Sulfanilamide compound and use thereof

Abstract

Disclosed are a sulfanilamide compound and a use thereof. The present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotopic isomer thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. The compound of the present invention can inhibit the KIF18A activity at a low nano-molar concentration, and has an excellent anti-tumor drug development prospect.

Description

A sulfonamide compound and its application

[0001] This application claims priority to Chinese patent application No. 202410329480X, filed on March 21, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a sulfonamide compound and application thereof. Background Art

[0003] KIF18A, a member of the kinesin-8 family of kinesins, uses the energy released by ATP hydrolysis to propel it along microtubules toward the positive pole within the cell. KIF18A is localized at the positive end of microtubules, where it regulates their dynamic instability, exerting an activity similar to that of a microtubule depolymerase. During mitosis, KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a key role in ensuring the timely alignment of chromosomes during mitosis, maintaining genomic stability, and enabling the successful completion of mitosis.

[0004] KIF18A is overexpressed in multiple cancer types, including but not limited to colon, breast, lung, pancreatic, prostate, bladder, head, neck, cervix, and ovarian cancers. Furthermore, in cancer cell lines, gene deletion or knockout, or KIF18A inhibition, affects the mitotic spindle apparatus. In a series of tumor cells harboring chromosomal instability, KIF18A knockdown triggers activation of the mitotic spindle assembly checkpoint and interferes with tumor cell proliferation. However, in normal mammary epithelial cells and tumor cells with near-normal karyotypes, KIF18A knockdown has no significant effect on cell proliferation. Furthermore, KIF18A knockout mice are viable but exhibit defects in germ cell division, indicating that KIF18A is not essential for normal somatic cell division. Therefore, KIF18A is a promising anti-tumor drug target.

[0005] Currently, there are no drugs available that inhibit the KIF18A pathway to treat a wide range of diseases, including cancer. Therefore, the development of new compounds that can inhibit KIF18A activity has positive implications for the treatment of diseases. Summary of the Invention

[0006] The present invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof:

[0007] in,

[0008] R1 is C 1-6 Alkyl, C 3-6Cycloalkyl, 1 to 3 R 1-1 Substituted C 1-6 Alkyl or 1 to 3 R 1-1 Substituted C 3-6 Cycloalkyl;

[0009] Each R 1-1 are independently halogen or hydroxy;

[0010] R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 1 to 3 halogen-substituted C 1-6 alkyl;

[0011] R3 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 1 to 3 halogen-substituted C 1-6 Alkyl or 1 to 3 halogen-substituted C 1-6 alkoxy;

[0012] R4 is a 3-6 membered heterocycloalkyl group, C 1-6 Alkyl, 1 to 3 R 4-1 Substituted C 1-6 Alkyl or 1 to 3 R 4-1 Substituted 3-6 membered heterocycloalkyl; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0013] Each R 4-1 are independently halogen or C 1-6 alkyl;

[0014] X is N or CH;

[0015] Y is N or CR5, wherein R5 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 1 to 3 halogen-substituted C 1-6 Alkyl or 1 to 3 halogen-substituted C 1-6 Alkoxy.

[0016] In a preferred embodiment of the present invention, the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0017] In a preferred embodiment of the present invention, the C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy or ethoxy.

[0018] In a preferred embodiment of the present invention, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0019] In a preferred embodiment of the present invention, the C 3-6 Cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0020] In a preferred embodiment of the present invention, the heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or two of N and O.

[0021] In a preferred embodiment of the present invention, the number of heteroatoms in the 3-6 membered heterocycloalkyl group is 1 or 2.

[0022] In a preferred embodiment of the present invention, the 3-6 membered heterocycloalkyl group is a 6 membered heterocycloalkyl group, for example

[0023] In a preferred embodiment of the present invention, R1 is methyl, ethyl

[0024] In a preferred embodiment of the present invention, R2 is trifluoromethyl.

[0025] In a preferred embodiment of the present invention, R3 is hydrogen or methyl.

[0026] In a preferred embodiment of the present invention, R4 is

[0027] In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (I-1) or a compound of formula (I-2):

[0028] In a preferred embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0029] The present invention also provides a compound of formula (IA), its salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate,

[0030] X, Y, R3, R2 and R4 are as described above; W is halogen (eg, iodine), nitro or amino.

[0031] The present invention also provides a pharmaceutical composition comprising a substance Z or a pharmaceutically acceptable carrier; the substance Z is a compound of the structure of formula (I) as described above, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof.

[0032] The present invention also provides a use of a substance Z or the pharmaceutical composition as described above in the preparation of a KIF18A inhibitor, wherein the substance Z is a compound of the structure of formula (I) as described above, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof.

[0033] The present invention also provides a use of a substance Z or the pharmaceutical composition as described above in the preparation of a drug for treating KIF18A-mediated disorders and / or diseases, wherein the substance Z is a compound having the structure of formula (I) as described above, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof; and the disease is cancer, inflammation or ciliopathy.

[0034] The present invention also provides a use of a substance Z or the pharmaceutical composition as described above in the preparation of a drug, wherein the substance Z is a compound having the structure of formula (I) as described above, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof; the drug is used to treat cancer, inflammation or ciliary disease.

[0035] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0036] The reagents and raw materials used in the present invention are commercially available.

[0037] The positive progress of the present invention is that the compound of the present invention can inhibit KIF18A activity at low nanomolar concentrations and has excellent prospects for development of anti-tumor drugs. DETAILED DESCRIPTION

[0038] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0039] Example 1 Synthesis of 4-iodo-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzoic acid (IIa)

[0040] Step 1 tert-Butyl 4-(trifluoromethyl)-3,6-dihydropyridine-1(2H)-carboxylate (II-1)

[0041] Under nitrogen, tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 60.37 mmol), potassium fluoride (7.1 g, 120.73 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (2.6 g, 6.04 mmol), (trifluoromethyl)trimethylsilane (17.9 mL, 120.73 mmol), and tris(dibenzylideneacetone)dipalladium (2.8 g, 3.02 mmol) were dissolved in 1,4-dioxane (200 mL). The mixture was stirred at 110°C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel flash chromatography (petroleum ether / ethyl acetate) to obtain the title compound (12.2 g, colorless oil). LCMS (ESI, m / z) 252 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ6.37-6.20(m,1H),4.03-4.00(m,2H),3.56(t,2H),2.33-2.20(m,2H),1.48(s,9H).

[0042] Step 2 4-(Trifluoromethyl)-1,2,3,6-tetrahydropyridine hydrochloride (II-2)

[0043] Compound II-1 (10.0 g, 5.6 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4N, 120 mL) and stirred at 30° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain compound II-2 (7.3 g, white solid). 1 H NMR (400MHz, DMSO-d6) δ10.01-9.68(m,2H),6.51-6.50(m,1H),3.80-3.66(m,2H),3.31-3.16(m,2H),2.50-2.38(m,2H).

[0044] Step 3 4-iodo-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzoic acid (IIa)

[0045] Methyl 2-fluoro-4-iodobenzoic acid (1.5 g, 5.4 mmol) was dissolved in dimethyl sulfoxide (30 mL), and compound II-2 (2.51 g, 13.5 mmol) and potassium carbonate (2.09 g, 16.2 mmol) were added. The reaction was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by C18 reverse phase chromatography to obtain the target compound IIa (800 mg, yellow solid). LCMS (ESI, m / z) 398 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ14.07(s,1H),7.64(s,1H),7.51(s,2H),6.64-6.52(m,1H),3.84-3.63(m,2H),3.24(t,2H),2.44-2.35(m,2H).

[0046] Example 1-1 Synthesis of 4-nitro-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzoic acid (IIb)

[0047] 2-Fluoro-4-nitrobenzoic acid (10.0 g, 54.02 mmol), compound II-1 (10.1 g, 54.02 mmol), and potassium carbonate (14.9 g, 108.04 mmol) were dissolved in dimethyl sulfoxide (V / V = 8 / 1, 100 mL) at 25°C, and the reaction mixture was stirred for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with water, the pH was adjusted to 4 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to yield the target compound IIb (13.8 g). MS (ESI, m / z) 317 [M+H] + ;

[0048] Example 2 Synthesis of 2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-amine (IIIa)

[0049] 2-Chloropyridin-4-amine (2.0 g, 15.4 mmol) was dissolved in N,N-dimethylformamide (DMF, 20 mL), and 4,4-difluoropiperidine (3.73 g, 30.8 mmol) and N,N-diisopropylethylamine (5.97 g, 46.2 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was obtained by concentration under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to obtain the target compound IIIa (2.5 g, yellow solid). LCMS (ES, m / z) 215 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.76(d,1H),6.48(s,2H),5.77(s,1H),3.91-3.65(m,4H),1.99-1.91(m,4H).

[0050] Example 2-1: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (IIIb)

[0051] 2-Chloro-6-methylpyrimidin-4-amine (2.21 g, 15.4 mmol) was dissolved in N,N-dimethylformamide (DMF, 20 mL), and 4,4-difluoropiperidine (3.73 g, 30.8 mmol) and N,N-diisopropylethylamine (5.97 g, 46.2 mmol) were added. The mixture was heated to 120°C and stirred for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was obtained by concentration under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to obtain the target compound IIIb (2.53 g). LCMS (ESI, m / z) 229 [M+H] + .

[0052] Example 2-2: Synthesis of 3-(4,4-difluoropiperidin-1-yl)aniline (IIIc)

[0053] Step 1: 4,4-difluoro-1-(3-nitrophenyl)piperidine (IIIc-1)

[0054] 1-Fluoro-3-nitrobenzene (10.0 g, 70.87 mmol) and 4,4-difluoropiperidine (8.6 g, 70.87 mmol) were dissolved in dimethyl sulfoxide (100 mL). The reaction mixture was then heated to 150°C and stirred for 8 hours. After monitoring the reaction for completion, the mixture was diluted with ethyl acetate and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound IIIc-1 (5.5 g). MS (ESI, m / z) 243 [M+H] + ;

[0055] Step 2: 3-(4,4-difluoropiperidin-1-yl)aniline (IIIc)

[0056] Compound IIIc-1 (5.5 g, 22.71 mmol) was dissolved in isopropanol (100 mL) at room temperature, and 10% wt palladium on carbon (1.2 g, 1.14 mmol) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) for 5 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound IIIc (4.6 g). MS (ESI, m / z) 213 [M+H] + ;

[0057] Example 2-3 Synthesis of (R)-6-(2-methylmorpholinyl)pyridin-2-amine (IIId)

[0058] 6-Fluoropyridin-2-amine (8.0 g, 71.36 mmol), diisopropylethylamine (18.5 g, 142.72 mmol), and (R)-2-methylmorpholine (7.2 g, 71.36 mmol) were dissolved in dimethyl sulfoxide (100 mL). The reaction mixture was then heated to 160°C and stirred for 16 hours. After monitoring the reaction for completion, the mixture was diluted with ethyl acetate and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to yield the title compound IIId (4.1 g). MS (ESI, m / z) 194 [M+H] + ;

[0059] Example 2-4 Synthesis of 6-(3,3,3-trifluoropropoxy)pyridin-2-amine (IIIe)

[0060] Under nitrogen, 3,3,3-trifluoro-1-propanol (7.8 g, 68.68 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL) and cooled to 0°C. Sodium hydride (10.0 g, 249.76 mmol, 60% wt in mineral oil) was added portionwise and allowed to react for 30 minutes. Then, 6-fluoropyridin-2-amine (7.0 g, 62.44 mmol) was added, and the temperature was raised to 60°C and stirred for 10 hours. The reaction was monitored for completion and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to yield the title compound IIIe (8.6 g). MS (ESI, m / z) 207 [M+H] + ;

[0061] Example 2-6 3-Amino-N-(tert-butyl)benzenesulfonamide (IIIf)

[0062] Step 1: N-(tert-Butyl)-3-nitrobenzenesulfonamide (IIIf-1)

[0063] Dissolve 3-nitrobenzenesulfonyl chloride (6.0 g, 27.07 mmol), triethylamine (5.5 g, 54.15 mmol), and tert-butylamine (2.2 g, 29.78 mmol) in dichloromethane (60 mL) and stir at room temperature for 6 hours. Monitor the reaction for completion, dilute with ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is then purified by silica gel column chromatography to obtain the target compound IIIf-1 (2.8 g). MS (ESI, m / z) 257 [MH] + ; 1 H NMR(500MHz,Chloroform-d)δ8.28(t,1H),7.94(d,1H),7.26(t,1H),0.81(s,9H).

[0064] Step 2: 3-Amino-N-(tert-butyl)benzenesulfonamide (IIIf)

[0065] At room temperature, compound IIIg-1 (2.5 g, 9.68 mmol) was dissolved in methanol (35 mL), and 10% wt palladium on carbon (515 mg, 483.95 μmol) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) for 6 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound IIIg (5.1 g). MS (ESI, m / z) 229 [M+H] + ; 1H NMR(400MHz,Chloroform-d)δ7.25-7.18(m,3H),6.81(dq,1H),1.23(s,9H).

[0066] Example 2-5 Synthesis of 4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (IIIg)

[0067] Step 1: 5-(4,4-difluoropiperidin-1-yl)-2-nitroaniline (IIIg-1)

[0068] 5-Fluoro-2-nitroaniline (8.0 g, 71.36 mmol), diisopropylethylamine (9.9 g, 76.87 mmol), and 4,4-difluoropiperidine (4.9 g, 40.35 mmol) were dissolved in dimethyl sulfoxide (100 mL). The reaction mixture was then heated to 120°C and stirred for 8 hours. After monitoring the reaction for completion, the mixture was diluted with ethyl acetate and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound IIIg-1 (7.6 g). MS (ESI, m / z) 258 [M+H] + ;

[0069] Step 2: 4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (IIIg)

[0070] Compound IIIg-1 (6.0 g, 23.32 mmol) was dissolved in isopropanol (100 mL) at room temperature, and 10% wt palladium on carbon (1.2 g, 1.17 mmol) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) for 6 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound IIIf (5.1 g). MS (ESI, m / z) 228 [M+H] + ;

[0071] Example 2-7 Synthesis of (3,4-diaminophenyl)(4,4-difluoropiperidin-1-yl)methanone (IIIh)

[0072] Step 1: (4-Amino-3-nitrophenyl)(4,4-difluoropiperidin-1-yl)methanone (IIIh-1)

[0073] At room temperature, 4-amino-3-nitrobenzoic acid (5.0 g, 27.45 mmol), diisopropylethylamine (7.1 g, 54.90 mmol), and 4,4-difluoropiperidine (3.3 g, 27.45 mmol) were dissolved in N,N-dimethylformamide (100 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (11.0 g, 28.82 mmol) was added portionwise. The reaction was stirred for 3 hours. TLC confirmed the completion of the reaction. The reaction solution was diluted with ethyl acetate, washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound IIIh-1 (7.5 g). MS (ESI, m / z) 286 [M+H] + ;

[0074] Step 2: (3,4-Diaminophenyl)(4,4-difluoropiperidin-1-yl)methanone (IIIh)

[0075] At room temperature, compound IIIh-1 (7.0 g, 24.54 mmol) was dissolved in isopropanol (100 mL), and 10% wt palladium on carbon (1.3 g, 1.23 mmol) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) for 6 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound IIIh (6.1 g). MS (ESI, m / z) 256 [M+H] + ;

[0076] Example 3 Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-iodo-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (IVa)

[0077] Compound IIa (480 mg, 1.2 mmol) and DMF (5 mg, 0.06 mmol) were dissolved in dry dichloromethane (10 mL), and a solution of oxalyl chloride (306 mg, 2.42 mmol) in dichloromethane (10 mL) was added dropwise. After stirring at 30°C for 30 minutes, the mixture was concentrated to give a crude product, which was redissolved in dichloromethane (10 mL). Compound IIIa (388 mg, 1.81 mmol) was then dissolved in dry THF (10 mL), and lithium bis(trimethylsilyl)amide (2.4 mL, 2.42 mmol, 1 M tetrahydrofuran solution) was added. After stirring at 30°C for 30 minutes, the above dichloromethane solution was added dropwise. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel flash chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give the target compound IVa (200 mg, yellow solid). LCMS (ES, m / z) 594 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.00(s,1H),8.33(d,1H),7.82(s,1H),7.70(s,2H),7.47(s,1 H),6.60(s,1H),3.80(s,4H),3.71(s,2H),3.25(t,2H),2.45(s,2H),1.99-1.81(m,4H).

[0078] Example 4 Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-1)

[0079] Compound IVa (200 mg, 0.34 mmol), hydroxyethylsulfonamide (42 mg, 0.34 mmol), potassium phosphate (215 mg, 1.01 mmol) and sarcosine (15 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (32 mg, 0.17 mmol) was added. Under a nitrogen atmosphere, the reaction mixture was stirred at 100°C for 17 hours. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-1 (59.4 mg, white solid). LCMS (ES, m / z) 591 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.45-9.91(m,1H),8.32(d,1H),8.00(d,1H),7.50(d, 1H),7.25(d,1H),7.13(dd,1H),6.66-6.59(m,1H),5.20-4.66(m,1H),3.81-3.75(m,6H),3.70 -3.61(m,2H),3.37(t,2H),3.22(t,2H),2.56-2.51(m,2H),1.97-1.91(m,4H).

[0080] Example 5 Synthesis of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-2)

[0081] Step 1: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-nitro-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-2-1)

[0082] At room temperature, compound IIb (2.0 g, 6.32 mmol), diisopropylethylamine (1.6 g, 12.65 mmol), and compound IIIb (1.4 g, 6.32 mmol) were dissolved in N,N-dimethylformamide (15 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.7 g, 6.96 mmol) was added portionwise. The mixture was stirred for 3 hours. After monitoring for completion, the reaction was diluted with ethyl acetate and washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound I-2-1 (2.8 g). MS (ESI, m / z) 527 [M+H] + ;

[0083] Step 2: 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-2-2)

[0084] Compound I-2-1 (2.0 g, 3.80 mmol) and ammonium chloride (2.3 g, 37.99 mmol) were dissolved in a mixed solvent of ethanol and water (V / V = 8 / 1, 30 mL). Iron powder (1.1 g, 18.99 mmol) was added portionwise. The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound I-2-2 (1.7 g). MS (ESI, m / z) 497 [M+H] + ;

[0085] Step 3: Ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)aminosulfonyl)acetate (I-2-3)

[0086] Compound I-2-3 (0.8 g, 1.61 mmol) and triethylamine (326 mg, 3.22 mmol) were dissolved in dichloromethane (10 mL). 2-(chlorosulfonyl)acetic acid ethyl ester (330 mg, 1.77 mmol) was added and stirred at room temperature for 3 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound I-2-3 (767 mg). MS (ESI, m / z) 647 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.56(s,1H),7.75(s,1H),7.11-7.02(m,2H),6.53(d,2H),4.3 8(s,2H),4.10(q,2H),3.59(s,6H),3.15(t,2H),2.50(d,2H),2.18(s,3H),1.92(s,4H),1.16(t,3H).

[0087] Step 4: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(methylsulfonamido)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-2)

[0088] Compound I-2-3 (0.7 g, 1.08 mmol) was dissolved in tetrahydrofuran (12 mL), and lithium aluminum tetrahydride tetrahydrofuran solution (1 M, 2.17 mL, 2.17 mmol) was added. The mixture was stirred at room temperature for 3 hours. After monitoring the reaction completion, the mixture was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-2 (182 mg). MS (ESI, m / z) 605 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ11.45(s,1H),10.14(s,1H),7.75(s,1H),7.20-6.93(m,2H),6.53(d,2H),4.96( t,1H),3.76(d,2H),3.68-3.53(m,6H),3.35(d,2H),3.14(t,2H),2.49(s,2H),2.17(s,3H),1.92(m,4H).

[0089] Example 6 N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-3)

[0090] Step 1: N-[3-(4,4-difluoropiperidin-1-yl)phenyl]-4-nitro-2-[4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl]benzamide (I-3-1)

[0091] At room temperature, compound IIb (2.0 g, 6.32 mmol), diisopropylethylamine (1.6 g, 12.65 mmol), and compound IIIc (1.34 g, 6.32 mmol) were dissolved in N,N-dimethylformamide (15 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.7 g, 6.96 mmol) was added portionwise. The reaction was stirred for 3 hours. After monitoring the reaction for completion, the mixture was diluted with ethyl acetate and washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound I-3-1 (2.8 g). MS (ESI, m / z) 511 [M+H] + ;

[0092] Step 2: 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-3-2)

[0093] Compound I-3-1 (1.95 g, 3.80 mmol) and ammonium chloride (2.3 g, 37.99 mmol) were dissolved in a mixed solvent of ethanol and water (V / V = 8 / 1, 30 mL). Iron powder (1.1 g, 18.99 mmol) was added portionwise. The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound I-3-2 (1.7 g). MS (ESI, m / z) 481 [M+H] + ;

[0094] Step 3: N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)benzamide (I-3)

[0095] Compound I-3-2 (1.01 g, 2.09 mmol) and triethylamine (530 mg, 5.24 mmol) were dissolved in dichloromethane (13 mL), and 2-hydroxyethyl-1-sulfonyl chloride (333 mg, 2.30 mmol) was added. The mixture was stirred at room temperature for 3 hours. After monitoring the reaction completion, the mixture was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-7 (112 mg). MS (ESI, m / z) 589 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.12(s,1H),7.76(d,1H),7.26(t,1H),7.19-7.12(m,2H),7.10(d,1H),7.03(dd,1H),6.7 4(dt,1H),6.61(s,1H),4.97(s,1H),3.76(t,2H),3.64(t,2H),3.32(s,2H),3.28(t,4H),3.22(t,2H),2.41(s,2H),2.05(td,4H).

[0096] The preparation methods of the following example compounds are the same as those of Example 6. Compound IIb is condensed with the corresponding amine intermediate, the nitro group is reduced to an amino group, and then condensed with 2-hydroxyethyl-1-sulfonyl chloride or alkylsulfonyl chloride to obtain the corresponding target compound:

[0097] Example 14 Synthesis of N-(4-(6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-2-hydroxyethane-1-sulfonamide (I-11)

[0098] Step 1: 6-(4,4-difluoropiperidin-1-yl)-2-(4-nitro-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-1H-benzo[d]imidazole (I-11-1)

[0099] Compound IIb (2.0 g, 6.32 mmol), diisopropylethylamine (1.6 g, 12.65 mmol), and compound IIIg (1.4 g, 6.32 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.7 g, 6.96 mmol) was added portionwise. The mixture was stirred for 3 hours, then heated to 80°C and allowed to react overnight. The reaction was monitored for completion, diluted with dichloromethane, and washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound I-11-1 (2.6 g). MS (ESI, m / z) 508 [M+H] + ;

[0100] Step 2: 4-(6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)aniline

[0101] Compound I-11-1 (2.3 g, 4.53 mmol) and ammonium chloride (2.4 g, 45.32 mmol) were dissolved in a mixed solvent of ethanol and water (v / v = 8 / 1, 30 mL). Iron powder (1.3 g, 22.66 mmol) was added in portions. The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound I-11-2 (1.8 g). MS (ES, m / z) 478 [M+H] + ;

[0102] Step 3: N-(4-(6-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0103] Compound I-11-2 (1.0 g, 2.09 mmol) and triethylamine (530 mg, 5.24 mmol) were dissolved in dichloromethane (13 mL), and 2-hydroxyethyl-1-sulfonyl chloride (333 mg, 2.30 mmol) was added. The mixture was stirred at room temperature for 3 hours. After monitoring the reaction completion, the mixture was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-11 (152 mg). MS (ESI, m / z) 586 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.00(d,1H),7.78(dd,1H),7.47(d,1H),7.35(d,0.5H),7.19(d,0.5H),7.02-6 .90(m,4H),6.58(s,1H),3.75(t,2H),3.62(s,2H),3.24(d,6H),2.99(q,2H),2.22(s,2H),2.11(dq,4H).

[0104] Example 15 Synthesis of N-(4-(6-(4,4-difluoropiperidin-1-formyl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-2-hydroxyethane-1-sulfonamide (I-12)

[0105] Step 1: (4,4-difluoropiperidin-1-yl)(2-(4-nitro-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-1H-benzo[d]imidazol-6-yl)methanone (I-12-1)

[0106] Compound IIb (2.0 g, 6.32 mmol), diisopropylethylamine (1.8 g, 13.91 mmol), and compound IIIh (1.6 g, 6.32 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.7 g, 6.96 mmol) was added portionwise. The mixture was stirred for 3 hours, then heated to 80°C and allowed to react overnight. The reaction was monitored for completion, diluted with dichloromethane, and washed with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound I-12-1 (2.9 g). MS (ESI, m / z) 536 [M+H] + ;

[0107] Step 2: (2-(4-amino-2-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-1H-benzo[d]imidazol-6-yl)(4,4-difluoropiperidin-1-yl)methanone

[0108] Compound I-12-1 (2.5 g, 4.67 mmol) and ammonium chloride (2.5 g, 46.69 mmol) were dissolved in a mixed solvent of ethanol and water (V / V = 8 / 1, 30 mL). Iron powder (1.3 g, 23.34 mmol) was added portionwise. The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography to obtain the target compound I-12-2 (2.1 g). MS (ESI, m / z) 506 [M+H] + ;

[0109] Step 3: N-(4-(6-(4,4-difluoropiperidin-1-carbonyl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-2-hydroxyethane-1-sulfonamide

[0110] Compound I-12-2 (1.5 g, 2.97 mmol) and triethylamine (600 mg, 5.93 mmol) were dissolved in dichloromethane (15 mL), and 2-hydroxyethyl-1-sulfonyl chloride (472 mg, 3.26 mmol) was added. The mixture was stirred at room temperature for 3 hours. After monitoring the reaction completion, the mixture was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-12 (388 mg). MS (ESI, m / z) 614 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),7.83(dd,1H),7.71(d,0.5H),7.65(d,0.5H),7.61-7.56(m,0.5H),7.53(d,0.5H),7.26(d dd,1H),7.00(s,1H),6.95(dd,1H),6.58(s,1H),3.75(t,2H),3.63(s,6H),3.25(t,2H),3.00(s,2H),2.23(s,2H),2.05(s,4H).

[0111] Example 16 Synthesis of N-(4-(6-((4,4-difluoropiperidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(4-(trifluoromethyl)-3,6-dihydropyridin-1(2H)-yl)phenyl)-2-hydroxyethane-1-sulfonamide (I-13)

[0112] Compound I-12 (200 mg, 325.94 μmol) was dissolved in tetrahydrofuran (8 mL), and lithium aluminum tetrahydride tetrahydrofuran solution (1 M, 0.652 mL, 651.89 μmol) was added. The mixture was stirred at room temperature for 3 hours. After monitoring the reaction completion, the mixture was concentrated under reduced pressure. The crude product was then separated and purified by preparative liquid chromatography to obtain the target compound I-13 (68 mg). MS (ESI, m / z) 600 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.22(d,1H),10.01(s,1H),7.96-7.80(m,1H),7.59-7.51(m,1H),7.47-7.40(m,1H),7.17-7.07(m, 2H),7.00(dd,1H),6.58(s,1H),4.96(s,1H),3.76(d,2H),3.64(d,4H),3.31(s,4H),3.00(d,2H),2.20(s,2H),1.95(s,4H).

[0113] Effect Example 1 In vitro inhibition test of KIF18A enzyme activity by the compounds of the present invention

[0114] The quantitative detection of KIF18A enzyme activity was performed according to the instructions of the ADP-Glo™ Kinase Assay Kit (Promega Inc), as briefly described below:

[0115] The reaction system consisted of the test compound, recombinant KIF18A protein (aa 1-467), ATP (Promega Inc), and assay buffer. Test compounds were prepared in DMSO (Sigma Inc) to a 0.5 mM stock solution and serially diluted using DMSO. The assay buffer consisted of 15 mM Tris, 10 mM MgCl2 (Sigma Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 μM paclitaxel (Cytoskeleton Inc), 30 μg / mL porcine tubulin (Cytoskeleton Inc), and 2% DMSO in water. KIF18A protein (final concentration 80 nM) and various concentrations of the compound (1 μL) were added to the prepared assay buffer (50 μL) and incubated at room temperature for 15 minutes. ATP was then added to the reaction mixture (final concentration 80 μM) and incubated at room temperature for 3 hours. After the reaction, 5 μL of ADP-Glo™ reagent (Promega, catalog number v9102) and 2.5 μL of reaction mixture were added to a 384-well plate (Grenier Inc). After mixing, the plates were sealed with aluminum foil and incubated at room temperature in the dark for 40 minutes. Finally, 10 μL of ADP-Glo™ detection reagent was added to each well and incubated at room temperature in the dark for 40 minutes. After all reactions were completed, the luminescence value of each well was read using a microplate reader, and the data was processed using Excel and Graphpad Prism software to calculate the inhibition rate of the test compound [the calculation formula is: inhibition rate % = (1-(compound group-blank group) / (negative control group-blank group)) × 100%] and IC 50 value.

[0116] The two positive reference compounds in this experiment are BTB-1 and AMG650 (Solvilnesib), and their chemical structures are as follows:

[0117] Table 1. Results of the in vitro inhibition of KIF18A activity by the compounds of the present invention

[0118] The results showed that the compound of the present invention can inhibit KIF18A activity at low nanomolar concentrations and has excellent prospects for development of anti-tumor drugs.

[0119] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other manner. Any person skilled in the art may utilize the above-disclosed technical content to modify or modify the present invention into equivalent embodiments. However, any simple modifications, equivalent variations, and modifications to the above embodiments that do not depart from the technical content of the present invention and are based on the technical essence of the present invention remain within the scope of protection of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate thereof: in, R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, 1 to 3 R 1-1 Substituted C 1-6 Alkyl or 1 to 3 R 1-1 Substituted C 3-6 Cycloalkyl; Each R 1-1 are independently halogen or hydroxy; R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 1 to 3 halogen-substituted C 1-6 alkyl; R3 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 1 to 3 halogen-substituted C 1-6 Alkyl or 1 to 3 halogen-substituted C 1-6 alkoxy; R4 is a 3-6 membered heterocycloalkyl group, C 1-6 Alkyl, 1 to 3 R 4-1 Substituted C 1-6 Alkyl or 1 to 3 R 4-1 Substituted 3-6 membered heterocycloalkyl; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 4-1 are independently halogen or C 1-6 alkyl; X is N or CH; Y is N or CR5, wherein R5 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 1 to 3 halogen-substituted C 1-6 Alkyl or 1 to 3 halogen-substituted C 1-6 Alkoxy.

2. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, characterized in that: The compound of formula (I) satisfies one or more of the following conditions: (1) C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl; (2) C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy or ethoxy; (3) The halogen is fluorine, chlorine, bromine or iodine, for example, fluorine; (4) C 3-6 Cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane; (5) The heteroatoms of the 3-6 membered heterocycloalkyl group are selected from one or two of N and O; (6) The number of heteroatoms in the 3-6 membered heterocycloalkyl group is 1 or 2; and (7) the 3-6 membered heterocycloalkyl group is a 6 membered heterocycloalkyl group, for example 3. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, characterized in that: The compound of formula (I) is a compound of formula (I-1) or a compound of formula (I-2):

4. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, characterized in that: The compound of formula (I) satisfies one or more of the following conditions: (1) R1 is methyl, ethyl, (2) R2 is trifluoromethyl; (3) R3 is hydrogen or methyl; (4) R4 is 5. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, characterized in that: R1 is C 1-4 Alkyl or C substituted with one hydroxyl group 1-4 alkyl; R2 is 1 to 3 halogen-substituted C 1-6 alkyl; R3 is hydrogen or C 1-6 alkyl; R4 is a 3-6 membered heterocycloalkyl group, C 1-6 Alkyl, 1 to 3 R 4-1 Substituted C 1-6 Alkyl or 1 to 3 R 4-1 Substituted 3-6 membered heterocycloalkyl; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or two of N and O, and the number of heteroatoms is one or two; Each R 4-1 are independently halogen or C 1-6 alkyl; X is N; Y is N.

6. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, characterized in that: The compound represented by formula (I) is selected from any one of the following compounds:

7. A compound of formula (IA), its salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate, X, Y, R3, R2 and R4 are as described in any one of claims 1 to 6; W is halogen (such as iodine), nitro or amino.

8. A pharmaceutical composition comprising a substance Z or a pharmaceutically acceptable carrier; the substance Z is a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof.

9. Use of a substance Z or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating KIF18A-mediated disorders and / or diseases, wherein the substance Z is a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof; and the disease is cancer, inflammation or ciliopathy.

10. Use of a substance Z or the pharmaceutical composition according to claim 8 in the preparation of a medicament, wherein the substance Z is a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof; the medicament is used to treat cancer, inflammation or ciliopathy.

Images