KIF18A inhibitors

Abstract

The present invention discloses a group of KIF18A inhibitors. Specifically, the present invention relates to a compound of general formula (1), a method for preparing the same, and the use of the compound of general formula (1) or its isomers, its crystals, its pharmaceutically acceptable salts, its hydrates or solvates as KIF18A inhibitors in the preparation of antitumor agents. [Formula 1] TIFF2026511443000162.tif43168

Description

[Technical Field]

[0001] This application claims priority to China Patent Application No. 202310256056.2, filed on 16 March 2023, which are incorporated herein by reference in their entirety.

[0002] The present invention relates to the field of pharmaceutical chemistry, and more particularly to a group of compounds having an inhibitory effect on the KIF18A protein, a method for preparing the same, and the use of the said group of compounds in the preparation of antitumor drugs. [Background technology]

[0003] Genomic instability is a common characteristic of most tumor cells. Most tumor cells exhibit abnormal increases or deletions of chromosomes. Chromosomal instability in tumor cells leads to interactions between abnormal chromosomes and mitotic spindle microtubules, which cause chromosome segregation errors. Cells with chromosomal instability have increased spindle microtubule polymerization and decreased contact turnover between spindle microtubules and centromeres compared to cells with normal chromosomes. Therefore, anti-mitotic therapies targeting the microtubule skeleton may be particularly effective against cells with chromosomal instability.

[0004] Kinesin is a type of molecular motor that plays a crucial role in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesin plays a vital role in several aspects, including spindle assembly, chromosome segregation, centrosome segregation, and dynamics. Human kinesins are classified into 14 subfamilies based on differences in the amino acid sequence of the motor domain. The ATPase activity present in the motor domain allows the protein to move unidirectionally along microtubules. The non-motile domain of these proteins is responsible for interacting with substrates, and various membrane organelles, signaling scaffold systems, and chromosomes function as substrates to which the non-motile domain interacts. Kinesin gains energy through ATP hydrolysis and moves substrates along polarized microtubules. Therefore, kinesin is commonly referred to as a "plus-end" or "minus-end" directional motor.

[0005] The KIF18A protein belongs to the kinesin-8 subfamily. It is overexpressed in various types of cancer, including lung cancer, ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, prostate cancer, colon cancer, and bladder cancer. Studies have shown that KIF18A influences the dynamics of the plus end of centromere microtubules, regulating chromosome positioning and spindle tension. In chromosomally unstable tumor cells, microtubule dynamics are abnormal, and such cells are particularly dependent on the KIF18A protein to reduce spindle microtubule-centromere contact turnover and limit microtubule growth (Nat Commun. 2021, 12, 1213). Deletion of the KIF18A protein in chromosomally unstable tumor cells leads to centrosome fragmentation and slowed or halted mitotic progression. However, these phenomena do not occur in cells with normal chromosomes. Therefore, while the activity of the KIF18A protein does not significantly affect the proliferation of normal cells, it is extremely important for the proliferation of chromosomally unstable tumors. [Prior art documents] [Non-patent literature]

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] Therefore, the development of KIF18A inhibitors is a new and promising approach for tumors with chromosomal instability.

Means for Solving the Problems

[0008] (Summary) The present invention provides a compound of general formula (1), or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

Chemical Formula

Chemical formula

[0009] In another preferred embodiment, in general formula (1), Y 2 These are H, -F, -Cl, -Br, -NO2, -CN, -OH, -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 ,-P(O)R c7 R c8 -N=S(O)R c9 R c10 -S(O)(NR c11 )R c12 -S(O)2R c13 , -NR c14 C(O)OR c15, -NR c16 S(O)2(CH2) 1~3 NR c17 C(O)R c18 , -NR c16 S(O)2(CH2) 1~3 OC(O)R c18 , and C substituted with 1, 2, or 3 -OH or -F 1~6 Selected from alkyl.

[0010] In another preferred embodiment, in general formula (1), R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , R c14 , R c15 , R c16 , R c17 , and R c18 These are H and C, respectively, independently. 3~6 Cycloalkyl and C substituted with 1 or 2 H, -OH, -NH2, or halogens 1~6 Selected from alkyl.

[0011] In another preferred embodiment, in general formula (1), R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R c10 , R c11 , R c12 , R c13 , R c14 , R c15 , R c16 , R c17 , and R c18 These are H, independently of each other. [ka] Selected from.

[0012] In another preferred embodiment, in general formula (1), Y 2 teeth, [ka] Selected from.

[0013] In another preferred embodiment, in general formula (1), Y 2 teeth, [ka] Selected from.

[0014] In another preferred embodiment, in general formula (1), R b1 and R b2 However, along with the carbon atoms bonded to them, the structural units: [ka] When forming, ring A is C 6~10 It is an aryl or (5-10 member) heteroaryl, where C 6~10 Each aryl or the (5-10 membered) heteroaryl is independently H, -F, -Cl, -Br, -OH, C 1~6 Alkyl, (3-10 member) heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 -N=S(O)R a8 R a9 , -OR a10 ,-S(O)R a11 -S(O)(NR a12 )R a13 -S(O)2NR a14R a15 -S(O)2R a16 ,-(CR a17 R a18 ) 0~1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , and -NR a23 S(O)2R a24 The C may be optionally substituted with one, two, three, four, or five of the groups, where C 1~6 Alkyl or the (3-10 membered) heterocycloalkyl group can independently be H, -F, -Cl, -Br, [ka] -OH, -CN, C 3~6 It may be optionally substituted with one, two, three, or four groups from among cycloalkyls and (3-10 member) heterocycloalkyls substituted with one or two -F, -Cl, or -Br groups.

[0015] In another preferred embodiment, in general formula (1), R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 , R a23 , and R a24 These are H and C, respectively, independently. 1~6 Alkyl, C 2~6 Alkenil, C 3~6 Cycloalkyl, C 3~6Cycloalkenyl, (4-9 member) heterocycloalkyl, (3-6 member) heterocycloalkenyl, C 6~10 Selected from aryls and (5-10 membered) heteroaryls, where C 1~6 Alkyl, the C 2~6 Alkenyl, the C 3~6 Cycloalkyl, the C 3~6 Cycloalkenyl, the (4-9 member) heterocycloalkyl, the (3-6 member) heterocycloalkenyl, the C 6~10 The aryl, or the (5-10 membered) heteroaryl, is independently H, -F, -Cl, -CN, -OH, -O(C) 1~3 Alkyl), C 2~4 Alkenil, C 3~6 Cycloalkyl, -S(C 1~3 Alkyl), [ka] , and 1, 2, or 3 H, -F, -Cl, -OH, or -O(C) 1~3 C substituted with alkyl 1~6 The alkyl group may be optionally substituted with one, two, three, or four of the alkyl groups.

[0016] In another preferred embodiment, in general formula (1), R b1 and R b2 However, along with the carbon atoms bonded to them, the structural units: [ka] When forming, ring A is phenyl, naphthyl, or a (5-10 membered) heteroaryl, where each of the phenyl, naphthyl, or (5-10 membered) heteroaryl is independently H, -F, -Cl, -Br, -OH, -OCH3, [ka] , -NH2, [ka] [ka] [ka] One, two, or three of these groups may be optionally substituted.

[0017] In another preferred embodiment, in general formula (1), ring A is phenyl or a (5-6 membered) heteroaryl.

[0018] In another preferred embodiment, in general formula (1), ring A is phenyl, thienyl, furanyl, pyridinyl, or pyrimidinyl.

[0019] In another preferred embodiment, in general formula (1), R b1 and R b2 However, along with the carbon atoms bonded to them, the structural units: [ka] When forming, ring A is R x C replaced by 6~10 Aryl or R x A heteroaryl (5-10 member) substituted with, where R x C replaced by 6~10 aryl or the R x The (5-10 member) heteroaryls substituted with each of these are independently -O(C 1~3 Alkyl), -S(C 1~3 The C may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups from alkyl, -NH2, -NH(CH3), -N(CH3)2, -NO2, or -CN, where the C 1~3 The alkyl group may be substituted with 0, 1, 2, or 3 groups from H or -F.

[0020] In another preferred embodiment, in general formula (1), R b1 and R b2 However, along with the carbon atoms bonded to them, the structural units: [ka] When forming, ring A is R x C replaced by 6~10 Aryl or R x A heteroaryl (5-10 member) substituted with, where R x C replaced by 6~10 aryl or the R x The (5-10 member) heteroaryls substituted with each of these are independently -NO2, -CN, [ka] It may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups from -NH2, -NH(CH3), or -N(CH3)2.

[0021] In another preferred embodiment, in general formula (1), R x is a (4-7 member) heterocycloalkyl, where each of the (4-7 member) heterocycloalkyls is independently -F, C 1~3 Alkyl, or [ka] It may be optionally substituted with one, two, three, four, or five of the groups.

[0022] In another preferred embodiment, in general formula (1), R x teeth, [ka] That is the case.

[0023] This disclosure further provides compounds of general formula (2), or isomers thereof, crystals thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof. [ka] (In general formula (2), A is a phenyl group or a (5-6 membered) heteroaryl group, where the phenyl group or the (5-6 membered) heteroaryl group is independently H, -F, -OH, and C. 1~3 Alkyl, (3-6 member) heterocycloalkyl, -NR a6 R a7 ,-OC 1~3 Alkyl, -S(O)R a11 -S(O)(NR a12 )R a13 -S(O)2NR a14 R a15 -S(O)2R a16 ,-(CR a17 R a18 ) O~1 C(O)NR a19 R a20 , -SR a21 , and -C(O)R a22 The C may be optionally substituted with one, two, three, four, or five of the groups, where C 1~3 Each alkyl group or the (3-6 membered) heterocycloalkyl group may be independently substituted with any one, two, three, or four groups selected from H or -F; Y 5 -S(O)2NHR c19 And R c19 is C 1~3 It is alkyl, where the C 1~3 The alkyl group may be substituted with one or two of the following: H, -OH, -NH2, or F.

[0024] In various embodiments of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It has one of the following.

[0025] The present invention further aims to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and as an active ingredient, a compound of general formula (1) of the present invention or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate or its solvate.

[0026] The present invention further aims to provide the use of a compound of general formula (1) of the present invention, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate or solvate, or the above-mentioned pharmaceutical composition, in the preparation of a pharmaceutical for treating, modulating, or preventing diseases associated with the KIF18A protein.

[0027] The present invention further aims to provide a method for treating, regulating or preventing related diseases mediated by the KIF18A protein, comprising administering a therapeutically effective amount of a compound of general formula (1) of the present invention, or its isomer, its crystals, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or the pharmaceutical composition thereof, to the subject. [Modes for carrying out the invention]

[0028] Through the synthesis and detailed study of various novel compounds exhibiting KIF18A protein inhibitory activity, the inventors discovered that the compound of general formula (1) possesses remarkably potent KIF18A protein inhibitory activity.

[0029] The above general description and the following detailed description of the present invention are both illustrative and descriptive, and should be understood as being intended to provide a further description of the claimed invention.

[0030] (Synthesis of compounds) The following describes specific methods for preparing the compound of general formula (1) of the present invention, but these specific methods do not limit the present invention in any way.

[0031] The compound of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, combined with the methods described herein. Furthermore, the solvent, temperature, and other reaction conditions described herein may vary. The starting materials for the synthesis of the compound may be obtained by synthesis or may be commercially available. The compound described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS, 3rd The compounds can be synthesized using well-known techniques and starting materials, including the method found in Ed., (Wiley 1999). General methods for preparing the compounds can be modified by using appropriate reagents and conditions for introducing various groups into the molecular formulas described herein.

[0032] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to those described below. Furthermore, the compounds of the present invention can be easily prepared by any combination of various synthesis methods described herein or known in the art, and such combinations can be readily determined by those skilled in the art to whom the present invention relates. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), which can be prepared by the following general reaction schemes 1, 2, or 3.

[0033] General reaction scheme 1 [ka]

[0034] Embodiments of the compound of general formula (1) can be prepared according to general reaction scheme 1. Here, rings A and R b1 , R b2 , Y 1 , Y 2 , Y 3 , and Y 4 As defined above, H represents hydrogen and N represents nitrogen. As shown in General Reaction Scheme 1, compound 1-1 is reacted with compound 1-2 to produce compound 1-3, and then compound 1-3 is subjected to a condensation reaction with compound 1-4 to produce compound 1-5.

[0035] General reaction scheme 2 [ka]

[0036] Embodiments of the compound of general formula (1) can be prepared according to general reaction scheme 2. Here, rings A and R b1 , R b2 , Y 1 , Y 2 , Y 3 , and Y 4 As defined above, X represents bromine or iodine, H represents hydrogen, and N represents nitrogen. 2 The reagents are, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane-3-amine, (3) tert-butyl3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoethyl, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethane-1-ol, or (11) cyclopropanechol. As shown in General Reaction Scheme 2, compound 2-1 is reacted with compound 2-2 to produce compound 2-3, compound 2-3 is subjected to a condensation reaction with 2-4 to produce compound 2-5, and compound 2-5 is converted to Y 2 Compound 2-6 is produced by reacting it with the reagent.

[0037] General reaction scheme 3 [ka]

[0038] Embodiments of the compound of general formula (1) can be prepared according to general reaction scheme 3, where rings A and R b1 , R b2 , Y 1 , Y 2 , Y 3 , and Y 4 As defined above, X represents bromine or iodine, H represents hydrogen, and N represents nitrogen. 2The reagents are, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane-3-amine, (3) tert-butyl3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoethyl, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethane-1-ol, or (11) cyclopropanechol. As shown in General Reaction Scheme 3, compound 3-1 is reacted with compound 3-2 to produce compound 3-3, the amino group of compound 3-3 is protected with a protecting group to obtain compound 3-4, and compound 3-4 is converted to Y 2 Compound 3-5 is produced by reacting it with a reagent, compound 3-5 is deprotected to obtain compound 3-6, and compound 3-6 is subjected to a condensation reaction with 3-7 to produce compound 3-8.

[0039] Further forms of compounds In this specification, "pharmaceutically acceptable" means a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties in a compound. For example, when a substance is administered to an individual, such a substance does not cause undesirable biological effects or harmful interactions with any of its components.

[0040] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism receiving the administration, nor does it eliminate the biological activity and properties of the compound. In certain specific embodiments, the pharmaceutically acceptable salt is obtained by reacting the compound of the general formula with an acid or a base, where the acid or base is as defined in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 1 st Examples include, but are not limited to, those listed in Ed., (Wiley, 2002).

[0041] It should be understood that pharmaceutically acceptable salts include solvated or crystalline forms, particularly solvates or polymorphs. Solvates are formed selectively upon crystallization in pharmaceutically acceptable solvents, such as water and ethanol, with stoichiometric or non-stoichiometric amounts of solvent. Hydrates are formed when the solvent is water, and alkoxides are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, the organic solvents used including, but not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein may exist in either a non-solvated or solvated form. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

[0042] In other specific examples, compounds of general formula (1) may be prepared in different forms, including but not limited to amorphous, pulverized, and nanoparticle forms. Furthermore, compounds of general formula (1) may include crystalline forms, but may also be polymorphs. Polymorphs involve different lattice arrangements of the same elements of the compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline forms, optical properties, electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature may result in a single dominant crystalline form.

[0043] In another embodiment, compounds of general formula (1) may have chiral centers and / or axial chirality, and thus may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, single diastereomers, and cis-trans isomers. Each chiral center or axial chirality independently produces two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are included in the scope of the present invention. The present invention means that it includes all such isomers of these compounds.

[0044] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) and C-14 ( 14 They can be labeled with radioactive isotopes such as C). As another example, deuterated compounds can be formed by substituting hydrogen atoms with deuterium. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have advantages such as reduced adverse effects, improved drug stability, enhanced potency, and extended in vivo half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

[0045] Any atom of a compound in this disclosure refers to an isotope of the atom in the stable state of the compound, unless otherwise specified. Unless otherwise specified, when a site in the molecular structure is selected as "H" or "hydrogen", that site should be understood to have the natural abundance of the hydrogen isotope. Similarly, unless otherwise specified, when a site is selected as "D" or "deuterium", that site should be understood to have a deuterium isotope abundance at least 3000 times the natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0046] More preferably, each deuterated site of the deuterated compound of this disclosure has a deuterium atom abundance of at least 3500 times its natural abundance (deuterium atom enrichment of 52.2%). More preferably, the deuterium atom abundance is at least 4500 times its natural abundance (deuterium atom enrichment of 67.5%). More preferably, the deuterium atom abundance is at least 5000 times its natural abundance (deuterium atom enrichment of 75%). More preferably, the deuterium atom abundance is at least 6000 times its natural abundance (deuterium atom enrichment of 90%). More preferably, the deuterium atom abundance is at least 6333 times its natural abundance (deuterium atom enrichment of 95%). More preferably, the deuterium atom abundance is at least 6466.7 times its natural abundance (deuterium atom enrichment of 97%). More preferably, the deuterium atom abundance is at least 6600 times its natural abundance (deuterium atom enrichment of 99%). More preferably, the deuterium atom abundance is at least 6633.3 times that of the natural abundance (deuterium atom enrichment of 99.5%).

[0047] Explanation of terms Unless otherwise specified, terms used in this specification, including those used in the specification and claims, are defined as follows: Note that in this specification and the appended claims, the singular forms “a” and “an” have plural meanings unless otherwise specified. Unless otherwise specified, conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this specification, “or” or “and” means “and / or” unless otherwise specified.

[0048] Unless otherwise specified, "C α~β "Hydrocarbyl" refers to a hydrocarbyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, where α and β are integers. Hydrocarbyls described in this section may also contain one or two double or triple bonds. The notation C0 hydrocarbyl indicates a direct bond. Examples of C1-6 hydrocarbyls are as follows: [ka] These include, but are not limited to, the following:

[0049] Unless otherwise specified, "C α~β "Halohydrocarbyl" refers to the hydrocarbyl group described above, in which any number (at least one) of the hydrogen atoms attached to the hydrocarbyl chain are substituted with F, Cl, Br, or I.

[0050] Unless otherwise specified, "oxo" and "thio" represent =O (e.g., carbonyl) and =S (e.g., thiocarbonyl), respectively.

[0051] Unless otherwise specified, "halo" or "halogen" refers to a halogen atom selected from F, Cl, Br, and I.

[0052] Unless otherwise specified, "alkoxy" refers to an alkyl group that is bonded to the rest of the molecule via an ether oxygen atom. Typical alkoxy groups have 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxys, in particular alkoxys substituted with one or more halogens. Preferred alkoxys include OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO and t- Selected from BuO.

[0053] Unless otherwise specified, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon ring system. The ring carbon atoms of the cycloalkyl may optionally be oxidized to form an oxo group or a sulfide group. The cycloalkyl further comprises a cycloalkylene. In some embodiments, the cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cycloheptatrienyl.

[0054] Unless otherwise specified, "heterocycloalkylidene" refers to the divalent heterocycloalkyl group as defined above.

[0055] Unless otherwise specified, "bicyclic ring" refers to a group characterized by two linked rings. The bicyclic ring may be a carbocyclic ring (where all ring atoms are carbon atoms) or a heterocyclic ring (where the ring atoms contain carbon atoms plus one, two, or three heteroatoms, such as N, O, or S). These two rings may be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include: (a) A spirocyclic compound in which the two rings share only one single atom (usually a quaternary carbon, a spiro atom), and an example of a spirocyclic compound is: [ka] Examples include, but are not limited to, spirocyclic compounds; (b) A fused bicyclic compound in which two rings share two adjacent atoms, i.e., the rings share a covalent bond, i.e., a bridgehead atom is directly bonded (e.g., α-thugen and decalin), and examples of fused bicyclic rings are: [ka] Examples include, but are not limited to, condensed bicyclic compounds; and (c) A bridged bicyclic compound in which two rings share three or more atoms and two bridgehead atoms are separated by a bridge containing at least one atom, for example norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings, each sharing three of five carbon atoms, and examples of bridged bicyclic rings are: [ka] Examples include, but are not limited to, cross-linked bicyclic compounds.

[0056] Unless otherwise specified, "carbocyclic ring" or "carbocyclic formula" is used either by itself or in combination with other terms as "C α~β This represents the cyclic form of "hydrocarbyl". Examples of carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl.

[0057] Unless otherwise specified, “heterocyclic ring” or “heterocyclic formula” means a ring comprising at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocyclic rings that may be found in the claims are: [ka] These include, but are not limited to, the following:

[0058] The words "optional" or "at will" mean that the event or situation described thereafter may occur, but is not necessarily so, and that description includes examples of when the event or situation may occur and examples of when it may not.

[0059] "Saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogen, substituents that are not saturated with hydrogen at all, and substituents that are partially saturated with hydrogen.

[0060] If one of the variables is selected from chemical bonds, it means that the two groups linked by this variable are directly linked. For example, if L in XLY represents a chemical bond, it actually means that the structure is XY.

[0061] N(C0 hydrocarbyl)-C 0~4 In the case of a molecule with zero groups, such as hydrocarbyl-, the linker group is -NH-C 0~4 It means hydrocarbyl-.

[0062] When the number of linker groups is 0, as in -(CH2)0-, it means that the linker groups are chemical bonds.

[0063] Unless otherwise specified, the absolute arrangement of the center of a solid is determined by a wedge-shaped solid line connection. [ka] and wedge-shaped dashed line connections [ka] The relative arrangement of the three-dimensional centers is represented by the combination of straight lines and solid lines. [ka] and dashed line connections [Chemistry] is represented by. The wavy line [Chemistry] is a wedge-shaped solid line bond [Chemistry] or a wedge-shaped dashed line bond [Chemistry] represents, or the wavy line [Chemistry] is a straight solid line bond [Chemistry] or a straight dashed line bond [Chemistry] represents.

[0064] Unless otherwise specified, a single bond or a double bond is [Chemistry] represented by.

[0065] Specific pharmaceutical and medical terms As used herein, the term "acceptable" means that a formulation ingredient or an active ingredient does not have an excessive and harmful effect on the health of a typical subject of treatment.

[0066] As used herein, the terms “treatment,” “treatment course,” and “therapy” include alleviating, inhibiting, or improving the symptoms or condition of a disease; inhibiting the development of complications; improving or preventing an underlying metabolic syndrome; inhibiting the development of a disease or symptom (e.g., controlling the progression of a disease or condition); alleviating a disease or symptom; regressing a disease or symptom; alleviating complications caused by a disease or symptom; or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving the severity of the disease, delaying its onset, slowing its progression, or shortening its duration. A fixed or single dose, or a continuous or intermittent dose, may be caused by or related to the administration.

[0067] "Active ingredient" refers to the compound of general formula (1), and pharmaceutically acceptable inorganic or organic salts of the compound of general formula (1). The compounds of the present invention may contain one or more chiral centers (chiral centers or axial chirality) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, and single diastereomers. The possible chiral centers may exist depending on the properties of various substituents on the molecule. Each such chiral center independently produces two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are included in the scope of the present invention. The present invention means that it includes all such isomeric forms of these compounds.

[0068] In this specification, terms such as “compound,” “composition,” “drug,” or “pharmaceutical or medicinal product” are used interchangeably and all refer to compounds or compositions that, when administered to an organism (human or animal), can induce a desired pharmacological and / or physiological response through local and / or systemic effects.

[0069] The terms “administered, administered, or given” as used herein mean the direct administration of a compound or composition, or the administration of a prodrug, derivative, analog, etc., of an active compound.

[0070] While the numerical ranges and parameters defining the broad scope of this invention are approximations, the relevant values ​​shown in specific embodiments are presented herein as accurately as possible. However, any numerical value inherently includes a standard deviation that inevitably arises from certain test methods. Here, “approximately” generally means that the actual value is within a specific value or range of ±10%, 5%, 1%, or 0.5%. Alternatively, the term “approximately” indicates that the actual numerical value is within the acceptable standard error of the mean, as those skilled in the art would understand. Except for experimental examples or unless otherwise specifically stated, all ranges, quantities, values, and percentages used herein (e.g., to describe quantities of material, lengths of time, temperatures, operating conditions, proportions of quantities, etc.) are understood to be modified by the term “approximately.” Thus, unless otherwise specifically stated, all numerical parameters described herein and in the appended claims are approximations that may vary as desired. At a minimum, these numerical parameters should be interpreted as numerical values ​​obtained using the indicated significant figures or conventional rounding rules.

[0071] The scientific and technical terms used herein have the same meanings as those generally understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plural forms unless inconsistent with the context, and plural nouns used include their singular forms.

[0072] therapeutic use The present invention provides the use of a compound or pharmaceutical composition of general formula (1) of the present invention in the inhibition of KIF18A protein and thus in the treatment of one or more disorders associated with the activity of KIF18A protein. Thus, in certain embodiments, the present invention provides a method for treating a disorder mediated by KIF18A protein, the method comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0073] In some embodiments, there is provided a method for treating cancer comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of structural general formula (1). In some embodiments, the cancer is mediated by KIF18A protein. In other embodiments, the cancer is a hematological cancer and a solid cancer, preferably a chromosomally unstable tumor, including hematological malignancies (leukemia, lymphoma, and multiple myeloma, myelodysplastic syndrome, and myeloproliferative familial syndrome including myeloma), solid tumors (prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, and soft tissue cancer, carcinomas such as osteosarcoma, and stromal tumors), etc., but is not limited thereto. Leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain tumor, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases are preferred. In other embodiments, the cancer is colon cancer, ovarian cancer, breast cancer, uterine cancer, cervical cancer, fallopian tube cancer, peritoneal cancer, lung cancer, liver cancer, head and neck cancer, pancreatic cancer, prostate cancer, oral cancer, esophageal cancer, and cancer metastases of these cancers. In other embodiments, the breast cancer is preferably triple negative breast cancer. In other embodiments, the ovarian cancer is preferably high-grade ovarian cancer, more preferably platinum-resistant high-grade ovarian cancer, more preferably platinum-resistant high-grade serous ovarian cancer. In other embodiments, the peritoneal cancer is preferably primary peritoneal cancer. In other embodiments, the uterine cancer is preferably serous endometrial cancer.

[0074] Route of administration The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations comprising a safe and effective amount of the compound or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient or carrier, where “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious adverse effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject being treated.

[0075] "Pharmacopoeia-acceptable excipients or carriers" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must be of sufficient purity and low toxicity. "Compatibility" means that the components of the composition can be mixed with the compounds of the present invention without significantly reducing the pharmaceutically active properties of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), humectants (e.g., sodium lauryl sulfate), colorants, fragrances, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0076] The compounds of the present invention can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0077] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or any of the following components: (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may further contain a buffering agent.

[0078] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. These may contain opacifying agents, and the active compound or compound in such compositions may be released with delay in specific parts of the gastrointestinal tract. Examples of embedding components that can be used include polymers and waxes. If necessary, the active compound may form microcapsules with one or more of the above excipients.

[0079] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compound, the liquid dosage form may contain water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof, which are commonly used in the art.

[0080] In addition to such inert diluents, the composition may further contain adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0081] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar, or mixtures thereof.

[0082] Parenteral injection compositions may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0083] Dosage forms for topical administration of the compound of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or sprays as required.

[0084] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal to be treated (such as a human), where the dose is a pharmaceutically effective dose. For a 60 kg human, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, factors such as the route of administration and the patient's health condition are also taken into consideration when determining the specific dose, but these are well known to those skilled in the art.

[0085] The features described herein, or the features described in the embodiments, can be combined in any way. All features disclosed herein can be used in the form of any composition, and various features disclosed herein can be replaced with any alternative features that provide the same, equivalent, or similar purpose. Thus, unless otherwise specified, the features disclosed herein are merely general examples of equivalent or similar features. [Examples]

[0086] (Detailed explanation) Various specific embodiments, features, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions are described in detail below, which will make the scope of the present invention very clear. Please understand that the following detailed description and examples describe specific examples for reference purposes only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of this application as defined herein.

[0087] In all embodiments, 1 ¹H-NMR spectra were recorded using a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the eluent ratio was expressed as a volume ratio.

[0088] The following abbreviations are used in this disclosure: (Boc)2O is di-tert-butyl dicarbonate; BOPCl is bis(2-oxo-3-oxazolidinyl)phosphinate chloride; CDCl3 is deuterated chloroform; Cs2CO3 is cesium carbonate; CuI is cuprous iodide; Â is ethyl acetate; Hexane is n-hexane; HPLC is high-performance liquid chromatography; MeCN is acetonitrile; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIPEA is diisopropylethylamine; 1,4-Dioxane is 1,4-dioxane Xane; DMF is N,N-dimethylformamide; DMAP is 4-(dimethylamino)pyridine; DMSO is dimethyl sulfoxide; h is time; HATU is N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-methylene]-N-methylmethaneaminium hexafluorophosphate-N-oxide; IPA is isopropanol; min is minutes; K2CO3 is potassium carbonate; KOAc is potassium acetate; K3PO4 is potassium phosphate; LiBH4 is lithium borohydride; min is minutes; MeOH is me Tanol; MS is mass spectrometry; NMR is nuclear magnetic resonance; Pd / C is palladium carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); PE is petroleum ether; RuPhos-Pd-G3 is (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-11'-biphenylyl)]palladium(II) methanesulfonate; Sarcosine is sarcosine; TFA is triflu Oloacetic acid; TMSCl is trimethylchlorosilane; T3P is 1-propanephosphonic anhydride; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; X-Phos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; TLC is thin-layer chromatography; XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; and XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0089] Example 1: Synthesis of Compound 1

[0090] [ka]

[0091] Step 1: Synthesis of compound int_1-2

[0092] [ka]

[0093] int_1-1 (907 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.32 g, yield: 78%). ESI-MS m / z: 565 [M+H] + .

[0094] Step 2: Synthesis of Compound 1

[0095] [ka]

[0096] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_1-2 (1.35 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (1.05 g, yield: 75%). ESI-MS m / z: 580 [M+H] + .

[0097] Example 2: Synthesis of Compound 2

[0098] [ka]

[0099] Step 1: Synthesis of compound int_2-2

[0100] [ka]

[0101] int_2-1 (765 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (869 mg, yield: 52%). ESI-MS m / z: 551 [M+H] + .

[0102] Step 2: Synthesis of Compound 2

[0103] [ka]

[0104] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_2-2 (1.32 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (910 mg, yield: 67%). ESI-MS m / z: 566 [M+H] + .

[0105] Example 3: Synthesis of Compound 3

[0106] [ka]

[0107] Step 1: Synthesis of Compound 3

[0108] [ka]

[0109] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_6-7 (1.32 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (1.06 g, 77% yield). ESI-MS m / z: 568 [M+H] + .

[0110] Example 4: Synthesis of Compound 4 [ka]

[0111] Step 1: Synthesis of compound int_4-2

[0112] [ka]

[0113] int_4-1 (915 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.36 g, yield: 75%). ESI-MS m / z: 601 [M+H] + .

[0114] Step 2: Synthesis of Compound 4

[0115] [ka]

[0116] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_4-2 (1.44 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (855 mg, yield 57%). ESI-MS m / z: 616 [M+H] + .

[0117] Example 5: Synthesis of Compound 5

[0118] [ka]

[0119] Step 1: Synthesis of Compound 5

[0120] [ka]

[0121] int_5-1 (300 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_4-2 (1.44 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (776 mg, yield: 50%). ESI-MS m / z: 646 [M+H] + .

[0122] Example 6: Synthesis of Compound 6

[0123] [ka]

[0124] Step 1: Synthesis of compound int_6-2

[0125] [ka]

[0126] int₆-1 (11.2 g, 55 mmol) was dissolved in THF (300 mL), and LiAlH₄ (3.1 g, 81 mmol) was added under ice bath. The mixture was heated to room temperature and reacted for 4 hours. LC-MS monitoring indicated completion of the reaction. 2 M NaOH solution (3 mL) was added to the reaction solution, followed by Na₂SO₄ (30 g). The reaction solution was filtered, the filtrate was collected, and dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a white solid (7 g, crude product). This solid was used directly in the next step.

[0127] Step 2: Synthesis of compound int_6-3

[0128] [ka]

[0129] int_6-2 (8.7 g, 54 mmol) was dissolved in dichloromethane (250 mL), and Dess-Martin oxidizing agent (28 g, 66 mmol) was added. The reaction solution was allowed to react at room temperature for a further 6 hours. Completion of the reaction was confirmed by LC-MS monitoring. The reaction solution was filtered, the filtrate was collected, and the crude product was obtained by vacuum distillation. The crude product was subjected to column chromatography (SiO2, siRNA:hexane = 1:10) to obtain the target product (8 g, yield: 93%).

[0130] Step 3: Synthesis of compound int_6-5

[0131] [ka]

[0132] int_6-4 (2.2 g, 12 mmol) was dissolved in dichloromethane (50 mL), and TFA (4.5 mL, 61 mmol) and int_6-3 (2.4 g, 15 mmol) were added at room temperature. The reaction solution was heated to 40 °C and stirred for 6 hours. The reaction solution was cooled to 0 °C, and TFA (6.3 mL, 85 mmol) and Et3SiH (6.3 mL, 4.6 mmol) were added. The reaction solution was allowed to react at room temperature for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the target product (2.5 g, yield: 53%). ESI-MS m / z: 314 [M+H] + .

[0133] Step 4: Synthesis of compound int_6-7

[0134] [ka]

[0135] int_6-6 (771 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. Completion of the reaction was confirmed by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.2 g, yield: 75%). ESI-MS m / z: 553 [M+H] + .

[0136] Step 5: Synthesis of Compound 6

[0137] [ka]

[0138] int_6-8 (261 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). After purging the solution three times with argon, int_6-7 (1.3 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. Completion of the reaction was confirmed by LC-MS monitoring. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (910 mg, yield: 65%). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.01 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 3.92 (s, 2H), 3.03 (q, J = 7.4 Hz, 2H), 2.33 (d, J = 14.1 Hz, 2H), 1.77 (d, J = 12.8 Hz, 4H), 1.59 (t, J = 13.0 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H), 1.09 (s, 9H). ESI-MS m / z: 582 [M+H] + .

[0139] Example 7: Synthesis of Compound 7 [ka]

[0140] Step 1: Synthesis of Compound 7

[0141] [ka]

[0142] int_5-1 (300 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_6-7 (1.32 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (862 mg, 60% yield). ESI-MS m / z: 598 [M+H] + .

[0143] Example 8: Synthesis of Compound 8 [ka]

[0144] Step 1: Synthesis of compound int_8-2

[0145] [ka]

[0146] int_8-1 (843 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.2 g, yield: 69%). ESI-MS m / z: 577 [M+H] + .

[0147] Step 2: Synthesis of Compound 8

[0148] [ka]

[0149] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_8-2 (1.38 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (760 mg, yield 53%). ESI-MS m / z: 592 [M+H] + .

[0150] Example 9: Synthesis of Compound 10 [ka]

[0151] Step 1: Synthesis of compound int_10-2

[0152] [ka]

[0153] int_10-1 (762 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (880 mg, yield: 53%). ESI-MS m / z: 550 [M+H] + .

[0154] Step 2: Synthesis of Compound 10

[0155] [ka]

[0156] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_10-2 (1.32 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (726 mg, yield 53%). ESI-MS m / z: 565 [M+H] + .

[0157] Example 10: Synthesis of Compound 141 [ka]

[0158] Step 1: Synthesis of compound int_141-2

[0159] [ka]

[0160] int_141-1 (813 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.05 g, yield: 61%). ESI-MS m / z: 567 [M+H] + .

[0161] Step 2: Synthesis of Compound 141

[0162] [ka]

[0163] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_141-2 (1.36 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (950 mg, yield 68%). ESI-MS m / z: 582 [M+H] + .

[0164] Example 11: Synthesis of Compound 144 [ka]

[0165] Step 1: Synthesis of compound int_144-2

[0166] [ka]

[0167] int_144-1 (729 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_6-5 (942 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (915 mg, yield: 56%). ESI-MS m / z: 539 [M+H] + .

[0168] Step 2: Synthesis of Compound 144

[0169] [ka]

[0170] int_1-3 (228 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_144-2 (1.29 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and then purified by column chromatography to obtain a solid (1.0 g, 75% yield). ESI-MS m / z: 554 [M+H] + .

[0171] Example 12: Synthesis of Compound 157 [ka]

[0172] Step 1: Synthesis of Compound 157

[0173] [ka]

[0174] int_6-8 (261 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). The solution was purged three times with argon, and int_141-2 (1.36 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (1.11 g, yield: 78%). ESI-MS m / z: 596 [M+H] + .

[0175] Example 13: Synthesis of Compound 160

[0176] [ka]

[0177] Step 1: Synthesis of Compound 160

[0178] [ka]

[0179] int_6-8 (261 mg, 2.4 mmol), dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and potassium phosphate (1.5 g, 7.0 mmol) were dissolved in DMF (20 mL). After purging the solution three times with argon, int_144-2 (1.29 g, 2.4 mmol) was added. Under an argon atmosphere, the reaction solution was heated to 90°C and reacted for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was cooled to room temperature, concentrated to dryness using a rotary evaporator, and purified by column chromatography to obtain a solid (1.15 g, yield: 84%). ESI-MS m / z: 568 [M+H] + .

[0180] Example 14: Synthesis of Compound 197

[0181] [ka]

[0182] Step 1: Synthesis of compound int_197-1

[0183] [ka]

[0184] int_6-5 (942 mg, 3 mmol) and (Boc)2O (1.3 g, 6 mmol) were dissolved in DCM (20 mL), and DMAP (36 mg, 0.3 mmol) and Et3N (1.01 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.2 g, 96% yield). ESI-MS m / z: 414 [M+H] + .

[0185] Step 2: Synthesis of compound int_197-3

[0186] [ka]

[0187] int_197-1 (6.2 g, 15 mmol) was dissolved in dioxane (40 mL), and benzyl mercaptan (5.7 g, 45.9 mmol), Pd2(dba)3 (2 g, 2.2 mmol), Xantphos (2 g, 3.6 mmol), and DIPEA (7.9 g, 61.2 mmol) were added. The mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain the target product (6 g, yield: 88%). ESI-MS m / z: 458 [M+H] + .

[0188] Step 3: Synthesis of compound int_197-4

[0189] [ka]

[0190] int_197-3 (19.6 g, 43 mmol) was dissolved in a mixed solvent of acetonitrile / water / acetic acid (40 mL / 1 mL / 0.5 mL), and dichlorohydantoin (3.4 g, 17.3 mmol) was added under ice bath conditions. The mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was dissolved in a mixed solution of acetonitrile and tetrahydrofuran (30 mL / 10 mL), and methylamine hydrochloride (2.9 g, 43 mmol) and potassium carbonate (12 g, 87 mmol) were added. The mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the target product (5.5 g, yield 29%). ESI-MS m / z: 429 [M+H] + .

[0191] Step 4: Synthesis of compound int_197-5

[0192] [ka]

[0193] int_197-4 (1.28 g, 3 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction solution was stirred at room temperature for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (950 mg, yield: 96%). ESI-MS m / z: 329 [M+H] + .

[0194] Step 5: Synthesis of Compound 197

[0195] [ka]

[0196] int_6-6 (771 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, and then int_197-5 (985 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.2 g, yield: 70%). ESI-MS m / z: 569 [M+H] + .

[0197] Example 15: Synthesis of Compound 198 [ka]

[0198] Step 1: Synthesis of compound int_198-1

[0199] [ka]

[0200] int_197-3 (19.6 g, 43 mmol) was dissolved in a mixed solvent of acetonitrile / water / acetic acid (40 mL / 1 mL / 0.5 mL), and dichlorohydantoin (3.4 g, 17.3 mmol) was added under ice bath conditions. The mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered, and the crude product was obtained by vacuum distillation. The crude product was dissolved in a mixed solution of acetonitrile and tetrahydrofuran (30 mL / 10 mL), and ethylamine hydrochloride (3.5 g, 43 mmol) and potassium carbonate (12 g, 87 mmol) were added. The mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the target product (6.1 g, yield: 32%). ESI-MS m / z: 443 [M+H] + .

[0201] Step 2: Synthesis of compound int_198-2

[0202] [ka]

[0203] int_198-1 (1.32 g, 3 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction solution was stirred at room temperature for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (990 mg, yield: 96%). ESI-MS m / z: 343 [M+H] + .

[0204] Step 3: Synthesis of Compound 198

[0205] [ka]

[0206] int_6-6 (771 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_198-2 (1.02 g, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. Completion of the reaction was indicated by LC-MS monitoring. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.3 g, yield: 68%). ESI-MS m / z: 582 [M+H] + .

[0207] Example 16: Synthesis of Compound 199 [ka]

[0208] Step 1: Synthesis of compound int_199-1

[0209] [ka]

[0210] int_197-3 (19.6 g, 43 mmol) was dissolved in a mixed solvent of acetonitrile / water / acetic acid (40 mL / 1 mL / 0.5 mL), and dichlorohydantoin (3.4 g, 17.3 mmol) was added under ice bath conditions. The mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was dissolved in a mixed solution of acetonitrile and tetrahydrofuran (30 mL / 10 mL), and glycine methyl ester hydrochloride (5.4 g, 43 mmol) and potassium carbonate (12 g, 87 mmol) were added. The mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the target product (4.2 g, yield 20%). ESI-MS m / z: 487 [M+H] + .

[0211] Step 2: Synthesis of compound int_199-2

[0212] [ka]

[0213] int_199-1 (1.45 g, 3 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction solution was stirred at room temperature for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1 g, yield: 86%). ESI-MS m / z: 387 [M+H] + .

[0214] Step 3: Synthesis of compound int_199-3

[0215] [ka]

[0216] int_6-6 (771 mg, 3 mmol) was dissolved in DCM (10 mL), and HATU (2.6 g, 7 mmol) and DIPEA (1.29 g, 10 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours, after which int_199-2 (1.15 g, 3 mmol) was added. The reaction solution was stirred at room temperature for 10 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (1.35 g, yield: 72%). ESI-MS m / z: 626 [M+H] + .

[0217] Step 4: Synthesis of Compound 199

[0218] [ka]

[0219] int_199-3 (250 mg, 0.4 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (5 mL / 5 mL), and sodium borohydride (43 mg, 1.1 mmol) and lithium chloride (48 mg, 1.1 mmol) were slowly added under ice bath conditions. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the target product (200 mg, yield: 83%). ESI-MS m / z: 598 [M+H] + .

[0220] By using different starting materials and employing the synthesis method described above, we obtained the target compounds 9, 11-140, 142, 143, 145-156, 158, 159, 161-196, and 200-224 shown in Table 1.

[0221] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0222] Biological Example 1: In vitro inhibition assay of KIF18A enzyme activity by the compound of the present invention

[0223] KIF18A enzyme assay: The enzymatic activity of KIF18A after treatment with the compound was measured by a microtubule-stimulated ATPase activity assay. ADP generated from the ATPase reaction was measured by this assay. The compound was serially diluted 2-fold with DMSO over a range of 22 concentration points. Recombinant human KIF18A (1-467His tag) protein was expressed using a baculovirus system. The concentrations of KIF18A protein, microtubules, and ATP in the reaction were optimized for a homogeneous enzyme assay standardized using an ADP-Glo ​​kinase / ATPase assay kit. Reaction buffer [(15 mM Tris, pH 7.5), 10 mM MgCl2, 0.01% Pluronic® F-68, 1 μM paclitaxel, and 30 μg / mL pig microtubules)] was prepared. The compound and KIF18A protein (30 nM) were added to the prepared reaction buffer, and the reaction mixture was incubated at room temperature for 15 minutes, after which ATP (Km, 75 μM) was added. The resulting reaction mixture was incubated at room temperature for another 15 minutes. 5 μL of ADP-Glo ​​reagent was mixed with 2.5 μL of the reaction mixture, and the resulting mixture was incubated at room temperature for 40 minutes. 10 μL of ADP-Glo ​​detection reagent was added, and the mixture was incubated at room temperature for 40 minutes. The luminescence was measured using a microplate reader and compared with the luminescence of the DMSO group to determine the inhibition rate and IC50 of the compound. 50 The values ​​were calculated. The results are shown in Tables 2 and 3 below.

[0224] [Table 2]

[0225] +++ is IC 50 This indicates that the value is 100 nM or less. ++ is IC 50 This indicates that the concentration is between 100 nM and 500 nM. + is IC 50 This indicates that it is greater than 500 nM.

[0226] As can be seen from the data in Table 2, the compounds of the present invention have good inhibitory activity against the enzyme activity of KIF18A.

[0227] [Table 3]

[0228] +++ is IC 50 This indicates that the value is 100 nM or less. ++ is IC 50 This indicates that the concentration is between 100 nM and 500 nM. + is IC 50 This indicates that it is greater than 500 nM.

[0229] As can be seen from the data in Table 3, the compounds of the present invention have good inhibitory activity against the enzyme activity of KIF18A.

[0230] Biological Example 2: In vitro antiproliferative activity of the compound of the present invention against HT-29 cells HT-29 cells were seeded at 3000 cells / well in a 384-well plate. After overnight adherent culture, DMSO or compounds sequentially diluted at a ratio of 1:5 starting from 5 μM were added. Cell viability 72 hours after administration was evaluated by measuring intracellular ATP content. The inhibition rate of viable cells by the compounds was calculated compared to the DMSO group, and IC50 was determined. 50 The value was also calculated.

[0231] Biological Example 3: In vitro antiproliferative activity of the compound of the present invention against HCT116 cells HCT116 cells were seeded at 3000 cells / well in a 384-well plate. After overnight adherent culture, DMSO or compounds sequentially diluted at a ratio of 1:5 starting from 5 μM were added. Cell viability 72 hours after administration was evaluated by measuring intracellular ATP content. The inhibition rate of viable cells by the compounds was calculated compared to the DMSO group, and IC50 was calculated. 50 The value was also calculated.

[0232] Biological Example 4: In vivo pharmacodynamic study - Mouse HT29 subcutaneous xenograft tumor model 5 x 10 on the left dorsal side of a BALB / c nude mouse. 6 Individual HT29 cells were subcutaneously inoculated. The tumor was 100-150 mm. 3 After proliferation, mice were randomly divided into the following groups and administered intragastricly once daily: Group 1: Vehicle control group; Group 2: Compound 661 (80 mg / kg); Group 3: Compound 669 (80 mg / kg); Group 4: Compound 677 (80 mg / kg); Group 5: Compound 714 (80 mg / kg); Group 6: Compound 727 (80 mg / kg); Group 7: Compound 740 (80 mg / kg); Group 8: AMG650 (80 mg / kg). Tumor volume was measured twice a week and at the end of administration. The tumor growth inhibition rate of the compound was calculated according to the following formula: Tumor growth inhibition rate (TGI) = 1 - (Tumor volume of the treatment group on day 28 - Tumor volume of the treatment group on day 1) / (Tumor volume of the vehicle control group on day 28 - Tumor volume of the treatment group on day 1).

[0233] Biological Example 5: Phosphorylation assay of the histone H3 Ser10 site in HT29 cells (immunofluorescence assay) HT29 cells were seeded at 8000 cells / well in a 96-well plate (Fisher 160376). The following day, serially diluted compounds were added. Six hours after compound addition, the cells were washed once with 1×PBS, fixed with 4% PFA for 15 minutes, washed three more times with 1×PBS, and permeabilized with 0.02% Triton-X100 for 10 minutes. Blocking buffer was then added and the cells were blocked for 15-30 minutes, followed by the addition of a 1:3000 diluted primary antibody (Phospho-Histone H3(Ser10)(D7N8E) XP(registered trademark) Rabbit mAb #53348). The plates were left standing overnight at 4°C. The following day, the cells were washed three times with 1×PBS, and a 1:1000 diluted secondary antibody (Fluorescein(FITC)-conjugated Affinipure Goat Anti-Rabbit IgG(H+L)) was added. Cells were incubated in the dark for 1-2 hours and washed three times with 1×PBS. The nuclei were stained with DAPI, and after staining, images were taken using the MD ImageXpress Pico personal high-content imaging analysis system. The phosphorylation ratio (FITC / DAPI) at the H3 Ser10 site of HT29 cells was quantified. To evaluate the effect of compounds on mitosis in HT29 cells, the EC of the compounds was measured. 50 The value was calculated.

[0234] Although specific embodiments of the present invention have been described above, these embodiments are merely illustrative, and those skilled in the art will understand that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims

1. Compounds of general formula (1), their isomers, crystals thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof. 【Chemistry 1】 (In general formula (1), Y １ is -CH=, -CF=, or N, Y ２ is H, halogen, -CN, -OH, -NO ２ , -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ , -P(O)R ｃ７ R ｃ８ , -N=S(O)R ｃ９ Rc １０ , -S(O)(NR ｃ１１ )R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S(O)<{ ２ (CH ２ ) １～６ NR ｃ１７ C(O)R ｃ１８ , -NR ｃ１６ S(O) ２ (CH ２ ) １～６ O C(O)R ｃ１８ or C １～６ alkyl substituted with one or more -OH or halogen, and Y ３ is -CH=, -CF=, or N; Y ４ is -CH= or N, and Y １ , Y ３ , and Y ４ Not all of them are N; R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , R ｃ９ , R ｃ１０ , R ｃ１１ , R ｃ１２ , R ｃ１３ , R ｃ１４ , R ｃ１５ , R ｃ１６ , R ｃ１７ , and R ｃ１８ These are H and C, respectively, independently. ３～１０ Cycloalkyl, and one or more H, -OH, -NH ２ , or C substituted with halogen １～６ Selected from alkyl; R ｂ１ and R ｂ２ These, along with the carbon atoms bonded to them, form a structural unit: 1) 【Chemistry 2】 ; or 2) 【Transformation 3】 Forming; R ｂ１ and R ｂ２ However, together with the carbon atoms bonded to them, the structural units are: 【Chemistry 4】 When forming, ring A is C ６～１４ aryl or (5- to 12-membered) heteroaryl, where the C ６～１４ aryl or the (5- to 12-membered) heteroaryl is each independently H, halogen, -OH, C １～６ alkyl, (3- to 10-membered) heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ 、-NR ａ４ C(O)OR ａ５ 、-NR ａ６ R ａ７ 、-N=S(O)R ａ８ R ａ９ 、-OR ａ１０ 、-S(O)R ａ１１ 、-S(O)(NR ａ１２ )R ａ１３ 、-S(O) ２ NR ａ１４ R ａ１５ 、-S(O) ２ R ａ１６ 、-(CR ａ１７ R ａ１８ ) ０～１ C(O)NR ａ１９ R ａ２０ 、-SR ａ２１ 、-C(O)R ａ２２ 、and -NR ａ２３ S(O) ２ R ａ２４ may be optionally substituted with 1, 2, 3, 4, or 5 groups of the following: H, halogen, -OH, C １～６ alkyl or the (3- to 10-membered) heterocycloalkyl is independently optionally substituted with 1, 2, 3, 4, or 5 groups selected from H, halogen, C １～３ alkyl, -OH, -CN, C ３～１０ cycloalkyl, and (3- to 10-membered) heterocycloalkyl substituted with one or more halogens; R ｂ１ and R ｂ２ together with the carbon atoms to which they are attached form a structural unit: 【Transformation 5】 When forming, ring A is R ｘ C replaced by ６～１４ Aryl or R ｘ A heteroaryl (5-12 member) substituted with the R ｘ C replaced by ６～１４ aryl or the R ｘ The (5- to 12-membered) heteroaryls substituted with each independently are -O(C １～６ Alkyl), -S (C １～６ Alkyl), -NR ｄ１ R ｄ２ , -NO ２ , or may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups of -CN, where C １～６ The alkyl group may be substituted with 0, 1, 2, or 3 groups of H or halogen. R ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ , R ａ８ , R ａ９ , R ａ１０ , R ａ１１ , R ａ１２ , R ａ１３ , R ａ１４ , R ａ１５ , R ａ１６ , R ａ１７ , R ａ１８ , R ａ１２９ , R ａ２０ , R ａ２１ , R ａ２２ , R ａ２３ , and R ａ２４ These are H and C, respectively, independently. １～６ Alkyl, C ２～６ Alkenil, C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, (3-10 member) heterocycloalkyl, (3-10 member) heterocycloalkenyl, C ６～１４ Selected from aryls and (5-12 membered) heteroaryls, where C １～６ alkyl, the C ２～６ Alkenyl, the C ３～１０ Cycloalkyl, the C ３～１０ Cycloalkenyl, the (3-10 member) heterocycloalkyl, the (3-10 member) heterocycloalkenyl, the C ６～１４ The aryl, or the (5-12 membered) heteroaryl, is independently composed of H, halogen, -CN, -OH, and -O(C). １～６ Alkyl), C ２～６ Alkenil, C ３～１０ Cycloalkyl, -S(C １～６ Alkyl), 【Transformation 6】 , and one or more H, halogen, -OH, or -O(C) １～６ C substituted with alkyl １～６ Alkyl groups may be optionally substituted with one, two, three, four, or five of them; R ｄ１ and R ｄ２ These are H and C, respectively, independently. １～６ Selected from alkyl groups; R ｘ This is a (3-10 member) heterocycloalkyl, where the (3-10 member) heterocycloalkyl is independently a halogen, C １～６ Alkyl, or 【Transformation 7】 (One, two, three, four, or five of these groups may be arbitrarily substituted.)

2. In general formula (1), Y ２ However, H, -F, -Cl, -Br, -NO ２ , -CN, -OH, -C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S(O) ２ R ｃ６ ,-P(O)R ｃ７ R ｃ８ -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ ,-NR ｃ１６ S(O) ２ (CH ２ ) １～３ NR ｃ１７ C(O)R ｃ１８ , -NR ｃ１６ S(O) ２ (CH ２ ) １～３ OC(O)R ｃ１８ , and C substituted with 1, 2, or 3 -OH or -F groups １～６ A compound according to claim 1, selected from alkyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

3. In general formula (1), R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , R ｃ９ , R ｃ１０ , R ｃ１１ , R ｃ１２ , R ｃ１３ , R ｃ１４ , R ｃ１５ , R ｃ１６ , R ｃ１７ , and R ｃ１８ However, H and C are independent of each other. ３～６ Cycloalkyl, and 1 or 2 H, -OH, -NH ２ , or C substituted with halogen １～６ A compound according to claim 1 or 2, selected from alkyl, an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

4. In general formula (1), R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ , R ｃ７ , R ｃ８ , R ｃ９ , R ｃ１０ , R ｃ１１ , R ｃ１２ , R ｃ１３ , R ｃ１４ , R ｃ１５ , R ｃ１６ , R ｃ１７ , and R ｃ１８ However, each is independent of H, 【Transformation 8】 A compound according to claim 3, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, selected from the above.

5. In general formula (1), Y ２ but, 【Chemistry 9】 A compound selected from any one of claims 1 to 4, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

6. In general formula (1), Y ２ but, 【Chemistry 10】 A compound selected from any one of claims 1 to 4, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

7. In general formula (1), R ｂ１ and R ｂ２ However, together with the carbon atoms bonded to them, the structural units are: 【Chemistry 11】 When forming, ring A is C ６～１０ It is an aryl or (5-10 membered) heteroaryl, where C ６～１０ Each aryl or the (5-10 membered) heteroaryl is independently H, -F, -Cl, -Br, -OH, C １～６ Alkyl, (3-10 member) heterocycloalkyl, -NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ ,-(CR ａ１７ R ａ１８ ) ０～１ C(O)NR ａ１９ R ａ２０ ,-SR ａ２１ , -C(O)R ａ２２ , and -NR ａ２３ S(O) ２ R ａ２４ It may be arbitrarily substituted with one, two, three, four, or five of the groups, where C １～６ Alkyl or the (3-10 member) heterocycloalkyl group can independently be H, -F, -Cl, -Br, 【Chemistry 12】 , -OH, -CN, C ３～６ A compound according to any one of claims 1 to 6, or an isomer thereof, the same, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with one, two, three, or four groups from a cycloalkyl group and a (3- to 10-membered) heterocycloalkyl group substituted with one or two -F, -Cl, or -Br groups.

8. In general formula (1), R ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ , R ａ８ , R ａ９ , R ａ１０ , R ａ１１ , R ａ１２ , R ａ１３ , R ａ１４ , R ａ１５ , R ａ１６ , R ａ１７ , R ａ１８ , R ａ１９ , R ａ２０ , R ａ２１ , R ａ２２ , R ａ２３ , and R ａ２４ These are H and C, respectively, independently. １～６ Alkyl, C ２～６ Alkenil, C ３～６ Cycloalkyl, C ３～６ Cycloalkenyl, (4-9 member) heterocycloalkyl, (3-6 member) heterocycloalkenyl, C ６～１０ Selected from aryls and (5-10 membered) heteroaryls, where C １～６ alkyl, the C ２～６ Alkenyl, the C ３～６ Cycloalkyl, the C ３～６ Cycloalkenyl, the (4-9 member) heterocycloalkyl, the (3-6 member) heterocycloalkenyl, the C ６～１０ Each aryl, or the (5-10 membered) heteroaryl, is independently H, -F, -Cl, -CN, -OH, -O(C １～３ Alkyl), C ２～４ Alkenil, C ３～６ Cycloalkyl, -S(C １～３ Alkyl), 【Chemistry 13】 , and 1, 2, or 3 H, -F, -Cl, -OH, or -O(C) １～３ C substituted with alkyl １～６ A compound according to any one of claims 1 to 7, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with one, two, three, or four alkyl groups.

9. In general formula (1), R ｂ１ and R ｂ２ However, together with the carbon atoms bonded to them, the structural units are: 【Chemistry 14】 When forming, ring A is phenyl, naphthyl, or a (5-10 membered) heteroaryl, where each of the phenyl, naphthyl, or (5-10 membered) heteroaryl is independently H, -F, -Cl, -Br, -OH, -OCH ３ , 【Chemistry 15】 、-NH ２ 、 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 The compound according to claim 7 or 8, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with one, two, or three of the groups.

10. A compound according to any one of claims 1 to 9, wherein ring A in general formula (1) is phenyl or a (5-6 membered) heteroaryl, and ring A is preferably phenyl, thienyl, furanyl, pyridinyl, or pyrimidinyl, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

11. In general formula (1), R ｂ１ and R ｂ２ However, together with the carbon atoms bonded to them, the structural units are: 【Chemistry 17】 When forming, ring A is R ｘ C replaced by ６～１０ Aryl or R ｘ A heteroaryl (5-10 member) substituted with, where R ｘ C replaced by ６～１０ aryl or the R ｘ The (5-10 member) heteroaryls substituted with each of these are independently -O(C) １～３ Alkyl), -S (C １～３ Alkyl), -NH ２ ,-NH(CH ３ ), -N(CH ３ ) ２ , -NO ２ , or may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups of -CN, where C １～３ The alkyl group may be substituted with 0, 1, 2, or 3 groups of H or -F, the compound according to any one of claims 1 to 6, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

12. In general formula (1), R ｂ１ and R ｂ２ However, together with the carbon atoms bonded to them, the structural units are: [Chemistry 18] When forming, ring A is R ｘ C replaced by ６～１０ Aryl or R ｘ A heteroaryl (5-10 member) substituted with, where R ｘ C replaced by ６～１０ aryl or the R ｘ The (5-10 member) heteroaryls substituted with each of these are independently -NO ２ ,-CN, 【Chemistry 19】 , -NH ２ ,-NH(CH ３ ), or -N(CH ３ ) ２ The compound according to claim 11, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with 0, 1, 2, 3, 4, or 5 of the groups.

13. In general formula (1), R ｘ However, it is a (4-7 member) heterocycloalkyl, where each of the (4-7 member) heterocycloalkyls is independently -F, C １～３ Alkyl, or 【Chemistry 20】 The compound according to claim 11 or 12, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with one, two, three, four, or five of the groups.

14. In general formula (1), R ｘ but, 【Chemistry 21】 The compound according to claim 13, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

15. Compounds of general formula (2), their isomers, their crystals, their pharmaceutically acceptable salts, their hydrates, or their solvates. 【Chemistry 22】 (In general formula (2), A is a phenyl group or a (5-6 membered) heteroaryl group, where the phenyl group or the (5-6 membered) heteroaryl group is independently H, -F, -OH, C １～３ Alkyl, (3-6 member) heterocycloalkyl, -NR ａ６ R ａ７ , -OC １～３ Alkyl, -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ ,-(CR ａ１７ R ａ１８ ) Ｏ～１ C(O)NR ａ１９ R ａ２０ ,-SR ａ２１ , and -C(O)R ａ２２ The C may be arbitrarily substituted with one, two, three, four, or five of the groups, where C １～３ Each alkyl group or the (3-6 membered) heterocycloalkyl group may be independently substituted with any one, two, three, or four groups selected from H or -F; Y ５ ha-S(O) ２ NHR ｃ１９ And R ｃ１９ is C １～３ It is alkyl, and here, C １～３ Alkyl groups are H, -OH, -NH ２ (Or it may be replaced with one or two of F.)

16. The compound has the following structure: 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 [Chemistry 23-4] 【Chemistry 23-5】 【Chemistry 23-6】 【Chemistry 23-7】 【Chemistry 23-8】 【Chemistry 23-9】 A compound according to any one of claims 1 to 15, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having any one of the above.

17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient, a compound or its isomer, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as described in any one of claims 1 to 16.

18. Use of a compound according to any one of claims 1 to 16, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition according to claim 17, in the preparation of a pharmaceutical for treating a disease mediated by the KIF18A protein.

19. The disease according to claim 18, wherein the disease is cancer, and the cancer is a blood cancer or a solid tumor.

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