturated brine (10 mL) in sequence. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 11 (129 mg), which was directly used for the next step reaction.

[0205] MS m / z(ESI):513.3[M+H] +

[0206] Step 12

[0207] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4-(ethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0208] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4-(ethylsulfonamido)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide

[0209] 4-Amino-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 11 (129 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (76 mg, 0.75 mmol) and ethylsulfonyl chloride (65 mg, 0.5 mmol) were added under nitrogen atmosphere, and reacted at room temperature for 5 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with water (20 mL) and saturated brine (20 mL) in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved in a mixed solvent of methanol (1 mL), tetrahydrofuran (1 mL) and water (2 mL), sodium hydroxide (20 mg, 0.52 mmol) was added, and stirred at room temperature for 5 hours. The reaction solution was added with 1M hydrochloric acid solution to adjust pH=7, diluted with ethyl acetate (20 mL), washed with water (20 mL) and saturated brine (20 mL) in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: B system) and preparative liquid separation (separation column: Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.1% FA+H2O, mobile phase B: CH3CN) to obtain N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4-(ethylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)-2,3-dihydrobenzofuran-7-carboxamide 1 (17 mg), yield: 20%.

[0210] MS m / z(ESI):605.3[M+H] +

[0211] 1 H NMR (400MHz, DMSO-d6): δ9.96(s,1H),8.34(s,1H),7.37-7.27(m,2H),6.90(d,J=8.9Hz,1H),6.60(s,1H),4.51(t,J=8 .4Hz,2H),3.77(s,3H),3.17-2.99(m,8H),2.92(s,4H),2.09(s,4H),1.34(s,4H),1.23(t,J=7.3Hz,3H),0.25(s,4H).

[0212] Biological evaluation

[0213] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on OVCAR-3 cell proliferation

[0214] The following method was used to determine the effect of the compounds of the present invention on the proliferation of OVCAR-3 cells. OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).

[0215] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 72 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then the luminescence value of each well of the sample was read on the microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC of the compound to inhibit cell proliferation. 50 value.

[0216] IC of the compounds of the present invention 50 The value results are represented by A, B, and C, respectively:

[0217] "A" stands for IC 50 ≤50nM; "B" means 50nM <IC 50 ≤500nM; "C" indicates IC 50 >500nM.

[0218] Table 1 The inhibitory activity of the compounds of the present invention on OVCAR-3 cell proliferation

[0219] Example No. <![CDATA[IC 50 (nM)]]> 1 A

[0220] Conclusion: The compounds of the present invention have an IC inhibitory effect on the proliferation of OVCAR-3 cells. 50 <50nM, with good inhibitory effect.

[0221] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on HT-29 cell proliferation

[0222] The following method was used to determine the effect of the compounds of the present invention on HT-29 cell proliferation. HT-29 cells (containing the TP53R273H mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).

[0223] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 120 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then the luminescence value of each well of the sample was read on the microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC of the compound to inhibit cell proliferation. 50 value.

[0224] IC of the compounds of the present invention 50 The value results are represented by A, B, and C, respectively:

[0225] "A" stands for IC 50 ≤50nM; "B" means 50nM <IC 50 ≤500nM; "C" indicates IC 50 >500nM.

[0226] Table 2 The inhibitory activity of the compounds of the present invention on HT-29 cell proliferation

[0227] Example No. <![CDATA[IC 50 (nM)]]> 1 A

[0228] Conclusion: The compounds of the present invention have an IC 50 <200nM, with good inhibitory effect.

[0229] Test Example 3: Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention

[0230] The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of recombinant human KIF18A enzyme under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay Kit (Cat. No. V9102). For detailed experimental procedures, please refer to the kit instructions.

[0231] The experimental process is briefly described as follows: the test compound is first dissolved in DMSO to prepare a storage solution, and then gradient dilution is performed using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68). The final concentration range of the test compound in the reaction system is 10000nM to 0.15nM; KIF18A protein and ATP working solution are prepared using reaction buffer B (15mM Tris, pH7.5, 10mM MgCl2, 0.01% Pluronic F-68, 37.5ug / ml tubulin, 1.25uM paclitaxel). The reaction is carried out in a 384-well microplate. First, the compound and recombinant human KIF18A protein (final concentration 100nM, commissioned by GenScript for expression) are added to the wells and incubated at room temperature for 20 minutes. Then, ATP solution (from ADP-Glo TM Kinase Assay kit component V915A, final concentration 60uM) and incubate at room temperature for 20 minutes. Then add 5μL ADP-Glo ​​Reagent to the reaction system and incubate at room temperature for 50 minutes. Then add 10μL Kinase Detection Reagent to the reaction system and incubate at room temperature for 30 minutes. After the incubation, the chemiluminescence intensity value of each well was measured in the ELISA reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing with the luminescence intensity ratio of the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration logarithm-inhibition rate was performed using GraphPad Prism 5 software to obtain the IC value of the compound. 50 Values ​​are shown in Table 3.

[0232] IC of the compounds of the present invention 50 The value results are represented by A, B, and C, respectively:

[0233] "A" stands for IC 50 ≤100nM; "B" means 100nM <IC 50 ≤500nM; "C" indicates IC 50 >500nM.

[0234] Table 3 IC of the compounds of the present invention for inhibiting KIF18A enzyme activity 50 data

[0235] Example No. <![CDATA[IC 50 (nM)]]> 1 A

[0236] Conclusion: The compounds of the present invention have an inhibitory effect on KIF18A enzyme activity. 50 <100nM, with significant inhibitory effect.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: Select from single or double bonds as required so that each atom thereof assumes a normal valence state; Y1, Y2, Y3 are each independently selected from C, N or CR d , and at most two atoms among Y1, Y2, and Y3 are N atoms at the same time; R d is selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl; Ring A is selected from 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl, 6-membered aryl or 5- to 7-membered heterocyclyl; R c are the same or different and are independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; Ring B is selected from a 4- to 8-membered monocyclic heterocyclic group, wherein the heterocyclic group contains at least one nitrogen atom; R a Does not exist; or two R a Together with the same or different atoms to which it is connected, it forms a 3-6-membered cycloalkyl or 3-6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more R A replace; R A are the same or different and are independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or hydroxyalkyl; or, two R A It forms a -C(=O) with the same carbon atom to which it is attached; R b are the same or different and are each independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or =O; Or, two R b The same carbon atom to which it is attached forms a -C(=O) or -C=CR g R h ; R g , R h are each independently selected from a hydrogen atom, a deuterium atom, a halogen or an alkyl group; X1 and X2 are each independently selected from CR e or N atoms; R e Selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl, alkoxy, -C(=O)NH2, -N(CH3)2 or acetyl; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, -N(CH3)2 or alkoxy; R 2 , R 3 Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group, a cycloalkyl group or an alkoxy group; wherein the alkyl group, the cycloalkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; Or, R 2 and R 3 The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace; R 4 is selected from cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(=O)R 5 、-C(=O)OR 5 、-NHC(=O)R 5 、-NHC(=O)OR 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-CH2NHC(=O)OR 5 、-CH2NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; Or, when X2 is CR e When R 3 or R 4 and R e The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace; Or, when X1 is CR e When R 4 and R e The carbon atom to which it is connected forms a 5- to 7-membered cycloalkyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclic group, wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by one or more R D replace; R D Each independently selected from halogen, hydroxyl, cyano, alkyl, cycloalkyl, alkoxy, heterocyclic, -OR 11 or =0, wherein the alkyl, cycloalkyl, alkoxy or heterocyclic group may be further substituted by halogen, hydroxyl, cyano, alkyl, cycloalkyl or alkoxy substituents; R 11 Each is independently selected from cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, alkyl, alkoxy, haloalkyl; L1 is selected from a bond, -C 1-6 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-SC 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-OC 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )S(=O)2NR f -C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )C(=O)NR f -C 0-4 Alkylene-, -C 0-4 Alkylene-C(=O)N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-N(R f )C(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-PC 0-4 Alkylene-, -C 0-4 Alkylene-P(=O)2-C 0-4 Alkylene, -C 0-4 Alkylene-C(=O)-C 0-4 Alkylene- or -C 0-4 Alkylene-C(=N(OH))-C 0-4 Alkylene-, wherein the -C 1-6 Alkylene- or -C 0-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cycloalkyl or alkoxy; R f are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group; R 1 is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; L2 is selected from or a 5-6 membered heteroaryl; R B Each is independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy. Preferably, R B is a hydrogen atom; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(=O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-S(=O)2NR 9 R 10 or -NR 9 C(=O)R 10 substituted by a substituent; R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; r is independently 0, 1 or 2.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to general formula (II-1) or (II-2): in, Ring A, Ring B, X1, X2, Y1, Y2, Y3, R 1 ~R 4 , R a , R b , R c , L1, m or n are as defined in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Each is independently selected from the following groups:

4. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein is a double bond, and Y1 and Y2 are C atoms.

5. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Each independently selected from:

6. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: L1 is selected from a bond, -N(R f )-C 0-4 Alkylene-, -N(R f )S(=O)2-C 0-4 Alkylene-, -S(=O)2N(R f )-C 0-4 Alkylene-, -N(R f )S(=O)2N(R f )-、-S(=O)(=NH)-、-N(R f )S(=O)(=NH)-、-C 1-4 Alkylene-, -S(=O)-, -O-, -C(=O)-, -C(=O)N(R f )-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)2-C 0-4 Alkylene- or -N(R f )-C(=O)-, wherein the -C 0-4 Alkylene- or -C 1-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cyclopropyl or methoxy; R f Each is independently selected from a hydrogen atom or a methyl group.

7. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: L1 is selected from a bond, -NHCH2CH2-, -NHS(=O)2-, -NHS(=O)2CH2-, -NHS(=O)2CH2CH2-, -S(=O)2NH-, -S(=O)2NHCH2CH2-, -NHS(=O)2NH-, -NHS(=O)2N(CH3)-, -S(=O)2-, -CH2S(=O)2-, -S(=O)(=NH)-, -NHC(CH3)2CH2-, -C(=O)NHC H2CH2-, -C(=O)NHC(CH3)2CH2-, -C(=O)N(CH3)CH2CH2-, -NHS(=O)2CH(CH3)CH2-, -S(=O)2NHC(CH3)2CH2-, -C(=O)NH- or -CH2S(=O)2CH2CH2-.

8. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.

9. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein for 10. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently selected from CR e or N atoms; R e is selected from a hydrogen atom or an alkoxy group; preferably, the alkoxy group is a methoxy group.

11. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 , R 3 are each independently selected from a hydrogen atom.

12. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 Each is independently selected from a 3- to 10-membered heterocyclyl or a 3- to 10-membered cycloalkyl, wherein the heterocyclyl or cycloalkyl is optionally further substituted by one or more alkyl or halogen.

13. The compound according to claim 12, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 for 14. The compound according to any one of claims 1 to 13 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the compound is:

15. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

16. Use of the compound according to any one of claims 1 to 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a KIF18A inhibitor.

17. Use of the compound according to any one of claims 1 to 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease mediated by KIF18A; preferably, the disease mediated by KIF18A is cancer.

18. The method of claim 17, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer or lung adenocarcinoma.

19. Use of the compound according to any one of claims 1 to 14, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating cancer.

20. The use according to claim 19, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer or lung adenocarcinoma.

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