KIF18A inhibitory activity small molecule compound and pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of biomedicine, and discloses a KIF18A inhibitory activity small molecule compound, and the chemical structure of the small molecule compound is as shown in formula (I). The invention further discloses a derivative and a pharmaceutical composition of the KIF18A inhibitory activity small molecule compound. The invention also provides a preparation method of the KIF18A inhibitory activity small molecule compound and the KIF18A inhibitory activity small molecule compound derivative. The invention further discloses application of the KIF18A inhibitory activity small molecule compound, the KIF18A inhibitory activity small molecule compound derivative and the combined medicine in preparation of medicine for treating or preventing hyperproliferative diseases. According to the invention, targeted inhibition of KIF18A at a molecular level and a cellular level is realized, a basis is provided for development of selective inhibitor inhibition drugs of the subprotein, and proliferation of various tumor cells can be effectively inhibited.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly relates to a small molecule compound with KIF18A inhibitory activity, a pharmaceutical composition thereof, and applications thereof. Background Art

[0002] Recently, targeting enzymes essential for CIN-directed mitosis has become a hot topic in the development of new anti-tumor drugs. Anti-mitotic drugs are an important part of anti-tumor drugs. The most important ones among them are microtubule stabilizers or microtubule polymerization inhibitors. The representative drug of the former is paclitaxel, and the representative drug of the latter is vincristine. However, due to the lack of selectivity for normal cells, these drugs exhibit toxic side effects such as bone marrow suppression, resulting in limited clinical applications.

[0003] Compared with normal cells, cells with chromosomal instability will lead to an increase in the polymerization of spindle microtubules and a decrease in the contact conversion between spindle microtubules and centromeres. Therefore, anti-mitotic therapy targeting the microtubule skeleton is extremely effective for chromosomally unstable cells. Utilizing the chromosomal instability of tumor cells may achieve the selectivity of drugs for tumor cells and normal cells, thereby reducing the toxic side effects of drugs, and is expected to become a way to discover new anti-tumor drugs.

[0004] KIF18A is one of the members of the N-type kinesin-8 subfamily. Kinesin is a motor protein that moves directionally along microtubule filaments by hydrolyzing ATP and coordinates bipolar spindle formation, chromosome alignment, and separation. In tumor cells with CIN characteristics, the knockout of KIF18A will lead to more unstable mitosis, further inducing the activation of the spindle assembly checkpoint, mitotic delay, the formation of multipolar spindles, and tumor cell apoptosis.

[0005] More and more studies have shown that KIF18A plays an important role in the occurrence and development of various tumors. High expression of KIF18A has been found in various tumors such as liver cancer, breast cancer, and ovarian cancer, and the expression level is highly correlated with the severity and migration of the disease. Knocking down KIF18A can reduce the proliferation and migration of tumor cells and increase the sensitivity to radiotherapy. Targeting KIF18A may avoid the toxicity of drugs to highly proliferating bone marrow cells. However, the existing means of targeting KIF18A have only appeared in research, and specific inhibitors, inhibitory means, etc. have not been reported.

[0006] In summary, KIF18A is a very promising drug target. How to specifically inhibit the expression of KIF18A and develop a selective inhibitor for this sub-protein is an urgent problem to be solved in the prior art. Summary of the Invention

[0007] The object of the present invention is to provide a small molecule compound with KIF18A inhibitory activity, its pharmaceutical composition and application, so as to solve the technical problem of how to inhibit KIF18A in the prior art.

[0008] To solve the above technical problems, the present invention specifically provides the following technical solutions:

[0009] The present invention provides a small molecule compound with KIF18A inhibitory activity, and the chemical structure of the small molecule compound is shown in formula (I):

[0010]

[0011] R 1 is selected from any one of the following groups:

[0012]

[0013] X, Y, and Z are independently N or CH;

[0014] R 2 is any one of formylamino, acetylamino, propionylamino, cyclopropionylamino, methanesulfonamido, ethanesulfonamido, propanesulfonamido, cyclopropanesulfonamido, 2-hydroxyethylsulfonamido;

[0015] R 3 and R 4 is a hydrogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkylamide, and C 1 -C 6 sulfonamido; wherein, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkylamide, and C 1 -C 6 sulfonamido further contains one or more halogens, hydroxyl groups, amino groups, heteroatoms, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C6 Alkanamido and C 1 -C 6 Sulfonamido;

[0016] R 5 is a hydrogen atom, C 1 -C 6 alkyl, halogen, cyano or C 1 -C 6 haloalkyl;

[0017] R 6 is any one of N-methylsulfamoyl, N-(tert-butyl)sulfamoyl, methylsulfonyl, N-methylcarbamoyl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, (R)-2-methylmorpholin-4-yl, 3,3-difluorocyclobutyl, 3,3-difluorotetrahydro-1H-pyrrol-1-yl;

[0018] R 7 , R8 and R9 are a hydrogen atom, halogen, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkanamido and C 1 -C 6 sulfonamido;

[0019] wherein the small molecule compound is used to inhibit the expression of KIF18A subprotein.

[0020] As a preferred embodiment of the present invention, in the structure of the small molecule compound,

[0021] R 1 is selected from any one of the following groups:

[0022]

[0023] R 2 is any one of ethylsulfonamido, propanesulfonamido, cyclopropanesulfonamido, 2-hydroxyethylsulfonamido;

[0024] R 3 and R 4 are a hydrogen atom, methyl, ethyl, methylamino, ethylamino, methoxy, ethoxy, formamido, acetamido.

[0025] The present invention also provides a small molecule compound with KIF18A inhibitory activity, and the small molecule compound is any one of the following compounds:

[0026] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-1);

[0027] 4-(ethylsulfonamido)-2-methyl-N-(3-(methylcarbamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-2);

[0028] N-(3-(N-(tert-Butyl)sulfamoyl)-4-methylphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-3);

[0029] 4-(ethylsulfonamido)-2-methyl-N-(3-(N-methylsulfamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-4);

[0030] N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-5);

[0031] 4-(ethylsulfonamido)-2-methyl-N-(3-(methylsulfonyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-6);

[0032] N-(3-(4,4-Difluoropiperidin-1-yl)-5-methoxyphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-7);

[0033] N-(3-(4,4-Difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-8);

[0034] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-9);

[0035] N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-10);

[0036] N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-11);

[0037] N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-ethylsulfonamido-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-12);

[0038] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-13);

[0039] N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-14);

[0040] N-(2-(3,3-difluorocyclopentyl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-15);

[0041] (R)-N-(6-(3-cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-16);

[0042] N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-17);

[0043] N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-18);

[0044] N-(5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-19);

[0045] N-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-20);

[0046] (R)-4-(ethylsulfonamido)-2-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-21);

[0047] N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-22);

[0048] 4-(ethylsulfonamido)-5-methyl-N-(3-(methylcarbamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-23);

[0049] N-(3-(N-(tert-butyl)sulfamoyl)-4-methylphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-24);

[0050] 4-(ethylsulfonamido)-5-methyl-N-(3-(N-methylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-25);

[0051] N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-26);

[0052] 4-(ethylsulfonamido)-5-methyl-N-(3-(methylsulfonyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-27);

[0053] N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-28);

[0054] N-(3-(4,4-Difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-29);

[0055] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-30);

[0056] N-(6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-31);

[0057] N-(6-(4,4-Difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-32);

[0058] N-(6-(4,4-Difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-methylsulfonamido-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-33);

[0059] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-34);

[0060] N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-35);

[0061] N-(2-(3,3-Difluorocyclopentyl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-36);

[0062] (R)-N-(6-(3-Cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-37);

[0063] N-(8-(4,4-Difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-38);

[0064] N-(6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-39);

[0065] N-(5-Chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-40);

[0066] N-(6-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-41);

[0067] (R)-4-(Ethylsulfonamido)-5-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-42);

[0068] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-43);

[0069] 4-((2-Hydroxyethyl)sulfonamido)-2-methyl-N-(3-(methylcarbamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-44);

[0070] N-(3-(N-(tert-Butyl)sulfamoyl)-4-methylphenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-45);

[0071] 4-((2-Hydroxyethyl)sulfonamido)-2-methyl-N-(3-(N-methylsulfamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-46);

[0072] N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-47);

[0073] 4-((2-hydroxyethyl)sulfamoyl)-2-methyl-N-(3-(methylsulfonyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-48);

[0074] N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-49);

[0075] N-(3-(4,4-difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-50);

[0076] N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-51);

[0077] N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-52);

[0078] N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-53);

[0079] N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-54);

[0080] N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-55);

[0081] N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-56);

[0082] N-(2-(3,3-Difluorocyclopentyl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-57);

[0083] (R)-N-(6-(3-Cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-58);

[0084] N-(8-(4,4-Difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-59);

[0085] N-(6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-60);

[0086] N-(5-Chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-61);

[0087] N-(6-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-62);

[0088] (R)-4-((2-Hydroxyethyl)sulfamoyl)-2-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-63);

[0089] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-64);

[0090] 4-((2-Hydroxyethyl)sulfamoyl)-5-methyl-N-(3-(methylcarbamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-65);

[0091] N-(3-(N-(tert-Butyl)sulfamoyl)-4-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-66);

[0092] 4-((2-Hydroxyethyl)sulfamoyl)-5-methyl-N-(3-(N-methylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-67);

[0093] N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-68);

[0094] 4-((2-Hydroxyethyl)sulfamoyl)-5-methyl-N-(3-(methylsulfonyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-69);

[0095] N-(3-(4,4-Difluoropiperidin-1-yl)-5-methoxyphenyl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-70);

[0096] N-(3-(4,4-Difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-71);

[0097] N-(6-(4,4-Difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-72);

[0098] N-(6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-73);

[0099] N-(6-(4,4-Difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-74);

[0100] N-(6-(4,4-Difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-[(2-hydroxyethyl)sulfamoyl]-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-75);

[0101] N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-76);

[0102] N-(2-(4,4-Difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-77);

[0103] N-(2-(3,3-Difluorocyclopentyl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-78);

[0104] (R)-N-(6-(3-Cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-79);

[0105] N-(8-(4,4-Difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-80);

[0106] N-(6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-81);

[0107] N-(5-Chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-82);

[0108] N-(6-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfamoyl)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-83);

[0109] (R)-4-((2-Hydroxyethyl)sulfamoyl)-5-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-84).

[0110] The present invention further provides a pharmaceutically acceptable salt of a small molecule compound with KIF18A inhibitory activity, and the pharmaceutically acceptable salt is a salt formed by the small molecule compound and an acid or a base;

[0111] Wherein, the acid is any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, malic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid;

[0112] The base is any one or more of inorganic bases containing alkaline metal cations, alkaline earth metal cations or ammonium cation salts.

[0113] The present invention further provides a preparation method of a small molecule compound with KIF18A inhibitory activity or a pharmaceutically acceptable salt, comprising the following steps:

[0114] Reacting a halogenated aromatic compound 1 with an aromatic carboxamide compound 2 through Ullmann reaction to obtain the small molecule compound (I);

[0115] Wherein, the structural formula of the halogenated aromatic compound 1 is as follows:

[0116]

[0117] The structural formula of the aromatic carboxamide compound 2 is as follows:

[0118]

[0119] R 1 、R 2 、R 3 and R 4 As described in any one of claims 1 to 2, G is a halogen;

[0120] Adding a solution of the acid or the base described in claim 4 to a solution of the small molecule compound (I), and removing the solvent after the salt formation is complete to obtain the pharmaceutically acceptable salt.

[0121] The present invention provides a pharmaceutical composition, which comprises a small molecule compound with KIF18A inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0122] The present invention provides the use of a small molecule compound with KIF18A inhibitory activity or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a medicament for treating or preventing hyperproliferative diseases.

[0123] As a preferred embodiment of the present invention, the hyperproliferative diseases are ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, liver cancer, gastric cancer, melanoma, renal cancer, colon cancer, central nervous system tumors, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma.

[0124] The present invention has the following beneficial effects compared with the prior art:

[0125] The small molecule compounds and their derivatives provided by the present invention can have excellent biological activities at both the molecular and cellular levels, and are used to inhibit the expression of KIF18A. At the molecular level, the KIF18A inhibition IC 50 value is optimally less than 50 nM, reaching the nanomolar concentration level; at the cellular level, the OVCAR-3 tumor cell proliferation inhibition IC 50 value is optimally less than 100 nM, reaching the nanomolar concentration level, which is of great significance for the development of selective inhibitors of this sub-protein and meeting the clinical needs of patients;

[0126] The small molecule compounds and their derivatives and the pharmaceutical composition provided by the present invention can effectively inhibit the proliferation of a variety of tumor cells;

[0127] The small molecules, their derivatives and the pharmaceutical composition provided by the present invention have a wide range of applications, can be prepared into medicaments for treating and / or preventing hyperproliferative diseases related to KIF18A, can exert drug effects at both the molecular and cellular levels, and have more excellent therapeutic effects. The IC50 value can optimally reach the nanomolar concentration level;

[0128] The preparation methods of the small molecule compounds and their derivatives provided by the present invention, the salts containing such small molecule compounds and their derivatives, and the medicaments are simple, easy to operate, have a wide applicability of reaction substrates, and the raw materials are easily available. Description of the Drawings

[0129] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only exemplary, and for those of ordinary skill in the art, without creative efforts, other implementation drawings can also be obtained based on the provided drawings.

[0130] Figure 1 The present invention provides a preparation equation for small molecule compounds with KIF18A inhibitory activity. Specific embodiments

[0131] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0132] The present invention specifically provides a small molecule with KIF18A inhibitory activity, and at the same time provides a preparation method for the small molecule with KIF18A inhibitory activity and its derivatives; and provides a pharmaceutical composition containing the small molecule with KIF18A inhibitory activity and / or its derivatives, and at the same time provides the application of the small molecule with KIF18A inhibitory activity and its derivatives, and the pharmaceutical composition in the preparation of drugs for treating and / or preventing hyperproliferative diseases.

[0133] Specifically, the chemical structure of the small molecule compound is shown in formula (I):

[0134]

[0135] X, Y, and Z are independently N or CH.

[0136] 2-(6-Azaspiro[2.5]octan-6-yl)benzamide in Structure I is an important structure that determines whether the compound has KIF18A inhibitory activity.

[0137] Specifically, in the small molecule compound with KIF18A inhibitory activity, R 1 is selected from any one of the following groups:

[0138]

[0139] R 2 is formylamino, acetylamino, propionylamino, cyclopropionylamino, methanesulfonamido, ethanesulfonamido, propanesulfonamido, cyclopropanesulfonamido, 2-hydroxyethylsulfonamido, and more preferably, R 2is any one of ethylsulfonamido, propanesulfonamido, cyclopropanesulfonamido, and 2-hydroxyethylsulfonamido.

[0140] R 3 and R 4 is a hydrogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkanamido, and C 1 -C 6 sulfonamido; wherein, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkanamido, and C 1 -C 6 sulfonamido further contains one or more halogens, hydroxyl groups, amino groups, heteroatoms, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkanamido, and C 1 -C 6 sulfonamido; more preferably, R 3 and R 4 are any one of a hydrogen atom, methyl, ethyl, methylamino, ethylamino, methoxy, ethoxy, formamido, and acetamido.

[0141] In the structure of R 1 R 5 is a hydrogen atom, C 1 -C 6 alkyl, a halogen, a cyano group, or C 1 -C 6 haloalkyl.

[0142] R 6 is any one of N-methylsulfamoyl, N-(tert-butyl)sulfamoyl, methylsulfonyl, N-methylcarbamoyl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, (R)-2-methylmorpholin-4-yl, 3,3-difluorocyclobutyl, and 3,3-difluorotetrahydro-1H-pyrrol-1-yl.

[0143] R 7 , R8, and R9 are each independently a hydrogen atom, a halogen, a C 1 -C 6 -alkyl, a cyano group, a C 1 -C 6 -haloalkyl, a C 1 -C 6 -alkylamino, a C 1 -C 6 -alkoxy, a C 1 -C 6 -alkanoylamino, and a C 1 -C 6 -sulfonamido, any one of which.

[0144] Preferably, R 1 is selected from any one of the following groups:

[0145]

[0146] Wherein, the small molecule compound is used to inhibit the expression of KIF18A subprotein.

[0147] The present invention also provides a small molecule compound having KIF18A inhibitory activity.

[0148] Based on the above compound, the present invention also provides a pharmaceutically acceptable salt of the small molecule compound having KIF18A inhibitory activity, and the pharmaceutically acceptable salt is a salt formed by the small molecule compound and an acid or a base.

[0149] Wherein, the acid is any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, malic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid.

[0150] The base is any one or more of inorganic bases containing an alkaline metal cation, an alkaline earth metal cation, or an ammonium cation salt.

[0151] Such a salt can be used as a raw material for anti-cancer drugs.

[0152] As Figure 1 shown, the present invention also provides a preparation method of a small molecule compound having KIF18A inhibitory activity or a pharmaceutically acceptable salt, comprising the following steps:

[0153] S100. Reacting a halogenated aromatic compound 1 with an aromatic formamide compound 2 through an Ullmann reaction to obtain the small molecule compound (I);

[0154] Wherein, the structural formula of the halogenated aromatic compound 1 is as follows:

[0155]

[0156] The structural formula of compound 2 of the arylformamide is as follows:

[0157]

[0158] R 1 and R 2 and R 3 and R 4 As described in any one of claims 1 to 2, G is a halogen;

[0159] S200. Add the solution of the acid or base described in claim 4 to the solution of the small molecule compound (I). After the salt formation is complete, remove the solvent to obtain the pharmaceutically acceptable salt.

[0160] The present invention also provides a pharmaceutical composition, comprising a small molecule compound with KIF18A inhibitory activity or a pharmaceutically acceptable salt containing such a compound, and a pharmaceutically acceptable carrier, such as starch and the like.

[0161] The preparation methods of the small molecule compounds, their derivatives, salts containing such small molecule compounds and derivatives, and drugs provided by the present invention are simple, easy to operate, have a wide applicability of reaction substrates, and the raw materials are easily available.

[0162] Furthermore, the small molecule compounds with KIF18A inhibitory activity and their derivatives provided by the present invention are used in the preparation of drugs for treating or preventing hyperproliferative diseases.

[0163] The hyperproliferative diseases are ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, liver cancer, gastric cancer, melanoma, kidney cancer, colon cancer, central nervous system tumors, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma.

[0164] The following provides examples for illustration:

[0165] Reagents and materials:

[0166] The chemical reagents used in the compound preparation are sourced from Shanghai Bide Pharmaceutical Technology Co., Ltd. and Shanghai Haohong Biopharmaceutical Technology Co., Ltd.;

[0167] KIF18A is sourced from Beijing Ace Medicine & Biology Co., Ltd., and the OVCAR-3 tumor cell line is sourced from Zhejiang Meisen Cell Technology Co., Ltd.

[0168] Instruments:

[0169] 1H-NMR was measured using a BRUKER AVANCE-300 nuclear magnetic resonance spectrometer (Brucker, Switzerland), with TMS as the internal standard, and the displacement value (δ) in ppm; low-resolution mass spectrometry was measured using an expression compact Fourier transform mass spectrometer.

[0170] Example 1:

[0171] Taking N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-1) as an example:

[0172] The synthesis equation of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-1) is as follows:

[0173]

[0174] (1) Synthesis of tert-butyl 4-bromo-2-fluoro-6-methylbenzoate (Compound M1)

[0175] 4-Bromo-2-fluoro-6-methylbenzoic acid (1.0 g, 4.292 mmol) was added to a 50 mL eggplant-shaped flask, dissolved in 20 mL of dichloromethane, and oxalyl chloride (727 μL, 8.584 mmol) was added dropwise under an ice bath, and the reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was redissolved in anhydrous tetrahydrofuran. Potassium tert-butoxide (481 mg, 4.292 mmol) was added in batches, and the reaction was carried out at room temperature for 12 hours. The solvent was removed under reduced pressure, and then 100 mL of a mixed solution of petroleum ether:ethyl acetate (10:1) was added. After filtering the insoluble matter, the clear solution was concentrated under reduced pressure to obtain 1.0 g of a pale yellow solid with a yield of 81%. 1 H-NMR(400MHz,CDCl 3 )δ7.78-7.71(m,1H),7.36-7.28(m,2H),1.59(s,9H).ESI-MS m / z:290.1[M+H] + .

[0176] (2) Synthesis of tert-butyl 4-bromo-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoate (Compound M2)

[0177] In a 100 mL thick-walled pressure-resistant flask, add M1 (1.0 g, 3.460 mmol), 6-azaspiro[2.5]octane hydrochloride (763 mg, 5.190 mmol) and potassium carbonate (1.43 g, 10.381 mmol). Add 10 mL of DMSO and react at 120 °C for 6 h. Detect by TLC until the raw material spots disappear. Cool the reaction solution to room temperature, add 100 mL of water, adjust the pH to about 5 with acetic acid, extract with ethyl acetate (100 mL × 3), combine the organic layers, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 736 mg of a yellow oily liquid with a yield of 56%. 1 H-NMR(400MHz,CDCl 3 )δ7.78-7.71(m,1H),7.36-7.28(m,2H),2.78–2.51(m,4H),1.78–1.51(m,8H),1.59(s,9H).ESI-MS m / z:381.3[M+H] + .

[0178] (3) Synthesis of tert-butyl 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoate (Compound M3)

[0179] In a 100 mL thick-walled pressure-resistant flask, add tert-butyl 4-bromo-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoate (736 mg, 1.937 mmol), ethylsulfonamide (211 mg, 1.937 mmol), copper(I) iodide (736 mg, 3.874 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (927 μL, 5.811 mmol) and potassium phosphate (1.23 g, 5.811 mmol). Use 20 mL of DMF as the solvent, purge with nitrogen, react at 90 °C for 3 h. Detect by TLC until the raw material spots disappear. Pour the reaction solution into 100 mL of saturated ammonium chloride aqueous solution, extract with ethyl acetate (200 mL × 3), combine the organic layers, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 537 mg of a yellow oily liquid with a yield of 68%. 1 H NMR(400MHz,DMSO-d 6 )δ11.84(s,1H),7.78-7.71(m,1H),7.36-7.28(m,2H),2.78–2.51(m,4H),2.24(q,2H),1.42(t,3H),1.78–1.51(m,8H),1.59(s,9H).ESI-MS m / z:409.4[M+H]+.

[0180] (4) Synthesis of 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoic acid (Compound M4)

[0181] Add tert-butyl 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoate (537 mg, 1.316 mmol) and 20 mL of dichloromethane to a 100 mL eggplant-shaped flask. Dropwise add 5 mL of trifluoroacetic acid, and react at room temperature for 3 h. Monitor the reaction by TLC until the starting material spot disappears. Dropwise add saturated aqueous sodium bicarbonate solution to the reaction mixture to adjust the pH to 7. Collect the organic layer and remove the solvent under reduced pressure to obtain 380 mg of a pale yellow solid with a yield of 82%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 7.78 - 7.71 (m, 1H), 7.36 - 7.28 (m, 2H), 2.78–2.51 (m, 4H), 2.24 (q, 2H), 1.81 (t, 3H), 1.78–1.51 (m, 8H). ESI-MS m / z: 353.2 [M+H] + .

[0182] (5) Synthesis of 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound M5)

[0183] Add 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzoic acid (380 mg, 1.079 mmol), ammonium chloride (58 mg, 1.079 mmol), HATU (820 mg, 2.159 mmol) and DIPEA (752 μL, 4.318 mmol) to a 100 mL eggplant-shaped flask, and use 20 mL of DMF as the solvent. Stir at room temperature for 3 h. Monitor the reaction by TLC until the starting material spot disappears. Pour the reaction mixture into 120 mL of water and extract with ethyl acetate (200 mL × 3). Collect the organic layer and remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 280 mg of a white solid with a yield of 74%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 9.93 (s, 2H), 7.78 - 7.71 (m, 1H), 7.36 - 7.28 (m, 2H), 2.78–2.51 (m, 4H), 2.24 (q, 2H), 1.81 (t, 3H), 1.78–1.51 (m, 8H). ESI-MS m / z: 352.4 [M+H]+.

[0184] (6)Synthesis of N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound I-1)

[0185] Add 4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (280 mg, 0.798 mmol), N-tert-butyl-3-bromobenzenesulfonamide (233 mg, 0.798 mmol), copper(I) iodide (303 mg, 1.595 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (381 μL, 2.394 mmol) and potassium phosphate (507 mg, 2.394 mmol) into a 100 mL thick-walled pressure-resistant bottle, add 10 mL of DMF, react at 90 °C for 3 h, and detect by TLC until the raw material spots disappear. Pour the reaction solution into 100 mL of saturated ammonium chloride aqueous solution, extract with ethyl acetate (200 mL × 3), combine the organic layers, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 261 mg of white solid, with a yield of 58%. 1 H NMR(400MHz,DMSO-d 6 )δ11.84(s,1H),10.79(s,1H),9.93(s,1H),7.78-7.71(m,1H),7.60(s,1H),7.53-7.40(m,3H),7.36-7.28(m,2H),2.78–2.51(m,4H),2.24(q,2H),1.81(t,3H),1.78–1.51(m,8H),1.48(s,9H).ESI-MS m / z:563.7[M+H] + .

[0186] Other examples:

[0187] Using operations similar to those in Example 1, the following compounds were prepared:

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Thus, the present invention discloses 84 preferred embodiments of small molecules with KIF18A inhibitory activity. The following is a functional verification of the above preferred embodiments:

[0207] Verification Example 1: Inhibitory Activity of Small Molecules against KIF18A Protein

[0208] Beijing Ace Medicine Co., Ltd. tested the inhibitory activity of the above small molecules against KIF18A by the ADP-GLO method.

[0209] Specific operation method: The ADP-Glo method can detect the ADP formed in the kinase reaction; ADP is converted into ATP, and then ATP is converted into light by luciferase. The luminescence signal is positively correlated with the kinase activity. This kit is suitable for detecting the effects of compounds on the activities of various purified kinases, making it an ideal tool for primary screening and studying the selectivity of kinase actions.

[0210] The specific operation steps are as follows: Transfer 0.1 μL of the diluted compound solution to a 384-well plate using Echo550. Add 5 μL of the enzyme working solution to the 384-well assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 10 minutes. Then add 5 μL of the ATP solution to initiate the reaction, and centrifuge at 1000 rpm for 1 minute. Incubate at 25 °C for 60 minutes. Add 5 μL of the ADP-Glo working solution to initiate the reaction, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 40 minutes. Add 10 μL of the detection solution to initiate the reaction, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 40 minutes. Finally, read the RLU (Relative Luminescence Unit) signal using a BMG microplate reader and calculate the inhibition rate. IC 50 It is obtained by plotting the percentage inhibition rate against the logarithmic concentration value, and the analysis results are shown in Table 1.

[0211] Table 1 Inhibitory activity of KIF18A

[0212] Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> I-1 B I-22 B I-43 B I-64 B I-2 B I-23 B I-44 B I-65 C I-3 A I-24 B I-45 B I-66 B I-4 A I-25 B I-46 B I-67 B I-5 A I-26 A I-47 B I-68 B I-6 B I-27 B I-48 B I-69 B I-7 B I-28 B I-49 C I-70 C I-8 B I-29 C I-50 C I-71 C I-9 A I-30 A I-51 A I-72 A I-10 A I-31 A I-52 A I-73 A I-11 B I-32 B I-53 C I-74 C I-12 C I-33 C I-54 C I-75 C I-13 A I-34 A I-55 A I-76 A I-14 A I-35 A I-56 A I-77 A I-15 B I-36 B I-57 B I-78 C I-16 B I-37 B I-58 B I-79 B I-17 B I-38 B I-59 B I-80 B I-18 A I-39 A I-60 A I-81 A I-19 B I-40 B I-61 B I-82 B I-20 C I-41 C I-62 C I-83 C I-21 C I-42 C I-63 C I-84 C

[0213] Note: "A" represents an IC 50 value less than 0.05 μM, "B" represents an IC 50 value between 0.05 μM and 0.5 μM, and "C" represents an IC 50 value greater than 0.5 μM.

[0214] As can be seen from Table 1, all the tested small molecules have inhibitory activity against KIF18A. Specifically, the IC 50 values of small molecules I-3 to I-5, I-9 to I-10, I-13 to I-14, I-18, I-26, I-30 to I-31, I-34 to I-35, I-39, I-51 to I-52, I-55 to I-56, I-60, I-72 to I-73, I-76 to I-77, and I-87 against KIF18A inhibitory activity are all less than 0.05 μM, at the two-digit nanomolar concentration level.

[0215] It can be seen that the examples provided by the present invention can all have excellent biological activity at the molecular level and are used to inhibit the expression of KIF18A.

[0216] Verification Example 2: Anti-proliferative activity of small molecules against tumor cells

[0217] Specific operation method: Prepare the compound at a storage concentration of 10 mM using DMSO. Dilute the compound with DMSO to a top dose of 2 mM (100% DMSO), and triple-dilute the highest concentration point, with a total of ten points.

[0218] Dilute the compound 100-fold with the corresponding cell culture medium to make the top dose of the compound concentration 20 μM (1% DMSO). The seeding density of OVCAR-3 cells is 6000 cells / well. The cells are seeded overnight with a volume of 20 μL. The volume of the added drug is 20 μL. At this time, the volume in each well is 40 μL, and the top dose of the final concentration of the compound is 10 μM (0.5% DMSO). After adding the drug, it acts for 96 h. Aspirate the original liquid in the wells, add 20 μL of CCL to each well, and perform detection using the program Luminescence after 20 min. The detection results are shown in Table 2.

[0219] Table 2 Anti-proliferative effects of OVCAR-3 tumor cells

[0220] Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> Cpd. <![CDATA[IC 50 (μM)]]> I-1 C I-22 B I-43 B I-64 C I-2 C I-23 C I-44 B I-65 C I-3 B I-24 B I-45 C I-66 C I-4 B I-25 C I-46 C I-67 C I-5 A I-26 A I-47 B I-68 B I-6 B I-27 B I-48 C I-69 C I-7 C I-28 C I-49 C I-70 C I-8 C I-29 C I-50 C I-71 C I-9 A I-30 A I-51 A I-72 A I-10 A I-31 A I-52 A I-73 A I-11 C I-32 B I-53 C I-74 C I-12 C I-33 C I-54 C I-75 C I-13 A I-34 A I-55 A I-76 A I-14 A I-35 A I-56 A I-77 A I-15 B I-36 B I-57 C I-78 C I-16 B I-37 B I-58 C I-79 C I-17 B I-38 C I-59 C I-80 C I-18 B I-39 A I-60 A I-81 A I-19 B I-40 B I-61 B I-82 B I-20 C I-41 C I-62 C I-83 C I-21 C I-42 C I-63 C I-84 C AMG650 A

[0221] Note: "A" represents an IC 50 value less than 0.1 μM, "B" represents an IC 50 value between 0.1 μM and 0.5 μM, "C" represents an IC 50 value greater than 0.5 μM. The structure of the reference compound AMG650 is the same as that of compound 4 in patent WO2020132648A1.

[0222] As can be seen from Table 2, all the tested small molecules have inhibitory effects on OVCAR-3 cells. Specifically, the anti-proliferative IC50 values of compounds I-5, I-9-I-10, I-13-I-14, I-26, I-30-I-31, I-34-I-35, I-39, I-51-I-52, I-55-I-56, I-60, I-72-I-73, I-76-I-77, and I-87 on OVCAR-3 tumor cells are all less than 0.1 μM, reaching the nanomolar concentration level; the other small molecules all reach the nanomolar concentration level. In addition, the anti-proliferative IC 50 values of these compounds are comparable to those of the compound AMG650.

[0223] It can be seen that the examples provided by the present invention all have excellent biological activities at the cellular level and are used to inhibit the expression of KIF18A.

[0224] Verification Example 3: Detection of the anti-tumor cell spectrum of small molecules

[0225] Experimental materials: All the materials used in the experiment are from Zhejiang Meisen Cell Technology Co., Ltd.

[0226] Experimental method: Select the more prominent examples in Verification Example 2 and perform tests with reference to the test method in Verification Example 2. The IC 50 values are shown in Table 3.

[0227] Table 3 Anti-tumor cell spectrum

[0228]

[0229]

[0230] Note: "A" represents an IC 50 value less than 0.1 μM, "B" represents an IC 50 value between 0.1 μM and 0.5 μM, "C" represents an IC 50 value greater than 0.5 μM. The reference compound AMG650 has the same structure as compound 4 in patent WO2020132648A1.

[0231] As can be seen from Table 3, the test small molecules in the above examples all have inhibitory activity against cancer cells of various vital organs, and the IC50 values all reach the nanomolar concentration level. The IC 50 values of some compounds even exceed those of the reference compound AMG650.

[0232] In other verification examples, the applicable diseases include but are not limited to various solid malignant tumors such as ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, liver cancer, gastric cancer, melanoma, kidney cancer, colon cancer, and central nervous system tumors, as well as hematological malignancies such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and follicular lymphoma.

[0233] By verifying the above examples, it can be known that the small molecule compounds, their derivatives, and pharmaceutical compositions containing such compounds disclosed in the present invention have the following remarkable advantages:

[0234] (1) Such small molecules and their derivatives have high inhibitory activity. At the molecular level, the optimal IC 50 value of KIF18A inhibition is less than 50 nM, reaching the nanomolar concentration level; at the cellular level, the optimal IC 50 value of OVCAR-3 tumor cell proliferation inhibition is less than 100 nM, reaching the nanomolar concentration level; and they can effectively inhibit the proliferation of a variety of tumor cells, reaching the nanomolar concentration level, with the optimal value less than 100 nM; the anti-proliferation IC 50 values of some compounds are equivalent to or lower than those of the reference compound AMG650;

[0235] (2) Such small molecules, their derivatives and pharmaceutical compositions have a wide range of applications and can be prepared into drugs for treating and / or preventing hyperproliferative diseases related to KIF18A; they can exert pharmacological effects at both the molecular level and the cellular level, and the therapeutic effect is more excellent, and the IC 50 value can optimally reach the nanomolar concentration level.

[0236] Through the KIF18A inhibitory active small molecule compound, its pharmaceutical composition and application of this example, targeted inhibition of KIF18A at the molecular level and the cellular level can be achieved, providing a basis for the development of selective inhibitor drugs for this subprotein, and capable of effectively inhibiting the proliferation of a variety of tumor cells.

[0237] The above embodiments are only exemplary embodiments of the present application and are not used to limit the present application. The protection scope of the present application is defined by the claims. Those skilled in the art can make various modifications or equivalent replacements within the essence and protection scope of the present application, and such modifications or equivalent replacements should also be regarded as falling within the protection scope of the present application.

Claims

1. A small molecule compound with KIF18A inhibitory activity, characterized in that: The chemical structure of the small molecule compound is shown in formula (I): R 1 Select from any of the following groups: X, Y, and Z are independently N or CH; R 2 Any one of formamide, acetamido, propionamide, cyclopropionamide, methanesulfonamide, ethylsulfonamide, propanesulfonamide, cyclopropanesulfonamide, and hydroxyethylsulfonamide; R 3 and R 4 is any one of a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkanoylamide group and a C1-C6 sulfonamide group; Wherein, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkanoylamide and C1-C6 sulfonamide further contain one or more halogen, hydroxyl, amino, heteroatom, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 alkanoylamide and C1-C6 sulfonamide; R 5 is a hydrogen atom, a C1-C6 alkyl group, a halogen, a cyano group or a C1-C6 haloalkyl group; R 6 It is any one of N-methylsulfamoyl, N-(tert-butyl)sulfamoyl, methylsulfonyl, N-methylcarbamoyl, piperidin-1-yl, 4,4-difluoropiperidin-1-yl, (R)-2-methylmorpholin-4-yl, 3,3-difluorocyclobutyl, and 3,3-difluorotetrahydro-1H-pyrrol-1-yl; R 7 , R8 and R9 are any one of a hydrogen atom, a halogen, a C1-C6 alkyl group, a cyano group, a C1-C6 haloalkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, a C1-C6 alkanoylamide group and a C1-C6 sulfonamide group; Wherein, the small molecule compound is used to inhibit the expression of KIF18A subprotein.

2. A KIF18A inhibitory activity small molecule compound according to claim 1, characterized in that: In the structure of the small molecule compound, R 1 Select from any of the following groups: R 2 Any one of ethylsulfonamide, propanesulfonamide, cyclopropanesulfonamide and hydroxyethylsulfonamide; R 3 and R 4 It is any one of a hydrogen atom, a methyl group, an ethyl group, a methylamino group, an ethylamino group, a methoxy group, an ethoxy group, a formamide group, and an acetamido group.

3. A small molecule compound having KIF18A inhibitory activity, as claimed in claim 1, characterized in that: The small molecule compound is any one of the following compounds: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-1); 4-(Ethylsulfonamido)-2-methyl-N-(3-(methylcarbamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-2); N-(3-(N-(tert-butyl)sulfamoyl)-4-methylphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-3); 4-(Ethylsulfonamido)-2-methyl-N-(3-(N-methylsulfamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-4); N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-5); 4-(Ethylsulfonamido)-2-methyl-N-(3-(methylsulfonyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-6); N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-7); N-(3-(4,4-difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-8); N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-9); N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-10); N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-11); N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-ethylsulfonamide-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-12); N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-13); N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-14); N-(2-(3,3-difluorocyclopentyl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-15); (R)-N-(6-(3-cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-16); N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-17); N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-18); N-(5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-19); N-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-20); (R)-4-(ethylsulfonamido)-2-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-21); N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-22); 4-(Ethylsulfonamido)-5-methyl-N-(3-(methylcarbamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-23); N-(3-(N-(tert-butyl)sulfamoyl)-4-methylphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-24); 4-(Ethylsulfonamido)-5-methyl-N-(3-(N-methylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-25); N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-26); 4-(Ethylsulfonamido)-5-methyl-N-(3-(methylsulfonyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-27); N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-28); N-(3-(4,4-difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-29); N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-30); N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-31); N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-32); N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-methylsulfonamide-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-33); N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-34); N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-35); N-(2-(3,3-difluorocyclopentyl)-6-methylpyridin-4-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-36); (R)-N-(6-(3-cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-37); N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-38); N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-39); N-(5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-40); N-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methylpyridin-2-yl)-4-(ethylsulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-41); (R)-4-(ethylsulfonamido)-5-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-42); N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-43); 4-((2-Hydroxyethyl)sulfonamido)-2-methyl-N-(3-(methylcarbamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-44); N-(3-(N-(tert-butyl)sulfamoyl)-4-methylphenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-45); 4-((2-Hydroxyethyl)sulfonamido)-2-methyl-N-(3-(N-methylsulfamoyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-46); N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-47); 4-((2-Hydroxyethyl)sulfonamido)-2-methyl-N-(3-(methylsulfonyl)phenyl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-48); N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-49); N-(3-(4,4-difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-50); N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-51); N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-52); N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-53); N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-54); N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-55); N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-56); N-(2-(3,3-difluorocyclopentyl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-57); (R)-N-(6-(3-cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-58); N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-59); N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-60); N-(5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-61); N-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-62); (R)-4-((2-hydroxyethyl)sulfonamido)-2-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-6-(6-azaspiro[2.5]octan-6-yl)benzamide (I-63); N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-64); 4-((2-Hydroxyethyl)sulfonamido)-5-methyl-N-(3-(methylcarbamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-65); N-(3-(N-(tert-butyl)sulfamoyl)-4-methylphenyl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-66); 4-((2-Hydroxyethyl)sulfonamido)-5-methyl-N-(3-(N-methylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-67); N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfonamide)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-68); 4-((2-Hydroxyethyl)sulfonamido)-5-methyl-N-(3-(methylsulfonyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-69); N-(3-(4,4-difluoropiperidin-1-yl)-5-methoxyphenyl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-70); N-(3-(4,4-difluoropiperidin-1-yl)-5-(methylamino)phenyl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-71); N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-72); N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-73); N-(6-(4,4-difluoropiperidin-1-yl)-4-methoxypyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-74); N-(6-(4,4-difluoropiperidin-1-yl)-4-(methylamino)pyridin-2-yl)-4-[(2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-75); N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-76); N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-77); N-(2-(3,3-difluorocyclopentyl)-6-methylpyridin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-78); (R)-N-(6-(3-cyanopiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-79); N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-80); N-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-81); N-(5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-82); N-(6-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-5-methyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-83); (R)-4-((2-Hydroxyethyl)sulfonamido)-5-methyl-N-(4-methyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (I-84).

4. A pharmaceutically acceptable salt of a small molecule compound having KIF18A inhibitory activity according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable salt is a salt formed by the small molecule compound and an acid or a base; Wherein, the acid is any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, malic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; The base is any one or more of an inorganic base containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.

5. A method for preparing the KIF18A inhibitory active small molecule compound according to any one of claims 1 to 2 or the pharmaceutically acceptable salt according to claim 4, comprising the following steps: The halogenated aromatic compound 1 and the aromatic formamide compound 2 are subjected to an Ullmann reaction to obtain the small molecule compound (I); in, The structural formula of the halogenated aromatic compound 1 is as follows: The structural formula of the aromatic formamide compound 2 is as follows: R 1 , R 2 , R 3 and R 4 As described in any one of claims 1 to 2, G is a halogen; The solution of the acid or base according to claim 4 is added to the solution of the small molecule compound (I), and the solvent is removed after the salt is completely formed to obtain the pharmaceutically acceptable salt.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the KIF18A inhibitory active small molecule compound according to any one of claims 1 to 3 or the pharmaceutically acceptable salt according to claim 4 and a pharmaceutically acceptable carrier.

7. Use of a small molecule compound having KIF18A inhibitory activity according to any one of claims 1 to 3 in the preparation of a drug for treating or preventing a hyperproliferative disease.

8. Use of the pharmaceutically acceptable salt according to claim 4 in the preparation of a drug for treating or preventing a hyperproliferative disease.

9. Use of the pharmaceutical composition according to claim 6 in the preparation of a drug for treating or preventing a hyperproliferative disease.

10. The use according to any one of claims 7, 8 and 9, characterized in that: The hyperproliferative diseases are ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, liver cancer, gastric cancer, melanoma, kidney cancer, colon cancer, central nervous system tumors, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and follicular lymphoma.

Images