Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • 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
  • C07D401/02—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 two hetero rings
  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • 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
  • C07D405/02—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 two hetero rings
  • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present invention relates to the field of medicinal chemistry, and more specifically, to a class of compounds with KIF18A protein inhibitory effects, preparation methods thereof and applications of such compounds in the preparation of anti-tumor drugs.
• Genomic 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 chromosome interactions with mitotic spindle microtubules, resulting in chromosome segregation errors. Cells with chromosomal instability produce increased spindle microtubule polymerization and reduced spindle microtubule-to-kinetochore contact switching 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 transport of vesicles and organelles. Mitotic kinesins play important roles in many aspects such as spindle assembly, chromosome segregation, centrosome separation and dynamics. Human kinesins are classified into 14 subtypes based on differences in the amino acid sequences of the motor domains. The ATPase activity located in the motor domain drives the protein to move in one direction along microtubules. The non-motor domains of these proteins are responsible for interacting with substrates, and various membranous organelles, signal transduction scaffold systems, and chromosomes serve as substrates that can interact with non-motor domains. Kinesins obtain energy from ATP hydrolysis to move substrates along polarized microtubules. Therefore, kinesins are often referred to as "plus-end” or "minus-end” directed motors.
• KIF18A protein belongs to the kinesin-8 isoform. KIF18A protein is overexpressed in various types of cancer, such as lung, ovarian, cervical, breast, pancreatic, prostate, colon, and bladder cancers. Studies suggest that KIF18A affects the movement of the plus ends of mitochore microtubules to control correct chromosome positioning and spindle tension. In tumor cells with chromosomal instability, abnormal microtubule movement makes such cells particularly dependent on KIF18A protein to reduce the contact switching between spindle microtubules and kinetochores and limit microtubule growth (Nat Commun. 2021, 12, 1213).
• KIF18A protein When the KIF18A protein is deleted in tumor cells with chromosomal instability, the centrosomes of the cells become fragmented, and mitotic progression is slowed or terminated. 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 tumors with chromosomal instability.
• KIF18A inhibitors is a new potential approach to combat tumors with chromosomal instability.
• the invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
• Ring A is a 7-10 membered cycloalkylene group, a 7-10 membered heterocycloalkylene group, a 7-10 membered heteroarylene group or a 10-membered arylene group, wherein the 7-10 membered cycloalkylene group, 7 -10-membered heterocycloalkylene, 7-10-membered heteroarylene or 10-membered arylene may be optionally substituted by 0, 1, 2 or 3 of the following groups: H, halogen, -C 1-4 hydrocarbyl , -C 1-4 halogenated hydrocarbon group or -OC 1-4 hydrocarbon group;
• R 3 is H or C 1-6 hydrocarbon group
• 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 8 is selected from the group consisting 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 may be independently associated with
• the carbon atoms connected to each of them constitute a saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring spliced to the R8 ring; wherein the 3-membered, 4-membered, 5-membered or 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, 5-membered, 6-membered monocyclic ring is selected from the following 0, 1, 2 or 3 groups substituted: F, Cl, Br, C 1-6 hydrocarbyl, C 1-4 haloal
• R 10 is H, R 10a , R 10b or R 10c ;
• R 11 is H, R 11a or R 11b ;
• R 12 is R 12a or R 12b ;
• R 6b , R 10b , R 11b , R 12b or R 13n is in each case independently selected from: C 1-6 hydrocarbyl, wherein said hydrocarbyl may optionally be replaced by 0, 1, 2, 3, 4 or 5 Substituted with the following groups: F, Cl, Br, -R a , -OR a , -OC 1-4 haloalkyl and CN;
• R 10c is in each case independently selected from: C 1-6 hydrocarbyl, wherein said hydrocarbyl may be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a , -R c , -OR a , -OC 1-4 haloalkyl and CN;
• R a is in each case independently H or R b ;
• the general formula (1) has the following structure:
• ring A is a 9-10-membered cycloalkylene group, a 9-10-membered heterocycloalkylene group, a 9-10-membered heteroarylene group or a 10-membered Arylene group, wherein the 9-10 membered cycloalkylene group, 9-10 membered heterocycloalkylene group, 9-10 membered heteroarylene group or 10 membered arylene group may be optionally replaced by 0, 1, 2 or 3 of the following groups are substituted: H, F, Cl, Br, -C 1-4 hydrocarbyl, -C 1-4 haloalkyl or -OC 1-4 hydrocarbyl.
• ring A is: Among them, * represents the L end connected; and the above-mentioned groups can be optionally substituted by 0, 1, 2 or 3 of the following groups: H, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -OCH 3 or -OCH 2 CH 3 .
• ring A is: Among them, * represents the L end connected; and the above-mentioned groups can be optionally substituted by 0, 1, 2 or 3 of the following groups: H, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -OCH 3 or -OCH 2 CH 3 .
• R 3 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 hydrocarbyl or C 1-4 halogenated hydrocarbyl; and R 13a and R 13b in the pair of R 13a and R 13b and the carbon atoms to which they are respectively connected can be combined to form a saturated ring spliced to the R 8 ring.
• 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 of R 13a and R 13b and the carbon atoms to which they are respectively attached may be combined to form a cyclopropyl group spliced to the R 8 ring , cyclobutyl or cyclopentyl ring.
• it is a C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH groups; more preferably it is a C 1-6 hydrocarbon group substituted by 1 OH group.
• C 1-6 hydrocarbon group the C 1-6 hydrocarbon group may be optionally substituted by 1, 2 or 3 of the following groups: And the C 1-6 hydrocarbon group may be optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH 3 .
• the individually linked sulfur atoms combine to form a saturated or partially saturated 3-, 4-, 5- or 6-membered molecule containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S monocyclic ring;
• preferred group -ZR 10 is selected from:
• R 1 is the group -ZR 10 , Z is -NHSO 2 - or -SO 2 NH-; and R 10 is oxetane group, cyclopropyl; or R 10 is a C 1-6 hydrocarbon group substituted by 0, 1 , 2 or 3 OH groups; or R 10 is a C 1-6 hydrocarbon group, wherein the C 1-6 hydrocarbon group can be any Choose to be substituted by 1, 2 or 3 of the following groups:
• R 10 is selected from C 1-6 hydrocarbon groups, and the hydrocarbon groups may be optionally substituted by 0, 1, 2 or 3 of the following groups:
• Z is -NHSO 2 - or -SO 2 NH-;
• Z is preferably -NHSO 2 -.
• R 10 is selected from C 1-6 hydrocarbon groups, and the hydrocarbon groups may be optionally substituted by 1, 2 or 3 of the following groups: Z is -NHSO 2 - or -SO 2 NH-.
• R 2 is halogen or the group -YR 12
• Y is a chemical bond, -NH-, -NH-(CH 2 ) 0-4 - or -O-(CH 2 ) 0-4 -
• 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-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings, wherein the monocyclic ring and bicyclo may each be independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 hydrocarbyl, C 1-4 haloalkyl, -OH, -OC 1-4 halo Substituted hydrocarbyl, CN, R 14 and oxo; or R 12 is C 1-6 hydrocarbyl, which may
• R 2 is a saturated 5-membered or 6-membered monocyclic ring, wherein each ring contains 0, 1 or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted with 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 hydrocarbyl, C 1-4 haloalkyl, -OH, -OC 1-4 haloalkyl, CN, R 14 and oxo.
• R 2 is (a) halogen; (b) group -YR 12 , where Y is a chemical bond; and R 12 is morpholinyl, piperidine base, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each said ring is substituted with 0, 1, 2 or 3 groups selected from: F, Cl, Br, methyl, CF3 , -OH, -OCHF2 , CN, and oxo; or (c ) group -YR 12 , where Y is -NH-, -O-, -O-(CH 2 )-, -O-(CH 2 )-(CH 2 )- or -O-(CH 2 )-( CH 2 )-(CH 2 )-, and where R 12 is Or
• R 2 is morpholinyl or piperidinyl, and the morpholinyl and piperidinyl groups can be optionally substituted by 0, 1, 2 or 3 The following groups are substituted: F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 and CN.
• R 2 is a piperidinyl group substituted by 1, 2 or 3 fluorine groups.
• R 2 is:
• R 2 is a morpholinyl group substituted by 1, 2 or 3 methyl groups.
• R 2 is
• R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl Or 1,3,4-oxothiazinyl.
• R 5 is H or F, preferably H.
• R 6 is H or F, preferably H.
• R 7 is H.
• compounds of general formula (1) have one of the following structures:
• the compound of general formula (1) also 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 a compound of general formula (1) of the present invention, or each isomer thereof, Each crystal form, pharmaceutically acceptable salt, hydrate or solvate serves as the active ingredient.
• Another object of the present invention is to provide the compound represented by the general formula (1) of the present invention, or its respective isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above pharmaceutical compositions.
• Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to KIF18A protein, which includes administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its Each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above pharmaceutical composition.
• the compounds of general formula (1) described above can be synthesized using standard synthesis techniques or known techniques combined with the methods described herein.
• the solvents, temperatures and other reaction conditions mentioned herein may be varied.
• Starting materials for the synthesis of compounds may be synthesized or obtained 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 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 3rd Ed., Vols.
• the compounds described herein are 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, time required for reaction, etc. are not limited to the following explanations.
• the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations 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 , A ring, R 8 , X 1 , X 2 and X 3 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-methylpropan-1-ol, (10)2 -Aminoeth-1-ol or (11)cycloprop
• Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , A ring, R 8 , X 1 , X 2 and X 3 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-methylpropan-1-ol, (10)2 -Aminoeth-1-ol or (11)cycloprop
• Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 3, wherein R 1 , R 2 , A ring, R 8 , X 1 , X 2 and X 3 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 the ester group; R 1 reagent such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxeterocycle Butane-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-ol, (10) 2-a
• 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 , A ring, R 8 , X 1 , X 2 and X 3 are as defined above; W 1 represents fluorine, chlorine, Bromine or iodine; H represents hydrogen; N represents nitrogen; P 2 is the protective group of the amino group; R 1 reagent such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxeterocycle Butane-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) 2-sulfamate Ethyl acylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropane-1 -alcohol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-amin
• compound 4-1 reacts with R 1 reagent 4-2 to generate compound 4-3, and compound 4-3 removes the amino protecting group P 2 to obtain compound 4-4, compound 4-4 and compound 4-5 undergoes amidation reaction to generate compound 4-6.
• “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not obliterate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance will not cause undesirable biological effects or Interact in a harmful way with any of its components.
• 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 obliterate the biological activity and properties of the compound.
• pharmaceutically acceptable salts are obtained by reacting a compound of general formula with an acid or base including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection , and Acids and Bases in Use 1st Ed., (Wiley, 2002).
• references to pharmaceutically acceptable salts include solvent-added 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, etc. 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.
• the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
• the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
• compounds of formula (1) are prepared in different forms, including, but not limited to, amorphous, comminuted, and nano-particulate forms.
• the compound of general formula (1) includes a crystalline form and may also be a polymorphic form.
• 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, density, hardness, crystalline form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
• compounds of general formula (1) may present 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 isomer forms occur.
• Each chiral center or axis of chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
• the present invention is intended to include all such isomeric forms of these compounds.
• the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
• 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).
• hydrogen atoms can be replaced with heavy hydrogen to form deuterated compounds.
• the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
• deuterated drugs usually have the advantages of reducing side effects and increasing the number of drugs. Stability, enhanced efficacy, extended half-life of drugs in vivo and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
• C ⁇ - ⁇ hydrocarbyl means a hydrocarbon radical containing a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched or linear relationship, where ⁇ and ⁇ represent integers.
• the hydrocarbyl groups described in this section may also contain one or two double or triple bonds.
• the designation of C 0 hydrocarbon group indicates a direct bond.
• Examples of C 1-6 hydrocarbyl groups include, but are not limited to, the following:
• C alpha-beta haloalkyl 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.
• hydrocarbylene refers to a divalent hydrocarbyl group as defined above.
• alkylene groups include, but are not limited to, -CH2- , -CH2CH2- , or -CH( CH3 ) -CH2- .
• halo or halogen means a halogen atom selected from the group consisting of F, Cl, Br and I.
• alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
• Representative alkoxy groups are alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
• alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted by 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.
• cycloalkyl refers to a monocyclic non-aromatic hydrocarbon ring system.
• the definition of cycloalkyl also includes fusion with one or more carbocyclic aromatic groups and a monocyclic cycloalkyl group.
• the connection point between the cycloalkyl group and other structures can be at On an aromatic carbon ring, it can also be on a non-aromatic carbon ring.
• the ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form oxo or sulfide radicals.
• Cycloalkyl also includes cycloalkylene.
• cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, wait.
• aryl refers to a hydrocarbon aromatic group, which may be monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups.
• aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
• arylene refers to a divalent aryl group as defined above.
• arylene groups include, but are not limited to, phenylene, naphthylene, and phenylene.
• heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which may be monocyclic or polycyclic.
• a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
• heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrole[3,2-b]pyridyl, 1H-pyridyl Pyrrole[2,3-c]pyridyl, 1H-pyrrole[3,2-c]pyridyl, 1H-pyrrole[2,3-b]pyridyl,
• heteroaryl refers to a divalent heteroaryl group as defined above.
• heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one independently selected from the group consisting of boron, phosphorus , heteroatom ring members of nitrogen, sulfur, oxygen and phosphorus.
• Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic or polycyclic (eg, having two fused or bridged rings) ring systems.
• heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
• the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be oxidized to form oxo or sulfide radicals or other oxidative linkages (e.g., C(O), S(O), C(S), or S(O) 2. N-oxide, etc.), or the nitrogen atom can be quaternized.
• Heterocycloalkyl groups may be attached via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds.
• heterocycloalkyl moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, etc. benzo or thienyl derivatives.
• Heterocycloalkyl groups containing fused aromatic rings may be linked via any ring-forming atom, including ring-forming atoms of fused aromatic rings.
• heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuryl, dihydropyranyl, N-morpholinyl, 3-oxa-9- Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxypiperazinyl, pyranyl, pyrrolidinyl, Quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, scopolanoyl, 4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolact
• heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
• bicyclic means a group having two connected rings.
• Bicycles can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (such as decalin and norbornane), or they can be aromatic (such as naphthalene), or a combination of aliphatic and aromatic (such as tetralin).
• Bicycles include (a) spiro 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 two rings share three or more atoms and are connected by a bridge containing at least one atom Two bridgehead atoms are separated.
• norbornane also known as bicyclo[2.2.1]heptane
• bridged dual rings include, but are not limited to:
• carbocyclic or “carbocyclic” means a ring encompassed by itself or in combination with other terms, indicating the cyclic form of "C alpha-beta hydrocarbyl".
• carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, Norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, etc.
• heterocycle or “heterocyclic” means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S.
• heterocycles that may appear in the claims include, but are not limited to, the following:
• “Saturated, partially saturated or unsaturated” includes substituents that are saturated with hydrogen, substituents that are completely unsaturated with hydrogen, and substituents that are 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.
• ring includes any cyclic structure.
• element is intended to indicate the number of backbone atoms constituting the ring.
• cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
• cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
• fragment refers to a specific part or functional group of a molecule. Chemical fragments are generally thought of as chemical entities contained in or attached to molecules.
• wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
• using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
• wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
• acceptable means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.
• treatment include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or symptoms; making a disease or symptoms subside; alleviating complications caused by a disease or symptoms, or preventing or treating signs caused by a disease or symptoms.
• a compound or pharmaceutical composition when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributable to or related to administration, whether fixed or temporary, continuous or intermittent.
• Active ingredients refer to compounds represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of 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- appear as enantiomers.
• the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
• the present invention is intended to include all such isomeric forms of these compounds.
• composition refers to a substance when administered to an individual (human or animal), a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
• administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound. wait.
• the present invention provides that compounds of general formula (1) or pharmaceutical compositions of the present invention can generally be used to inhibit KIF18A protein and therefore can be used to treat one or more conditions associated with KIF18A protein activity. Accordingly, in certain embodiments, the present invention provides methods for treating a KIF18A protein-mediated disorder, said method comprising the step of administering a compound of the invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof .
• cancer is mediated by KIF18A protein.
• the cancer is a hematological cancer and a solid tumor, preferably tumors with chromosomal instability, including, but not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumors), etc.
• hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome
• solid tumors cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumors
• 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 ;
• the breast cancer is preferably triple-negative breast cancer;
• 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;
• the peritoneal cancer is preferably primary peritoneal cancer; in other embodiments, the uterine cancer is preferably se
• the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within a safe and effective amount and pharmaceutically acceptable excipients or carriers.
• the "safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
• the safe and effective dosage of the compound is determined based on the age, condition, course of treatment and other specific conditions of the treatment subject.
• “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity .
• “Compatibility” here refers to the ability of the components of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
• Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, Stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
• cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
• gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
• administering When administering the compounds of the present invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
• the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
• Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form 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 employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, 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.
• inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
• compositions may 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 may contain, in addition to the active compound, 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 contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
• Dosage forms for topical administration of the compounds 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 that may be required.
• 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, and the dosage when administered is a pharmaceutically effective dosage.
• the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
• the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
• 1 H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance instrument, and the chemical shift was expressed in ⁇ (ppm); the silica gel used for separation was all 200-300 mesh (not specified), and the eluent ratios were all volume ratios.
• (Boc) 2 O represents di-tert-butyl dicarbonate
• BINAP represents 2,2′-bisdiphenylphosphino-1,1′-binaphthyl
• BOPCl represents bis(2-oxygen) Generation-3-oxazolidinyl) hypophosphoryl chloride
• t-BuONa represents sodium tert-butoxide
• CDCl 3 represents deuterated chloroform
• Cs 2 CO 3 represents cesium carbonate
• CuI represents cuprous iodide
• EtOAc represents ethyl acetate
• Hexane represents n-hexane
• HPLC represents high performance liquid chromatography
• MeCN represents acetonitrile
• DCE represents 1,2-dichloroethane
• DCM represents dichloromethane
• DIPEA represents diisopropylethylamine
• 1,4-Dioxane represents 1 , 4-dioxane
• DMF represents N,N-d
• Dissolve int_1-5 (70 mg, 0.196 mmol) in DCM (3 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_65-9 (50 mg, 0.196 mmol) in THF (5 mL), add sodium hydrogen (30 mg, 0.75 mmol, 60% purity) at 0°C under nitrogen protection, and raise the reaction solution to room temperature for 1 hour, then react The liquid was cooled to 0°C, the acid chloride prepared above was slowly added to the reaction solution, and the reaction solution was raised to 45°C and stirred for 12 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (92 mg, yield: 79%).
• Int_1-8 (39mg, 0.309mmol), dimethylcyclohexane-1,2-diamine (11mg, 0.077mmol), copper iodide (15mg, 0.077mmol) and potassium phosphate (98mg, 0.464mmol) , dissolved in DMF (5mL), replaced with argon three times, added int_65-10 (92mg, 0.155mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (50 mg, yield: 55%).
• Dissolve int_1-5 (124 mg, 0.3 mmol) in DCM (10 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_513-9 (76 mg, 0.3 mmol) in THF (5 mL), add sodium hydride (72 mg, 1.8 mmol, 60% purity) at 0°C under nitrogen protection, and raise the reaction solution to room temperature for 1 hour. Then react The liquid was cooled to 0°C, the acid chloride prepared above was slowly added to the reaction solution, and the reaction solution was raised to 40°C and stirred for 12 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (100 mg, yield: 56.2%).
• Int_1-8 (63 mg, 0.51 mmol), dimethylcyclohexane-1,2-diamine (12 mg, 0.085 mmol), copper iodide (16 mg, 0.085 mmol) and potassium phosphate (108 mg, 0.51 mmol) , dissolved in DMF (5 mL), replaced with argon three times, added int_513-10 (100 mg, 0.17 mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (33 mg, yield: 33%).
• Dissolve int_1-5 (140 mg, 0.396 mmol) in DCM (10 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_522-5 (100 mg, 0.396 mmol) in DCM (10 mL), add DIPEA (255 mg, 1.98 mmol) under nitrogen protection, then cool the reaction solution to 0°C, and slowly add the acid chloride prepared above to the reaction solution. , the reaction solution was raised to room temperature and stirred for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (106 mg, yield: 45.2%).
• Int_1-8 (45mg, 0.358mmol), dimethylcyclohexane-1,2-diamine (13mg, 0.0895mmol), copper iodide (17mg, 0.0895mmol) and potassium phosphate (114mg, 0.537mmol) , dissolved in DMF (10 mL), replaced with argon three times, added int_522-6 (106 mg, 0.179 mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (10 mg, yield: 9.5%).
• Dissolve int_1-5 (124 mg, 0.3 mmol) in DCM (10 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_530-5 (80 mg, 0.3 mmol) in DCM (10 mL), add NaH (72 mg, 1.8 mmol, 60% purity) under nitrogen protection, then cool the reaction solution to 0°C, and slowly add the acid chloride prepared above into the reaction solution, the reaction solution was raised to 40°C and stirred for 12 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (58 mg, yield: 32.2%).
• Dissolve int_1-5 (100 mg, 0.28 mmol) in DCM (10 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_537-1 (71.7 mg, 0.28 mmol) in DCM (10 mL), add NaH (112 mg, 2.8 mmol, 60% purity) under nitrogen protection, then cool the reaction solution to 0°C, and slowly add the acid chloride prepared above Add to the reaction solution, raise the reaction solution to 45°C and stir for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (127 mg, yield: 76.1%).
• Int_1-8 (25mg, 0.2mmol), dimethylcyclohexane-1,2-diamine (18mg, 0.125mmol), copper iodide (26mg, 0.125mmol) and potassium phosphate (164mg, 0.747mmol) , dissolved in DMF (5 mL), replaced with argon three times, added int_537-2 (120 mg, 0.2 mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (76 mg, yield: 64.1%).
• Dissolve int_1-5 200mg, 0.559mmol
• DCM (10mL) oxalyl chloride
• oxalyl chloride 253.8mg, 2mmol
• the solvent was concentrated under reduced pressure to obtain an acid chloride solid.
• Dissolve int_539-5 120 mg, 0.447 mmol
• DCM (10 mL) oxalyl chloride
• DIPEA 173 mg, 1.34 mmol
• the reaction solution was raised to 40°C and stirred at room temperature for 1 hour.
• LC-MS monitoring showed the reaction was complete.
• the reaction solution was concentrated under reduced pressure to obtain crude product.
• the crude product was purified by column chromatography to obtain a solid (235 mg, yield: 74.3%).
• Dissolve int_1-5 (100 mg, 0.28 mmol) in DCM (10 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_530-5 (74 mg, 0.28 mmol) in DCM (10 mL), add NaH (112 mg, 2.8 mmol, 60% purity) under nitrogen protection, then cool the reaction solution to 0°C, and slowly add the acid chloride prepared above into the reaction solution, the reaction solution was raised to 45°C and stirred for 3 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (150 mg, yield: 88.8%).
• Int_1-8 (34mg, 0.249mmol), dimethylcyclohexane-1,2-diamine (18mg, 0.125mmol), copper iodide (26mg, 0.125mmol) and potassium phosphate (164mg, 0.747mmol) , dissolved in DMF (5 mL), replaced with argon three times, added int_583-2 (150 mg, 0.249 mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (57 mg, yield: 38%).
• Dissolve int_584-1 (100 mg, 0.341 mmol) in DCM (5 mL), add oxalyl chloride (253.8 mg, 2 mmol), stir the reaction solution at room temperature for 2 hours, and then concentrate under reduced pressure to remove the solvent to obtain an acid chloride solid.
• Dissolve int_584-2 (90 mg, 0.321 mmol) in THF (5 mL), add NaH (112 mg, 2.8 mmol, 60% purity) under nitrogen protection, then cool the reaction solution to 0°C, and slowly add the acid chloride prepared above into the reaction solution, the reaction solution was raised to 45°C and stirred for 12 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a solid (150 mg, yield: 83.8%).
• Int_1-8 (84mg, 0.674mmol), dimethylcyclohexane-1,2-diamine (32mg, 0.225mmol), copper iodide (43mg, 0.225mmol) and potassium phosphate (286mg, 1.348mmol) , dissolved in DMF (10 mL), replaced with argon three times, added int_584-3 (150 mg, 0.270 mmol), and heated the reaction solution to 100°C for 16 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, spun to dryness, and purified by column chromatography to obtain a solid (50 mg, yield: 30.9%).
• KIF18A enzyme assay KIF18A enzyme activity after treatment with compounds was measured using a microtubule-stimulated ATPase activity assay. This assay measures ADP generated by the ATPase reaction. Compounds were serially diluted 2-fold in DMSO over a range of 22 concentration points. make Recombinant human KIF18A (1-467His-tagged) protein was expressed using a baculovirus system. The concentrations of KIF18A protein, Microtubules, and ATP in the reaction were optimized using the ADP-Glo Kinase/ATPase Assay Kit for standardized homogeneous enzyme assays.
• reaction buffer [(15mM Tris, pH 7.5), 10mM MgCl2 , 0.01% PluronicF-68, 1 ⁇ M paclitaxel and 30 ⁇ g/mL porcine microtubules].
• the compound and KIF18A protein (30 nM) were added to the prepared reaction buffer and incubated at room temperature for 15 min.
• ATP Km, 75 ⁇ M
• ATP Km, 75 ⁇ M
• Use a microplate reader to read the luminescence and compare it with the DMSO group to calculate the compound inhibition percentage and IC 50 . The results are shown in Table 2 below.
• Inhibitory activity of compounds of the present invention on KIF18A (IC50, nM) +++ means IC 50 is less than or equal to 100nM ++ indicates IC 50 from 100nM to 500nM + indicates IC50 is greater than 500nM.
• 3000/well HT-29 cells were plated in a 384-well plate. After adhesion overnight, DMSO or a compound with a maximum concentration of 5 ⁇ M and a 1:5 gradient dilution was added. 72 hours after adding the drug, cell survival was evaluated by measuring intracellular ATP content. Compared with the DMSO group, the percentage of compound inhibiting cell survival was calculated, and the IC 50 value was calculated. The results are shown in Table 3 below.
• the reference compound AMG650 is compound 4 in WO2020132648A1.
• 3000/well HCT116 cells were plated in a 384-well plate. After adhesion overnight, DMSO or a compound with a maximum concentration of 5 ⁇ M and a 1:5 gradient dilution was added. 72 hours after adding the drug, cell survival was evaluated by measuring intracellular ATP content. Compared with the DMSO group, the percentage of compound inhibiting cell survival was calculated, and the IC 50 value was calculated. The results are shown in Table 4 below.

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