KIF18A inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a formula (1) and a preparation method thereof, a composition containing the compound as shown in the formula (1) and / or pharmaceutically acceptable salt thereof, a preparation method and application of the composition as a KIF18A inhibitor in preparation of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of KIF18A inhibitors and a preparation method and use thereof. Background Art

[0002] Cell division can be divided into three types: mitosis, amitosis and meiosis. The characteristic of mitosis is that chromosomes are reorganized under the guidance of the spindle, and sister chromosomes are separated and evenly distributed to daughter cells. This is a common way for higher animals and plants to carry out life activities such as proliferation. Various kinases and kinesins have been identified to play a key role in the regulation and progression of the cell cycle and mitosis of normal dividing cells and cancer cells.

[0003] 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 [Nature Review Cancer, 2012, 12, 527-539]. KIF18A is a member of the Kinesin-8 family. It is a molecular kinesin that uses microtubules as tracks to move toward the positive end of microtubules. It regulates the midplate assembly of chromosomes by affecting the dynamic instability of the microtubule ends and functions during mitosis. KIF18A is believed to affect the dynamics of the positive end of the centromere microtubule to control the correct chromosome positioning and spindle tension.

[0004] Changes in the number of chromosomal gene copies can produce aneuploid cells, which is the most common genetic change in human cancer. Since cancer cells are almost all aneuploid, while normal cells are almost all euploid. Aneuploid cells exhibit abnormal spindle geometry and dynamics, and maintain division when the spindle assembly checkpoint is inhibited, resulting in more and more mitotic defects and the formation of less stable and less matched karyotypes. Studies have found that the activity of the mitotic kinesin KIF18A in aneuploid cancer cells is disturbed. Depletion of KIF18A can significantly inhibit aneuploid cancer cells, while overexpression of KIF18A can restore their response to spindle assembly checkpoint inhibitors. The synthetic lethal interaction between aneuploidy and spindle assembly checkpoints has therapeutic significance. Aneuploidy can sensitize cancer cells to mitotic checkpoint inhibitors. KIF18A is expected to become a new target for aneuploid malignancies such as triple-negative breast cancer [Nature, 2021, 590, 486-491].

[0005] KIF18A is overexpressed in many types of cancer, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, prostate cancer, bladder cancer, head and neck cancer, uterine cancer, and ovarian cancer.

[0006] The KIF18A inhibitor AMG-650 developed by Amgen has entered the Phase 1 clinical study stage for the treatment of adult patients with locally advanced or metastatic solid tumors carrying p53 gene mutations (TP53MUT) or triple-negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC) or serous endometrial cancer.

[0007]

[0008] However, current KIF18A inhibitors still have disadvantages such as insufficient activity or high toxicity and side effects. Therefore, there is an urgent need in the art to develop new KIF18A inhibitors with high activity, strong specificity and / or high safety. Summary of the invention

[0009] The purpose of the present invention is to provide a novel KIF18A inhibitor with high activity, strong specificity and / or high safety, and a preparation method and application thereof.

[0010] In the first aspect of the present invention, a compound having a general structural formula as shown in formula (1), or its isomers (such as optical isomers), various crystal forms, pharmaceutically acceptable salts, hydrates or solvates is provided:

[0011]

[0012] In formula (1):

[0013] n is 1, 2, 3 or 4;

[0014] X 1 , X 2 , X 3 Each is N or CR independently 5 ;

[0015] Ring A is selected from 6-10 membered aryl or 5-14 membered heteroaryl;

[0016] Y is selected from -C(O)NR b -、-NR b C(O)- or 5-6 membered heteroaryl;

[0017] L is selected from the following group: chemical bond, -NR a -、-SO 2 -、-O-、-NR a S(O) 2 -、-S(O) 2 NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0018] R a and R bEach independently is H or C 1-3 alkyl;

[0019] R 1 and R 2 Each is independent of C 1-3 Alkyl; or R 1 and R 2 The Si atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S;

[0020] R 3 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or -O(CO)R 6 ;

[0021] Each R 4 Independently selected from the group consisting of halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-10 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0022] R 5 Selected from the group consisting of H, halogen, C 1-3 Alkyl or C 1-3 Alkoxy;

[0023] R 6 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclyl; the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, C(O)OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or NR d R e ; where R d and R e Each independently selected from the following group: H or C 1-3 Alkyl; or R d and R e The nitrogen atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S.

[0024] In another preferred embodiment, in the compound of formula (1), Y is selected from the following groups: -C(O)NH-, -NHC(O)-,

[0025]

[0026] Wherein, “*” indicates the position connected to ring A.

[0027] In another preferred embodiment, in the compound of formula (1), X 1 , X 2 , X 3 Each is independently selected from the group consisting of N, CH, CF, CMe or C(OMe).

[0028] In another preferred embodiment, wherein the compound of formula (1) is Select from the following group:

[0029]

[0030] Where n and R 4 The definitions are as above.

[0031] In another preferred embodiment, in the compound of formula (1), each R 4 Selected from the group consisting of F, Cl, CN, Me, Et, CF 3 、OMe、OEt、OCD 3 、OCF 3 、OCH 2 CF 3 ,

[0032] In another preferred embodiment, in the compound of formula (1), Select from the following group:

[0033] In another preferred embodiment, in the compound of formula (1), LR 3Select from the following group:

[0034]

[0035] In another preferred embodiment, the compound has a structure selected from the following group:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049] In the second aspect of the present invention, a pharmaceutical composition is provided, which contains a pharmaceutically acceptable excipient or carrier and the compound of formula (1) described in the first aspect of the present invention, or its isomers, polymorphs, pharmaceutically acceptable salts (inorganic salts or organic salts), hydrates or solvates as active ingredients.

[0050] In the third aspect of the present invention, there is provided a use of the compound described in the first aspect of the present invention, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition described in the second aspect of the present invention, which is used to prepare a drug for preventing and / or treating diseases mediated by KIF18A.

[0051] In another preferred embodiment, the diseases mediated by KIF18A are selected from the following groups: brain tumors, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, leukemia, lymphoma and other solid tumors and blood tumors.

[0052] In the fourth aspect of the present invention, a method for treating, regulating and / or preventing diseases mediated by KIF18A is provided, comprising the steps of administering to an individual in need thereof the compound described in the first aspect of the present invention, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition described in the second aspect of the present invention.

[0053] In another preferred embodiment, the individual includes humans and non-human mammals.

[0054] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0055] After extensive and in-depth research, the inventors have discovered for the first time a class of compounds of formula (1) through a large number of screenings and tests, which have significant therapeutic effects on diseases related to KIF18A. The compounds of the present invention have good cell proliferation inhibitory activity on the OVCAR-3 cell line with TP53 mutation and CCNE1 amplification, and the present invention was completed on this basis.

[0056] Compounds of the present invention and their synthesis

[0057] The present invention provides an inhibitor targeting KIF18A, namely, a compound of formula (1), or each isomer thereof, or an isomer, crystal form, pharmaceutically acceptable salt (inorganic salt or organic salt), hydrate or solvate thereof. Preferably, the compound of the present invention is as described in the first aspect.

[0058] The present invention also provides a method for preparing the compound of formula (1) of the present invention. The following specifically describes the method for preparing the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0059] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanation. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction schemes 1 to 5:

[0060] General reaction scheme 1:

[0061]

[0062] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G 1 is halogen or amino, A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , L and n are as defined above.

[0063] General reaction scheme 2:

[0064]

[0065] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G 1 is halogen or amino, A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , L and n are as defined above.

[0066] General reaction scheme 3:

[0067]

[0068] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G 1 is halogen or amino, A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , L and n are as defined above.

[0069] General reaction scheme 4:

[0070]

[0071] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G 1 is halogen or amino, A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4, L and n are as defined above.

[0072] General reaction scheme 5:

[0073]

[0074] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein G 1 is halogen or amino, A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , L and n are as defined above.

[0075] Related definitions

[0076] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0077] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0079] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0080] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0081] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0082] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0083] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0084] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0085] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0086]

[0087] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0088] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereoisomer resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0089] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14(14 C). For another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0090] "Optional" or "optionally" means 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.

[0091] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0092] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0093] When the number of a linking group is 0, such as -(CH 2 ) 0 -, indicating that the connecting group is a single bond.

[0094] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0095] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7, C 8 , C 9 , C 10 , C 11 and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring and 6-10-membered ring, etc.

[0096] Unless otherwise specified, “C 1-6 "Alkyl" is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-4 , C 2-6 , C 3-5 , C 5 and C 6 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, 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, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and various branched chain isomers thereof, and the like.

[0097] Unless otherwise specified, “C 1-3 "Alkyl" is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, and the like.

[0098] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic aliphatic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0099] Unless otherwise specified, “C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2 and C 3 Alkoxy, etc.; C 1-3 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.

[0100] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur or nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.

[0101] Unless otherwise specified, "heterocyclyl" by itself or in combination with other terms means a saturated or partially saturated cyclic group consisting of 4 to 14 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are optionally oxidized (i.e., C(=O), NO, SO and SO 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings. In addition, heteroatoms can occupy the connecting position of the heterocyclic group to the rest of the molecule, and the heterocyclic group includes saturated and partially unsaturated heterocyclic groups. Non-limiting examples of heterocyclic groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like.

[0102] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0103] "Hydroxy" refers to -OH.

[0104] "Cyano" refers to -CN.

[0105] Specific pharmaceutical and medical terms

[0106] The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

[0107] The terms "treat", "treatment" or "therapy" as used herein include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.

[0108] "Active ingredient" refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0109] The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0110] The term "administered," "administering," or "administration" as used herein refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.

[0111] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it should be understood that all ranges, quantities, values ​​and percentages used herein (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and the like) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values ​​and can be changed as needed. At least these numerical parameters should be understood as the number of significant digits indicated and the values ​​obtained using the general rounding method.

[0112] Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as those commonly understood by those skilled in the art. In addition, singular nouns used in this specification include plural forms of the nouns, and plural nouns used also include singular forms of the nouns, unless they conflict with the context.

[0113] Route of administration

[0114] The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.

[0115] "Pharmaceutically acceptable excipients or carriers" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0116] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0117] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0118] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0119] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0120] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0121] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0122] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0123] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0124] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0125] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0126] The main advantages of the present invention include:

[0127] (a) Unexpectedly, compared with AMG650, the compound of formula (1) of the present invention showed good in vitro inhibition of KIF18A enzyme activity;

[0128] (b) The compounds of the present invention have good drugability.

[0129] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0130] In the following description, each specific aspect, characteristic and advantage of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail to make the content of the present invention become very clear. It should be understood that the following detailed description and examples describe specific embodiments and are for reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the application.

[0131] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, with the light source being CuKα phase radiation and the scanning mode being: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0132] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm). The silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratios of the eluents were all by volume.

[0133] The present invention adopts the following abbreviations: ACN (CH 3 CN) represents acetonitrile; Cs 2 CO 3 represents cesium carbonate; CsF represents cesium fluoride; CuI represents cuprous iodide; DCM represents dichloromethane; DIAD represents diisopropyl azodicarboxylate; DIPEA (DIEA) represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA (EtOAc) represents ethyl acetate; EtOH represents ethanol; Fe represents iron; h represents hour; K represents 2 CO 3 K stands for potassium carbonate; 3 PO 4 stands for potassium phosphate; MeOH stands for methanol; min stands for minute; MS stands for mass spectrometry; N 2 stands for nitrogen; NaH stands for sodium hydride; NaNO 2 stands for sodium nitrite; NaOH stands for sodium hydroxide; NH 4 Cl stands for ammonium chloride; NMI stands for N-methylimidazole; NMR stands for nuclear magnetic resonance; Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium; PE stands for petroleum ether; PPh 3 represents triphenylphosphine; Ruphos-Pd-G3 represents methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); t-BuONa stands for sodium tert-butoxide; TCFH stands for tetramethyl chlorouronium hexafluorophosphate; TEA stands for triethylamine; TFA stands for trifluoroacetic acid; TFAA stands for trifluoroacetic anhydride; THF stands for tetrahydrofuran; TLC stands for thin layer chromatography; Ts 2 O represents p-toluenesulfonic anhydride; TMSN 3 Xantphos stands for 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

[0134] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0135] Example 1: Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-(((2-hydroxyethyl)sulfonamido)benzamide (Compound 1)

[0136]

[0137] Step 1:

[0138] 3-Bromo-5-nitropyridine (500 mg, 2.46 mmol), XantPhos (145 mg, 0.25 mmol), Pd 2 (dba) 3 (229 mg, 0.25 mmol), Cs 2 CO 3 (2.40g, 7.38mmol), 4,4-difluoropiperidine hydrochloride (582mg, 3.69mmol) were dissolved in dioxane (20mL), nitrogen protection, and the temperature was raised to 100℃ for overnight reaction. LC-MS monitoring showed that the raw material reaction was complete. Filter, directly concentrate, column chromatography (PE / EA=20 / 1to 5 / 1) to obtain a light yellow solid (300mg, yield 50%), ESI-MS m / z: 244.1[M+H] + .

[0139] Step 2:

[0140] Dissolve the 2-ethoxy-3-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (243 mg, 1.0 mmol) obtained in ethanol and water (EtOH / H 2O=5 / 1,8mL), add iron powder (280mg, 5mmol), ammonium chloride (268mg, 5mmol), and heat to 80℃ under nitrogen protection for 1h. LC-MS monitoring shows that the raw material reaction is complete. Filter, dilute the filtrate with water (30mL), extract with EA (30mL*3), combine the organic phases, dry, filter, concentrate, and column chromatography (PE / EA=10 / 1to 1 / 1) to obtain a light yellow solid (192mg, yield 90%), ESI-MS m / z: 214.1[M+H] + .

[0141] Step 3:

[0142] Methyl 2-fluoro-4-bromobenzoate (7.0 g, 30.0 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (5.5 g, 33.0 mmol) were dissolved in DMSO (100 mL) and K 2 CO 3 (12.4 g, 90.0 mmol), nitrogen protection, heating to 140 ° C overnight. LC-MS monitoring, the raw material reaction is complete. Pour into ice water (300 mL), EA (100 mL * 3) extraction, combine the organic phase, concentrate, column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a white solid (8.2 g, yield 80%), ESI-MS m / z: 342.0.1 [M + H] + .

[0143] Step 4:

[0144] Methyl 4-bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)benzoate (6.84 g, 20.0 mmol) was dissolved in MeOH / H 2 O (5 / 1, 50mL), add sodium hydroxide (4.0g, 100mmol), react at 50℃ for 6h, LC-MS monitoring, the reaction of raw materials is complete. The reaction solution is adjusted to pH about 5, concentrated, filtered, and dried to obtain a light yellow solid (4.0g, yield 61%), ESI-MS m / z: 328.0 [M+H] + .

[0145] Step 5:

[0146] 4-Bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)benzoic acid (164 mg, 0.5 mmol) was dissolved in ACN (10 mL), and 5-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (107 mg, 0.5 mmol) was added. 2Under protection, add TCFH (281 mg, 1.0 mmol) and NMI (164 mg, 2.0 mmol), stir at room temperature overnight, and monitor by LC-MS. The reaction of the raw materials is complete. Pour into ice water (30 mL), extract with EA (30 mL*2), combine the organic phases, dry, concentrate, and column chromatography (PE / EA=20 / 1 to 2 / 1) to obtain a light yellow solid (185 mg, yield 71%), ESI-MS m / z: 523.1 [M+H] + .

[0147] Step 6:

[0148] 4-Bromo-N-[5-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]-2-(4,4-dimethyl-1,4-azasilanyl)benzamide (185 mg, 0.353 mmol), 2-hydroxyethane-1-sulfonamide (88 mg, 0.706 mmol), CuI (67 mg, 0.353 mmol), K 3 PO 4 (150mg, 0.706mmol),(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (25 mg, 0.177 mmol) was dissolved in DMF (10 mL), N 2 Protect, heat to 100℃ and react overnight. LC-MS monitoring shows that the raw material has reacted completely. Pour into ice water (30mL), extract with DCM (30mL*3), combine the organic phases, dry, concentrate, and column chromatography (DCM / MeOH=100 / 1to 10 / 1) to obtain a light yellow solid (90mg, yield 45%).

[0149] 1 H NMR (400 MHz, DMSO-d 6 ): δ12.87(s,1H),8.76(s,1H),8.36(s,2H),7.53(s,1H),7.32(d,J=1.8Hz,1H),7.18(dd,J=1.8,8.8Hz,1H),3.98-3.90(m ,4H),3.77(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),2.98-2.90(m,4H),2.16-1.99(m,4H),0.92(s,4H),0.15(s,6H); ESI-MS m / z:568.2[M+H] + .

[0150] Example 2-77: Synthesis of Compound 2-77

[0151] Using different amines as raw materials, the following compounds 2-77 were obtained according to a similar synthesis method to Example 1.

[0152]

[0153]

[0154]

[0155]

[0156] Example 78: Synthesis of 2-(4,4-difluoropiperidin-1-yl)-N-(2-(4,4-dimethyl-1,4-azasilan-1-yl)-4-((2-hydroxyethyl)sulfonamido)phenyl)-6-methylpyrimidine-4-carboxamide (Compound 78)

[0157]

[0158] Step 1:

[0159] 6-Bromo-5-methoxymethylpyridinate (1.0 g, 4.06 mmol), Xantphos (231 mg, 0.4 mmol), Pd 2 (dba) 3 (366 mg, 0.4 mmol), CS 2 CO 3 (3.97 g, 12.18 mmol), 4,4-difluoropiperidine hydrochloride (960 mg, 6.09 mmol) was dissolved in Dioxane (30 mL), N 2 Replace 5 times, heat to 100℃ and react for 20h. LC-MS monitoring shows that the raw material has reacted completely. Filter, concentrate directly, and column chromatography (PE / EA=20 / 1to 3 / 1) to obtain a light yellow solid (640mg, yield 55%), ESI-MS m / z: 287.1[M+H] + .

[0160] Step 2:

[0161] 6-(4,4-difluoropiperidin-1-yl)-5-methoxymethylpicolinic acid methyl ester (640 mg, 2.24 mmol) was dissolved in methanol / water (5 / 1), and NaOH (448 mg, 11.2 mmol) was added. The mixture was stirred at 60°C for 2 h. After LC-MS monitoring, the reaction of the raw material was complete. A 2M HCl aqueous solution was added to adjust the pH to 4-5, and the mixture was concentrated. After the solid precipitated, it was filtered and the filter cake was dried to obtain a light yellow solid crude product (335 mg, yield 55%). ESI-MS m / z: 273.2 [M+H] + .

[0162] Step 3:

[0163] 4-Bromo-2-fluoro-1-nitrobenzene (6.6 g, 30.0 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (5.5 g, 33.0 mmol) were dissolved in DMSO (100 mL) and K 2 CO 3 (12.4 g, 90.0 mmol), nitrogen protection, heating to 100 ° C overnight. LC-MS monitoring, the raw material reaction is complete. Pour into ice water (300 mL), EA (100 mL * 2) extraction, combine the organic phases, concentrate, column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a white solid (8.1 g, yield 82%), ESI-MS m / z: 329.0 [M + H] + .

[0164] Step 4:

[0165] Dissolve 1-(5-bromo-2-nitrophenyl)-4,4-dimethyl-1,4-azasilane (328 mg, 1.0 mmol) obtained in EtOH / H 2 O (5 / 1, 20 mL), added Fe powder (336 mg, 6.0 mmol), NH 4 Cl (321 mg, 6.0 mmol), N 2 The reaction was heated to 80°C and refluxed for 1 h under protection. The reaction of the raw material was completed after LC-MS monitoring. The filtrate was filtered, diluted with water (40 mL), extracted with EA (40 mL*3), and the organic phases were combined, dried, filtered, concentrated, and column chromatographed (PE / EA=10 / 1 to 1 / 1) to obtain a light yellow solid (240 mg, yield 80%), ESI-MS m / z: 299.1 [M+H] + .

[0166] Step 5:

[0167] 6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridine-2-carboxylic acid (136 mg, 0.5 mmol) was dissolved in ACN (10 mL), and 4-bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)aniline (150 mg, 0.5 mmol) was added. 2Under protection, add TCFH (281 mg, 1.0 mmol) and NMI (164 mg, 2.0 mmol), stir at room temperature overnight, and monitor by LC-MS. The reaction of the raw materials is complete. Pour into ice water (30 mL), extract with EA (30 mL*2), combine the organic phases, dry, concentrate, and column chromatography (PE / EA=20 / 1 to 2 / 1) to obtain a light yellow solid (205 mg, yield 74%), ESI-MS m / z: 553.1 [M+H] + .

[0168] Step 6:

[0169] The N-[4-bromo-2-(4,4-dimethyl-1,4-azasilanyl)phenyl]-6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridine-2-carboxamide (205 mg, 0.371 mmol), 2-hydroxyethane-1-sulfonamide (93 mg, 0.743 mmol), CuI (71 mg, 0.371 mmol), K 3 PO 4 (158mg, 0.743mmol),(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (26 mg, 0.186 mmol) was dissolved in DMF (10 mL), N 2 Protect, heat to 100℃ and react overnight. LC-MS monitoring shows that the raw material has reacted completely. Pour into ice water (30mL), extract with DCM (30mL*2), combine the organic phases, dry, concentrate, and column chromatography (DCM / MeOH=100 / 1to 10 / 1) to obtain a light yellow solid (150mg, yield 67%).

[0170] 1 H NMR (400 MHz, DMSO-d 6 ): δ12.56(s,1H),8.38(d,J=2.0Hz,1H),7.78(d,J=8.6Hz,1H),7.67(d,J=2.2Hz,1H),7.11(d,J=2.4Hz,1H),6.85(dd,J=8.6,2.4Hz,1H),4.98( s,3H),3.88-3.80(m,4H),3.78(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H), 2.93-2.82(m,4H),2.10-1.90(m,4H),0.90(s,4H),0.17(s,6H); ESI-MS m / z:598.2[M+H] + .

[0171] Examples 79-82: Synthesis of Compounds 79-82

[0172] Using different carboxylic acids as raw materials, the following compounds 79-82 were obtained according to a similar synthesis method to Example 78.

[0173]

[0174] Example 83: Synthesis of N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(4,4-dimethyl-1,4-azasilan-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 83)

[0175]

[0176] Step 1:

[0177] 4-Bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)aniline (450 mg, 1.5 mmol) was dissolved in MeCN (20 mL) and TMSN was added at 0°C. 3 (426 mg, 3.7 mmol) / MeCN (2.5 mL) solution was stirred at 0°C for 0.5 h, and a solution of tert-butyl nitrite (382 mg, 3.7 mmol) in MeCN (2.5 mL) was added dropwise, and stirred at 20°C for 6 h. 2 O (40 mL), extracted with EA (40 mL * 2), and washed with Na 2 SO 4 Dry, filter, concentrate, and column chromatography (PE / EA=100 / 1 to 3 / 1) to obtain a light yellow solid (342 mg, yield 70%). ESI-MS m / z: 325.0 [M+H] + .

[0178] Step 2:

[0179] Under nitrogen protection, 2,4-dichloro-6-methylpyrimidine (1.63 g, 10.0 mmol) was dissolved in THF (50 mL), and ethynyltrimethylsilane (982 mg, 10.0 mmol) and Pd(Ph 3 P) 2 Cl 2(702 mg, 1.0 mmol), CuI (190 mg, 1.0 mmol), TEA (3.04 g, 30.0 mmol), react at 50°C for 5 h. LC-MS monitoring showed that the raw material was completely reacted, and the crude product was concentrated. Column chromatography (PE / EA = 20 / 1 to 5 / 1) gave a light yellow solid (1.12 mg, yield 50%), ESI-MS m / z: 225.0 [M+H] + .

[0180] Step 3:

[0181] Dissolve 2-chloro-4-methyl-6-((trimethylsilyl)ethynyl)pyrimidine (675 mg, 3.0 mmol) in DMF (10 mL), add DIPEA (1.16 g, 9.0 mmol), 4,4-difluoropiperidine hydrochloride (567 mg, 3.6 mmol), and heat to 60 ° C for 8 h. LC-MS monitoring shows that the raw material reaction is complete, the reaction solution is poured into water, and EA is extracted. Dry, filter, and concentrate to obtain a crude product. Column chromatography (PE / EA=20 / 1to 5 / 1) gives a white solid (696 mg, yield 75%), ESI-MS m / z: 310.1 [M+H] + .

[0182] Step 4:

[0183] 2-(4,4-difluoropiperidin-1-yl)-4-methyl-6-((trimethylsilyl)ethynyl)pyrimidine (309 mg, 1.0 mmol) was dissolved in MeOH (10 mL) and K 2 CO 3 (276 mg, 2.0 mmol), react at room temperature for 5 h, LC-MS monitoring, the raw material reaction is complete, filtered, concentrated, column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a light yellow solid (130 mg, yield 55%), ESI-MS m / z: 238.1 [M+H] + .

[0184] Step 5:

[0185] 2-(4,4-difluoropiperidin-1-yl)-4-ethynyl-6-methylpyrimidine (130 mg, 0.55 mmol) and 1-(2-azido-5-bromophenyl)-4,4-dimethyl-1,4-azasilane (215 mg, 0.66 mmol) were dissolved in THF / H 2 O (15mL / 3mL), add CuSO 4 ·5H 2O (39 mg, 0.165 mmol), sodium ascorbate (55 mg, 0.28 mmol), stirred at 25 ° C overnight, LC-MS monitoring, the raw material reaction was complete. Add ice water (30 mL), EA (20 mL * 3) extraction, combined organic phases, dried, concentrated, column chromatography (PE / EA = 20 / 1 to 2 / 1) to obtain a white solid (217 mg, yield 70%), ESI-MS m / z: 562.1 [M + H] + .

[0186] Step 6:

[0187] 4-(1-(4-bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)-2-(4,5-difluoropiperidin-1-yl)-6-methylpyrimidine (150 mg, 0.267 mmol), 2-hydroxyethane-1-sulfonamide (67 mg, 0.533 mmol), CuI (51 mg, 0.267 mmol), K 3 PO 4 (113 mg, 0.533 mmol), (1R, 2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (19 mg, 0.133 mmol) was dissolved in DMF (8 mL), N 2 Protect, heat to 130℃ for 3h. LC-MS monitoring shows that the raw material has reacted. Pour into ice water (30mL), extract with DCM (30mL*3), combine the organic phases, dry, concentrate, purify with reverse phase, and freeze-dry to obtain a light yellow solid (100mg, yield 62%).

[0188] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.22(s,1H),8.03(s,1H),7.62(d,J=8.5Hz,1H),7.09(d,J=2.1Hz,1H),6.96(dd,J=8.5,2.1Hz,1H),3.95(t,J=5.8Hz,4H),3.7 8(t,J=6.5Hz,2H),3.34(t,J=6.5Hz,2H),2.96(t,J=5.1Hz,4H),2.46(s,3H),2.08-1.96(m,4H),0.96(s,4H),0.21(s,6H); ESI-MS m / z:607.2[M+H] + .

[0189] Example 84-130: Synthesis of Compound 84-130

[0190] Using different alkynes as starting materials, the following compounds 84-130 were obtained according to a similar synthesis method as Example 83.

[0191]

[0192]

[0193]

[0194]

[0195] Example 131: Synthesis of N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(4,4-dimethyl-1,4-azasilan-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 131)

[0196]

[0197] Step 1:

[0198] 2-Fluoro-4-iodobenzaldehyde (1.00 g, 4.00 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (994 mg, 6.0 mmol) were dissolved in DMSO (15 mL) and K 2 CO 3 (1.65g, 12.mol), nitrogen protection, heating to 120℃ for overnight reaction. LC-MS monitoring, the raw material reaction is complete. Pour into ice water (300mL), extract with EA (100mL*3), combine the organic phases, concentrate, column chromatography (PE / EA=20 / 1to 5 / 1) to obtain a white solid (934mg, yield 65%), ESI-MS m / z: 360.0[M+H] + .

[0199] Step 2:

[0200] Dissolve 2-(4,4-dimethyl-1,4-azasilane-1-yl)-4-iodobenzaldehyde (1.8g, 5.0mmol) and potassium carbonate (1.38g, 10.0mmol) in methanol (50ml) solution, add (1-diazo-2-oxypropylene)phosphonic acid dimethyl ester (1.15g, 6.0mmol), stir at room temperature for 16 hours. LC-MS monitoring shows that the raw material reaction is complete. Pour into ice water (150mL), extract with EA (100mL*2), combine the organic phases, concentrate, and column chromatography (PE / EA=20 / 1to 5 / 1) to obtain a white solid (977mg, yield 55%), ESI-MS m / z: 356.0[M+H] + .

[0201] Step 3:

[0202] Dissolve 4-chloro-6-methyl-2-(methylthio)pyrimidine (1.74 g, 10.0 mmol) in DMF (25 mL), add sodium azide (975 mg, 15.0 mmol), and react at room temperature for 16 hours. Pour into ice water (150 mL), extract with EA (100 mL*2), combine the organic phases, concentrate, and column chromatography (PE / EA=20 / 1 to 5 / 1) to obtain a white solid (906 mg, yield 50%), ESI-MS m / z: 182.0 [M+H] + .

[0203] Step 4:

[0204] 1-(2-ethyl-5-iodophenyl)-4,4-dimethyl-1,4-azasilane (710 mg, 2.0 mmol) and 4-azido-6-methyl-2-(methylthio)pyrimidine (400 mg, 2.2 mmol) were dissolved in t- BuOH / H 2 O (15mL / 5mL), add CuSO 4 ·5H 2 O (150 mg, 0.6 mmol), sodium ascorbate (198 mg, 1.0 mmol), stirred at 25 ° C overnight, LC-MS monitoring, the raw material reaction was complete. Add ice water (30 mL), EA (30 mL * 2) extraction, combined organic phases, dried, concentrated, column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain a white solid (685 mg, yield 70%), ESI-MS m / z: 489.1 [M + H] + .

[0205] Step 5:

[0206] 4-(4-(4-bromo-2-(4,4-dimethyl-1,4-azasilane-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-6-methyl-2-(methylthio)pyrimidine (490 mg, 1.0 mmol) was dissolved in DCM (15 mL), cooled to 0°C, 3-chloroperoxybenzoic acid (406 mg, 85%, 2.0 mmol) was added, and the reaction was allowed to slowly reach room temperature. The reaction was stirred at room temperature for 2 h and quenched by adding aqueous sodium sulfite solution. The phases were separated and the DCM phase was treated with 10% Na 2 CO 3 The solution was washed, dried, filtered, concentrated, and column chromatography (PE / EA=20 / 1 to 2 / 1) gave a light yellow solid (443 mg, yield 85%), ESI-MS m / z: 521.1 [M+H] + . .

[0207] Step 6:

[0208] 4-(4-(4-bromo-2-(4,4-dimethyl-1,4-azasilane-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-6-methyl-2-(methylsulfonyl)pyrimidine (443 mg, 0.85 mmol) was dissolved in DMF (5 mL), and DIPEA (330 mg, 2.55 mmol) and 4,4-difluoropiperidine hydrochloride (147 mg, 0.935 mmol) were added. The temperature was raised to 80°C and the reaction was allowed to proceed for 12 h. LC-MS monitoring showed that the raw material reaction was complete. The reaction solution was poured into water, extracted with EA, dried, filtered, and concentrated to obtain a crude product. Column chromatography (PE / EA=20 / 1to 5 / 1) gave a white solid (330 mg, yield 69%), ESI-MS m / z: 562.1[M+H] + Step 7:

[0209] 4-(4-(4-bromo-2-(4,4-dimethyl-1,4-azasilan-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-2-(4,5-difluoropiperidin-1-yl)-6-methylpyrimidine (150 mg, 0.267 mmol), 2-hydroxyethane-1-sulfonamide (67 mg, 0.533 mmol), CuI (51 mg, 0.267 mmol), K 3 PO 4 (113 mg, 0.533 mmol), (1R, 2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (19 mg, 0.133 mmol) was dissolved in DMF (8 mL), N 2The reaction mixture was protected and heated to 130°C for 3 h. After LC-MS monitoring, the reaction of the raw material was complete. The mixture was poured into ice water (30 mL), extracted with DCM (30 mL*3), and the organic phases were combined, dried, concentrated, purified by reverse phase, and freeze-dried to obtain a light yellow solid (90 mg, yield 56%).

[0210] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.15(s,1H),8.96(s,1H),7.52(d,J=8.5Hz,1H),7.03(d,J=2.1Hz,1H),6.91(dd,J=8.5,2.1Hz,1H),3.92-3.82(m,4H),3.77 (t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),2.93(t,J=5.1Hz,4H),2.46(s,3H),2.05-1.93(m,4H),0.93(s,4H),0.20(s,6H); m / z:607.2[M+H] + .

[0211] Examples 132-154: Synthesis of Compounds 132-154

[0212] Using different azides as starting materials, the following compounds 132-154 were obtained according to a similar synthesis method to Example 131.

[0213]

[0214]

[0215] Example 155: Synthesis of N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-(4,4-dimethyl-1,4-azasilan-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 155)

[0216]

[0217] Step 1:

[0218] Dissolve methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.86 g, 10.0 mmol) in DMF (30 mL), add DIPEA (5.17 g, 40.0 mmol), 4,4-difluoropiperidine hydrochloride (2.36 g, 15.0 mmol), and heat to 100 ° C for 6 h. LC-MS monitoring shows that the reaction of the raw materials is complete, and the reaction solution is poured into water and extracted with EA. Dry, filter, and concentrate to obtain a crude product. Column chromatography (PE / EA=20 / 1to 5 / 1) gives a white solid (1.9 g, yield 70%), ESI-MS m / z: 272.1 [M+H] + .

[0219] Step 2:

[0220] Dissolve 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid methyl ester (1.36 g, 5.0 mmol) in anhydrous ethanol (20 mL), add hydrazine hydrate (2.5 g, 50.0 mmol), and stir at room temperature overnight. LC-MS monitoring shows that the raw material reaction is complete. The reaction solution is concentrated under reduced pressure and column chromatography (DCM / MeOH=100 / 1 to 5 / 1) is concentrated to obtain an off-white solid (1.2 g, yield 88%). ESI-MS m / z: 272.1 [M+H] + .

[0221] Step 3:

[0222] 4-Bromo-2-(4,4-dimethyl-1,4-azasilane-1-yl)benzoic acid (328 mg, 1.0 mmol) was dissolved in ACN (10 mL), and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carboxylic acid hydrazide (298 mg, 1.1 mmol) was added. 2 Under protection, add TCFH (337 mg, 1.2 mmol) and NMI (288 mg, 3.5 mmol) and stir at room temperature for 2 h. After monitoring by LC-MS, the reaction of the raw material is complete. Pour into ice water (30 mL), extract with EA (30 mL*2), combine the organic phases, dry, concentrate, and column chromatography (PE / EA=20 / 1 to 1 / 1) to obtain a light yellow solid (407 mg, yield 70%), ESI-MS m / z: 581.1 [M+H] + .

[0223] Step 4:

[0224] Dissolve N'-(4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)benzoyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidine-4-carbohydrazide (200 mg, 0.344 mmol) in Dioxane (15 mL), add POCl 3 (2 mL), heat to 90 °C and react overnight. Monitor by LC-MS until the raw materials are completely reacted. Concentrate directly, dissolve the residue in EA, wash with saturated aqueous sodium bicarbonate solution, concentrate, and perform column chromatography (PE / EA = 20 / 1 to 2 / 1) to obtain a light yellow solid (150 mg, yield 77%); ESI-MS m / z: 563.1 [M+H] + .

[0225] Step 5:

[0226] Dissolve 2-(4-bromo-2-(4,4-dimethyl-1,4-azasilinan-1-yl)phenyl)-5-(2-(4,4-fluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1,3,4-oxadiazole (150 mg, 0.266 mmol), 2-hydroxyethane-1-sulfonamide (67 mg, 0.532 mmol), CuI (51 mg, 0.266 mmol), K 3 PO 4 (113 mg, 0.532 mmol), (1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (19 mg, 0.133 mmol) in DMF (8 mL), under N 2 protection, heat to 100 °C and react overnight. Monitor by LC-MS until the raw materials are completely reacted. Pour into ice water (30 mL), extract with EA (30 mL * 2), combine the organic phases, dry, concentrate, perform reverse-phase purification, and lyophilize to obtain a light yellow solid (90 mg, yield 56%).

[0227] 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.02 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.5, 2.1 Hz, 1H), 4.02 (t, J = 5.8 Hz, 4H), 3.75 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 5.1 Hz, 4H), 2.45 (s, 3H), 2.11 - 1.98 (m, 4H), 0.93 (s, 4H), 0.18 (s, 6H); ESI-MS m / z: 608.2 [M+H] + .

[0228] Examples 156-178: Synthesis of Compounds 156-178

[0229] Using different carboxylic acids as raw materials, the following compounds 156-178 were obtained according to a similar synthesis method to Example 155.

[0230]

[0231]

[0232] Example 179: Synthesis of ethyl 2-(N-(4-((7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)carbamoyl)-3-(4,4-methyl-1,4-azasilan-1-yl)phenyl)sulfamoyl)acetate (Compound 179)

[0233]

[0234] N-(7-(4,4-difluoropiperidin-1-yl)furo[2,3-c]pyridin-5-yl)-2-(4,4-methyl-1,4-azasilane-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (Compound 11, 120 mg, 0.2 mmol) and acetic acid (60 mg, 1.0 mmol) were dissolved in THF (10 mL), and 3-nitro-1,2,4-triazole (57 mg, 0.5 mmol), BOPCl (255 mg, 0.5 mmol) and DIPEA (129 mg, 1.0 mmol) were added and reacted at room temperature for 2 h. LC-MS monitoring showed that the reaction of the raw materials was complete. Pour into ice water (30 mL), extract with EA (20 mL*2), combine the organic phases, dry, concentrate, and perform column chromatography (PE / EA=10 / 1 to 1 / 1) to obtain a light yellow solid (80 mg, yield 62%).

[0235] 1 H NMR (400 MHz, DMSO-d 6): δ12.19(s,1H),10.12(s,1H),8.09(d,J=2.2Hz,1H),7.99(t,J=4.3Hz,2H),7.23 (d,J=2.2Hz,1H),7.08(dd,J=8.7,2.0Hz,1H),7.01(d,J=2.1Hz,1H),4.95(s,1H),3 .90(t,J=5.8Hz,4H),3.75(t,J=6.5Hz,2H),3.4-0-3.30(m,2H),3.18(t,J=6.2Hz, 4H),2.20-2.02(m,7H),1.00(t,J=5.8Hz,4H),0.14(s,6H); ESI-MSm / z:650.2[M+H] + .

[0236] Examples 180-256: Synthesis of Compounds 180-256

[0237] According to the similar synthetic method of Example 179, the following compounds 180-256 were obtained.

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] Example 257: Screening of KIF18A enzyme activity

[0245] This study evaluated the ability of the compounds of the invention to inhibit KIF18A protease activity in vitro. The experiment used the ADP-Glo ​​(Promega) kinase assay to characterize KIF18A inhibitors at 10 μM ATP (Promega). In this experiment, the final concentration of the enzyme was 1 nM, the final concentration of the substrate was 10 μM, and the final concentration of DMSO was 0.5%.

[0246] Compounds were dissolved in DMSO to obtain a stock solution at a concentration of 20 mM. Dose gradient reactions were prepared to have an initial compound concentration of 10 μM, and then four-fold dilutions were performed in DMSO (control compounds were three-fold diluted) for a total of ten data points. 0.025 μL of the diluted compound solution was transferred to a 384 assay plate (Greiner) using an ECHO acoustic pipetting device (LABCYTE), 2.5 μL of KIF18A enzyme working solution was added to the 384-well assay plate, centrifuged at 1000 prm for 1 min, incubated at 25°C for 10 min, and then 2.5 μL of ATP working solution was added to start the reaction, and continued to incubate at 25°C for 60 min, 4 μL of ADP-Glo ​​working solution was added for reaction, the reaction was incubated at 25°C for 40 min, and finally 8 μL of detection working solution was added for reaction, and incubated at 25°C for 40 min. Then the detection was performed under the HTS high-throughput drug screening multifunctional microplate reader (BMG).

[0247] Among them, the structure of the positive drug AMG650 is as follows:

[0248]

[0249] The inhibition rate of the compound on KIF18A protein activity was calculated using the following formula:

[0250] Inhibition percentage (%) = 100*(mean value of DMSO group - mean value of compound) / (mean value of DMSO group - mean value of blank control group).

[0251] The IC values ​​of the compounds were fitted according to the nonlinear regression equation using the software XLfit 5.5.0. 50 The screening results are shown in Table 1.

[0252] Table 1: Inhibitory activity of compounds on KIF18A protein (IC 50 )

[0253]

[0254]

[0255]

[0256] +++: indicates IC 50 ≤100nM

[0257] ++: indicates 100nM <IC 50 ≤500nM

[0258] +: indicates IC 50 >500nM

[0259] It can be seen from the data in the above table that the compounds of the present invention have strong inhibitory activity on KIF18A protein.

[0260] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound having a structure as shown in formula (1), or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof: In formula (1): n is 1, 2, 3 or 4; X1, X2, and X3 are each independently N or CR 5 ; Ring A is selected from 6-10 membered aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl; Y is selected from -C(O)NR b -、-NR b C(O)- or 5-6 membered heteroaryl; L is selected from the following group: chemical bond, -NR a -、-SO2-、-O-、-NR a S(O)2-、-S(O)2NR a -、C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; R a and R b Each independently is H or C 1-3 alkyl; R 1 and R 2 Each is independent of C 1-3 Alkyl; or R 1 and R 2 The Si atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S; R 3 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or -O(CO)R 6 ; Each R 4 Independently selected from the group consisting of halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-10 membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; R 5 Selected from the group consisting of H, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; R 6 Select from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclyl; the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of OH, C(O)OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl or NR d R e ; where R d and R e Each independently selected from the following group: H or C 1-3 Alkyl; or R d and R e The nitrogen atom connected thereto forms a 3-6 membered ring structure, and the ring structure optionally contains 1 or 2 heteroatoms selected from N, O, and S.

2. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), Y is selected from the following groups: -C(O)NH-, -NHC(O)-, Wherein, "*" indicates the position connected to ring A.

3. The compound according to claim 1, or its isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), X1, X2, and X3 are independently selected from the following group: N, CH, CF, CMe or C(OMe).

4. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group: Where n and R 4 Definitions as set forth in claim 1.

5. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), each R 4 Selected from the group consisting of F, Cl, CN, Me, Et, CF3, OMe, OEt, OCD3, OCF3, OCH2CF3, 6. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), Select from the following group:

7. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), LR 3 Select from the following group:

8. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound has a structure selected from the group consisting of:

9. A pharmaceutical composition for treating, regulating and / or preventing diseases mediated by KIF18A, characterized in that: The pharmaceutical composition contains a pharmaceutically acceptable excipient or carrier and, as an active ingredient, the compound according to any one of claims 1 to 8, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate.

10. Use of a compound according to any one of claims 1 to 8, or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 9, characterized in that: Used for preparing drugs for preventing and / or treating diseases mediated by KIF18A.

11. A method for treating, regulating and / or preventing diseases mediated by KIF18A, characterized in that: The method comprises the steps of administering to an individual in need thereof the compound according to any one of claims 1 to 8, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 9.

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