WO2023041055A1 - Inhibiteur de kif18a - Google Patents

Inhibiteur de kif18a Download PDF

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Publication number
WO2023041055A1
WO2023041055A1 PCT/CN2022/119392 CN2022119392W WO2023041055A1 WO 2023041055 A1 WO2023041055 A1 WO 2023041055A1 CN 2022119392 W CN2022119392 W CN 2022119392W WO 2023041055 A1 WO2023041055 A1 WO 2023041055A1
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membered
hydrocarbon group
general formula
pharmaceutically acceptable
formula
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PCT/CN2022/119392
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English (en)
Chinese (zh)
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谢雨礼
吴应鸣
钱立晖
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微境生物医药科技(上海)有限公司
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Publication of WO2023041055A1 publication Critical patent/WO2023041055A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and more specifically, relates to a class of compounds with KIF18A protein inhibitory effect, a preparation method thereof and the application of the compounds in the preparation of antitumor drugs.
  • Genome instability is a common feature of most tumor cells. Most tumor cells have abnormal gains or losses of chromosomes. Chromosome instability in tumor cells can lead to abnormal chromosomes interacting with mitotic spindle microtubules, resulting in chromosome segregation errors. Cells with chromosomal instability develop increased spindle microtubule aggregation and reduced spindle microtubule-centromere contact turnover compared with cells with normal chromosomes. Therefore, antimitotic therapies targeting the microtubule skeleton may be particularly effective in cells with chromosomal instability.
  • Kinesins are a class of molecular motors that play important roles in cell division and intracellular trafficking of vesicles and organelles. Mitotic kinesins play important roles in spindle assembly, chromosome segregation, centrosome segregation, and dynamics. Human kinesins are classified into 14 subtypes based on the amino acid sequence of the motor domain, and the ATPase activity located in the motor domain drives the protein to move unidirectionally along the microtubules. The non-motor domains of these proteins are responsible for interacting with substrates, and a variety of different membranous organelles, signal transduction scaffold systems, and chromosomes serve as substrates with which non-motor domains can interact. Kinesins gain energy through ATP hydrolysis to move substrates along polarized microtubules. Therefore, kinesins are often referred to as "plus-end” or "minus-end” oriented motors.
  • the KIF18A protein belongs to the kinesin-8 subtype.
  • the KIF18A protein is overexpressed in various types of cancer, such as lung, ovarian, cervical, breast, pancreatic, prostate, colon, and bladder cancers.
  • abnormal microtubule movement makes such cells particularly dependent on KIF18A protein to reduce the contact transition between spindle microtubules and centromeres and limit microtubule growth (Nat Commun.2021, 12, 1213).
  • KIF18A protein When the KIF18A protein is missing in tumor cells with chromosomal instability, the cells' centrosomes become fragmented and mitotic progression is slowed or stopped. But these phenomena do not occur in cells with normal chromosomes. Therefore, the activity of KIF18A protein does not have a great impact on the proliferation of normal cells, but it is very critical for the growth of chromosomally unstable tumors.
  • KIF18A inhibitors are a new potential approach to combat tumors with chromosomal instability.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 3 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
  • R 4 is H, halogen, R 4a or R 4b ;
  • R 5 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl
  • R 6 is H, halogen, C 1-8 alkyl, C 1-4 haloalkyl, -OH, -OR 6a or -OR 6b ;
  • R 7 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
  • R is selected from the group consisting of:
  • R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j , R 13k and R 13l are each independently H, halogen, R 13m or R 13n ; or Each pair of R 13a and R 13b , R 13c and R 13d , R 13e and R 13f , R 13g and R 13h , R 13i and R 13j , or R 13k and R 13l can be independently combined with The carbon atoms they are connected to form a saturated or partially saturated 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring spliced to R ring; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring Contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further, wherein the 3-membered, 4-membered
  • R 9 is H or C 1-6 hydrocarbon group
  • R 10 is H, R 10a or R 10b ;
  • R 11 is H, R 11a or R 11b ;
  • R 12 is R 12a or R 12b ;
  • R 15 is H, halogen, C 1-8 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OC 1-8 hydrocarbon group or -OR 15a , wherein R 15a contains 0, 1, 2 or 3 N atoms and 0, A saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring with 1 or 2 atoms selected from O and S;
  • R 4b , R 6b , R 10b , R 11b , R 12b or R 13n are in each case independently selected from: C 1-6 hydrocarbyl, wherein said hydrocarbyl can be optionally replaced by 0, 1, 2, 3, 4 or 5 of the following groups are substituted: F, Cl, Br, -R a , -OR a , -OC 1-4 halohydrocarbyl and CN;
  • R a is independently H or R b at each occurrence
  • R 9 is H, methyl or ethyl, preferably H.
  • R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j , R 13k and R 13l are each independently H, halogen, C 1-6 hydrocarbon group or C 1-4 halogenated hydrocarbon group; and R 13a and R 13b in the pair of R 13a and R 13b and their respective carbon atoms can be combined to form a saturated ring spliced to R 8 3-membered, 4-membered or 5-membered monocyclic ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; preferably, R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j , R 13k and R 13l are each independently H, methyl or ethyl; and R 13a and R 13b in the pair
  • the structural unit for: preferably
  • R 10 is selected from (a) H; or (b) C 1-6 hydrocarbon group
  • R 1 is a group -ZR 10 , wherein Z is -NHSO 2 - or -SO 2 NH-; and R 10 is oxetane radical, cyclopropyl, or R 10 is a C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH groups; preferably, R 1 is a group -ZR 10 , wherein Z is -NHSO 2 -or- SO 2 NH-, and R 10 is -CH 2 -CH 2 -OH or -CH(CH 3 )-CH 2 -OH; more preferably Z is -NHSO 2 -, and R 10 is -CH 2 -CH 2 - Oh.
  • R 2 is a halogen or a group -YR 12 , wherein Y is a chemical bond, -NH-, -NH-(CH 2 ) 0-4 - or -O-(CH 2 ) 0-4 -; and R 12 is saturated, partially saturated or unsaturated containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S 3-membered, 4-membered, 5-membered, 6-membered or 7-membered single ring or 4-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered double ring, wherein the single ring and bicyclic rings can be independently and optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OH, -OC 1-4 halogen Hydro
  • R 2 is a saturated 5-membered or 6-membered monocyclic ring, wherein each of the rings contains 0, 1 or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OH, -OC 1-4 halohydrocarbyl, CN, R 14 and oxo.
  • R 2 is (a) halogen; (b) group -YR 12 , wherein Y is a chemical bond; and R 12 is morpholinyl, piperidine base, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 , CN and oxo; or (c ) group -YR 12 , wherein Y is -NH-, -O-, -O-(CH 2 )-, -O-(CH 2 )-(CH 2 )- or -O-(CH 2 )-( CH 2 )-(CH 2 )-
  • R 2 is morpholinyl or piperidinyl
  • the morpholinyl and piperidinyl can be optionally replaced by 0, 1, 2 or 3
  • R 2 is piperidinyl substituted by 1, 2 or 3 fluorine groups.
  • R is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl or 1,3,4-oxathiazinyl.
  • R 4 is selected from (a) H; (b) C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH groups; or (c) cyclopropyl; or (d) F; R 4 is preferably H, F or methyl; R 4 is more preferably H.
  • R 5 is H or F, preferably H.
  • R 6 is H or F, preferably H.
  • R 15 is H or F, preferably H.
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to KIF18A protein.
  • said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
  • Another object of the present invention is also to provide a method for treating, regulating or preventing related diseases mediated by KIF18A protein, comprising administering a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its Various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
  • the inventors found that among the compounds of the general formula (1), the compound unexpectedly has a strong KIF18A protein inhibitory activity.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found 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), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by using the following general reaction scheme 1, 2, 3 or 4:
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 8 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined above; W 1 represents fluorine, chlorine, bromine or iodine; H represents hydrogen; N represents nitrogen; R 1 reagents such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane- 3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide , (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropane-1- Alcohol, (10) 2-aminoethan-1-
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , R 8 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined above; W 1 represents fluorine, chlorine, bromine or iodine, H represents hydrogen; N represents nitrogen; R 1 reagents such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane- 3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide , (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropane-1- Alcohol, (10) 2-aminoethan-1-
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 3, wherein R 1 , R 2 , R 3 , R 8 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined above; W 1 represents fluorine, chlorine, bromine or iodine; H represents hydrogen; N represents nitrogen; P 1 is the protecting group of ester group; R 1 reagent such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3 -Methyloxetane-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-Hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto -2-methyl
  • compound 3-1 reacts with R 1 reagent 3-2 to generate compound 3-3, and compound 3-3 removes the ester protecting group P 1 to obtain compound 3-4, compound 3-4 and compound 3-5 undergoes amidation reaction to generate compound 3-6.
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 4, wherein R 1 , R 2 , R 3 , R 8 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined above; W 1 represents fluorine, chlorine, bromine or iodine; H represents hydrogen; N represents nitrogen ; P 2 is the protecting group of amine group; -Methyloxetane-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-Hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto -2-methylpropan-1-ol, (10) 2-aminoethan-1-ol or (11) cycl
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates 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.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • C alpha-beta hydrocarbyl means a hydrocarbyl group containing a minimum of alpha and a maximum of beta carbon atoms in a branched or linear relationship, where alpha and beta represent integers.
  • the hydrocarbyl groups described in this section may also contain one or two double or triple bonds.
  • the designation of C 0 alkyl indicates a direct bond.
  • Examples of C 1-6 hydrocarbon groups include, but are not limited to the following:
  • C ⁇ - ⁇ halohydrocarbyl means a hydrocarbyl group as described above wherein any number (at least one) of the hydrogen atoms attached to the hydrocarbyl chain is replaced by F, Cl, Br or I.
  • Halo or halogen means a halogen atom selected from F, Cl, Br, and I, unless otherwise specified.
  • alkoxy means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • bicyclic means a group having two connecting rings.
  • a bicyclic ring can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S, in addition to carbon atoms). Both rings can be aliphatic (such as decalin and norbornane), or can be aromatic (such as naphthalene), or a combination of aliphatic and aromatic (such as tetralin).
  • Bicyclics include (a) spirocyclic compounds in which the two rings share only a single atom (the spiro atom, which is usually a quaternary carbon). Examples of spiro compounds include, but are not limited to:
  • bridged bicyclic compounds in which the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom.
  • norbornane also known as bicyclo[2.2.1]heptane
  • bridged double rings include, but are not limited to:
  • carbocycle or “carbocyclic” means a ring encompassed by itself or in combination with other terms, denoting a cyclic version of "C alpha-beta hydrocarbyl".
  • carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, Norpinenyl, norcarcinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • Heterocycle or “heterocyclic” means a ring comprising at least one carbon atom and at least one other atom selected from N, O, and S, unless otherwise specified.
  • heterocycles that may appear in the claims include, but are not limited to the following:
  • “Saturated, partially saturated or unsaturated” includes substituents saturated with hydrogen, substituents fully unsaturated with hydrogen and substituents partially saturated with hydrogen.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a chemical bond.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
  • the present invention provides that the compound of the general formula (1) or the pharmaceutical composition of the present invention can generally be used to inhibit KIF18A protein, and thus can be used to treat one or more diseases related to the activity of KIF18A protein. Therefore, in some embodiments, the present invention provides a method for treating a KIF18A protein-mediated disorder, the method comprising the step of administering the compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need .
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general structural formula (1) to an individual in need.
  • the cancer is mediated by the KIF18A protein.
  • the cancer is a hematological cancer and a solid tumor, including, but not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome) and Solid tumors (carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue carcinomas and osteosarcomas, and stromal tumors) and the like.
  • hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome
  • Solid tumors carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue carcinomas and osteosarcomas, and stromal tumors
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • Dissolve int_1-5 (100 mg, 0.3 mmol) in DCM (10 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_1-6 (71 mg, 0.3 mmol) in THF (5 mL), add NaH (72 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Step 2 the synthesis of compound int_65-4:
  • Dissolve int_65-4 50 mg, 0.188 mmol
  • DCM 10 mL
  • oxalyl chloride 1 mL
  • DMF dimethyl sulfoxide
  • Dissolve int_1-6 45 mg, 0.188 mmol
  • THF 5 mL
  • NaH 35 mg, 60% content
  • stir at room temperature for half an hour then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours.
  • LC-MS monitoring showed the reaction was complete.
  • Int_65-5 (57mg, 0.117mmol), xantphos (7mg, 0.0117mmol), cesium carbonate (57mg, 0.175mmol), Pd 2 (dba) 3 (11mg, 0.011mmol) and int_65-6 (22mg, 0.175mmol) It was dissolved in 1,4-dioxane (10 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (35 mg, yield: 50%).
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (10 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_1-6 (90 mg, 0.375 mmol) in THF (5 mL), add NaH (70 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_65-4 (300 mg, 1.125 mmol) in DCM (10 mL), add oxalyl chloride (1.5 mL) and a drop of DMF, react at room temperature for 1 hour, and then concentrate the reaction solution to obtain an acid chloride intermediate.
  • Dissolve int_161-3 (268mg, 1.125mmol) in THF (5mL), add NaH (300mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (50 mg, 0.187 mmol) in DCM (5 mL), add oxalyl chloride (0.5 mL) and a drop of DMF, react at room temperature for 1 hour, and then concentrate the reaction solution to obtain an acid chloride intermediate.
  • Dissolve int_161-3 (35 mg, 0.15 mmol) in THF (5 mL), add NaH (70 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_226-3 (82mg, 0.375mmol) in THF (5mL), add NaH (90mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_227-3 (82mg, 0.375mmol) in THF (5mL), add NaH (90mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_227-4 (55mg, 0.118mmol), xantphos (8mg, 0.0118mmol), cesium carbonate (66mg, 0.203mmol), Pd 2 (dba) 3 (10.5mg, 0.0118mmol) and int_227-5 (18mg, 0.141mmol ) was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (25 mg, yield: 38%).
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_228-3 (78 mg, 0.375 mmol) in THF (5 mL), add NaH (90 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_228-4 (57mg, 0.124mmol), xantphos (9mg, 0.0124mmol), cesium carbonate (60mg, 0.186mmol), Pd 2 (dba) 3 (11mg, 0.0124mmol) and int_228-5 (19mg, 0.124mmol) It was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (15 mg, yield: 20%).
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_229-3 (87 mg, 0.375 mmol) in THF (5 mL), add NaH (90 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_229-4 (220mg, 0.46mmol), xantphos (110mg, 0.19mmol), cesium carbonate (301mg, 0.928mmol), Pd 2 (dba) 3 (110mg, 0.12mmol) and int_229-5 (116mg, 0.928mmol) It was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (39 mg, yield: 47%).
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_230-3 (82mg, 0.375mmol) in THF (5mL), add NaH (90mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_230-4 (138mg, 0.298mmol), xantphos (20mg, 0.0298mmol), cesium carbonate (187mg, 0.447mmol), Pd 2 (dba) 3 (26mg, 0.0298mmol) and int_230-5 (45mg, 0.298mmol) It was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (35 mg, yield: 20%).
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_231-3 (70mg, 0.375mmol) in THF (5mL), add NaH (90mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (100 mg, 0.375 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_236-3 (78 mg, 0.375 mmol) in THF (5 mL), add NaH (100 mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40 ° C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (171 mg, 0.643 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_321-3 (100mg, 0.42mmol) in THF (10mL), add NaH (200mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_321-1 400mg, 0.82mmol
  • xantphos 200mg, 0.346mmol
  • cesium carbonate 536mg, 1.65mmol
  • Pd 2 (dba) 3 200mg, 0.218mmol
  • int_321-5 206mg, 1.65mmol
  • Int_353-5 (4 g, 21.9 mmol) was suspended in methanol (100 mL), and trimethylsilyl chloride (7 g, 64.65 mmol) was added. The reaction solution was reacted at room temperature for 4 hours, and the reaction solution gradually became clear. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (4.1 g, yield: 95%).
  • the organic phase was filtered and distilled under reduced pressure to obtain the crude product.
  • Int_354-1 (4 g, 21.9 mmol) was suspended in methanol (100 mL), and trimethylsilyl chloride (7 g, 64.65 mmol) was added. The reaction solution was reacted at room temperature for 4 hours, and the reaction solution gradually became clear. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (4.1 g, yield: 95%).
  • the organic phase was filtered and distilled under reduced pressure to obtain the crude product.
  • Int_449-4 (60mg, 0.113mmol), xantphos (7mg, 0.0113mmol), cesium carbonate (55mg, 0.170mmol), Pd 2 (dba) 3 (10mg, 0.0113mmol) and int_449-5 (17mg, 0.135mmol) It was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (12 mg, yield: 18%).
  • Dissolve int_449-4 (130 mg, 0.42 mmol) in DCM (10 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_321-3 (100mg, 0.42mmol) in THF (10mL), add NaH (200mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Dissolve int_97-4 (80 mg, 0.3 mmol) in DCM (5 mL), add oxalyl chloride (1 mL) and a drop of DMF, react at room temperature for 1 hour, then concentrate the reaction solution to obtain the acid chloride intermediate.
  • Dissolve int_609-1 (76mg, 0.3mmol) in THF (5mL), add NaH (100mg, 60% content), stir at room temperature for half an hour, then slowly add the acid chloride obtained before, and raise the temperature to 40°C for 5 hours. LC-MS monitoring showed the reaction was complete.
  • Int_609-2 (60mg, 0.120mmol), xantphos (7mg, 0.012mmol), cesium carbonate (59mg, 0.180mmol), Pd 2 (dba) 3 (11mg, 0.012mmol) and int_609-3 (45mg, 0.360mmol) It was dissolved in 1,4-dioxane (5 mL), replaced with argon three times, and under the protection of argon, the reaction solution was heated to 100° C. for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was spin-dried, and purified by column chromatography to obtain a solid (50 mg, yield: 71%).
  • Embodiment 21-610 Synthesis of compounds 2-64,66-96,98-160,162-224,232-235,237-320,322-352,355-384,386-448,450-576,578-610
  • the target compounds 2-64, 66-96, 98-160, 162-224, 232-235, 237-320, 322-352, 355-384, 386-448, 450-576, 578-610 in Table 1 can be obtained.
  • Example 611 Compounds of the present invention inhibit KIF18A enzyme activity test in vitro
  • KIF18A Enzyme Assay KIF18A enzymatic activity after compound treatment was measured using a microtubule-stimulated ATPase activity assay. This assay measures the ADP generated by the ATPase reaction. Compounds were serially diluted 2-fold in DMSO over a range of 22 concentration points. The recombinant human KIF18A (1-467His-tagged) protein was expressed using the baculovirus system. The concentrations of KIF18A protein, Microtubules and ATP in the reaction were optimized for a standardized homogeneous enzyme assay using the ADP-Glo Kinase/ATPase Assay Kit.
  • Reaction buffer [(15 mM Tris, pH 7.5), 10 mM MgCl 2 , 0.01% Pluronic F-68, 1 ⁇ M paclitaxel and 30 ⁇ g/mL porcine microtubes] was prepared. Compounds and KIF18A protein (30 nM) were added to the prepared reaction buffer and incubated at room temperature for 15 min, then ATP (Km, 75 ⁇ M) was added to the reaction mixture and incubated at room temperature for another 15 min. 5 ⁇ L of ADP-Glo reagent and 2.5 ⁇ L of reaction mixture were mixed and incubated at room temperature for 40 min. Add 10 ⁇ L ADP-Glo detection reagent and incubate at room temperature for 40 min. The luminescence was read using a microplate reader, compared with the DMSO group, and then the compound inhibition percentage and IC 50 were calculated. The results are shown in Table 2 below.
  • +++ means IC 50 less than or equal to 100nM
  • Example 612 In vitro antiproliferative activity of compounds of the present invention on HT-29 and HCT116 cells
  • HCT116 (IC 50 ,nM) 1 >1000 >10000 65 >1000 >10000 97 >1000 >10000 161 129 >10000 225 56 >10000 226 1185 >10000 227 >1000 >10000 228 774 >10000 229 >1000 >10000 230 316 >10000 231 897 >10000 236 >1000 >10000 321 675 >10000 353 >1000 >10000 385 266 >10000 449 >1000 >10000 577 1000 >10000 609 253 >10000 610 >1000 2484

Abstract

L'invention concerne une classe d'inhibiteurs de KIF18A. Spécifiquement, la présente invention concerne un composé représenté par la formule générale (1), son procédé de préparation et l'utilisation du composé tel que représenté par la formule générale (1), ainsi que des isomères, des formes cristallines, des sels, des hydrates ou des solvates pharmaceutiquement acceptables de ceux-ci en tant qu'inhibiteurs de KIF18A dans la préparation de médicaments contre des tumeurs.
PCT/CN2022/119392 2021-09-16 2022-09-16 Inhibiteur de kif18a WO2023041055A1 (fr)

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