WO2023041055A1 - Kif18a inhibitor - Google Patents

Kif18a inhibitor 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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French (fr)
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/en

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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

Disclosed is a class of KIF18A inhibitors. Specifically, the present invention relates to a compound as represented by general formula (1), a preparation method therefor, and the use of the compound as represented by general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as KIF18A inhibitors in the preparation of drugs against tumors.

Description

KIF18A抑制剂KIF18A inhibitor
本申请要求申请日为2021年9月16日的中国专利申请202111085957.7和申请日为2021年11月19日的中国专利申请202111399463.6的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202111085957.7 with a filing date of September 16, 2021 and Chinese patent application 202111399463.6 with a filing date of November 19, 2021. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明属涉及药物化学领域，更具体而言，涉及一类及具有KIF18A蛋白抑制作用的化合物，及其制备方法和该类化合物用于制备抗肿瘤药物中的应用。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.
背景技术Background technique
基因组的不稳定性是绝大多数肿瘤细胞的一个共同特点。大部分的肿瘤细胞具有染色体的异常获得或缺失。肿瘤细胞的染色体不稳定性(chromosome instability)会导致异常的染色体与有丝***纺锤体微管(spindle microtubules)的相互作用，进而造成染色体分离错误。与具有正常染色体的细胞相比，具有染色体不稳定性的细胞会产生增多的纺锤体微管聚合以及减少的纺锤体微管与着丝粒的接触转换。因此，针对微管骨架的抗有丝***疗法可能对于具有染色体不稳定性的细胞尤为有效。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.
驱动蛋白是一类分子马达，其在细胞***和细胞内囊泡和细胞器运输中起到重要作用。在纺锤体组件、染色体分离、中心体分离和动力学等多个方面，有丝***驱动蛋白都起到重要作用。基于马达域(motor domain)氨基酸序列的不同，人的驱动蛋白被分类为14个亚型，位于马达域的ATP酶活性驱动该蛋白沿着微管单向运动。这些蛋白质的非马达结构域负责与底物相互作用，各种不同的膜状细胞器、信号转导支架***和染色体作为底物都可以与非马达结构域相互作用。驱动蛋白通过ATP水解来获得能量，从而沿着极化微管移动底物。因此，驱动蛋白通常被称为“正端”或“负端”定向马达。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.
KIF18A蛋白属于驱动蛋白-8亚型。KIF18A蛋白在多种类型的癌症中过表达，例如肺癌、卵巢癌、子***、乳腺癌、胰腺癌、***癌、结肠癌和膀胱癌。研究认为KIF18A影响丝粒微管正端的运动从而控制正确的染色体定位和纺锤体张力。在具有染色体不稳定性的肿瘤细胞中，异常的微管运动使这类细胞尤为依赖KIF18A蛋白来减少纺锤体微管与着丝粒的接触转换以及限制微管生长(Nat Commun.2021,12,1213)。当具有染色体不稳定性的肿瘤细胞中缺失KIF18A蛋白时，细胞的中心体会发生碎片化，并且有丝***进程会变慢或者终止。但这些现象并不会发生在具有正常染色体的细胞中。因此KIF18A蛋白的活性对于正常细胞的增殖并不会有很大影响，但对于染色体不稳定的肿瘤的生长非常关键。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. Studies suggest that KIF18A affects the movement of the plus-end of mitotic 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 transition between spindle microtubules and centromeres and limit microtubule growth (Nat Commun.2021, 12, 1213). 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.
因此，开发KIF18A抑制剂是一种对抗具有染色体不稳定性的肿瘤的新的有潜力的方法。Therefore, the development of KIF18A inhibitors is a new potential approach to combat tumors with chromosomal instability.
发明内容Contents of the invention
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
Figure PCTCN2022119392-appb-000001
Figure PCTCN2022119392-appb-000001
通式(1)中：In general formula (1):
X 1为-CR 5＝或N； X 1 is -CR 5 = or N;
X 2为-CR 6＝或N； X 2 is -CR 6 = or N;
X 3为-CR 7＝或N； X 3 is -CR 7 = or N;
X 4为-CR 4＝或N； X 4 is -CR 4 = or N;
X 5为-CR 15＝或N； X 5 is -CR 15 = or N;
当X 2以及X 3中至少一个为N和X 4以及X 5中至少一个为N时，L为-(C＝O)-NR 9-或-NR 9-(C＝O)-；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When at least one of X 2 and X 3 is N and at least one of X 4 and X 5 is N, L is -(C=O)-NR 9 - or -NR 9 -(C=O)-; and X Among 1 , X 2 , X 3 , X 4 and X 5 , no more than 4 are N;
当X 1为N时，L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When X 1 is N, L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and among X 1 , X 2 , X 3 , X 4 and X 5 , Not more than 4 are N;
当X 4为N和X 5不为N时，L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When X 4 is N and X 5 is not N, L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 , X 2 , X 3 , X Among 4 and X 5 , no more than 4 are N;
当X 5为N和X 1、X 2、X 3均不为N时，L为-(C＝O)-NR 9-*； When X 5 is N and X 1 , X 2 , and X 3 are not N, L is -(C=O)-NR 9 -*;
*代表连接的是
Figure PCTCN2022119392-appb-000002
端； *Represents the connected
Figure PCTCN2022119392-appb-000002
end;
R 1为-CN或-Z-R 10，其中Z为化学键、-C 0-4烃基-、-NR 11-、-NR 11SO 2-、-SO 2NR 11-、-NR 11-S(＝O)(＝NH)-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-C 0-4烃基-O-、-(C＝O)-、-(C＝O)NR 11-、-C(＝N-OH)-或-NR 11(C＝O)-；或所述基团-Z-R 10为-N＝S(＝O)-(R 10) 2，其中所述两个R 10可以与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环； R 1 is -CN or -ZR 10 , wherein Z is a chemical bond, -C 0-4 alkyl-, -NR 11 -, -NR 11 SO 2 -, -SO 2 NR 11 -, -NR 11 -S(=O )(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -C 0-4 Hydrocarbyl-O-, -(C= O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 is -N=S(=O )-(R 10 ) 2 , wherein the two R 10 can be combined with their respective attached sulfur atoms to form a compound containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 selected from O and S Atomically saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic rings;
R 2为卤素或基团-Y-R 12，其中Y为化学键、-C 0-4烃基-、-N(C 0-1烃基)-C 0-4烃基-、-C(＝O)NR a-(C 1- 4烃基)-、-O-C 0-4烃基-、-S-、-S(＝O)-、-SO 2-、-SO 2NR 12-或-S(＝O)(＝NH)-； R 2 is halogen or a group -YR 12 , wherein Y is a chemical bond, -C 0-4 alkyl-, -N(C 0-1 alkyl)-C 0-4 alkyl-, -C(=O)NR a - (C 1- 4 alkyl)-, -OC 0-4 alkyl-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 12 - or -S(=O)(=NH )-;
R 3为H、卤素、C 1-8烃基或C 1-4卤代烃基； R 3 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
R 4为H、卤素、R 4a或R 4b； R 4 is H, halogen, R 4a or R 4b ;
R 5为H、卤素、C 1-8烷基或C 1-4卤代烷基； R 5 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl;
R 6为H、卤素、C 1-8烷基、C 1-4卤代烷基、-OH、-O-R 6a或-O-R 6b； R 6 is H, halogen, C 1-8 alkyl, C 1-4 haloalkyl, -OH, -OR 6a or -OR 6b ;
R 7为H、卤素、C 1-8烃基或C 1-4卤代烃基； R 7 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
R 8选自由以下组成的组： R is selected from the group consisting of:
Figure PCTCN2022119392-appb-000003
Figure PCTCN2022119392-appb-000003
R 13a、R 13b、R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立地为H、卤素、R 13m或R 13n；或R 13a和R 13b对、R 13c和R 13d对、R 13e和R 13f对、R 13g和R 13h对、R 13i和R 13j对或R 13k和R 13l对中的每一对可以独立地与它们各自连接的碳原子组成螺接到R 8环的饱和的或部分饱和的3元、4元、5元、6元单环；其中所述3元、4元、5元、6元单环含有0、1、2或3个N原子和0、1或2个选自O和S的原子，并且进一步地，其中所述3元、4元、5元、6元单环被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-NR aR a或氧代； 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, 5-membered, 6-membered monocyclic ring is selected from the following Substitution of 0, 1, 2 or 3 groups: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OR a , -OC 1-4 halogenated hydrocarbon group, CN, -NR a R a or oxo;
R 9为H或C 1-6烃基； R 9 is H or C 1-6 hydrocarbon group;
R 10为H、R 10a或R 10b； R 10 is H, R 10a or R 10b ;
R 11为H、R 11a或R 11b； R 11 is H, R 11a or R 11b ;
R 12为R 12a或R 12b； R 12 is R 12a or R 12b ;
R 15为H、卤素、C 1-8烃基、C 1-4卤代烃基、-O-C 1-8烃基或-O-R 15a，其中R 15a为含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环； 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 4a、R 6a、R 10a、R 11a、R 12a或R 13m为在每种情况下独立地选自：含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环可各自独立任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-C(＝O)R b、-C(＝O)OR a、-C(＝O)NR aR a、-C(＝NR a)NR aR a、-OC(＝O)R b、-OC(＝O)NR aR a、-OC 2-6烃基NR aR a、-OC 2-6烃基OR a、-SR a、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR aR a、-NR aR a、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR aR a、-N(R a)C(＝NR a)NR aR a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR aR a、-NR aC 2-6烃基NR aR a、-NR aC 2-6烃基OR a、-C 1-6烃基NR aR a、-C 1-6烃基OR a、-C 1-6烃基N(R a)C(＝O)R b、-C 1-6烃基OC(＝O)R b、-C 1-6烃基C(＝O)NR aR a、-C 1-6烃基C(＝O)OR a、R 14和氧代； R 4a , R 6a , R 10a , R 11a , R 12a or R 13m are in each case independently selected from: containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and Saturated, partially saturated or unsaturated 3-membered, 5-membered, 6-membered or 7-membered monocyclic rings or 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered rings of S atoms 11-membered or 12-membered bicyclic rings, wherein the monocyclic 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 halohydrocarbyl, -OR a , -OC 1-4 halohydrocarbyl, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , - C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2-6 alkyl NR a R a , -OC 2-6 alkyl OR a , -SR a , -S(=O)R b , -S(=O) 2 R b , -S(=O) 2 NR a R a , -NR a R a , -N(R a )C( =O)R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O) 2 R b , -N(R a )S(=O) 2 NR a R a , -NR a C 2-6 hydrocarbyl NR a R a , -NR a C 2-6 hydrocarbon group OR a , -C 1-6 hydrocarbon group NR a R a , -C 1-6 hydrocarbon group OR a , -C 1-6 hydrocarbon group N(R a )C(=O)R b , -C 1-6 hydrocarbyl OC(=O)R b , -C 1-6 hydrocarbyl C(=O)NR a R a , -C 1-6 hydrocarbyl C(=O)OR a , R 14 and oxo;
R 4b、R 6b、R 10b、R 11b、R 12b或R 13n为在每种情况下独立地选自：C 1-6烃基，其中所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、-R a、-OR a、-OC 1-4卤代烃基和CN； 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 14在每种情况下独立地选自由以下组成的组：含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环各自独立可任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-C(＝O)R b、-C(＝O)OR a、-C(＝O)NR aR a、-C(＝NR a)NR aR a、-OC(＝O)R b、-OC(＝O)NR aR a、-OC 2-6烃基NR aR a、-OC 2-6烃基OR a、-SR a、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR aR a、-NR aR a、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、 -N(R a)C(＝O)NR aR a、-N(R a)C(＝NR a)NR aR a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR aR a、-NR aC 2-6烃基NR aR a、-NR aC 2-6烃基OR a、-C 1-6烃基NR aR a、-C 1-6烃基OR a、-C 1-6烃基N(R a)C(＝O)R b、-C 1-6烃基OC(＝O)R b、-C 1-6烃基C(＝O)NR aR a、-C 1-6烃基C(＝O)OR a和氧代； R 14 is in each case independently selected from the group consisting of saturated, partially saturated or unsaturated 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 are independently 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, -OR a , -OC 1-4 Halogenated hydrocarbon group, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC( =O)R b , -OC(=O)NR a R a , -OC 2-6 alkylNR a R a , -OC 2-6 alkyl OR a , -SR a , -S(=O)R b , -S(=O) 2 R b , -S(=O) 2 NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C( =O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O) 2 R b , -N(R a )S(=O) 2 NR a R a , -NR a C 2-6 alkylNR a R a , -NR a C 2-6 alkyl OR a , -C 1-6 Hydrocarbyl NR a R a , -C 1-6 hydrocarbyl OR a , -C 1-6 hydrocarbyl N(R a )C(=O)R b , -C 1-6 hydrocarbyl OC(=O)R b , -C 1-6 hydrocarbyl C(=O)NR a R a , -C 1-6 hydrocarbyl C(=O)OR a and oxo;
R a在每种情况下独立地为H或R b；并且 R a is independently H or R b at each occurrence; and
R b在每种情况下独立地为C 1-6烃基、苯基或苄基，其中所述烃基可任选被0、1、2或3个下列基团取代：卤素、-OH、-OC 1-4烃基、-NH 2、-NHC 1-4烃基、-OC(＝O)C 1-4烃基或-N(C 1-4烃基)C 1-4烃基；并且其中所述苯基和苄基可各自独立任选被0、1、2或3个下列基团取代：卤素、C 1-4烃基、C 1-3卤代烃基、-OH、-OC 1-4烃基、-NH 2、-NHC 1-4烃基、-OC(＝O)C 1-4烃基或-N(C 1-4烃基)C 1-4烃基。 Each occurrence of R is independently C 1-6 hydrocarbyl, phenyl or benzyl, wherein said hydrocarbyl may be optionally substituted by 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 hydrocarbyl, -NH 2 , -NHC 1-4 hydrocarbyl, -OC(=O)C 1-4 hydrocarbyl or -N(C 1-4 hydrocarbyl)C 1-4 hydrocarbyl; and wherein the phenyl and Benzyl groups can be independently and optionally substituted by 0, 1, 2 or 3 of the following groups: halogen, C 1-4 alkyl, C 1-3 halogenated hydrocarbon, -OH, -OC 1-4 alkyl, -NH 2 , -NHC 1-4 hydrocarbon group, -OC(=O)C 1-4 hydrocarbon group or -N(C 1-4 hydrocarbon group)C 1-4 hydrocarbon group.
在另一优选例中，其中所述通式(1)中，(a)当X 1、X 2、X 3和X 5为-CH＝，X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(1a)和式(1b)： In another preferred example, in the general formula (1), (a) when X 1 , X 2 , X 3 and X 5 are -CH=, X 4 is N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (1a) and formula (1b):
Figure PCTCN2022119392-appb-000004
Figure PCTCN2022119392-appb-000004
在另一优选例中，其中所述通式(1)中，(b)当X 1、X 2和X 5为-CH＝，X 3和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(2a)和式(2b)： In another preferred example, in the general formula (1), (b) when X 1 , X 2 and X 5 are -CH=, X 3 and X 4 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (2a) and formula (2b):
Figure PCTCN2022119392-appb-000005
Figure PCTCN2022119392-appb-000005
在另一优选例中，其中所述通式(1)中，(c)当X 1、X 3和X 5为-CH＝，X 2和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(3a)和式(3b)： In another preferred example, in the general formula (1), (c) when X 1 , X 3 and X 5 are -CH=, X 2 and X 4 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (3a) and formula (3b):
Figure PCTCN2022119392-appb-000006
Figure PCTCN2022119392-appb-000006
在另一优选例中，其中所述通式(1)中，(d)当X 2、X 3和X 5为-CH＝，X 1和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(4a)和式(4b)： In another preferred example, in the general formula (1), (d) when X 2 , X 3 and X 5 are -CH=, X 1 and X 4 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (4a) and formula (4b):
Figure PCTCN2022119392-appb-000007
Figure PCTCN2022119392-appb-000007
在另一优选例中，其中所述通式(1)中，(e)当X 1、X 2和X 4为-CH＝，X 3和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(5a)和式(5b)： In another preferred example, in the general formula (1), (e) when X 1 , X 2 and X 4 are -CH=, X 3 and X 5 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (5a) and formula (5b):
Figure PCTCN2022119392-appb-000008
Figure PCTCN2022119392-appb-000008
在另一优选例中，其中所述通式(1)中，(f)当X 1、X 3和X 4为-CH＝，X 2和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(6a)和式(6b)： In another preferred example, in the general formula (1), (f) when X 1 , X 3 and X 4 are -CH=, X 2 and X 5 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (6a) and formula (6b):
Figure PCTCN2022119392-appb-000009
Figure PCTCN2022119392-appb-000009
在另一优选例中，其中所述通式(1)中，(g)当X 1和X 2为-CH＝，X 3、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(7a)和式(7b)： In another preferred example, in the general formula (1), (g) when X 1 and X 2 are -CH=, X 3 , X 4 and X 5 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (7a) and formula (7b):
Figure PCTCN2022119392-appb-000010
Figure PCTCN2022119392-appb-000010
在另一优选例中，其中所述通式(1)中，(h)当X 1和X 3为-CH＝，X 2、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(8a)和式(8b)： In another preferred example, in the general formula (1), (h) when X 1 and X 3 are -CH=, X 2 , X 4 and X 5 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (8a) and formula (8b):
Figure PCTCN2022119392-appb-000011
Figure PCTCN2022119392-appb-000011
在另一优选例中，其中所述通式(1)中，(i)当X 1、X 2、X 3和X 4为-CH＝，X 5为N，和L为-(C＝O)-NR 9-*时，具有式(9a)： In another preferred example, in the general formula (1), (i) when X 1 , X 2 , X 3 and X 4 are -CH=, X 5 is N, and L is -(C=O )-NR 9 -*, has formula (9a):
Figure PCTCN2022119392-appb-000012
Figure PCTCN2022119392-appb-000012
在另一优选例中，其中所述通式(1)中，(j)当X 1、X 2和X 3为-CH＝，X 4和X 5为N，和L为-(C＝O)-NR 9-*时，具有式(10a)： In another preferred example, in the general formula (1), (j) when X 1 , X 2 and X 3 are -CH=, X 4 and X 5 are N, and L is -(C=O )-NR 9 -*, has formula (10a):
Figure PCTCN2022119392-appb-000013
Figure PCTCN2022119392-appb-000013
在另一优选例中，其中所述通式(1)中，(k)当X 2、X 3、X 4和X 5为-CH＝，X 1为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(11a)和式(11b)： In another preferred example, in the general formula (1), (k) when X 2 , X 3 , X 4 and X 5 are -CH=, X 1 is N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (11a) and formula (11b):
Figure PCTCN2022119392-appb-000014
Figure PCTCN2022119392-appb-000014
在另一优选例中，其中所述通式(1)中，(l)当X 2、X 3、和X 4为-CH＝，X 1和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(12a)和式(12b)： In another preferred example, in the general formula (1), (l) when X 2 , X 3 , and X 4 are -CH=, X 1 and X 5 are N, and L is -(C= O)-NR 9 -* or -NR 9 -(C=O)-*, has formula (12a) and formula (12b):
Figure PCTCN2022119392-appb-000015
Figure PCTCN2022119392-appb-000015
在另一优选例中，其中所述通式(1)中，(m)当X 2和X 3为-CH＝，X 1、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(13a)和式(13b)： In another preferred example, in the general formula (1), (m) when X 2 and X 3 are -CH=, X 1 , X 4 and X 5 are N, and L is -(C=O )-NR 9 -* or -NR 9 -(C=O)-*, has formula (13a) and formula (13b):
Figure PCTCN2022119392-appb-000016
Figure PCTCN2022119392-appb-000016
在另一优选例中，其中所述通式(1)中，R 9为H、甲基或乙基，优选为H。 In another preferred example, in the general formula (1), R 9 is H, methyl or ethyl, preferably H.
在另一优选例中，其中所述通式(1)中，其中R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立为H、卤素、C 1-6烃基或C 1-4卤代烃基；并且R 13a和R 13b对中的R 13a和R 13b与它们各自连接的碳原子可以组合形成螺接到R 8环的饱和3元、4元或5元单环；其中所述环含有0、1、2或3个N原子和0、1或2个选自O和S的原子；优选，R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立为H、甲基或乙基；并且R 13a和R 13b对中的R 13a和R 13b与它们各自连接的碳原子可以组合形成螺接到R 8环的环丙基、环丁基或环戊基环。 In another preferred embodiment, in the general formula (1), wherein 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 of R 13a and R 13b and their respective The attached carbon atoms may combine to form a cyclopropyl, cyclobutyl or cyclopentyl ring spiro to the R ring .
在另一优选例中，其中所述通式(1)中，结构单元
Figure PCTCN2022119392-appb-000017
为：
Figure PCTCN2022119392-appb-000018
优选为
Figure PCTCN2022119392-appb-000019
In another preferred example, in the general formula (1), the structural unit
Figure PCTCN2022119392-appb-000017
for:
Figure PCTCN2022119392-appb-000018
preferably
Figure PCTCN2022119392-appb-000019
在另一优选例中，其中所述通式(1)中，其中Z为化学键、-NH-、-NHSO 2-、-SO 2NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-(C＝O)-、-(C＝O)NH-或-NH(C＝O)-。 In another preferred example, in the general formula (1), wherein Z is a chemical bond, -NH-, -NHSO 2 -, -SO 2 NH-, -S(=O)(=NH)-, - S-, -S(=O)-, -SO2- , -(C=O)-, -(C=O)NH- or -NH(C=O)-.
在另一优选例中，其中所述通式(1)中，其中R 10选自(a)H；或(b)C 1-6烃基，所述烃基可任选被0、1、2或3个下列基团取代：F、Cl、Br、-OH或-OCH 3；或(c)当所述基团-Z-R 10为-N＝S(＝O)-(R 10) 2，其中所述两个R 10可以与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环，其被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-C 1-6烃基OH、-OH、-OCH 3、-NH 2或氧代。 In another preference, wherein in the general formula (1), wherein R 10 is selected from (a) H; or (b) C 1-6 hydrocarbon group, the hydrocarbon group can be optionally replaced by 0, 1, 2 or 3 of the following groups are substituted: F, Cl, Br, -OH or -OCH 3 ; or (c) when the group -ZR 10 is -N=S(=O)-(R 10 ) 2 , wherein The two R 10 may be combined with their respective attached sulfur atoms to form a saturated, partially saturated or unsaturated compound 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 monocyclic ring, which is substituted by 0, 1, 2 or 3 groups selected from: F, Cl, Br, C 1-6 hydrocarbon group, C 1- 4 halogenated hydrocarbon group, -C 1-6 hydrocarbon group OH, -OH, -OCH 3 , -NH 2 or oxo.
在另一优选例中，其中所述通式(1)中，其中R 1为-CN或基团-Z-R 10，其中Z为化学键、-NH-、-NHSO 2-、-SO 2NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-(C＝O)-、-(C＝O)NH-或-NH(C＝O)-；并且R 10选自： In another preferred example, in the general formula (1), wherein R 1 is -CN or a group -ZR 10 , wherein Z is a chemical bond, -NH-, -NHSO 2 -, -SO 2 NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(C=O)-, -(C=O)NH- or -NH(C =0)-; and R is selected from:
(a)H；(a) H;
(b)环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、氮杂环丁烷基、咪 唑基、吗啉基、吡咯烷基、哌嗪基、
Figure PCTCN2022119392-appb-000020
Figure PCTCN2022119392-appb-000021
并且其中每个所述环可各自独立任选被0、1、2或3个下列基团取代：OH、F、甲基、-CH 2OH、-C(＝O)OCH 3、-C(＝O)OC(CH 3) 3、NH 2、CN和氧代；优选为氧杂环丁烷基、环丙基；或 (b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidine base, piperazinyl,
Figure PCTCN2022119392-appb-000020
Figure PCTCN2022119392-appb-000021
And wherein each of said rings can be independently and optionally substituted with 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH 2 OH, -C(=O)OCH 3 , -C( =O)OC(CH 3 ) 3 , NH 2 , CN and oxo; preferably oxetanyl, cyclopropyl; or
(c)被0、1、2或3个OH、F、-C(＝O)OCH 3、-NH 2、-NH(CH 3)或-N(CH 3) 2取代的C 1-6烃基；优选为被0、1、2或3个OH基团取代的C 1-6烃基；更优选为被1个OH基团取代的C 1-6烃基。 (c) C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH, F, -C(=O)OCH 3 , -NH 2 , -NH(CH 3 ) or -N(CH 3 ) 2 ; preferably a C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH groups; more preferably a C 1-6 hydrocarbon group substituted by 1 OH group.
在另一优选例中，其中所述通式(1)中，其中所述基团-Z-R 10为-N＝S(＝O)-(R 10) 2，其中两个R 10对可以与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环；优选基团-Z-R 10选自：
Figure PCTCN2022119392-appb-000022
Figure PCTCN2022119392-appb-000023
In another preferred example, in the general formula (1), wherein the group -ZR 10 is -N=S(=O)-(R 10 ) 2 , wherein two pairs of R 10 can be combined with their The sulfur atoms attached to each combine to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S membered monocyclic ring; preferred group -ZR 10 is selected from:
Figure PCTCN2022119392-appb-000022
Figure PCTCN2022119392-appb-000023
在另一优选例中，其中所述通式(1)中，其中R 1为基团-Z-R 10，其中Z为-NHSO 2-或-SO 2NH-；并且R 10为氧杂环丁烷基、环丙基，或R 10为被0、1、2或3个OH基团取代的C 1-6烃基；优选，R 1为基团-Z-R 10，其中Z为-NHSO 2-或-SO 2NH-，并且R 10为-CH 2-CH 2-OH或-CH(CH 3)-CH 2-OH；更优选Z为-NHSO 2-，并且R 10为-CH 2-CH 2-OH。 In another preferred example, in the general formula (1), wherein 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.
在另一优选例中，其中所述通式(1)中，其中R 2为卤素或基团-Y-R 12，其中Y为化学键、-NH-、-NH-(CH 2) 0-4-或-O-(CH 2) 0-4-；并且R 12为含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环可各自独立任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OH、-OC 1-4卤代烃基、CN、R 14和氧代；或R 12为C 1-6烃基，所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、-OH、-OC 1-4卤代烃基或CN。 In another preferred example, in the general formula (1), wherein 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 Hydrocarbyl, CN, R 14 and oxo; or R 12 is C 1-6 hydrocarbyl, which can be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br , -OH, -OC 1-4 halohydrocarbyl or CN.
在另一优选例中，其中所述通式(1)中，其中R 2为饱和5元或6元单环，其中每个所述环含有0、1或2个N原子和0或1个O原子，并且其中每个所述环被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OH、-OC 1-4卤代烃基、CN、R 14和氧代。 In another preference, wherein in the general formula (1), wherein 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.
在另一优选例中，其中所述通式(1)中，其中R 2为(a)卤素；(b)基团-Y-R 12，其中Y为化学键；并且R 12为吗啉基、哌啶基、氮杂环丁烷基、吡咯烷基、环丙基、环丁基、环戊基、环己基、哌嗪基、四氢呋喃基、
Figure PCTCN2022119392-appb-000024
Figure PCTCN2022119392-appb-000025
Figure PCTCN2022119392-appb-000026
其中每个所述环被选自以下的0、1、2或3个基团取代：F、Cl、Br、甲基、CF 3、-OH、-OCHF 2、CN和氧代；或(c)基团-Y-R 12，其中Y为-NH-、-O-、-O-(CH 2)-、-O-(CH 2)-(CH 2)-或-O-(CH 2)-(CH 2)-(CH 2)-，并且其中R 12为
Figure PCTCN2022119392-appb-000027
Figure PCTCN2022119392-appb-000028
或R 12为C 1-6烃基，所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、甲基、CF3、-OH或CN。 In another preferred example, in the general formula (1), wherein 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,
Figure PCTCN2022119392-appb-000024
Figure PCTCN2022119392-appb-000025
Figure PCTCN2022119392-appb-000026
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 )-, and wherein R 12 is
Figure PCTCN2022119392-appb-000027
Figure PCTCN2022119392-appb-000028
Or R 12 is C 1-6 hydrocarbon group, which can be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF 3 , -OH or CN.
在另一优选例中，其中所述通式(1)中，其中R 2为吗啉基或哌啶基，所述吗啉基和哌啶基可任选被0、1、2或3个下列基团取代：F、Cl、Br、甲基、CF 3、-OH、-OCHF 2和CN。 In another preference, wherein in the general formula (1), wherein R 2 is morpholinyl or piperidinyl, the morpholinyl and piperidinyl can be optionally replaced by 0, 1, 2 or 3 The following groups substituted: F, Cl, Br, methyl, CF3 , -OH, -OCHF2 and CN.
在另一优选例中，其中所述通式(1)中，其中R 2为被1、2或3个氟基团取代的哌啶基。 In another preferred embodiment, in the general formula (1), wherein R 2 is piperidinyl substituted by 1, 2 or 3 fluorine groups.
在另一优选例中，其中所述通式(1)中，其中R 2为：
Figure PCTCN2022119392-appb-000029
In another preference, wherein in the general formula (1), wherein R 2 is:
Figure PCTCN2022119392-appb-000029
在另一优选例中，其中所述通式(1)中，其中R 2为被1、2或3个甲基基团取代的吗啉基。 In another preferred example, in the general formula (1), wherein R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.
在另一优选例中，其中所述通式(1)中，其中R 2为
Figure PCTCN2022119392-appb-000030
Figure PCTCN2022119392-appb-000031
In another preferred embodiment, in the general formula (1), wherein R 2 is
Figure PCTCN2022119392-appb-000030
Figure PCTCN2022119392-appb-000031
在另一优选例中，其中所述通式(1)中，其中R 10选自环丙基、环丁基、环戊基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基或1,3,4-氧杂噻嗪烷基。 In another preference, wherein in the general formula (1), wherein R is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuryl or 1,3,4-oxathiazinyl.
在另一优选例中，其中所述通式(1)中，其中R 3为H。 In another preferred example, in the general formula (1), wherein R 3 is H.
在另一优选例中，其中所述通式(1)中，其中R 4选自(a)H；(b)被0、1、2或3个OH基团取代的C 1-6烃基；或(c)环丙基；或(d)F；R 4优选为H、F或甲基；R 4更优选为H。 In another preferred example, in the general formula (1), wherein 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.
在另一优选例中，其中所述通式(1)中，其中R 5为H或F，优选为H。 In another preferred example, in the general formula (1), wherein R 5 is H or F, preferably H.
在另一优选例中，其中所述通式(1)中，其中R 6为H或F，优选为H。 In another preferred example, in the general formula (1), wherein R 6 is H or F, preferably H.
在另一优选例中，其中所述通式(1)中，其中R 7为H。 In another preferred example, in the general formula (1), wherein R 7 is H.
在另一优选例中，其中所述通式(1)中，其中R 15为H或F，优选为H。 In another preferred example, in the general formula (1), wherein R 15 is H or F, preferably H.
在本发明的各种不同实施方式中，通式(1)化合物具有以下结构之一：In various embodiments of the present invention, the compound of general formula (1) has one of the following structures:
Figure PCTCN2022119392-appb-000032
Figure PCTCN2022119392-appb-000032
Figure PCTCN2022119392-appb-000033
Figure PCTCN2022119392-appb-000033
Figure PCTCN2022119392-appb-000034
Figure PCTCN2022119392-appb-000034
Figure PCTCN2022119392-appb-000035
Figure PCTCN2022119392-appb-000035
Figure PCTCN2022119392-appb-000036
Figure PCTCN2022119392-appb-000036
Figure PCTCN2022119392-appb-000037
Figure PCTCN2022119392-appb-000037
Figure PCTCN2022119392-appb-000038
Figure PCTCN2022119392-appb-000038
Figure PCTCN2022119392-appb-000039
Figure PCTCN2022119392-appb-000039
Figure PCTCN2022119392-appb-000040
Figure PCTCN2022119392-appb-000040
Figure PCTCN2022119392-appb-000041
Figure PCTCN2022119392-appb-000041
Figure PCTCN2022119392-appb-000042
Figure PCTCN2022119392-appb-000042
Figure PCTCN2022119392-appb-000043
Figure PCTCN2022119392-appb-000043
Figure PCTCN2022119392-appb-000044
Figure PCTCN2022119392-appb-000044
Figure PCTCN2022119392-appb-000045
Figure PCTCN2022119392-appb-000045
Figure PCTCN2022119392-appb-000046
Figure PCTCN2022119392-appb-000046
Figure PCTCN2022119392-appb-000047
Figure PCTCN2022119392-appb-000047
Figure PCTCN2022119392-appb-000048
Figure PCTCN2022119392-appb-000048
Figure PCTCN2022119392-appb-000049
Figure PCTCN2022119392-appb-000049
Figure PCTCN2022119392-appb-000050
Figure PCTCN2022119392-appb-000050
Figure PCTCN2022119392-appb-000051
Figure PCTCN2022119392-appb-000051
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。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.
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与KIF18A蛋白相关疾病的药物中的用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。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. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
本发明的再一个目的还提供治疗、调节或预防与KIF18A蛋白介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。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.
通过合成和仔细研究了多类涉及具有KIF18A蛋白抑制作用的新化合物，发明人发现在通式(1)化合物中，化合物意外地具有很强的KIF18A蛋白抑制活性。By synthesizing and carefully studying a variety of new compounds related to the KIF18A protein inhibitory effect, the inventors found that among the compounds of the general formula (1), the compound unexpectedly has a strong KIF18A protein inhibitory activity.
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
化合物的合成compound synthesis
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 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.
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1、2、3或4制备：In one aspect, 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. In one aspect, 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:
一般反应流程1General reaction scheme 1
Figure PCTCN2022119392-appb-000052
Figure PCTCN2022119392-appb-000052
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 3、R 8、X 1、X 2、X 3、X 4和X 5如上文中所定义；W 1表示氟、氯、溴或碘；H表示氢；N表示氮；R 1试剂例如(1)1-甲基环丙烷-1-磺酰胺、(2)3-甲基氧杂环丁烷-3-胺、(3)叔丁基3-巯基氮杂环丁烷-1-甲酸酯、(4)2-氨磺酰基丙酸乙酯、(5)2-羟基丙烷-1-磺酰胺、(6)2-羟基乙烷-1-磺酰胺、(7)碘乙酸乙酯、(8)2-巯基丙烷-1-醇、(9)2-巯基-2-甲基丙烷-1-醇、(10)2-氨基乙-1-醇或(11)环丙烷硫醇。如一般反应流程1所示，化合物1-1和化合物1-2发生酰胺化反应生成化合物1-3，化合物1-3与R 1试剂1-4反应生成化合物1-5。 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-ol or (11) cyclopropanethiol. As shown in general reaction scheme 1, compound 1-1 and compound 1-2 undergo amidation reaction to generate compound 1-3, and compound 1-3 reacts with R 1 reagent 1-4 to generate compound 1-5.
一般反应流程2General reaction scheme 2
Figure PCTCN2022119392-appb-000053
Figure PCTCN2022119392-appb-000053
通式(1)化合物的实施方式可根据一般反应流程2制备，其中R 1、R 2、R 3、R 8、X 1、X 2、X 3、X 4和X 5如上文中所定义；W 1表示氟、氯、溴或碘，H表示氢；N表示氮；R 1试剂例如(1)1-甲基环丙烷-1-磺酰胺、(2)3-甲基氧杂环丁烷-3-胺、(3)叔丁基3-巯基氮杂环丁烷-1-甲酸酯、(4)2-氨磺酰基丙酸乙酯、(5)2-羟基丙烷-1-磺酰胺、(6)2-羟基乙烷-1-磺酰胺、(7)碘乙酸乙酯、(8)2-巯基丙烷-1-醇、(9)2-巯基-2-甲基丙烷-1-醇、(10)2-氨基乙-1-醇或(11)环丙烷硫醇。如一般反应流程2所示，化合物2-1和化合物2-2发生酰胺化反应生成化合物2-3，化合物2-3与R 1试剂2-4反应生成化合物2-5。 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-ol or (11) cyclopropanethiol. As shown in general reaction scheme 2, compound 2-1 and compound 2-2 undergo amidation reaction to generate compound 2-3, and compound 2-3 reacts with R 1 reagent 2-4 to generate compound 2-5.
一般反应流程3General reaction scheme 3
Figure PCTCN2022119392-appb-000054
Figure PCTCN2022119392-appb-000054
通式(1)化合物的实施方式可根据一般反应流程3制备，其中R 1、R 2、R 3、R 8、X 1、X 2、X 3、X 4和X 5如上文中所定义；W 1表示氟、氯、溴或碘；H表示氢；N表示氮；P 1为酯基的保护基；R 1试剂例如(1)1-甲基环丙烷-1-磺酰胺、(2)3-甲基氧杂环丁烷-3-胺、(3)叔丁基3-巯基氮杂环丁烷-1-甲酸酯、(4)2-氨磺酰基丙酸乙酯、(5)2-羟基丙烷-1-磺酰胺、(6)2-羟基乙烷-1-磺酰胺、(7)碘乙酸乙酯、(8)2-巯基丙烷-1-醇、(9)2-巯基-2-甲基丙烷-1-醇、(10)2-氨基乙-1-醇或(11)环丙烷硫醇。如一般反应流程3所示，化合物3-1与R 1试剂3-2反应生成化合物3-3，化合物3-3脱去酯基保护基P 1得到化合物3-4，化合物3-4和化合物3-5发生酰胺化反应生成化合物3-6。 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-methylpropan-1-ol, (10) 2-aminoethan-1-ol or (11) cyclopropanethiol. As shown in general reaction scheme 3, 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.
一般反应流程4General reaction scheme 4
Figure PCTCN2022119392-appb-000055
Figure PCTCN2022119392-appb-000055
通式(1)化合物的实施方式可根据一般反应流程4制备，其中R 1、R 2、R 3、R 8、X 1、X 2、X 3、X 4和X 5如上文中所定义；W 1表示氟、氯、溴或碘；H表示氢；N表示氮；P 2为胺基的保护基；R 1试剂例如(1)1-甲基环丙烷-1-磺酰胺、(2)3-甲基氧杂环丁烷-3-胺、(3)叔丁基3-巯基氮杂环丁烷-1-甲酸酯、(4)2-氨磺酰基丙酸乙酯、(5)2-羟基丙烷-1-磺酰胺、(6)2-羟基乙烷-1-磺酰胺、(7)碘乙酸乙酯、(8)2-巯基丙烷-1-醇、(9)2-巯基-2-甲基丙烷-1-醇、(10)2-氨基乙-1-醇或(11)环丙烷硫醇。如一般反应流程4所示，化合物4-1与R 1试剂4-2反应生成化合物4-3，化合物4-3脱去胺基保护基P 2得到化合物4-4，化合物4-4和化合物4-5发生酰胺化反应生成化合物4-6。 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) cyclopropanethiol. As shown in general reaction scheme 4, compound 4-1 reacts with R reagent 4-2 to generate compound 4-3, and compound 4-3 removes the amino protecting group P to obtain compound 4-4, compound 4-4 and compound 4-5 undergoes amidation reaction to generate compound 4-6.
化合物的进一步形式Further forms of compounds
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"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.
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、碳酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。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. In some specific aspects, 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.
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的， 溶剂化形式被认为相当于非溶剂化形式。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. For example, 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. Furthermore, 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.
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, 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.
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, 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.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). For another example, 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.
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.
除非另有规定，“C α-β烃基”意指在支链或线性关系中包含最小α个和最大β个碳原子的烃基，其中α和β表示整数。在该部分中描述的烃基还可以含有一个或两个双键或三键。C 0烃基的指定表示直连键。C 1-6烃基的实例包括但不限于以下：
Figure PCTCN2022119392-appb-000056
Unless otherwise specified, "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:
Figure PCTCN2022119392-appb-000056
除非另有规定，“C α-β卤代烃基”意指如上所述的烃基，其中，任意数量(至少一个)的附接到烃基链的氢原子被F、Cl、Br或I替代。 Unless otherwise specified, "C α-β 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.
除非另有规定，“氧代”和“硫代”分别表示＝O(如羰基)和＝S(如硫代羰基)。Unless otherwise specified, "oxo" and "thioxo" represent =O (eg, carbonyl) and =S (eg, thiocarbonyl), respectively.
除非另有规定，“卤代”或“卤素”意指选自F、Cl、Br和I的卤素原子。"Halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I, unless otherwise specified.
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。 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. As used herein, "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.
除非另有规定，“双环”意指具有两个连接环的基团。双环可以为碳环(所有环原子为碳原子)或杂 环(除了碳原子之外，环原子包括例如1、2或3个杂原子，例如N、O或S)。这两个环都可以是脂肪族的(例如萘烷和降冰片烷)，或可以是芳香族(例如萘)，或脂肪族和芳香族的组合(例如四氢化萘)。双环包括(a)螺环化合物，其中两个环只共享一个单原子(螺原子，其通常为季碳)。螺环化合物的实例包括但不限于：
Figure PCTCN2022119392-appb-000057
Unless otherwise specified, "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:
Figure PCTCN2022119392-appb-000057
(b)稠合的双环化合物，其中两个环共享两个相邻原子。即环共享一个共价键，即桥头原子直接连接(例如α-崖柏烯和萘烷)。稠合的双环的实例包括但不限于：(b) Fused bicyclic compounds in which the two rings share two adjacent atoms. That is, the rings share a covalent bond, ie the bridgehead atoms are directly connected (eg α-thujene and decalin). Examples of fused bicyclic rings include, but are not limited to:
Figure PCTCN2022119392-appb-000058
Figure PCTCN2022119392-appb-000058
和(c)桥联的双环化合物，其中两个环共享三个或更多个原子，并通过包含至少一个原子的桥将两个桥头原子隔开。例如，降冰片烷，也称为双环[2.2.1]庚烷，可以被认为是一对环戊烷环，每个环共享它们的五个碳原子中的三个。桥联的双环的实例包括但不限于：and (c) 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. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged double rings include, but are not limited to:
Figure PCTCN2022119392-appb-000059
Figure PCTCN2022119392-appb-000059
除非另有规定，“碳环”或“碳环的”意指本身或与其他术语组合包含的环，表示“C α-β烃基”的环状形式。碳环的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等。 Unless otherwise specified, "carbocycle" or "carbocyclic" means a ring encompassed by itself or in combination with other terms, denoting a cyclic version of "C alpha-beta hydrocarbyl". Examples of 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.
除非另有规定，“杂环”或“杂环的”意指包含至少一个碳原子和至少一个选自N、O和S的其他原子的环。可在权利要求书中出现的杂环的实例包括但不限于以下："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. Examples of heterocycles that may appear in the claims include, but are not limited to the following:
Figure PCTCN2022119392-appb-000060
Figure PCTCN2022119392-appb-000060
Figure PCTCN2022119392-appb-000061
Figure PCTCN2022119392-appb-000061
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
“饱和的、部分饱和的或不饱和的”包括被氢饱和的取代基、完全被氢不饱和的取代基和部分被氢饱和的取代基。"Saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents fully unsaturated with hydrogen and substituents partially saturated with hydrogen.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.
当一个基团的数量为0时，比如-N(C 0烃基)-C 0-4烃基-，表示该连接基团为-NH-C 0-4烃基-。 When the number of a group is 0, such as -N(C 0 alkyl)-C 0-4 alkyl-, it means that the linking group is -NH-C 0-4 alkyl-.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为化学键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a chemical bond.
除非另有说明，用楔形实线键
Figure PCTCN2022119392-appb-000062
和楔形虚线键
Figure PCTCN2022119392-appb-000063
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022119392-appb-000064
和直形虚线键
Figure PCTCN2022119392-appb-000065
表示立体中心的相对构型，用波浪线
Figure PCTCN2022119392-appb-000066
表示楔形实线键
Figure PCTCN2022119392-appb-000067
或楔形虚线键
Figure PCTCN2022119392-appb-000068
或用波浪线
Figure PCTCN2022119392-appb-000069
表示直形实线键
Figure PCTCN2022119392-appb-000070
或直形虚线键
Figure PCTCN2022119392-appb-000071
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022119392-appb-000062
and dotted wedge keys
Figure PCTCN2022119392-appb-000063
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022119392-appb-000064
and straight dashed keys
Figure PCTCN2022119392-appb-000065
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022119392-appb-000066
Indicates wedge-shaped solid-line bond
Figure PCTCN2022119392-appb-000067
or dotted wedge key
Figure PCTCN2022119392-appb-000068
or with tilde
Figure PCTCN2022119392-appb-000069
Indicates a straight solid line key
Figure PCTCN2022119392-appb-000070
or straight dotted key
Figure PCTCN2022119392-appb-000071
特定药学及医学术语Certain pharmaceutical and medical terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The term "treatment", "course of treatment" or "therapy" as used herein 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. As used herein, 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.
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"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.
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.
治疗用途therapeutic use
本发明提供了使用本发明通式(1)化合物或药物组合物通常可用于抑制KIF18A蛋白，因此可用于治疗与KIF18A蛋白活性相关的一种或多种病症。因此，在某些实施方式中，本发明提供了用于治疗KIF18A蛋白介导的病症的方法，所述方法包括向有需要的患者施用本发明化合物、或其药学上可接受的组合物的步骤。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 .
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述 的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症由KIF18A蛋白介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于，血液恶性肿瘤(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓异常增生综合症和骨髓增生姓综合症)和实体瘤(癌例如***、乳腺、肺、结肠、胰腺、肾、卵巢以及软组织癌和骨肉瘤，以及间质瘤)等。In some embodiments, a method for treating cancer is provided, the method 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. In some embodiments, the cancer is mediated by the KIF18A protein. In other embodiments, 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.
给药途径Route of administration
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。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 . Wherein, "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.
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022119392-appb-000072
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "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
Figure PCTCN2022119392-appb-000072
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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. 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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和 香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。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.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, 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. Of course, 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.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.
具体实施方式Detailed ways
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions will be described in detail, so that the content of the present invention will become very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all the examples, 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
本发明采用下述缩略词：(Boc) 2O代表二碳酸二叔丁酯；CDCl 3代表氘代氯仿；Cs 2CO 3代表碳酸铯；CuI代表碘化亚铜；EtOAc代表乙酸乙酯；Hexane代表正己烷；HPLC代表高效液相色谱；MeCN代表乙腈；DCE代表1,2-二氯乙烷；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；1,4-Dioxane代表1,4-二氧六环；DMF代表N,N-二甲基甲酰胺；DMAP代表4-(二甲氨基)吡啶；DMSO代表二甲亚砜；hr代表小时；HATU代表N-[(二甲基氨基)-1H-1,2,3-***-[4,5-b]吡啶-1-亚甲基]-N-甲基甲铵六氟磷酸酯-N-氧化物；IPA代表异丙醇；min代表分钟；K 2CO 3代表碳酸钾；KOAc代表醋酸钾；K 3PO 4代表磷酸钾；LiBH 4代表硼氢化锂；min代表分钟；MeOH代表甲醇；MS代表质谱；NaOH代表氢氧化钠；NMR代表核磁共振；Pd/C代表钯碳；Pd(PPh 3) 4代表四三苯基膦钯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯(0)；PE代表石油醚；RuPhos Pd G 3代表(2-二环己基膦基-2′6′-二异丙氧基-11′-联苯)[2-(2′-氨基-11′-联苯基)]钯(II)甲磺酸盐；Sarcosine代表肌氨酸；TFA代表三氟乙酸；T 3P代表1-丙基磷酸酐；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；TLC代表薄层色谱；XPhos代表2-二环己基磷- 2′,4′,6′-三异丙基联苯。 The present invention adopts the following abbreviations: (Boc) 2 O represents di-tert-butyl dicarbonate; CDCl 3 represents deuterated chloroform; Cs 2 CO 3 represents cesium carbonate; CuI represents cuprous iodide; EtOAc represents ethyl acetate; Hexane stands for n-hexane; HPLC stands for high performance liquid chromatography; MeCN stands for acetonitrile; DCE stands for 1,2-dichloroethane; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; 1,4-Dioxane stands for 1 ,4-dioxane; DMF stands for N,N-dimethylformamide; DMAP stands for 4-(dimethylamino)pyridine; DMSO stands for dimethylsulfoxide; hr stands for hour; HATU stands for N-[(dimethyl Amino)-1H-1,2,3-triazole-[4,5-b]pyridine-1-methylene]-N-methylmethylammonium hexafluorophosphate-N-oxide; IPA stands for iso Propanol; min stands for minute; K2CO3 stands for potassium carbonate; KOAc stands for potassium acetate; K3PO4 stands for potassium phosphate ; LiBH4 stands for lithium borohydride; min stands for minute; MeOH stands for methanol; MS stands for mass spectrum; NaOH stands for hydrogen Sodium oxide; NMR stands for nuclear magnetic resonance; Pd/C stands for palladium on carbon; Pd(PPh 3 ) 4 stands for tetrakistriphenylphosphine palladium; Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium(0); PE stands for petroleum ether; RuPhos Pd G 3 stands for (2-dicyclohexylphosphino-2′6′-diisopropoxy-11′-biphenyl)[2-(2′-amino-11′-biphenyl base)] palladium(II) methanesulfonate; Sarcosine represents sarcosine; TFA represents trifluoroacetic acid; T 3 P represents 1-propyl phosphoric anhydride; XantPhos represents 4,5-bisdiphenylphosphine-9,9 - dimethylxanthene; TLC stands for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.
实施例1 化合物1的合成The synthesis of embodiment 1 compound 1
Figure PCTCN2022119392-appb-000073
Figure PCTCN2022119392-appb-000073
步骤1：化合物int_1-2的合成:Step 1: Synthesis of compound int_1-2:
Figure PCTCN2022119392-appb-000074
Figure PCTCN2022119392-appb-000074
将int_1-1(15g,56.3mmol)溶于甲醇(150mL)中，加入浓硫酸(2.5mL)，升温至80℃反应4小时，LC-MS监测显示反应结束。反应液减压浓缩得到粗产物，粗产物溶于乙酸乙酯，有机相用饱和的碳酸氢钠溶液洗涤后，再用饱和食盐水洗涤，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到白色固体(14g,收率：89％)，可直接用于下一步反应。Dissolve int_1-1 (15g, 56.3mmol) in methanol (150mL), add concentrated sulfuric acid (2.5mL), heat up to 80°C and react for 4 hours. LC-MS monitoring shows that the reaction is complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution, and then with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a white solid (14 g, yield: 89%), which could be directly used in the next reaction.
ESI-MS m/z:281[M+H] +。 ESI-MS m/z: 281 [M+H] + .
步骤2：化合物int_1-4的合成:Step 2: Synthesis of compound int_1-4:
Figure PCTCN2022119392-appb-000075
Figure PCTCN2022119392-appb-000075
将int_1-2(14g,49.9mmol)溶于DMSO(100mL)中，加入碳酸铯(23.4g,71.7mmol)，int_1-3(6.98g,62.8mmol)，升温至90℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释， 水相用乙酸乙酯萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物经柱层析(SiO 2,EtOAc:Hexane＝1:1)得到目标产物(16.3g,收率：88％)。 Dissolve int_1-2 (14g, 49.9mmol) in DMSO (100mL), add cesium carbonate (23.4g, 71.7mmol), int_1-3 (6.98g, 62.8mmol), heat up to 90°C for 24 hours, LC- MS monitoring showed the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO 2 , EtOAc:Hexane=1:1) to obtain the target product (16.3 g, yield: 88%).
ESI-MS m/z:372[M+H] +。 ESI-MS m/z: 372 [M+H] + .
步骤3：化合物int_1-5的合成:Step 3: Synthesis of compound int_1-5:
Figure PCTCN2022119392-appb-000076
Figure PCTCN2022119392-appb-000076
将int_1-4(16.3g,43.9mmol)溶于甲醇(100mL)和水(10mL)的混合溶剂中，室温下加入氢氧化锂(2.1g,87.8mmol)，室温搅拌反应6小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(17g,粗产物)。粗产物可直接用于下一步反应。Dissolve int_1-4 (16.3g, 43.9mmol) in a mixed solvent of methanol (100mL) and water (10mL), add lithium hydroxide (2.1g, 87.8mmol) at room temperature, and stir at room temperature for 6 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (17 g, crude product). The crude product can be directly used in the next reaction.
ESI-MS m/z:358[M+H] +。 ESI-MS m/z: 358 [M+H] + .
步骤4：化合物int_1-7的合成:Step 4: Synthesis of compound int_1-7:
Figure PCTCN2022119392-appb-000077
Figure PCTCN2022119392-appb-000077
将int_1-5(100mg,0.3mmol)溶于DCM(10mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_1-6(71mg,0.3mmol)溶于THF(5mL)中，加入NaH(72mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入100mL水淬灭反应，用DCM萃取(100mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化(EtOAc:Hexane＝1:5)，得到产物(130mg,收率：80.7％)。 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. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to quench the reaction, extracted with DCM (100 mL*3), the organic phases were combined and dried with Na 2 SO 4 , the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by a silica gel column (EtOAc: Hexane=1:5) to obtain the product (130 mg, yield: 80.7%).
ESI-MS m/z:578[M+H] +。 ESI-MS m/z: 578 [M+H] + .
步骤5：化合物1的合成:Step 5: Synthesis of compound 1:
Figure PCTCN2022119392-appb-000078
Figure PCTCN2022119392-appb-000078
将int_1-7(130mg,0.225mmol)，肌氨酸(10mg,0.113mmol)，碘化亚铜(22mg,0.113mmol)和磷酸钾(144mg,0.681mmol)，溶解在DMF(5mL)中，氩气置换三次，加入int_1-8(29mg,0.225mmol)，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(80mg,收率：62％)。Dissolve int_1-7 (130mg, 0.225mmol), sarcosine (10mg, 0.113mmol), cuprous iodide (22mg, 0.113mmol) and potassium phosphate (144mg, 0.681mmol) in DMF (5mL), argon The gas was replaced three times, int_1-8 (29mg, 0.225mmol) was added, 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 (80 mg, yield: 62%).
1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.49(d,J＝2.0Hz,1H),8.22(d,J＝2.1Hz,1H),7.76(d,J＝8.5Hz,1H),7.14(d,J＝2.1Hz,1H),7.01(dd,J＝8.5,2.0Hz,1H),3.74(t,J＝6.5Hz,2H),3.44–3.33(m,6H),2.95(t,J＝5.2Hz,4H),2.16(tt,J＝13.9,5.5Hz,4H),1.48(t,J＝5.1Hz,4H),0.32(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.89(s, 1H), 8.49(d, J=2.0Hz, 1H), 8.22(d, J=2.1Hz, 1H), 7.76(d, J=8.5 Hz, 1H), 7.14(d, J=2.1Hz, 1H), 7.01(dd, J=8.5, 2.0Hz, 1H), 3.74(t, J=6.5Hz, 2H), 3.44–3.33(m, 6H ), 2.95 (t, J = 5.2Hz, 4H), 2.16 (tt, J = 13.9, 5.5Hz, 4H), 1.48 (t, J = 5.1Hz, 4H), 0.32 (s, 4H).
ESI-MS m/z:575[M+H] +。 ESI-MS m/z: 575 [M+H] + .
实施例2 化合物65的合成The synthesis of embodiment 2 compound 65
Figure PCTCN2022119392-appb-000079
Figure PCTCN2022119392-appb-000079
步骤1：化合物int_65-3的合成:Step 1: Synthesis of compound int_65-3:
Figure PCTCN2022119392-appb-000080
Figure PCTCN2022119392-appb-000080
将int_65-1(10.3g,50mmol)溶于DMSO(100mL)中，加入碳酸铯(23.4g,71.7mmol)，int_65-2(6.98g,62.8mmol)，室温下反应12小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物经柱层析得到目标产物(12g,收率：85％)。Dissolve int_65-1 (10.3g, 50mmol) in DMSO (100mL), add cesium carbonate (23.4g, 71.7mmol), int_65-2 (6.98g, 62.8mmol), react at room temperature for 12 hours, LC-MS monitoring Indicates the end of the reaction. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography to obtain the target product (12 g, yield: 85%).
ESI-MS m/z:281[M+H] +。 ESI-MS m/z: 281 [M+H] + .
步骤2：化合物int_65-4的合成:Step 2: the synthesis of compound int_65-4:
Figure PCTCN2022119392-appb-000081
Figure PCTCN2022119392-appb-000081
将int_65-3(12.6g,45mmol)溶于甲醇(100mL)和水(10mL)的混合溶剂中，室温下加入氢氧化锂(2.1g,87.8mmol)，室温搅拌反应6小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(12g,粗产物)。粗产物可直接用于下一步反应。Dissolve int_65-3 (12.6g, 45mmol) in a mixed solvent of methanol (100mL) and water (10mL), add lithium hydroxide (2.1g, 87.8mmol) at room temperature, and stir at room temperature for 6 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (12 g, crude product). The crude product can be directly used in the next reaction.
ESI-MS m/z:267[M+H] +。 ESI-MS m/z: 267 [M+H] + .
步骤3：化合物int_65-5的合成:Step 3: Synthesis of compound int_65-5:
Figure PCTCN2022119392-appb-000082
Figure PCTCN2022119392-appb-000082
将int_65-4(50mg,0.188mmol)溶于DCM(10mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_1-6(45mg,0.188mmol)溶于THF(5mL)中，加入NaH(35mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相 并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(57mg,收率：62％)。 Dissolve int_65-4 (50 mg, 0.188 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 (45 mg, 0.188 mmol) in THF (5 mL), add 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (57 mg, yield: 62%).
ESI-MS m/z:578[M+H] +。 ESI-MS m/z: 578 [M+H] + .
步骤4：化合物65的合成:Step 4: Synthesis of compound 65:
Figure PCTCN2022119392-appb-000083
Figure PCTCN2022119392-appb-000083
将int_65-5(57mg,0.117mmol)，xantphos(7mg,0.0117mmol)，碳酸铯(57mg,0.175mmol)，Pd 2(dba) 3(11mg,0.011mmol)和int_65-6(22mg,0.175mmol)溶解在1,4-二氧六环(10mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(35mg,收率：50％)。 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%).
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.50(d,J＝2.0Hz,1H),8.06(d,J＝26.7Hz,2H),6.55(s,1H),3.75(t,J＝6.8Hz,2H),3.29(s,4H),3.16(d,J＝6.2Hz,4H),2.26–2.06(m,4H),1.37(t,J＝5.3Hz,6H),0.29(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ10.83(s, 1H), 8.50(d, J=2.0Hz, 1H), 8.06(d, J=26.7Hz, 2H), 6.55(s, 1H), 3.75(t, J=6.8Hz, 2H), 3.29(s, 4H), 3.16(d, J=6.2Hz, 4H), 2.26–2.06(m, 4H), 1.37(t, J=5.3Hz, 6H ), 0.29(s,4H).
ESI-MS m/z:576[M+H] +。 ESI-MS m/z: 576 [M+H] + .
实施例3 化合物97的合成The synthesis of embodiment 3 compound 97
Figure PCTCN2022119392-appb-000084
Figure PCTCN2022119392-appb-000084
步骤1：化合物int_97-3的合成:Step 1: Synthesis of compound int_97-3:
Figure PCTCN2022119392-appb-000085
Figure PCTCN2022119392-appb-000085
将int_97-1(10.3g,50mmol)溶于DMSO(100mL)中，加入碳酸铯(23.4g,71.7mmol)，int_97-2(6.98g,62.8mmol)，室温下反应12小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物经柱层析得到目标产物(10g,收率：70％)。Dissolve int_97-1 (10.3g, 50mmol) in DMSO (100mL), add cesium carbonate (23.4g, 71.7mmol), int_97-2 (6.98g, 62.8mmol), react at room temperature for 12 hours, LC-MS monitoring Indicates the end of the reaction. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography to obtain the target product (10 g, yield: 70%).
ESI-MS m/z:281[M+H] +。 ESI-MS m/z: 281 [M+H] + .
步骤2：化合物int_97-4的合成:Step 2: Synthesis of compound int_97-4:
Figure PCTCN2022119392-appb-000086
Figure PCTCN2022119392-appb-000086
将int_96-3(12.6g,45mmol)溶于甲醇(100mL)和水(10mL)的混合溶剂中，室温下加入氢氧化锂(2.1g,87.8mmol)，室温搅拌反应6小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(12g,粗产物)。粗产物可直接用于下一步反应。Dissolve int_96-3 (12.6g, 45mmol) in a mixed solvent of methanol (100mL) and water (10mL), add lithium hydroxide (2.1g, 87.8mmol) at room temperature, and stir at room temperature for 6 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (12 g, crude product). The crude product can be directly used in the next reaction.
ESI-MS m/z:267[M+H] +。 ESI-MS m/z: 267 [M+H] + .
步骤3：化合物int_97-5的合成:Step 3: Synthesis of compound int_97-5:
Figure PCTCN2022119392-appb-000087
Figure PCTCN2022119392-appb-000087
将int_97-4(100mg,0.375mmol)溶于DCM(10mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_1-6(90mg,0.375mmol)溶于THF(5mL)中，加入NaH(70 mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(100mg,收率：55％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (100 mg, yield: 55%).
ESI-MS m/z:487[M+H] +。 ESI-MS m/z: 487 [M+H] + .
步骤4：化合物97的合成:Step 4: Synthesis of compound 97:
Figure PCTCN2022119392-appb-000088
Figure PCTCN2022119392-appb-000088
将int_97-5(100mg,0.205mmol)，xantphos(12mg,0.02mmol)，碳酸铯(100mg,0.308mmol)，Pd 2(dba) 3(19mg,0.02mmol)和int_97-6(39mg,0.308mmol)溶解在1,4-二氧六环(10mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(17mg,收率：15％)。 Int_97-5 (100mg, 0.205mmol), xantphos (12mg, 0.02mmol), cesium carbonate (100mg, 0.308mmol), Pd 2 (dba) 3 (19mg, 0.02mmol) and int_97-6 (39mg, 0.308mmol) 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 (17 mg, yield: 15%).
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.67(s,1H),8.51(d,J＝2.0Hz,1H),8.12(s,1H),7.74(d,J＝8.1Hz,1H),6.34(d,J＝8.1Hz,1H),3.80–3.70(m,4H),3.29(s,8H),2.15(tt,J＝13.5,5.5Hz,4H),1.35(t,J＝5.3Hz,4H),0.28(s,4H)。 1 H NMR (400MHz,DMSO-d6)δ10.81(s,1H),10.67(s,1H),8.51(d,J=2.0Hz,1H),8.12(s,1H),7.74(d,J =8.1Hz,1H),6.34(d,J=8.1Hz,1H),3.80–3.70(m,4H),3.29(s,8H),2.15(tt,J=13.5,5.5Hz,4H),1.35 (t, J=5.3Hz, 4H), 0.28(s, 4H).
ESI-MS m/z:576[M+H] +。 ESI-MS m/z: 576 [M+H] + .
实施例4 化合物161的合成The synthesis of embodiment 4 compound 161
Figure PCTCN2022119392-appb-000089
Figure PCTCN2022119392-appb-000089
步骤1：化合物int_161-3的合成:Step 1: Synthesis of compound int_161-3:
Figure PCTCN2022119392-appb-000090
Figure PCTCN2022119392-appb-000090
将int_161-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_161-2(12.7g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(19.8g,收率：83％)。粗产物可直接用于下一步反应。Dissolve int_161-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_161-2 (12.7g, 105mmol), heat up to 80°C to react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (19.8 g, yield: 83%). The crude product can be directly used in the next reaction.
ESI-MS m/z:239[M+H] +。 ESI-MS m/z: 239 [M+H] + .
步骤2：化合物int_161-4的合成:Step 2: Synthesis of compound int_161-4:
Figure PCTCN2022119392-appb-000091
Figure PCTCN2022119392-appb-000091
将int_65-4(300mg,1.125mmol)溶于DCM(10mL)中，加入草酰氯(1.5mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_161-3(268mg,1.125mmol)溶于THF(5mL)中，加入NaH(300mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(62mg,收率：11.3％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (62 mg, yield: 11.3%).
ESI-MS m/z:487[M+H] +。 ESI-MS m/z: 487 [M+H] + .
步骤3：化合物161的合成:Step 3: Synthesis of Compound 161:
Figure PCTCN2022119392-appb-000092
Figure PCTCN2022119392-appb-000092
将int_161-4(20mg,0.045mmol)，xantphos(3mg,0.0045mmol)，碳酸铯(22mg,0.0675mmol)， Pd 2(dba) 3(4mg,0.0045mmol)和int_161-5(7mg,0.0542mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(10mg,收率：38％)。 Int_161-4 (20mg, 0.045mmol), xantphos (3mg, 0.0045mmol), cesium carbonate (22mg, 0.0675mmol), Pd 2 (dba) 3 (4mg, 0.0045mmol) and int_161-5 (7mg, 0.0542mmol) 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 (10 mg, yield: 38%).
1H NMR(400MHz,Chloroform-d)δ11.99(s,1H),8.42(s,1H),7.84(s,2H),7.32(d,J＝61.3Hz,1H),6.91(s,1H),4.14(s,2H),3.76(d,J＝64.2Hz,4H),3.21(s,3H),2.11(s,4H),1.62(d,J＝48.8Hz,4H),1.25(s,3H),0.39(s,4H)。 1 H NMR (400MHz, Chloroform-d) δ11.99(s,1H),8.42(s,1H),7.84(s,2H),7.32(d,J=61.3Hz,1H),6.91(s,1H ),4.14(s,2H),3.76(d,J=64.2Hz,4H),3.21(s,3H),2.11(s,4H),1.62(d,J=48.8Hz,4H),1.25(s ,3H), 0.39(s,4H).
ESI-MS m/z:576[M+H] +。 ESI-MS m/z: 576 [M+H] + .
实施例5 化合物225的合成The synthesis of embodiment 5 compound 225
Figure PCTCN2022119392-appb-000093
Figure PCTCN2022119392-appb-000093
步骤1：化合物int_225-1的合成:Step 1: Synthesis of compound int_225-1:
Figure PCTCN2022119392-appb-000094
Figure PCTCN2022119392-appb-000094
将int_97-4(50mg,0.187mmol)溶于DCM(5mL)中，加入草酰氯(0.5mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_161-3(35mg,0.15mmol)溶于THF(5mL)中，加入NaH(70mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(20mg,收率：27％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (20 mg, yield: 27%).
ESI-MS m/z:487[M+H] +。 ESI-MS m/z: 487 [M+H] + .
步骤2：化合物225的合成:Step 2: Synthesis of compound 225:
Figure PCTCN2022119392-appb-000095
Figure PCTCN2022119392-appb-000095
将int_225-1(66mg,0.135mmol)，xantphos(9mg,0.0135mmol)，碳酸铯(66mg,0.203mmol)，Pd 2(dba) 3(12mg,0.0135mmol)和int_225-2(21mg,0.163mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(20mg,收率：25％)。 Int_225-1 (66mg, 0.135mmol), xantphos (9mg, 0.0135mmol), cesium carbonate (66mg, 0.203mmol), Pd 2 (dba) 3 (12mg, 0.0135mmol) and int_225-2 (21mg, 0.163mmol) 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 (20 mg, yield: 25%).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.32(s,1H),8.07(d,J＝8.5Hz,1H),7.68(d,J＝8.5Hz,1H),7.35(s,1H),4.01(q,J＝7.1Hz,2H),3.76(q,J＝6.7,5.5Hz,4H),3.43(dt,J＝26.0,5.3Hz,4H),3.05(t,J＝5.3Hz,4H),2.10(td,J＝14.1,6.5Hz,2H),1.53(t,J＝5.3Hz,4H),1.29–1.05(m,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.33(s, 1H), 8.32(s, 1H), 8.07(d, J=8.5Hz, 1H), 7.68(d, J=8.5Hz, 1H), 7.35(s,1H),4.01(q,J=7.1Hz,2H),3.76(q,J=6.7,5.5Hz,4H),3.43(dt,J=26.0,5.3Hz,4H),3.05(t , J = 5.3Hz, 4H), 2.10 (td, J = 14.1, 6.5Hz, 2H), 1.53 (t, J = 5.3Hz, 4H), 1.29–1.05 (m, 4H).
ESI-MS m/z:576[M+H] +。 ESI-MS m/z: 576 [M+H] + .
实施例6 化合物226的合成The synthesis of embodiment 6 compound 226
Figure PCTCN2022119392-appb-000096
Figure PCTCN2022119392-appb-000096
步骤1：化合物int_226-3的合成:Step 1: Synthesis of compound int_226-3:
Figure PCTCN2022119392-appb-000097
Figure PCTCN2022119392-appb-000097
将int_226-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_226-2(10.6g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸 馏得到粗产物(20g,收率：91％)。粗产物可直接用于下一步反应。Dissolve int_226-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_226-2 (10.6g, 105mmol), heat up to 80°C to react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (20 g, yield: 91%). The crude product can be directly used in the next reaction.
ESI-MS m/z:219[M+H] +。 ESI-MS m/z: 219 [M+H] + .
步骤2：化合物int_226-4的合成:Step 2: Synthesis of compound int_226-4:
Figure PCTCN2022119392-appb-000098
Figure PCTCN2022119392-appb-000098
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_226-3(82mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(63mg,收率：35％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (63 mg, yield: 35%).
ESI-MS m/z:467[M+H] +。 ESI-MS m/z: 467 [M+H] + .
步骤3：化合物226的合成:Step 3: Synthesis of Compound 226:
Figure PCTCN2022119392-appb-000099
Figure PCTCN2022119392-appb-000099
将int_226-4(55mg,0.118mmol)，xantphos(8mg,0.0118mmol)，碳酸铯(66mg,0.203mmol)，Pd 2(dba) 3(10.5mg,0.0118mmol)和int_226-5(18mg,0.141mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(37mg,收率：56％)。 Int_226-4 (55mg, 0.118mmol), xantphos (8mg, 0.0118mmol), cesium carbonate (66mg, 0.203mmol), Pd 2 (dba) 3 (10.5mg, 0.0118mmol) and int_226-5 (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 (37 mg, yield: 56%).
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.41(s,1H),8.02(d,J＝8.5Hz,1H),7.69(d,J＝8.4Hz,1H),6.56(s,1H),4.14(t,J＝11.0Hz,2H),3.89(d,J＝11.4Hz,1H),3.71(t,J＝6.8Hz,2H),3.66–3.52(m,2H),3.45–3.19(m,4H),3.15–3.03(m,2H),2.74(dd,J＝13.2,10.3Hz,2H),1.57(s,3H),1.12(d,J＝6.2Hz,4H),0.33(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.69(s, 1H), 8.41(s, 1H), 8.02(d, J=8.5Hz, 1H), 7.69(d, J=8.4Hz, 1H), 6.56(s,1H),4.14(t,J=11.0Hz,2H),3.89(d,J=11.4Hz,1H),3.71(t,J=6.8Hz,2H),3.66–3.52(m,2H ),3.45–3.19(m,4H),3.15–3.03(m,2H),2.74(dd,J＝13.2,10.3Hz,2H),1.57(s,3H),1.12(d,J＝6.2Hz, 4H), 0.33(s, 4H).
ESI-MS m/z:556[M+H] +。 ESI-MS m/z: 556 [M+H] + .
实施例7 化合物227的合成The synthesis of embodiment 7 compound 227
Figure PCTCN2022119392-appb-000100
Figure PCTCN2022119392-appb-000100
步骤1：化合物int_227-3的合成:Step 1: Synthesis of compound int_227-3:
Figure PCTCN2022119392-appb-000101
Figure PCTCN2022119392-appb-000101
将int_227-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_227-2(10.6g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(17.5g,收率：80％)。粗产物可直接用于下一步反应。Dissolve int_227-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_227-2 (10.6g, 105mmol), heat up to 80°C and react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (17.5 g, yield: 80%). The crude product can be directly used in the next reaction.
ESI-MS m/z:219[M+H] +。 ESI-MS m/z: 219 [M+H] + .
步骤2：化合物int_227-4的合成:Step 2: Synthesis of compound int_227-4:
Figure PCTCN2022119392-appb-000102
Figure PCTCN2022119392-appb-000102
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_227-3(82mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有 机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(55mg,收率：31％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (55 mg, yield: 31%).
ESI-MS m/z:467[M+H] +。 ESI-MS m/z: 467 [M+H] + .
步骤3：化合物227的合成:Step 3: Synthesis of Compound 227:
Figure PCTCN2022119392-appb-000103
Figure PCTCN2022119392-appb-000103
将int_227-4(55mg,0.118mmol)，xantphos(8mg,0.0118mmol)，碳酸铯(66mg,0.203mmol)，Pd 2(dba) 3(10.5mg,0.0118mmol)和int_227-5(18mg,0.141mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(25mg,收率：38％)。 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%).
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.57(s,1H),8.03(d,J＝8.5Hz,1H),7.80(d,J＝8.5Hz,1H),6.34(s,1H),4.15(ddd,J＝12.0,5.5,3.0Hz,2H),3.92(dd,J＝11.5,3.1Hz,1H),3.74–3.58(m,4H),3.54–3.41(m,2H),3.23–3.05(m,4H),2.95(d,J＝5.7Hz,4H),2.77(dd,J＝13.1,10.2Hz,2H),1.16(d,J＝6.2Hz,3H),0.36(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ12.41(s, 1H), 8.57(s, 1H), 8.03(d, J=8.5Hz, 1H), 7.80(d, J=8.5Hz, 1H), 6.34(s,1H),4.15(ddd,J＝12.0,5.5,3.0Hz,2H),3.92(dd,J＝11.5,3.1Hz,1H),3.74–3.58(m,4H),3.54–3.41( m,2H),3.23–3.05(m,4H),2.95(d,J=5.7Hz,4H),2.77(dd,J=13.1,10.2Hz,2H),1.16(d,J=6.2Hz,3H ), 0.36(s,4H).
ESI-MS m/z:556[M+H] +。 ESI-MS m/z: 556 [M+H] + .
实施例8 化合物228的合成The synthesis of embodiment 8 compound 228
Figure PCTCN2022119392-appb-000104
Figure PCTCN2022119392-appb-000104
步骤1：化合物int_228-3的合成:Step 1: Synthesis of compound int_228-3:
Figure PCTCN2022119392-appb-000105
Figure PCTCN2022119392-appb-000105
将int_228-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_228-2(9.7g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(16g,收率：76％)。粗产物可直接用于下一步反应。Dissolve int_228-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_228-2 (9.7g, 105mmol), heat up to 80°C and react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (16 g, yield: 76%). The crude product can be directly used in the next reaction.
ESI-MS m/z:211[M+H] +。 ESI-MS m/z: 211 [M+H] + .
步骤2：化合物int_228-4的合成:Step 2: Synthesis of compound int_228-4:
Figure PCTCN2022119392-appb-000106
Figure PCTCN2022119392-appb-000106
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_228-3(78mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(57mg,收率：33％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (57 mg, yield: 33%).
ESI-MS m/z:459[M+H] +。 ESI-MS m/z: 459 [M+H] + .
步骤3：化合物228的合成:Step 3: Synthesis of Compound 228:
Figure PCTCN2022119392-appb-000107
Figure PCTCN2022119392-appb-000107
将int_228-4(57mg,0.124mmol)，xantphos(9mg,0.0124mmol)，碳酸铯(60mg,0.186mmol)， Pd 2(dba) 3(11mg,0.0124mmol)和int_228-5(19mg,0.124mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(15mg,收率：20％)。 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%).
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.35(s,1H),8.05(d,J＝8.5Hz,1H),7.68(s,1H),6.62(s,1H),4.62(t,J＝12.4Hz,4H),3.73(t,J＝6.8Hz,2H),3.03(s,4H),1.57(s,4H),1.21(s,2H),0.33(s,4H)。 1 H NMR (400MHz,DMSO-d6)δ11.72(s,1H),8.35(s,1H),8.05(d,J=8.5Hz,1H),7.68(s,1H),6.62(s,1H ),4.62(t,J=12.4Hz,4H),3.73(t,J=6.8Hz,2H),3.03(s,4H),1.57(s,4H),1.21(s,2H),0.33(s ,4H).
ESI-MS m/z:548[M+H] +。 ESI-MS m/z: 548[M+H] + .
实施例9 化合物229的合成The synthesis of embodiment 9 compound 229
Figure PCTCN2022119392-appb-000108
Figure PCTCN2022119392-appb-000108
步骤1：化合物int_229-3的合成:Step 1: Synthesis of compound int_229-3:
Figure PCTCN2022119392-appb-000109
Figure PCTCN2022119392-appb-000109
将int_229-2(12g,105mmol)溶于四氢呋喃(150mL)中，冰浴下加入NaH(4.2g,105mmol,60％含量)，反应液在室温反应半小时，在冰浴下向反应液中加入int_229-2(15.3g,100mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(15g,收率：65％)。粗产物可直接用于下一步反应。Dissolve int_229-2 (12g, 105mmol) in tetrahydrofuran (150mL), add NaH (4.2g, 105mmol, 60% content) under ice-cooling, react the reaction solution at room temperature for half an hour, add int_229-2 (15.3g, 100mmol), raised the temperature to 80°C and reacted for 24 hours. LC-MS monitoring showed that the reaction was completed. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (15 g, yield: 65%). The crude product can be directly used in the next reaction.
ESI-MS m/z:232[M+H] +。 ESI-MS m/z: 232 [M+H] + .
步骤2：化合物int_229-4的合成:Step 2: Synthesis of compound int_229-4:
Figure PCTCN2022119392-appb-000110
Figure PCTCN2022119392-appb-000110
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_229-3(87mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(75mg,收率：41％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (75 mg, yield: 41%).
ESI-MS m/z:480[M+H] +。 ESI-MS m/z: 480 [M+H] + .
步骤3：化合物229的合成:Step 3: Synthesis of compound 229:
Figure PCTCN2022119392-appb-000111
Figure PCTCN2022119392-appb-000111
将int_229-4(220mg,0.46mmol)，xantphos(110mg,0.19mmol)，碳酸铯(301mg,0.928mmol)，Pd 2(dba) 3(110mg,0.12mmol)和int_229-5(116mg,0.928mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(39mg,收率：47％)。 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%).
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.21(dd,J＝15.0,8.4Hz,1H),7.98(dd,J＝8.3,3.1Hz,1H),6.33(s,1H),4.61(t,J＝6.3Hz,2H),4.05–3.44(m,4H),3.13(dt,J＝10.2,6.9Hz,2H),2.90(d,J＝25.3Hz,4H),1.56(d,J＝50.5Hz,4H),0.30(d,J＝32.0Hz,4H)。 1 H NMR (400MHz, DMSO-d6) δ8.56(s, 1H), 8.21(dd, J=15.0, 8.4Hz, 1H), 7.98(dd, J=8.3, 3.1Hz, 1H), 6.33(s ,1H),4.61(t,J=6.3Hz,2H),4.05–3.44(m,4H),3.13(dt,J=10.2,6.9Hz,2H),2.90(d,J=25.3Hz,4H) , 1.56 (d, J=50.5Hz, 4H), 0.30 (d, J=32.0Hz, 4H).
ESI-MS m/z:569[M+H] +。 ESI-MS m/z: 569 [M+H] + .
实施例10 化合物230的合成The synthesis of embodiment 10 compound 230
Figure PCTCN2022119392-appb-000112
Figure PCTCN2022119392-appb-000112
步骤1：化合物int_230-3的合成:Step 1: Synthesis of compound int_230-3:
Figure PCTCN2022119392-appb-000113
Figure PCTCN2022119392-appb-000113
将int_230-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_230-2(10.2g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(18g,收率：84％)。粗产物可直接用于下一步反应。Dissolve int_230-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_230-2 (10.2g, 105mmol), heat up to 80°C to react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (18 g, yield: 84%). The crude product can be directly used in the next reaction.
ESI-MS m/z:215[M+H] +。 ESI-MS m/z: 215 [M+H] + .
步骤2：化合物int_230-4的合成:Step 2: Synthesis of compound int_230-4:
Figure PCTCN2022119392-appb-000114
Figure PCTCN2022119392-appb-000114
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_230-3(82mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(138mg,收率：79％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (138 mg, yield: 79%).
ESI-MS m/z:463[M+H] +。 ESI-MS m/z: 463 [M+H] + .
步骤3：化合物230的合成:Step 3: Synthesis of compound 230:
Figure PCTCN2022119392-appb-000115
Figure PCTCN2022119392-appb-000115
将int_230-4(138mg,0.298mmol)，xantphos(20mg,0.0298mmol)，碳酸铯(187mg,0.447mmol)，Pd 2(dba) 3(26mg,0.0298mmol)和int_230-5(45mg,0.298mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(35mg,收率：20％)。 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%).
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.41(s,1H),7.92(d,J＝8.4Hz,1H),7.47(d,J＝8.6Hz,1H),6.72(s,1H),3.85(t,J＝6.9Hz,2H),3.75(t,J＝6.7Hz,2H),3.55(s,2H),3.45(s,2H),3.02(t,J＝5.3Hz,4H),1.88(t,J＝6.8Hz,2H),1.59(s,4H),0.62(s,4H),0.31(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.45(s, 1H), 8.41(s, 1H), 7.92(d, J=8.4Hz, 1H), 7.47(d, J=8.6Hz, 1H), 6.72(s,1H),3.85(t,J=6.9Hz,2H),3.75(t,J=6.7Hz,2H),3.55(s,2H),3.45(s,2H),3.02(t,J =5.3Hz, 4H), 1.88(t, J=6.8Hz, 2H), 1.59(s, 4H), 0.62(s, 4H), 0.31(s, 4H).
ESI-MS m/z:552[M+H] +。 ESI-MS m/z: 552 [M+H] + .
实施例11 化合物231的合成The synthesis of embodiment 11 compound 231
Figure PCTCN2022119392-appb-000116
Figure PCTCN2022119392-appb-000116
步骤1：化合物int_231-3的合成:Step 1: Synthesis of compound int_231-3:
Figure PCTCN2022119392-appb-000117
Figure PCTCN2022119392-appb-000117
将int_231-2(7.5g,105mmol)溶于四氢呋喃(150mL)中，冰浴下加入NaH(4.2g,105mmol,60％含量)，反应液在室温反应半小时，在冰浴下向反应液中加入int_231-2(15.3g,100mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(15.5g,收率：82％)。粗产物可直接用于下一步反应。Dissolve int_231-2 (7.5g, 105mmol) in tetrahydrofuran (150mL), add NaH (4.2g, 105mmol, 60% content) under ice-cooling, react the reaction solution at room temperature for half an hour, and add Add int_231-2 (15.3g, 100mmol), raise the temperature to 80°C and react for 24 hours. LC-MS monitoring shows that the reaction is complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (15.5 g, yield: 82%). The crude product can be directly used in the next reaction.
ESI-MS m/z:190[M+H] +。 ESI-MS m/z: 190 [M+H] + .
步骤2：化合物int_231-4的合成:Step 2: Synthesis of compound int_231-4:
Figure PCTCN2022119392-appb-000118
Figure PCTCN2022119392-appb-000118
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_231-3(70mg,0.375mmol)溶于THF(5mL)中，加入NaH(90mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(67mg,收率：40％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (67 mg, yield: 40%).
ESI-MS m/z:438[M+H] +。 ESI-MS m/z: 438[M+H] + .
步骤3：化合物231的合成:Step 3: Synthesis of Compound 231:
Figure PCTCN2022119392-appb-000119
Figure PCTCN2022119392-appb-000119
将int_231-4(90mg,0.21mmol)，xantphos(12mg,0.021mmol)，碳酸铯(101mg,0.31mmol)，Pd 2(dba) 3(19mg,0.021mmol)和int_231-5(39mg,0.31mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(20mg,收率：18％)。 Int_231-4 (90mg, 0.21mmol), xantphos (12mg, 0.021mmol), cesium carbonate (101mg, 0.31mmol), Pd 2 (dba) 3 (19mg, 0.021mmol) and int_231-5 (39mg, 0.31mmol) 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 (20 mg, yield: 18%).
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.40(s,1H),8.21(d,J＝8.4Hz,1H),7.91(d,J＝8.4 Hz,1H),6.62(s,1H),3.75(t,J＝6.8Hz,2H),3.39(s,4H),3.06(s,4H),2.25–2.02(m,4H),1.84(q,J＝10.5Hz,1H),1.62(d,J＝16.9Hz,4H),0.37(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.65(s, 1H), 8.40(s, 1H), 8.21(d, J=8.4Hz, 1H), 7.91(d, J=8.4 Hz, 1H), 6.62(s,1H),3.75(t,J=6.8Hz,2H),3.39(s,4H),3.06(s,4H),2.25–2.02(m,4H),1.84(q,J=10.5Hz , 1H), 1.62 (d, J=16.9Hz, 4H), 0.37 (s, 4H).
ESI-MS m/z:527[M+H] +。 ESI-MS m/z: 527 [M+H] + .
实施例12 化合物236的合成The synthesis of embodiment 12 compound 236
Figure PCTCN2022119392-appb-000120
Figure PCTCN2022119392-appb-000120
步骤1：化合物int_236-3的合成:Step 1: Synthesis of compound int_236-3:
Figure PCTCN2022119392-appb-000121
Figure PCTCN2022119392-appb-000121
将int_236-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_236-2(9.1g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(20g,收率：91％)。粗产物可直接用于下一步反应。Dissolve int_236-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_236-2 (9.1g, 105mmol), heat up to 80°C and react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (20 g, yield: 91%). The crude product can be directly used in the next reaction.
ESI-MS m/z:205[M+H] +。 ESI-MS m/z: 205 [M+H] + .
步骤2：化合物int_236-4的合成:Step 2: Synthesis of compound int_236-4:
Figure PCTCN2022119392-appb-000122
Figure PCTCN2022119392-appb-000122
将int_97-4(100mg,0.375mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应 1小时后浓缩反应液得到酰氯中间体。将int_236-3(78mg,0.375mmol)溶于THF(5mL)中，加入NaH(100mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(120mg,收率：71％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (120 mg, yield: 71%).
ESI-MS m/z:453[M+H] +。 ESI-MS m/z: 453 [M+H] + .
步骤3：化合物236的合成:Step 3: Synthesis of Compound 236:
Figure PCTCN2022119392-appb-000123
Figure PCTCN2022119392-appb-000123
将int_236-4(120mg,0.265mmol)，xantphos(60mg,0.104mmol)，碳酸铯(174mg,0.534mmol)，Pd 2(dba) 3(60mg,0.065mmol)和int_236-5(67mg,0.536mmol)溶解在1,4-二氧六环(10mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(40mg,收率：28％)。 Int_236-4 (120mg, 0.265mmol), xantphos (60mg, 0.104mmol), cesium carbonate (174mg, 0.534mmol), Pd 2 (dba) 3 (60mg, 0.065mmol) and int_236-5 (67mg, 0.536mmol) 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 (40 mg, yield: 28%).
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.39(s,1H),8.08(d,J＝8.4Hz,1H),7.68(d,J＝8.4Hz,1H),6.70(s,1H),3.81–3.69(m,6H),3.66(q,J＝4.4,3.5Hz,4H),3.45(s,2H),3.06(t,J＝5.3Hz,4H),1.58(d,J＝5.7Hz,4H),0.35(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.55(s, 1H), 8.39(s, 1H), 8.08(d, J=8.4Hz, 1H), 7.68(d, J=8.4Hz, 1H), 6.70(s,1H),3.81–3.69(m,6H),3.66(q,J=4.4,3.5Hz,4H),3.45(s,2H),3.06(t,J=5.3Hz,4H),1.58 (d, J=5.7Hz, 4H), 0.35(s, 4H).
ESI-MS m/z:542[M+H] +。 ESI-MS m/z: 542 [M+H] + .
实施例13 化合物321的合成The synthesis of embodiment 13 compound 321
Figure PCTCN2022119392-appb-000124
Figure PCTCN2022119392-appb-000124
步骤1：化合物int_321-3的合成:Step 1: Synthesis of compound int_321-3:
Figure PCTCN2022119392-appb-000125
Figure PCTCN2022119392-appb-000125
将int_321-1(15.3g,100mmol)溶于1,4二氧六环(150mL)中，加入碳酸铯(34.2g,105mmol)，int_321-2(12.7g,105mmol)，升温至80℃反应24小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物经过柱层析纯化得到产物(18.7g,收率：78％)。Dissolve int_321-1 (15.3g, 100mmol) in 1,4-dioxane (150mL), add cesium carbonate (34.2g, 105mmol), int_321-2 (12.7g, 105mmol), heat up to 80°C and react 24 Hours, LC-MS monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product (18.7 g, yield: 78%).
ESI-MS m/z:240[M+H] +。 ESI-MS m/z: 240 [M+H] + .
步骤2：化合物int_321-4的合成:Step 2: Synthesis of compound int_321-4:
Figure PCTCN2022119392-appb-000126
Figure PCTCN2022119392-appb-000126
将int_97-4(171mg,0.643mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_321-3(100mg,0.42mmol)溶于THF(10mL)中，加入NaH(200mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(140mg,收率：41％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (140 mg, yield: 41%).
ESI-MS m/z:488[M+H] +。 ESI-MS m/z: 488 [M+H] + .
步骤3：化合物321的合成:Step 3: Synthesis of compound 321:
Figure PCTCN2022119392-appb-000127
Figure PCTCN2022119392-appb-000127
将int_321-1(400mg,0.82mmol)，xantphos(200mg,0.346mmol)，碳酸铯(536mg,1.65mmol)，Pd 2(dba) 3(200mg,0.218mmol)和int_321-5(206mg,1.65mmol)溶解在1,4-二氧六环(10mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷 却至室温，将反应液旋干，柱层析纯化得固体(65mg,收率：15％)。 Int_321-1 (400mg, 0.82mmol), xantphos (200mg, 0.346mmol), cesium carbonate (536mg, 1.65mmol), Pd 2 (dba) 3 (200mg, 0.218mmol) and int_321-5 (206mg, 1.65mmol) 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 (65 mg, yield: 15%).
1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),8.85(s,1H),8.34(s,1H),6.63(s,1H),3.85(t,J＝5.8Hz,4H),3.74(t,J＝6.8Hz,2H),3.41(s,2H),3.06(t,J＝5.4Hz,4H),2.18–2.02(m,4H),1.49(d,J＝6.1Hz,4H),0.32(s,4H)。 1 H NMR(400MHz,DMSO-d6)δ11.75(s,1H),8.85(s,1H),8.34(s,1H),6.63(s,1H),3.85(t,J＝5.8Hz,4H ), 3.74(t, J=6.8Hz, 2H), 3.41(s, 2H), 3.06(t, J=5.4Hz, 4H), 2.18–2.02(m, 4H), 1.49(d, J=6.1Hz ,4H), 0.32(s,4H).
ESI-MS m/z:577[M+H] +。 ESI-MS m/z: 577 [M+H] + .
实施例14 化合物353的合成The synthesis of embodiment 14 compound 353
Figure PCTCN2022119392-appb-000128
Figure PCTCN2022119392-appb-000128
步骤1：化合物int_353-3的合成:Step 1: Synthesis of compound int_353-3:
Figure PCTCN2022119392-appb-000129
Figure PCTCN2022119392-appb-000129
将int_353-1(1g,4.55mmol)溶于DMF(20mL)中，加入int_353-2(670mg,4.55mmol)，碳酸钾(1.8g,13.64mmol)，氩气保护下，100℃反应3小时，LC-MS监测显示反应结束。减压浓缩反应液，加入100mL水，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(1.5g,收率：100％)。Dissolve int_353-1 (1g, 4.55mmol) in DMF (20mL), add int_353-2 (670mg, 4.55mmol), potassium carbonate (1.8g, 13.64mmol), and react at 100°C for 3 hours under argon protection. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure, 100 mL of water was added, the aqueous phase was extracted with ethyl acetate (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (1.5 g, yield: 100%).
ESI-MS m/z:311[M+H] +。 ESI-MS m/z: 311 [M+H] + .
步骤2：化合物int_353-4的合成:Step 2: Synthesis of compound int_353-4:
Figure PCTCN2022119392-appb-000130
Figure PCTCN2022119392-appb-000130
将int_353-3(1.5g,4.82mmol)溶于甲醇(50mL)中，加入20mL乙酸，冰浴下搅拌10分重后，分批少量加入锌粉(1.5g，24.10mmol)。反应液升至室温反应1小时，LC-MS监测显示反应结束。将反应液过滤得到滤液，滤液减压浓缩得到粗产物。向粗产物中加入100mL水，水相用二氯甲烷萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物(1g,收率：77％)。Dissolve int_353-3 (1.5g, 4.82mmol) in methanol (50mL), add 20mL of acetic acid, stir in ice bath for 10 minutes, then add zinc powder (1.5g, 24.10mmol) in small amounts in batches. The reaction solution was raised to room temperature and reacted for 1 hour, and LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. 100 mL of water was added to the crude product, the aqueous phase was extracted with dichloromethane (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product (1 g, yield: 77%).
ESI-MS m/z:281[M+H] +。 ESI-MS m/z: 281 [M+H] + .
步骤3：化合物int_353-6的合成:Step 3: Synthesis of compound int_353-6:
Figure PCTCN2022119392-appb-000131
Figure PCTCN2022119392-appb-000131
将int_353-5(4g,21.9mmol)混悬于甲醇(100mL)中，加入三甲基氯化硅(7g,64.65mmol)。反应液于室温反应4小时，反应液逐渐澄清。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(4.1g,收率：95％)。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%).
ESI-MS m/z:197[M+H] +。 ESI-MS m/z: 197 [M+H] + .
步骤4：化合物int_353-8的合成:Step 4: Synthesis of compound int_353-8:
Figure PCTCN2022119392-appb-000132
Figure PCTCN2022119392-appb-000132
将int_353-6(3.2g,16.2mmol)以及int_353-7(2g,16.2mmol)溶于1，4-二氧六环(100mL)中，加入碳酸铯(20g,63.4mmol)，Pd 2(dba) 3(1.9g,2.11mmol)和Xantphos(1.2g,2.11mmol)。氩气保护下，升温至100℃反应18小时。LC-MS监测显示反应结束。向反应液加入水(300mL)稀释，水相用二氯甲烷萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物 粗产物经柱 层析纯化(SiO 2,正己烷/乙酸乙酯＝10:1)得到目标产物(3g,收率：66％)。 Dissolve int_353-6 (3.2g, 16.2mmol) and int_353-7 (2g, 16.2mmol) in 1,4-dioxane (100mL), add cesium carbonate (20g, 63.4mmol), Pd 2 (dba ) 3 (1.9 g, 2.11 mmol) and Xantphos (1.2 g, 2.11 mmol). Under the protection of argon, the temperature was raised to 100° C. for 18 hours. LC-MS monitoring showed the reaction was complete. Water (300 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with dichloromethane (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO 2 , n-hexane/ethyl acetate=10:1) to obtain the target product (3 g, yield: 66%).
ESI-MS m/z:282[M+H] +。 ESI-MS m/z: 282 [M+H] + .
步骤5：化合物int_353-9的合成:Step 5: Synthesis of compound int_353-9:
Figure PCTCN2022119392-appb-000133
Figure PCTCN2022119392-appb-000133
将int_353-8(4.2g,15mmol)溶于甲醇(50mL)中，室温搅拌下加入NaOH(2M,20mL)，反应液在室温下反应4小时，LC-MS监测显示反应结束。反应液过滤得到滤液，将滤液降压浓缩得到固体，向固体中加入水(100mL)，水相用二氯甲烷萃取(50mL*2)，水相减压蒸馏得到粗产物，粗产物经柱层析纯化得到目标产物(3g,收率：75％)。Dissolve int_353-8 (4.2g, 15mmol) in methanol (50mL), add NaOH (2M, 20mL) under stirring at room temperature, and react the reaction solution at room temperature for 4 hours. LC-MS monitoring shows that the reaction is complete. The reaction solution was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain a solid, and water (100 mL) was added to the solid, the aqueous phase was extracted with dichloromethane (50 mL*2), and the aqueous phase was distilled under reduced pressure to obtain a crude product, which was passed through a column layer Analysis and purification gave the target product (3 g, yield: 75%).
ESI-MS m/z:268[M+H] +。 ESI-MS m/z: 268 [M+H] + .
步骤6：化合物int_353-10的合成:Step 6: Synthesis of compound int_353-10:
Figure PCTCN2022119392-appb-000134
Figure PCTCN2022119392-appb-000134
将int_353-4(100mg,0.355mmol)，int_353-9(95mg,0.355mmol)，HATU(270mg,0.71mmol)溶于DMF(8mL)中，加入TEA(107mg,1.065mmol)，升温至60℃搅拌反应过夜，LC-MS监测反应结束，加入5mL冰水待固体完全析出，过滤并收集滤饼，滤饼用甲醇打浆，过滤得到滤饼，将滤饼烘干，得灰色固体(70mg,收率：37.2％)。Dissolve int_353-4 (100mg, 0.355mmol), int_353-9 (95mg, 0.355mmol), HATU (270mg, 0.71mmol) in DMF (8mL), add TEA (107mg, 1.065mmol), heat up to 60°C and stir React overnight, LC-MS monitors that the reaction ends, add 5mL of ice water and wait for the solid to separate out completely, filter and collect the filter cake, the filter cake is beaten with methanol, filter to obtain the filter cake, and the filter cake is dried to obtain a gray solid (70mg, yield : 37.2%).
ESI-MS m/z:530[M+H] +。 ESI-MS m/z: 530 [M+H] + .
步骤7：化合物353的合成:Step 7: Synthesis of compound 353:
Figure PCTCN2022119392-appb-000135
Figure PCTCN2022119392-appb-000135
将int_353-10(63mg,0.118mmol)，N,N-二甲基甘氨酸(12mg,0.118mmol)，碘化亚铜(11mg,0.059mmol)和磷酸钾(75mg,0.354mmol)，溶解在DMF(20mL)中，氩气置换三次，加入int_353-11(30mg,0.237mmol)，氩气保护下，微波反应液加热到130℃反应3.5小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(15mg,收率：17.4％)。Dissolve int_353-10 (63mg, 0.118mmol), N,N-dimethylglycine (12mg, 0.118mmol), cuprous iodide (11mg, 0.059mmol) and potassium phosphate (75mg, 0.354mmol) in DMF ( 20 mL), replaced with argon three times, added int_353-11 (30 mg, 0.237 mmol), under the protection of argon, the microwave reaction solution was heated to 130 ° C for 3.5 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: 17.4%).
1H NMR(400MHz,Chloroform-d)δ10.46(s,1H),8.57(d,J＝8.7Hz,1H),7.90(d,J＝9.0Hz,1H),7.30(d,J＝2.4Hz,1H),7.08(dd,J＝8.7,2.5Hz,1H),6.92(d,J＝9.0Hz,1H),4.11(t,J＝5.2Hz,2H),4.00(t,J＝5.9Hz,4H),3.31–3.24(m,2H),2.91(t,J＝5.3Hz,4H),2.16(tt,J＝12.9,5.8Hz,4H),1.51(s,4H),0.39(s,4H)。 1 H NMR (400MHz, Chloroform-d) δ10.46(s, 1H), 8.57(d, J=8.7Hz, 1H), 7.90(d, J=9.0Hz, 1H), 7.30(d, J=2.4 Hz, 1H), 7.08(dd, J=8.7, 2.5Hz, 1H), 6.92(d, J=9.0Hz, 1H), 4.11(t, J=5.2Hz, 2H), 4.00(t, J=5.9 Hz, 4H), 3.31–3.24(m, 2H), 2.91(t, J＝5.3Hz, 4H), 2.16(tt, J＝12.9, 5.8Hz, 4H), 1.51(s, 4H), 0.39(s ,4H).
ESI-MS m/z:575[M+H] +。 ESI-MS m/z: 575 [M+H] + .
实施例15 化合物354的合成The synthesis of embodiment 15 compound 354
Figure PCTCN2022119392-appb-000136
Figure PCTCN2022119392-appb-000136
步骤1：化合物int_354-2的合成:Step 1: Synthesis of compound int_354-2:
Figure PCTCN2022119392-appb-000137
Figure PCTCN2022119392-appb-000137
将int_354-1(4g,21.9mmol)混悬于甲醇(100mL)中，加入三甲基氯化硅(7g,64.65mmol)。反应 液于室温反应4小时，反应液逐渐澄清。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(4.1g,收率：95％)。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%).
ESI-MS m/z:197[M+H] +。 ESI-MS m/z: 197 [M+H] + .
步骤2：化合物int_354-4的合成:Step 2: Synthesis of compound int_354-4:
Figure PCTCN2022119392-appb-000138
Figure PCTCN2022119392-appb-000138
将int_354-2(3.2g,16.2mmol)以及int_354-3(1.6g,16.2mmol)溶于1，4-二氧六环(100mL)中，加入碳酸铯(20g,63.4mmol)，Pd 2(dba) 3(1.9g,2.11mmol)和Xantphos(1.2g,2.11mmol)。氩气保护下，升温至100℃反应18小时。LC-MS监测显示反应结束。向反应液加入水(300mL)稀释，水相用二氯甲烷萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物 粗产物经柱层析纯化(SiO 2,正己烷/乙酸乙酯＝10:1)得到目标产物(3.2g,收率：76％)。 Dissolve int_354-2 (3.2g, 16.2mmol) and int_354-3 (1.6g, 16.2mmol) in 1,4-dioxane (100mL), add cesium carbonate (20g, 63.4mmol), Pd 2 ( dba) 3 (1.9 g, 2.11 mmol) and Xantphos (1.2 g, 2.11 mmol). Under the protection of argon, the temperature was raised to 100° C. for 18 hours. LC-MS monitoring showed the reaction was complete. Water (300 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with dichloromethane (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO 2 , n-hexane/ethyl acetate=10:1) to obtain the target product (3.2 g, yield: 76%).
ESI-MS m/z:262[M+H] +。 ESI-MS m/z: 262 [M+H] + .
步骤3：化合物int_354-5的合成:Step 3: Synthesis of compound int_354-5:
Figure PCTCN2022119392-appb-000139
Figure PCTCN2022119392-appb-000139
将int_354-4(3.9g,15mmol)溶于甲醇(50mL)中，室温搅拌下加入NaOH(2M,20mL)，反应液在室温下反应4小时，LC-MS监测显示反应结束。反应液过滤得到滤液，将滤液降压浓缩得到固体，向固体中加入水(100mL)，水相用二氯甲烷萃取(50mL*2)，水相减压蒸馏得到粗产物，粗产物经柱层析纯化得到目标产物(3.1g,收率：83.7％)。Dissolve int_354-4 (3.9g, 15mmol) in methanol (50mL), add NaOH (2M, 20mL) under stirring at room temperature, and react the reaction solution at room temperature for 4 hours. LC-MS monitoring shows that the reaction is complete. The reaction solution was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain a solid, and water (100 mL) was added to the solid, the aqueous phase was extracted with dichloromethane (50 mL*2), and the aqueous phase was distilled under reduced pressure to obtain a crude product, which was passed through a column layer Analysis and purification gave the target product (3.1 g, yield: 83.7%).
ESI-MS m/z:248[M+H] +。 ESI-MS m/z: 248[M+H] + .
步骤4：化合物int_354-6的合成:Step 4: Synthesis of compound int_354-6:
Figure PCTCN2022119392-appb-000140
Figure PCTCN2022119392-appb-000140
将int_353-4(100mg,0.355mmol)，int_354-6(88mg,0.355mmol)，HATU(270mg,0.71mmol)溶于DMF(8mL)中，加入TEA(107mg,1.065mmol)，升温至60℃搅拌反应过夜，LC-MS监测反应结束，加入5mL冰水待固体完全析出，过滤并收集滤饼，滤饼用甲醇打浆，过滤得到滤饼，将滤饼烘干，得灰色固体(85mg,收率：46.9％)。Dissolve int_353-4 (100mg, 0.355mmol), int_354-6 (88mg, 0.355mmol), HATU (270mg, 0.71mmol) in DMF (8mL), add TEA (107mg, 1.065mmol), heat up to 60°C and stir React overnight, LC-MS monitors that the reaction is over, add 5mL of ice water and wait for the solid to separate out completely, filter and collect the filter cake, the filter cake is beaten with methanol, filter to obtain the filter cake, and the filter cake is dried to obtain a gray solid (85mg, yield : 46.9%).
ESI-MS m/z:510[M+H] +。 ESI-MS m/z: 510 [M+H] + .
步骤5：化合物354的合成:Step 5: Synthesis of compound 354:
Figure PCTCN2022119392-appb-000141
Figure PCTCN2022119392-appb-000141
将int_354-6(61mg,0.12mmol)，N,N-二甲基甘氨酸(12mg,0.12mmol)，碘化亚铜(11mg,0.059mmol)和磷酸钾(75mg,0.354mmol)，溶解在DMF(20mL)中，氩气置换三次，加入int_354-7(30mg,0.237mmol)，氩气保护下，微波反应液加热到130℃反应3.5小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(20mg,收率：30％)。Dissolve int_354-6 (61mg, 0.12mmol), N,N-dimethylglycine (12mg, 0.12mmol), cuprous iodide (11mg, 0.059mmol) and potassium phosphate (75mg, 0.354mmol) in DMF ( 20mL) was replaced with argon three times, and int_354-7 (30mg, 0.237mmol) was added. Under the protection of argon, the microwave reaction solution was heated to 130°C for 3.5 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 (20 mg, yield: 30%).
ESI-MS m/z:555[M+H] +。 ESI-MS m/z: 555 [M+H] + .
实施例16 化合物385的合成The synthesis of embodiment 16 compound 385
Figure PCTCN2022119392-appb-000142
Figure PCTCN2022119392-appb-000142
步骤1：化合物int_385-2的合成:Step 1: Synthesis of compound int_385-2:
Figure PCTCN2022119392-appb-000143
Figure PCTCN2022119392-appb-000143
将int_353-4(100mg,0.355mmol)，int_385-1(95mg,0.355mmol)，HATU(270mg,0.71mmol)溶于DMF(8mL)中，加入TEA(107mg,1.065mmol)，升温至60℃搅拌反应过夜，LC-MS监测反应结束，加入5mL冰水待固体完全析出，过滤并收集滤饼，滤饼用甲醇打浆，过滤得到滤饼，将滤饼烘干，得灰色固体(119mg,收率：63％)。Dissolve int_353-4 (100mg, 0.355mmol), int_385-1 (95mg, 0.355mmol), HATU (270mg, 0.71mmol) in DMF (8mL), add TEA (107mg, 1.065mmol), heat up to 60°C and stir React overnight, LC-MS monitors that the reaction ends, add 5mL of ice water and wait for the solid to separate out completely, filter and collect the filter cake, the filter cake is beaten with methanol, filter to obtain the filter cake, and the filter cake is dried to obtain a gray solid (119 mg, yield : 63%).
ESI-MS m/z:531[M+H] +。 ESI-MS m/z: 531 [M+H] + .
步骤2：化合物385的合成:Step 2: Synthesis of Compound 385:
Figure PCTCN2022119392-appb-000144
Figure PCTCN2022119392-appb-000144
将int_385-2(20mg,0.038mmol)，(1S,2S)-N2N1-二甲基环己烷-1,2-二胺(4mg,0.038mmol)，碘化亚铜(4mg,0.019mmol)和磷酸钾(24mg,0.113mmol)，溶解在DMF(5mL)中，氩气置换三次，加入int_385-3(7mg,0.056mmol)，氩气保护下，微波反应液加热到130℃反应3.5小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(12mg,收率：57％)。Will int_385-2 (20mg, 0.038mmol), (1S, 2S)-N2N1-dimethylcyclohexane-1,2-diamine (4mg, 0.038mmol), cuprous iodide (4mg, 0.019mmol) and Potassium phosphate (24 mg, 0.113 mmol) was dissolved in DMF (5 mL), replaced with argon three times, added int_385-3 (7 mg, 0.056 mmol), and heated to 130° C. for 3.5 hours under the protection of argon. 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: 57%).
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.74(s,1H),8.38(s,1H),8.27(d,J＝8.8Hz,1H),7.16(d,J＝2.5Hz,1H),7.00(dd,J＝8.8,2.3Hz,1H),4.00(t,J＝5.4Hz,4H),3.71(t,J＝6.7Hz,2H),3.18(t,J＝6.7Hz,3H),2.80(t,J＝5.2Hz,3H),2.21(d,J＝15.5Hz,4H),1.49(s,4H),0.35(s,4H)。 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.74(s,1H),8.38(s,1H),8.27(d,J＝8.8Hz,1H),7.16(d,J =2.5Hz,1H),7.00(dd,J=8.8,2.3Hz,1H),4.00(t,J=5.4Hz,4H),3.71(t,J=6.7Hz,2H),3.18(t,J =6.7Hz, 3H), 2.80(t, J=5.2Hz, 3H), 2.21(d, J=15.5Hz, 4H), 1.49(s, 4H), 0.35(s, 4H).
ESI-MS m/z:575[M+H] +。 ESI-MS m/z: 575 [M+H] + .
实施例17 化合物449的合成The synthesis of embodiment 17 compound 449
Figure PCTCN2022119392-appb-000145
Figure PCTCN2022119392-appb-000145
步骤1：化合物int_449-3的合成:Step 1: Synthesis of compound int_449-3:
Figure PCTCN2022119392-appb-000146
Figure PCTCN2022119392-appb-000146
将int_449-1(11.7g,50mmol)溶于DMSO(100mL)中，加入碳酸铯(23.4g,71.7mmol)，int_449-2(6.98g,62.8mmol)，室温下反应12小时，LC-MS监测显示反应结束。向反应液加入水(500mL)稀释，水相用乙酸乙酯萃取(300mL*3)，有机相用无水硫酸钠干燥。有机相过滤、减压蒸馏得到粗产物，粗产物经柱层析得到目标产物(11.6g,收率：72％)。Dissolve int_449-1 (11.7g, 50mmol) in DMSO (100mL), add cesium carbonate (23.4g, 71.7mmol), int_449-2 (6.98g, 62.8mmol), react at room temperature for 12 hours, LC-MS monitoring Indicates the end of the reaction. Water (500 mL) was added to the reaction solution for dilution, the aqueous phase was extracted with ethyl acetate (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography to obtain the target product (11.6 g, yield: 72%).
ESI-MS m/z:325[M+H] +。 ESI-MS m/z: 325 [M+H] + .
步骤2：化合物int_449-4的合成:Step 2: Synthesis of compound int_449-4:
Figure PCTCN2022119392-appb-000147
Figure PCTCN2022119392-appb-000147
将int_449-3(14.6g,45mmol)溶于甲醇(200mL)和水(20mL)的混合溶剂中，室温下加入氢氧化锂(2.1g,87.8mmol)，室温搅拌反应6小时。LC-MS监测显示反应结束。将反应液减压浓缩得到粗产物(15g,粗产物)。粗产物可直接用于下一步反应。Dissolve int_449-3 (14.6g, 45mmol) in a mixed solvent of methanol (200mL) and water (20mL), add lithium hydroxide (2.1g, 87.8mmol) at room temperature, and stir at room temperature for 6 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (15 g, crude product). The crude product can be directly used in the next reaction.
ESI-MS m/z:311[M+H] +。 ESI-MS m/z: 311 [M+H] + .
步骤3：化合物int_449-4的合成:Step 3: Synthesis of compound int_449-4:
Figure PCTCN2022119392-appb-000148
Figure PCTCN2022119392-appb-000148
将int_449-4(85mg,0.273mmol)，int_161-3(65mg,0.273mmol)，HATU(156mg,0.409mmol)溶于DMF(8mL)中，加入TEA(41mg,0.409mmol)，升温至60℃搅拌反应过夜，LC-MS监测反应结束，将反应液减压浓缩得到粗产物，粗产物经过柱层析纯化后得灰色固体(60mg,收率：41％)。Dissolve int_449-4 (85mg, 0.273mmol), int_161-3 (65mg, 0.273mmol), HATU (156mg, 0.409mmol) in DMF (8mL), add TEA (41mg, 0.409mmol), heat up to 60°C and stir After reacting overnight, LC-MS monitored the completion of the reaction, and concentrated the reaction solution under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a gray solid (60 mg, yield: 41%).
ESI-MS m/z:531[M+H] +。 ESI-MS m/z: 531 [M+H] + .
步骤4：化合物449的合成:Step 4: Synthesis of Compound 449:
Figure PCTCN2022119392-appb-000149
Figure PCTCN2022119392-appb-000149
将int_449-4(60mg,0.113mmol)，xantphos(7mg,0.0113mmol)，碳酸铯(55mg,0.170mmol)，Pd 2(dba) 3(10mg,0.0113mmol)和int_449-5(17mg,0.135mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(12mg,收率：18％)。 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%).
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.19–8.01(m,2H),7.76(d,J＝8.3Hz,1H),7.43(d,J＝2.2Hz,1H),4.06(d,J＝5.2Hz,2H),3.75(t,J＝6.1Hz,4H),3.15(d,J＝3.6Hz,3H),3.01(t,J＝5.3Hz,3H),2.19–1.91(m,4H),1.56(s,2H),1.22(s,2H),0.33(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ11.88(s, 1H), 8.19–8.01(m, 2H), 7.76(d, J=8.3Hz, 1H), 7.43(d, J=2.2Hz, 1H ), 4.06(d, J=5.2Hz, 2H), 3.75(t, J=6.1Hz, 4H), 3.15(d, J=3.6Hz, 3H), 3.01(t, J=5.3Hz, 3H), 2.19–1.91(m,4H), 1.56(s,2H), 1.22(s,2H), 0.33(s,4H).
ESI-MS m/z:576[M+H] +。 ESI-MS m/z: 576 [M+H] + .
实施例18 化合物577的合成The synthesis of embodiment 18 compound 577
Figure PCTCN2022119392-appb-000150
Figure PCTCN2022119392-appb-000150
步骤1：化合物int_577-1的合成:Step 1: Synthesis of compound int_577-1:
Figure PCTCN2022119392-appb-000151
Figure PCTCN2022119392-appb-000151
将int_449-4(130mg,0.42mmol)溶于DCM(10mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_321-3(100mg,0.42mmol)溶于THF(10mL)中，加入NaH(200mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(140mg,收率：41％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (140 mg, yield: 41%).
ESI-MS m/z:531[M+H] +。 ESI-MS m/z: 531 [M+H] + .
步骤2：化合物577的合成:Step 2: Synthesis of compound 577:
Figure PCTCN2022119392-appb-000152
Figure PCTCN2022119392-appb-000152
将int_577-1(140mg,0.264mmol)，xantphos(70mg,0.121mmol)，碳酸铯(172mg,0.527mmol，Pd 2(dba) 3(70mg,0.076mmol)和int_577-2(66mg,0.527mmol)溶解在1,4-二氧六环(10mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(69mg,收率：45％)。 Dissolve int_577-1 (140mg, 0.264mmol), xantphos (70mg, 0.121mmol), cesium carbonate (172mg, 0.527mmol, Pd 2 (dba) 3 (70mg, 0.076mmol) and int_577-2 (66mg, 0.527mmol) In 1,4-dioxane (10mL), argon was replaced three times, and under the protection of argon, the reaction solution was heated to 100°C for 3 hours. LC-MS monitoring showed that the reaction was over. The reaction solution was cooled to room temperature, and The reaction solution was spin-dried and purified by column chromatography to obtain a solid (69 mg, yield: 45%).
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.90(s,1H),8.12(d,J＝2.2Hz,1H),7.44(d,J＝2.2Hz,1H),3.84(t,J＝5.6Hz,4H),3.75(t,J＝6.3Hz,2H),3.34(d,J＝6.3Hz,2H),3.03(t,J＝5.2Hz,4H),2.12(td,J＝13.8,6.6Hz,4H),1.54(t,J＝5.1Hz,4H),0.34(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ12.09(s, 1H), 8.90(s, 1H), 8.12(d, J=2.2Hz, 1H), 7.44(d, J=2.2Hz, 1H), 3.84(t, J=5.6Hz, 4H), 3.75(t, J=6.3Hz, 2H), 3.34(d, J=6.3Hz, 2H), 3.03(t, J=5.2Hz, 4H), 2.12( td,J=13.8,6.6Hz,4H), 1.54(t,J=5.1Hz,4H),0.34(s,4H).
ESI-MS m/z:577[M+H] +。 ESI-MS m/z: 577 [M+H] + .
实施例19 化合物609的合成The synthesis of embodiment 19 compound 609
Figure PCTCN2022119392-appb-000153
Figure PCTCN2022119392-appb-000153
步骤1：化合物int_609-2的合成:Step 1: Synthesis of compound int_609-2:
Figure PCTCN2022119392-appb-000154
Figure PCTCN2022119392-appb-000154
将int_97-4(80mg,0.3mmol)溶于DCM(5mL)中，加入草酰氯(1mL)和一滴DMF，室温反应1小时后浓缩反应液得到酰氯中间体。将int_609-1(76mg,0.3mmol)溶于THF(5mL)中，加入NaH(100mg,60％含量)，室温搅拌半小时后将之前所得酰氯缓慢加入其中，升温至40℃反应5小时。LC-MS监测显示反应结束。减压浓缩反应液，加入50mL水淬灭反应，用DCM萃取(50mL*3)，合并有机相并用Na 2SO 4干燥，减压浓缩有机相得到粗产物，粗产物经过硅胶柱纯化，得到产物(61mg,收率：41％)。 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. Concentrate the reaction solution under reduced pressure, add 50 mL of water to quench the reaction, extract with DCM (50 mL*3), combine the organic phases and dry with Na 2 SO 4 , concentrate the organic phase under reduced pressure to obtain the crude product, the crude product is purified by silica gel column to obtain the product (61 mg, yield: 41%).
ESI-MS m/z:501[M+H] +。 ESI-MS m/z: 501 [M+H] + .
步骤2：化合物609的合成:Step 2: Synthesis of compound 609:
Figure PCTCN2022119392-appb-000155
Figure PCTCN2022119392-appb-000155
将int_609-2(60mg,0.120mmol)，xantphos(7mg,0.012mmol)，碳酸铯(59mg,0.180mmol)，Pd 2(dba) 3(11mg,0.012mmol)和int_609-3(45mg,0.360mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(50mg,收率：71％)。 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%).
1H NMR(400MHz,dmso)δ12.39(s,1H),8.54(d,J＝1.5Hz,1H),7.81(s,1H),6.30(s,1H),3.69(td,J＝14.1,12.8,6.4Hz,6H),3.15(t,J＝7.0Hz,2H),2.91(s,4H),2.40(s,3H),2.17–2.02(m,4H),1.62(s, 4H),0.33(s,4H)。 1 H NMR (400MHz,dmso)δ12.39(s,1H),8.54(d,J=1.5Hz,1H),7.81(s,1H),6.30(s,1H),3.69(td,J=14.1 ,12.8,6.4Hz,6H),3.15(t,J＝7.0Hz,2H),2.91(s,4H),2.40(s,3H),2.17–2.02(m,4H),1.62(s, 4H) ,0.33(s,4H).
ESI-MS m/z:590[M+H] +。 ESI-MS m/z: 590 [M+H] + .
实施例20 化合物610的合成The synthesis of embodiment 20 compound 610
Figure PCTCN2022119392-appb-000156
Figure PCTCN2022119392-appb-000156
步骤1：化合物610的合成:Step 1: Synthesis of compound 610:
Figure PCTCN2022119392-appb-000157
Figure PCTCN2022119392-appb-000157
将int_225-1(8 0mg,0.1643mmol)，xantphos(10mg,0.0164mmol)，碳酸铯(80mg,0.2464mmol)，Pd 2(dba) 3(15mg,0.0164mmol)和int_610-1(22mg,0.246mmol)溶解在1,4-二氧六环(5mL)中，氩气置换三次，氩气保护下，反应液加热到100℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，将反应液旋干，柱层析纯化得固体(30mg,收率：34％)。 Int_225-1 (80mg, 0.1643mmol), xantphos (10mg, 0.0164mmol), cesium carbonate (80mg, 0.2464mmol), Pd 2 (dba) 3 (15mg, 0.0164mmol) and int_610-1 (22mg, 0.246mmol ) 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 (30 mg, yield: 34%).
1H NMR(400MHz,dmso)δ11.68(s,1H),8.53(s,1H),8.34(s,1H),8.08(d,J＝8.4Hz,1H),7.73(d,J＝8.5Hz,1H),6.63(s,1H),4.14(s,6H),3.77(t,J＝5.7Hz,4H),2.09(dd,J＝13.3,7.3Hz,4H),1.57(t,J＝5.2Hz,4H),1.19(s,6H),0.33(s,4H)。 1 H NMR (400MHz, dmso) δ11.68(s, 1H), 8.53(s, 1H), 8.34(s, 1H), 8.08(d, J=8.4Hz, 1H), 7.73(d, J=8.5 Hz,1H),6.63(s,1H),4.14(s,6H),3.77(t,J=5.7Hz,4H),2.09(dd,J=13.3,7.3Hz,4H),1.57(t,J =5.2Hz, 4H), 1.19(s, 6H), 0.33(s, 4H).
ESI-MS m/z:540[M+H] +。 ESI-MS m/z: 540 [M+H] + .
实施例21-610 化合物2-64,66-96,98-160,162-224,232-235,237-320,322-352,355-384,386-448,450-576,578-610的合成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
使用上述合成方法，采用不同原料，可以得到表1中目标化合物2-64,66-96,98-160,162-224,232-235,237-320,322-352,355-384,386-448,450-576,578-610。Using the above synthesis method and using different raw materials, 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.
表1Table 1
Figure PCTCN2022119392-appb-000158
Figure PCTCN2022119392-appb-000158
Figure PCTCN2022119392-appb-000159
Figure PCTCN2022119392-appb-000159
Figure PCTCN2022119392-appb-000160
Figure PCTCN2022119392-appb-000160
Figure PCTCN2022119392-appb-000161
Figure PCTCN2022119392-appb-000161
Figure PCTCN2022119392-appb-000162
Figure PCTCN2022119392-appb-000162
Figure PCTCN2022119392-appb-000163
Figure PCTCN2022119392-appb-000163
Figure PCTCN2022119392-appb-000164
Figure PCTCN2022119392-appb-000164
Figure PCTCN2022119392-appb-000165
Figure PCTCN2022119392-appb-000165
Figure PCTCN2022119392-appb-000166
Figure PCTCN2022119392-appb-000166
Figure PCTCN2022119392-appb-000167
Figure PCTCN2022119392-appb-000167
Figure PCTCN2022119392-appb-000168
Figure PCTCN2022119392-appb-000168
Figure PCTCN2022119392-appb-000169
Figure PCTCN2022119392-appb-000169
Figure PCTCN2022119392-appb-000170
Figure PCTCN2022119392-appb-000170
Figure PCTCN2022119392-appb-000171
Figure PCTCN2022119392-appb-000171
Figure PCTCN2022119392-appb-000172
Figure PCTCN2022119392-appb-000172
Figure PCTCN2022119392-appb-000173
Figure PCTCN2022119392-appb-000173
Figure PCTCN2022119392-appb-000174
Figure PCTCN2022119392-appb-000174
Figure PCTCN2022119392-appb-000175
Figure PCTCN2022119392-appb-000175
Figure PCTCN2022119392-appb-000176
Figure PCTCN2022119392-appb-000176
Figure PCTCN2022119392-appb-000177
Figure PCTCN2022119392-appb-000177
Figure PCTCN2022119392-appb-000178
Figure PCTCN2022119392-appb-000178
Figure PCTCN2022119392-appb-000179
Figure PCTCN2022119392-appb-000179
Figure PCTCN2022119392-appb-000180
Figure PCTCN2022119392-appb-000180
Figure PCTCN2022119392-appb-000181
Figure PCTCN2022119392-appb-000181
Figure PCTCN2022119392-appb-000182
Figure PCTCN2022119392-appb-000182
Figure PCTCN2022119392-appb-000183
Figure PCTCN2022119392-appb-000183
Figure PCTCN2022119392-appb-000184
Figure PCTCN2022119392-appb-000184
Figure PCTCN2022119392-appb-000185
Figure PCTCN2022119392-appb-000185
Figure PCTCN2022119392-appb-000186
Figure PCTCN2022119392-appb-000186
Figure PCTCN2022119392-appb-000187
Figure PCTCN2022119392-appb-000187
Figure PCTCN2022119392-appb-000188
Figure PCTCN2022119392-appb-000188
Figure PCTCN2022119392-appb-000189
Figure PCTCN2022119392-appb-000189
实施例611 本发明化合物体外抑制KIF18A酶活试验Example 611 Compounds of the present invention inhibit KIF18A enzyme activity test in vitro
KIF18A酶测定：使用微管刺激的ATP酶活实验测量用化合物处理后的KIF18A酶活性。该测定测量由ATP酶反应生成的ADP。在22个浓度点范围内，将化合物在DMSO中连续稀释2倍。使用杆状病毒***表达重组人KIF18A(1-467His-标记的)蛋白。使用ADP-Glo激酶/ATP酶测定试剂盒对反应中的KIF18A蛋白、微管(Microtubules)和ATP的浓度进行优化以进行标准化的同质酶测定。制备反应缓冲液[(15mM Tris，pH 7.5)，10mM MgCl 2，0.01％PluronicF-68，1μM紫杉醇和30μg/mL猪微管]。向制备的反应缓冲液中添加化合物和KIF18A蛋白(30nM)并在室温下孵育15min，接下来向反应混合物中添加ATP(Km,75μM)，在室温下再孵育15min。将5μL的ADP-Glo试剂和2.5μL的反应混合物混合并在室温下孵育40min。添加10μLADP-Glo检测试剂，并在室温下孵育40min。使用酶标仪读取发光，与DMSO组相比，进而计算化合物抑制百分比和IC 50。结果见下列表2。 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 μM paclitaxel and 30 μg/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 μM) was added to the reaction mixture and incubated at room temperature for another 15 min. 5 μL of ADP-Glo reagent and 2.5 μL of reaction mixture were mixed and incubated at room temperature for 40 min. Add 10 μL 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.
表2.本发明化合物对KIF18A的抑制活性(IC 50,nM) Table 2. The inhibitory activity of the compounds of the present invention on KIF18A (IC 50 , nM)
化合物compound IC 50 IC50 化合物compound IC 50 IC50 化合物compound IC 50 IC50 化合物compound IC 50 IC50
11 ++++++ 22 ++++++ 33 ++++++ 44 ++++++
55 ++++++ 66 ++++++ 77 ++++++ 88 ++++++
99 ++++++ 1010 ++++++ 1111 ++++++ 1212 ++++++
1313 ++++++ 1414 ++++++ 1515 ++++++ 1616 ++++++
1717 ++++++ 1818 ++++++ 1919 ++++++ 2020 ++++++
21twenty one ++++++ 22twenty two ++++++ 23twenty three ++++++ 24twenty four ++++++
2525 ++++++ 2626 ++++++ 2727 ++++++ 2828 ++++++
2929 ++++++ 3030 ++++++ 3131 ++++++ 3232 ++++++
3333 ++++++ 3434 ++++++ 3535 ++++++ 3636 ++++++
3737 ++++++ 3838 ++++++ 3939 ++++++ 4040 ++++++
4141 ++++++ 4242 ++++++ 4343 ++++++ 4444 ++++++
4545 ++++++ 4646 ++++++ 4747 ++++++ 4848 ++++++
4949 ++++++ 5050 ++++++ 5151 ++++++ 5252 ++++++
5353 ++++++ 5454 ++++++ 5555 ++++++ 5656 ++++++
5757 ++++++ 5858 ++++++ 5959 ++++++ 6060 ++++++
6161 ++++++ 6262 ++++++ 6363 ++++++ 6464 ++++++
6565 ++++++ 6666 ++++++ 6767 ++++++ 6868 ++++++
6969 ++++++ 7070 ++++++ 7171 ++++++ 7272 ++++++
7373 ++++++ 7474 ++++++ 7575 ++++++ 7676 ++++++
7777 ++++++ 7878 ++++++ 7979 ++++++ 8080 ++++++
8181 ++++++ 8282 ++++++ 8383 ++++++ 8484 ++++++
8585 ++++++ 8686 ++++++ 8787 ++++++ 8888 ++++++
8989 ++++++ 9090 ++++++ 9191 ++++++ 9292 ++++++
9393 ++++++ 9494 ++++++ 9595 ++++++ 9696 ++++++
9797 ++++++ 9898 ++++++ 9999 ++++++ 100100 ++++++
101101 ++++++ 102102 ++++++ 103103 ++++++ 104104 ++++++
105105 ++++++ 106106 ++++++ 107107 ++++++ 108108 ++++++
109109 ++++++ 110110 ++++++ 111111 ++++++ 112112 ++++++
113113 ++++++ 114114 ++++++ 115115 ++++++ 116116 ++++++
117117 ++++++ 118118 ++++++ 119119 ++++++ 120120 ++++++
121121 ++++++ 122122 ++++++ 123123 ++++++ 124124 ++++++
125125 ++++++ 126126 ++++++ 127127 ++++++ 128128 ++++++
129129 ++++++ 130130 ++++++ 131131 ++++++ 132132 ++++++
133133 ++++++ 134134 ++++++ 135135 ++++++ 136136 ++++++
137137 ++++++ 138138 ++++++ 139139 ++++++ 140140 ++++++
141141 ++++++ 142142 ++++++ 143143 ++++++ 144144 ++++++
145145 ++++++ 146146 ++++++ 147147 ++++++ 148148 ++++++
149149 ++++++ 150150 ++++++ 151151 ++++++ 152152 ++++++
153153 ++++++ 154154 ++++++ 155155 ++++++ 156156 ++++++
157157 ++++++ 158158 ++++++ 159159 ++++++ 160160 ++++++
161161 ++++++ 162162 ++++++ 163163 ++++++ 164164 ++++++
165165 ++++++ 166166 ++++++ 167167 ++++++ 168168 ++++++
169169 ++++++ 170170 ++++++ 171171 ++++++ 172172 ++++++
173173 ++++++ 174174 ++++++ 175175 ++++++ 176176 ++++++
177177 ++++++ 178178 ++++++ 179179 ++++++ 180180 ++++++
181181 ++++++ 182182 ++++++ 183183 ++++++ 184184 ++++++
185185 ++++++ 186186 ++++++ 187187 ++++++ 188188 ++++++
189189 ++++++ 190190 ++++++ 191191 ++++++ 192192 ++++++
193193 ++++++ 194194 ++++++ 195195 ++++++ 196196 ++++++
197197 ++++++ 198198 ++++++ 199199 ++++++ 200200 ++++++
201201 ++++++ 202202 ++++++ 203203 ++++++ 204204 ++++++
205205 ++++++ 206206 ++++++ 207207 ++++++ 208208 ++++++
209209 ++++++ 210210 ++++++ 211211 ++++++ 212212 ++++++
213213 ++++++ 214214 ++++++ 215215 ++++++ 216216 ++++++
217217 ++++++ 218218 ++++++ 219219 ++++++ 220220 ++++++
221221 ++++++ 222222 ++++++ 223223 ++++++ 224224 ++++++
225225 ++++++ 226226 ++++++ 227227 ++++++ 228228 ++++++
229229 ++++++ 230230 ++++++ 231231 ++++++ 232232 ++++++
233233 ++++++ 234234 ++++++ 235235 ++++++ 236236 ++++++
237237 ++++++ 238238 ++++++ 239239 ++++++ 240240 ++++++
241241 ++++++ 242242 ++++++ 243243 ++++++ 244244 ++++++
245245 ++++++ 246246 ++++++ 247247 ++++++ 248248 ++++++
249249 ++++++ 250250 ++++++ 251251 ++++++ 252252 ++++++
253253 ++++++ 254254 ++++++ 255255 ++++++ 256256 ++++++
257257 ++++++ 258258 ++++++ 259259 ++++++ 260260 ++++++
261261 ++++++ 262262 ++++++ 263263 ++++++ 264264 ++++++
265265 ++++++ 266266 ++++++ 267267 ++++++ 268268 ++++++
269269 ++++++ 270270 ++++++ 271271 ++++++ 272272 ++++++
273273 ++++++ 274274 ++++++ 275275 ++++++ 276276 ++++++
277277 ++++++ 278278 ++++++ 279279 ++++++ 280280 ++++++
281281 ++++++ 282282 ++++++ 283283 ++++++ 284284 ++++++
285285 ++++++ 286286 ++++++ 287287 ++++++ 288288 ++++++
289289 ++++++ 290290 ++++++ 291291 ++++++ 292292 ++++++
293293 ++++++ 294294 ++++++ 295295 ++++++ 296296 ++++++
297297 ++++++ 298298 ++++++ 299299 ++++++ 300300 ++++++
301301 ++++++ 302302 ++++++ 303303 ++++++ 304304 ++++++
305305 ++++++ 306306 ++++++ 307307 ++++++ 308308 ++++++
309309 ++++++ 310310 ++++++ 311311 ++++++ 312312 ++++++
313313 ++++++ 314314 ++++++ 315315 ++++++ 316316 ++++++
317317 ++++++ 318318 ++++++ 319319 ++++++ 320320 ++++++
321321 ++++++ 322322 ++++++ 323323 ++++++ 324324 ++++++
325325 ++++++ 326326 ++++++ 327327 ++++++ 328328 ++++++
329329 ++++++ 330330 ++++++ 331331 ++++++ 332332 ++++++
333333 ++++++ 334334 ++++++ 335335 ++++++ 336336 ++++++
337337 ++++++ 338338 ++++++ 339339 ++++++ 340340 ++++++
341341 ++++++ 342342 ++++++ 343343 ++++++ 344344 ++++++
345345 ++++++ 346346 ++++++ 347347 ++++++ 348348 ++++++
349349 ++++++ 350350 ++++++ 351351 ++++++ 352352 ++++++
353353 ++++++ 354354 ++++++ 355355 ++++++ 356356 ++++++
357357 ++++++ 358358 ++++++ 359359 ++++++ 360360 ++++++
361361 ++++++ 362362 ++++++ 363363 ++++++ 364364 ++++++
365365 ++++++ 366366 ++++++ 367367 ++++++ 368368 ++++++
369369 ++++++ 370370 ++++++ 371371 ++++++ 372372 ++++++
373373 ++++++ 374374 ++++++ 375375 ++++++ 376376 ++++++
377377 ++++++ 378378 ++++++ 379379 ++++++ 380380 ++++++
381381 ++++++ 382382 ++++++ 383383 ++++++ 384384 ++++++
385385 ++++++ 386386 ++++++ 387387 ++++++ 388388 ++++++
389389 ++++++ 390390 ++++++ 391391 ++++++ 392392 ++++++
393393 ++++++ 394394 ++++++ 395395 ++++++ 396396 ++++++
397397 ++++++ 398398 ++++++ 399399 ++++++ 400400 ++++++
401401 ++++++ 402402 ++++++ 403403 ++++++ 404404 ++++++
405405 ++++++ 406406 ++++++ 407407 ++++++ 408408 ++++++
409409 ++++++ 410410 ++++++ 411411 ++++++ 412412 ++++++
413413 ++++++ 414414 ++++++ 415415 ++++++ 416416 ++++++
417417 ++++++ 418418 ++++++ 419419 ++++++ 420420 ++++++
421421 ++++++ 422422 ++++++ 423423 ++++++ 424424 ++++++
425425 ++++++ 426426 ++++++ 427427 ++++++ 428428 ++++++
429429 ++++++ 430430 ++++++ 431431 ++++++ 432432 ++++++
433433 ++++++ 434434 ++++++ 435435 ++++++ 436436 ++++++
437437 ++++++ 438438 ++++++ 439439 ++++++ 440440 ++++++
441441 ++++++ 442442 ++++++ 443443 ++++++ 444444 ++++++
445445 ++++++ 446446 ++++++ 447447 ++++++ 448448 ++++++
449449 ++++++ 450450 ++++++ 451451 ++++++ 452452 ++++++
453453 ++++++ 454454 ++++++ 455455 ++++++ 456456 ++++++
457457 ++++++ 458458 ++++++ 459459 ++++++ 460460 ++++++
461461 ++++++ 462462 ++++++ 463463 ++++++ 464464 ++++++
465465 ++++++ 466466 ++++++ 467467 ++++++ 468468 ++++++
469469 ++++++ 470470 ++++++ 471471 ++++++ 472472 ++++++
473473 ++++++ 474474 ++++++ 475475 ++++++ 476476 ++++++
477477 ++++++ 478478 ++++++ 479479 ++++++ 480480 ++++++
481481 ++++++ 482482 ++++++ 483483 ++++++ 484484 ++++++
485485 ++++++ 486486 ++++++ 487487 ++++++ 488488 ++++++
489489 ++++++ 490490 ++++++ 491491 ++++++ 492492 ++++++
493493 ++++++ 494494 ++++++ 495495 ++++++ 496496 ++++++
497497 ++++++ 498498 ++++++ 499499 ++++++ 500500 ++++++
501501 ++++++ 502502 ++++++ 503503 ++++++ 504504 ++++++
505505 ++++++ 506506 ++++++ 507507 ++++++ 508508 ++++++
509509 ++++++ 510510 ++++++ 511511 ++++++ 512512 ++++++
513513 ++++++ 514514 ++++++ 515515 ++++++ 516516 ++++++
517517 ++++++ 518518 ++++++ 519519 ++++++ 520520 ++++++
521521 ++++++ 522522 ++++++ 523523 ++++++ 524524 ++++++
525525 ++++++ 526526 ++++++ 527527 ++++++ 528528 ++++++
529529 ++++++ 530530 ++++++ 531531 ++++++ 532532 ++++++
533533 ++++++ 534534 ++++++ 535535 ++++++ 536536 ++++++
537537 ++++++ 538538 ++++++ 539539 ++++++ 540540 ++++++
541541 ++++++ 542542 ++++++ 543543 ++++++ 544544 ++++++
545545 ++++++ 546546 ++++++ 547547 ++++++ 548548 ++++++
549549 ++++++ 550550 ++++++ 551551 ++++++ 552552 ++++++
553553 ++++++ 554554 ++++++ 555555 ++++++ 556556 ++++++
557557 ++++++ 558558 ++++++ 559559 ++++++ 560560 ++++++
561561 ++++++ 562562 ++++++ 563563 ++++++ 564564 ++++++
565565 ++++++ 566566 ++++++ 567567 ++++++ 568568 ++++++
569569 ++++++ 570570 ++++++ 571571 ++++++ 572572 ++++++
573573 ++++++ 574574 ++++++ 575575 ++++++ 576576 ++++++
577577 ++++++ 578578 ++++++ 579579 ++++++ 580580 ++++++
581581 ++++++ 582582 ++++++ 583583 ++++++ 584584 ++++++
585585 ++++++ 586586 ++++++ 587587 ++++++ 588588 ++++++
589589 ++++++ 590590 ++++++ 591591 ++++++ 592592 ++++++
593593 ++++++ 594594 ++++++ 595595 ++++++ 596596 ++++++
597597 ++++++ 598598 ++++++ 599599 ++++++ 600600 ++++++
601601 ++++++ 602602 ++++++ 603603 ++++++ 604604 ++++++
605605 ++++++ 606606 ++++++ 607607 ++++++ 608608 ++++++
609609 ++++++ 610610 ++++  the  the  the  the
+++表示IC 50小于或等于100nM +++ means IC 50 less than or equal to 100nM
++表示IC 50为100nM至500nM ++ means IC50 from 100nM to 500nM
+表示IC 50大于500nM。 + indicates IC50 greater than 500nM.
从表2数据可知，本发明化合物对KIF18A的酶活性有较好的抑制活性。It can be seen from the data in Table 2 that the compounds of the present invention have better inhibitory activity on the enzyme activity of KIF18A.
实施例612 本发明化合物对HT-29以及HCT116细胞的体外抗增殖活性Example 612 In vitro antiproliferative activity of compounds of the present invention on HT-29 and HCT116 cells
2000/孔HT-29或1000/孔HCT116细胞铺于384孔板，过夜贴壁后，加入DMSO或者最高浓度为10μM,1:5梯度稀释的化合物。加药后72小时，通过测定细胞内ATP含量，评价细胞存活。与DMSO组相比计算化合物抑制细胞存活的百分比，计算IC 50值，结果见下列表3。 2000/well HT-29 or 1000/well HCT116 cells were plated in a 384-well plate, and after overnight attachment, DMSO or a compound with a maximum concentration of 10 μM and a 1:5 gradient dilution was added. 72 hours after adding the drug, the cell survival was evaluated by measuring the ATP content in the cells. Comparing with the DMSO group, the percentage of inhibition of cell survival by the compound was calculated, and the IC 50 value was calculated. The results are shown in Table 3 below.
表3 本发明化合物对HT-29或HCT116细胞的抗增殖活性Table 3 Compounds of the present invention have anti-proliferative activity on HT-29 or HCT116 cells
化合物compound HT-29(IC 50,nM) HT-29 (IC 50 ,nM) HCT116(IC 50,nM) HCT116 (IC 50 ,nM)
11 >1000>1000 >10000>10000
6565 >1000>1000 >10000>10000
9797 >1000>1000 >10000>10000
161161 129129 >10000>10000
225225 5656 >10000>10000
226226 11851185 >10000>10000
227227 >1000>1000 >10000>10000
228228 774774 >10000>10000
229229 >1000>1000 >10000>10000
230230 316316 >10000>10000
231231 897897 >10000>10000
236236 >1000>1000 >10000>10000
321321 675675 >10000>10000
353353 >1000>1000 >10000>10000
385385 266266 >10000>10000
449449 >1000>1000 >10000>10000
577577 10001000 >10000>10000
609609 253253 >10000>10000
610610 >1000>1000 24842484
从表3数据可知，本发明大多数化合物对具有染色体不稳定性的HT-29细胞有较好的抑制活性，而对不具有染色体不稳定性的HCT116细胞没有抑制活性。It can be seen from the data in Table 3 that most of the compounds of the present invention have good inhibitory activity on HT-29 cells with chromosomal instability, but have no inhibitory activity on HCT116 cells without chromosomal instability.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (29)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
    Figure PCTCN2022119392-appb-100001
    Figure PCTCN2022119392-appb-100001
    通式(1)中：In general formula (1):
    X 1为-CR 5＝或N； X 1 is -CR 5 = or N;
    X 2为-CR 6＝或N； X 2 is -CR 6 = or N;
    X 3为-CR 7＝或N； X 3 is -CR 7 = or N;
    X 4为-CR 4＝或N； X 4 is -CR 4 = or N;
    X 5为-CR 15＝或N； X 5 is -CR 15 = or N;
    当X 2以及X 3中至少一个为N和X 4以及X 5中至少一个为N时，L为-(C＝O)-NR 9-或-NR 9-(C＝O)-；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When at least one of X 2 and X 3 is N and at least one of X 4 and X 5 is N, L is -(C=O)-NR 9 - or -NR 9 -(C=O)-; and X Among 1 , X 2 , X 3 , X 4 and X 5 , no more than 4 are N;
    当X 1为N时，L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When X 1 is N, L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and among X 1 , X 2 , X 3 , X 4 and X 5 , Not more than 4 are N;
    当X 4为N和X 5不为N时，L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*；和X 1、X 2、X 3、X 4和X 5中，不超过4个为N； When X 4 is N and X 5 is not N, L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 , X 2 , X 3 , X Among 4 and X 5 , no more than 4 are N;
    当X 5为N和X 1、X 2、X 3均不为N时，L为-(C＝O)-NR 9-*； When X 5 is N and X 1 , X 2 , and X 3 are not N, L is -(C=O)-NR 9 -*;
    *代表连接的是
    Figure PCTCN2022119392-appb-100002
    端；     *Represents the connected
    Figure PCTCN2022119392-appb-100002
    end;
    R 1为-CN或-Z-R 10，其中Z为化学键、-C 0-4烃基-、-NR 11-、-NR 11SO 2-、-SO 2NR 11-、-NR 11-S(＝O)(＝NH)-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-C 0-4烃基-O-、-(C＝O)-、-(C＝O)NR 11-、-C(＝N-OH)-或-NR 11(C＝O)-；或所述基团-Z-R 10为-N＝S(＝O)-(R 10) 2，其中所述两个R 10与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环； R 1 is -CN or -ZR 10 , wherein Z is a chemical bond, -C 0-4 alkyl-, -NR 11 -, -NR 11 SO 2 -, -SO 2 NR 11 -, -NR 11 -S(=O )(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -C 0-4 Hydrocarbyl-O-, -(C= O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 is -N=S(=O )-(R 10 ) 2 , wherein the two R 10 are combined with their respective attached sulfur atoms to form a compound containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S A saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring;
    R 2为卤素或基团-Y-R 12，其中Y为化学键、-C 0-4烃基-、-N(C 0-1烃基)-C 0-4烃基-、-C(＝O)NR a-(C 1- 4烃基)-、-O-C 0-4烃基-、-S-、-S(＝O)-、-SO 2-、-SO 2NR 12-或-S(＝O)(＝NH)-； R 2 is halogen or a group -YR 12 , wherein Y is a chemical bond, -C 0-4 alkyl-, -N(C 0-1 alkyl)-C 0-4 alkyl-, -C(=O)NR a - (C 1- 4 alkyl)-, -OC 0-4 alkyl-, -S-, -S(=O)-, -SO 2 -, -SO 2 NR 12 - or -S(=O)(=NH )-;
    R 3为H、卤素、C 1-8烃基或C 1-4卤代烃基； R 3 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
    R 4为H、卤素、R 4a或R 4b； R 4 is H, halogen, R 4a or R 4b ;
    R 5为H、卤素、C 1-8烷基或C 1-4卤代烷基； R 5 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl;
    R 6为H、卤素、C 1-8烷基、C 1-4卤代烷基、-OH、-O-R 6a或-O-R 6b； R 6 is H, halogen, C 1-8 alkyl, C 1-4 haloalkyl, -OH, -OR 6a or -OR 6b ;
    R 7为H、卤素、C 1-8烃基或C 1-4卤代烃基； R 7 is H, halogen, C 1-8 hydrocarbon group or C 1-4 halogenated hydrocarbon group;
    R 8选自由以下组成的组： R is selected from the group consisting of:
    Figure PCTCN2022119392-appb-100003
    Figure PCTCN2022119392-appb-100003
    R 13a、R 13b、R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立地为H、卤素、R 13m或R 13n；或R 13a和R 13b对、R 13c和R 13d对、R 13e和R 13f对、R 13g和R 13h对、R 13i和R 13j对或R 13k和R 13l对中的每一对可以独立地与它们各自连接的碳原子组成螺接到R 8环的饱和的或部分饱和的3元、4元、5元、6元单环；其中所述3元、4元、5元、6元单环含有0、1、2或3个N原子和0、1或2个选自O和S的原子，并且进一步地，其中所述3元、4元、5元、6元单环被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-NR aR a或氧代； 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, 5-membered, 6-membered monocyclic ring is selected from the following Substitution of 0, 1, 2 or 3 groups: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OR a , -OC 1-4 halogenated hydrocarbon group, CN, -NR a R a or oxo;
    R 9为H或C 1-6烃基； R 9 is H or C 1-6 hydrocarbon group;
    R 10为H、R 10a或R 10b； R 10 is H, R 10a or R 10b ;
    R 11为H、R 11a或R 11b； R 11 is H, R 11a or R 11b ;
    R 12为R 12a或R 12b； R 12 is R 12a or R 12b ;
    R 15为H、卤素、C 1-8烃基、C 1-4卤代烃基、-O-C 1-8烃基或-O-R 15a，其中R 15a为含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环； 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 4a、R 6a、R 10a、R 11a、R 12a或R 13m为在每种情况下独立地选自：含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环可各自独立任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-C(＝O)R b、-C(＝O)OR a、-C(＝O)NR aR a、-C(＝NR a)NR aR a、-OC(＝O)R b、-OC(＝O)NR aR a、-OC 2-6烃基NR aR a、-OC 2-6烃基OR a、-SR a、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR aR a、-NR aR a、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR aR a、-N(R a)C(＝NR a)NR aR a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR aR a、-NR aC 2-6烃基NR aR a、-NR aC 2-6烃基OR a、-C 1-6烃基NR aR a、-C 1-6烃基OR a、-C 1-6烃基N(R a)C(＝O)R b、-C 1-6烃基OC(＝O)R b、-C 1-6烃基C(＝O)NR aR a、-C 1-6烃基C(＝O)OR a、R 14和氧代； R 4a , R 6a , R 10a , R 11a , R 12a or R 13m are in each case independently selected from: containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and Saturated, partially saturated or unsaturated 3-membered, 5-membered, 6-membered or 7-membered monocyclic rings or 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered rings of S atoms 11-membered or 12-membered bicyclic rings, wherein the monocyclic 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 halohydrocarbyl, -OR a , -OC 1-4 halohydrocarbyl, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , - C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2-6 alkyl NR a R a , -OC 2-6 alkyl OR a , -SR a , -S(=O)R b , -S(=O) 2 R b , -S(=O) 2 NR a R a , -NR a R a , -N(R a )C( =O)R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O) 2 R b , -N(R a )S(=O) 2 NR a R a , -NR a C 2-6 hydrocarbyl NR a R a , -NR a C 2-6 hydrocarbon group OR a , -C 1-6 hydrocarbon group NR a R a , -C 1-6 hydrocarbon group OR a , -C 1-6 hydrocarbon group N(R a )C(=O)R b , -C 1-6 hydrocarbyl OC(=O)R b , -C 1-6 hydrocarbyl C(=O)NR a R a , -C 1-6 hydrocarbyl C(=O)OR a , R 14 and oxo;
    R 4b、R 6b、R 10b、R 11b、R 12b或R 13n为在每种情况下独立地选自：C 1-6烃基，其中所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、-R a、-OR a、-OC 1-4卤代烃基和CN； 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 14在每种情况下独立地选自由以下组成的组：含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环各自独立可任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OR a、-OC 1-4卤代烃基、CN、-C(＝O)R b、-C(＝ O)OR a、-C(＝O)NR aR a、-C(＝NR a)NR aR a、-OC(＝O)R b、-OC(＝O)NR aR a、-OC 2-6烃基NR aR a、-OC 2-6烃基OR a、-SR a、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR aR a、-NR aR a、-N(R a)C(＝O)R b、-N(R a)C(＝O)OR b、-N(R a)C(＝O)NR aR a、-N(R a)C(＝NR a)NR aR a、-N(R a)S(＝O) 2R b、-N(R a)S(＝O) 2NR aR a、-NR aC 2-6烃基NR aR a、-NR aC 2-6烃基OR a、-C 1-6烃基NR aR a、-C 1-6烃基OR a、-C 1-6烃基N(R a)C(＝O)R b、-C 1-6烃基OC(＝O)R b、-C 1-6烃基C(＝O)NR aR a、-C 1-6烃基C(＝O)OR a和氧代； R 14 is in each case independently selected from the group consisting of saturated, partially saturated or unsaturated 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 are independently 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, -OR a , -OC 1-4 Halogenated hydrocarbon group, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC( =O)R b , -OC(=O)NR a R a , -OC 2-6 alkylNR a R a , -OC 2-6 alkyl OR a , -SR a , -S(=O)R b , -S(=O) 2 R b , -S(=O) 2 NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C( =O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O) 2 R b , -N(R a )S(=O) 2 NR a R a , -NR a C 2-6 alkylNR a R a , -NR a C 2-6 alkyl OR a , -C 1-6 Hydrocarbyl NR a R a , -C 1-6 hydrocarbyl OR a , -C 1-6 hydrocarbyl N(R a )C(=O)R b , -C 1-6 hydrocarbyl OC(=O)R b , -C 1-6 hydrocarbyl C(=O)NR a R a , -C 1-6 hydrocarbyl C(=O)OR a and oxo;
    R a在每种情况下独立地为H或R b；并且 R a is independently H or R b at each occurrence; and
    R b在每种情况下独立地为C 1-6烃基、苯基或苄基，其中所述烃基可任选被0、1、2或3个下列基团取代：卤素、-OH、-OC 1-4烃基、-NH 2、-NHC 1-4烃基、-OC(＝O)C 1-4烃基或-N(C 1-4烃基)C 1-4烃基；并且其中所述苯基和苄基可各自独立任选被0、1、2或3个下列基团取代：卤素、C 1-4烃基、C 1-3卤代烃基、-OH、-OC 1-4烃基、-NH 2、-NHC 1-4烃基、-OC(＝O)C 1-4烃基或-N(C 1-4烃基)C 1-4烃基。 Each occurrence of R is independently C 1-6 hydrocarbyl, phenyl or benzyl, wherein said hydrocarbyl may be optionally substituted by 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 hydrocarbyl, -NH 2 , -NHC 1-4 hydrocarbyl, -OC(=O)C 1-4 hydrocarbyl or -N(C 1-4 hydrocarbyl)C 1-4 hydrocarbyl; and wherein the phenyl and Benzyl groups can be independently and optionally substituted by 0, 1, 2 or 3 of the following groups: halogen, C 1-4 alkyl, C 1-3 halogenated hydrocarbon, -OH, -OC 1-4 alkyl, -NH 2 , -NHC 1-4 hydrocarbon group, -OC(=O)C 1-4 hydrocarbon group or -N(C 1-4 hydrocarbon group)C 1-4 hydrocarbon group.
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1),
    (a)当X 1、X 2、X 3和X 5为-CH＝，X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(1a)和式(1b)：
    Figure PCTCN2022119392-appb-100004
    (a) When X 1 , X 2 , X 3 and X 5 are -CH=, X 4 is N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (1a) and formula (1b):
    Figure PCTCN2022119392-appb-100004
    (b)当X 1、X 2和X 5为-CH＝，X 3和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(2a)和式(2b)：
    Figure PCTCN2022119392-appb-100005
    (b) When X 1 , X 2 and X 5 are -CH=, X 3 and X 4 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (2a) and formula (2b):
    Figure PCTCN2022119392-appb-100005
    (c)当X 1、X 3和X 5为-CH＝，X 2和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(3a)和 式(3b)：
    Figure PCTCN2022119392-appb-100006
    (c) When X 1 , X 3 and X 5 are -CH=, X 2 and X 4 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (3a) and formula (3b):
    Figure PCTCN2022119392-appb-100006
    (d)当X 2、X 3和X 5为-CH＝，X 1和X 4为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(4a)和式(4b)：
    Figure PCTCN2022119392-appb-100007
    (d) When X 2 , X 3 and X 5 are -CH=, X 1 and X 4 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (4a) and formula (4b):
    Figure PCTCN2022119392-appb-100007
    (e)当X 1、X 2和X 4为-CH＝，X 3和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(5a)和式(5b)：
    Figure PCTCN2022119392-appb-100008
    (e) When X 1 , X 2 and X 4 are -CH=, X 3 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (5a) and formula (5b):
    Figure PCTCN2022119392-appb-100008
    (f)当X 1、X 3和X 4为-CH＝，X 2和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(6a)和式(6b)：
    Figure PCTCN2022119392-appb-100009
    (f) When X 1 , X 3 and X 4 are -CH=, X 2 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (6a) and formula (6b):
    Figure PCTCN2022119392-appb-100009
    (g)当X 1和X 2为-CH＝，X 3、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(7a)和 式(7b)：
    Figure PCTCN2022119392-appb-100010
    (g) When X 1 and X 2 are -CH=, X 3 , X 4 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (7a) and formula (7b):
    Figure PCTCN2022119392-appb-100010
    (h)当X 1和X 3为-CH＝，X 2、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(8a)和式(8b)：
    Figure PCTCN2022119392-appb-100011
    (h) When X 1 and X 3 are -CH=, X 2 , X 4 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (8a) and formula (8b):
    Figure PCTCN2022119392-appb-100011
    (i)当X 1、X 2、X 3和X 4为-CH＝，X 5为N，和L为-(C＝O)-NR 9-*时，具有式(9a)： (i) When X 1 , X 2 , X 3 and X 4 are -CH=, X 5 is N, and L is -(C=O)-NR 9 -*, has formula (9a):
    Figure PCTCN2022119392-appb-100012
    Figure PCTCN2022119392-appb-100012
    (j)当X 1、X 2和X 3为-CH＝，X 4和X 5为N，和L为-(C＝O)-NR 9-*时，具有式(10a)： (j) When X 1 , X 2 and X 3 are -CH=, X 4 and X 5 are N, and L is -(C=O)-NR 9 -*, having the formula (10a):
    Figure PCTCN2022119392-appb-100013
    Figure PCTCN2022119392-appb-100013
    (k)当X 2、X 3、X 4和X 5为-CH＝，X 1为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(11a)和 式(11b)：
    Figure PCTCN2022119392-appb-100014
    (k) When X 2 , X 3 , X 4 and X 5 are -CH=, X 1 is N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (11a) and formula (11b):
    Figure PCTCN2022119392-appb-100014
    (l)当X 2、X 3、和X 4为-CH＝，X 1和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(12a)和式(12b)：
    Figure PCTCN2022119392-appb-100015
    (l) When X 2 , X 3 , and X 4 are -CH=, X 1 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O) -*, with formula (12a) and formula (12b):
    Figure PCTCN2022119392-appb-100015
    (m)当X 2和X 3为-CH＝，X 1、X 4和X 5为N，和L为-(C＝O)-NR 9-*或-NR 9-(C＝O)-*时，具有式(13a)和式(13b)：
    Figure PCTCN2022119392-appb-100016
    (m) When X 2 and X 3 are -CH=, X 1 , X 4 and X 5 are N, and L is -(C=O)-NR 9 -* or -NR 9 -(C=O)- *, with formula (13a) and formula (13b):
    Figure PCTCN2022119392-appb-100016
  3. 如权利要求1-2中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 9为H、甲基或乙基，优选为H。 The compound according to any one of claims 1-2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 9 is H, methyl or ethyl, preferably H.
  4. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立为H、卤素、C 1-6烃基或C 1-4卤代烃基；并且R 13a和R 13b对中的R 13a和R 13b与它们各自连接的碳原子可以组合形成螺接到R 8环的饱和3元、4元或5元单环；其中所述环含有0、1、2或3个N原子和0、1或2个选自O和S的原子；优选，R 13c、R 13d、R 13e、R 13f、R 13g、R 13h、R 13i、R 13j、R 13k和R 13l各自独立为H、甲基或乙基；并且R 13a和R 13b对中的R 13a和R 13b与它们各自连接的碳原子可以组合形成螺接到R 8环的环丙基、环丁基或环戊基环。 The compound according to claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein 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 R 13a and R 13b in the pair and their respective attached carbon atoms can combine to form a saturated 3-membered, 4-membered or 5-membered monocyclic ring spliced to the R ring; wherein the ring contains 0, 1, 2 or 3 N atom 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 is H, methyl or ethyl; and R 13a and R 13b in the pair of R 13a and R 13b can be combined with their respective carbon atoms to form a cyclopropyl, cyclobutyl or cyclopentyl spliced to the R ring base ring.
  5. 如权利要求1或4中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元
    Figure PCTCN2022119392-appb-100017
    为：
    Figure PCTCN2022119392-appb-100018
    优选为
    Figure PCTCN2022119392-appb-100019
    The compound according to any one of claims 1 or 4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structure unit
    Figure PCTCN2022119392-appb-100017
    for:
    Figure PCTCN2022119392-appb-100018
    preferably
    Figure PCTCN2022119392-appb-100019
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中Z为化学键、-NH-、-NHSO 2-、-SO 2NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-(C＝O)-、-(C＝O)NH-或-NH(C＝O)-。 The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein Z is a chemical bond, -NH-, -NHSO 2 -, -SO 2 NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -( C=O)-, -(C=O)NH- or -NH(C=O)-.
  7. 如权利要求1-6中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 10选自(a)H；或(b)C 1-6烃基，所述烃基可任选被0、1、2或3个下列基团取代：F、Cl、Br、-OH或-OCH 3；或(c)当所述-Z-R 10为-N＝S(＝O)-(R 10) 2，其中两个R 10可以与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环，其被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-C 1-6烃基OH、-OH、-OCH 3、-NH 2或氧代。 The compound according to any one of claims 1-6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 10 is selected from (a) H; or (b) C 1-6 hydrocarbyl, which can be optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH 3 ; or (c) when said -ZR 10 is -N=S(=O)-(R 10 ) 2 , wherein two R 10 can be combined with their respective attached sulfur atoms to form a compound containing 0, 1, 2 or a saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic ring of 3 N atoms and 0 or 1 atom selected from O and S, which is selected from Substitution of 0, 1, 2 or 3 groups: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -C 1-6 hydrocarbon group OH, -OH, -OCH 3 , -NH 2 or oxo.
  8. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 1为-CN或基团-Z-R 10，其中Z为化学键、-NH-、-NHSO 2-、-SO 2NH-、-S(＝O)(＝NH)-、-S-、-S(＝O)-、-SO 2-、-(C＝O)-、-(C＝O)NH-或-NH(C＝O)-；并且R 10选自： The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 1 is -CN or a group -ZR 10 , where Z is a bond, -NH-, -NHSO 2 -, -SO 2 NH-, -S(=O)(=NH)-, -S-, -S (=O)-, -SO2- , -(C=O)-, -(C=O)NH- or -NH(C=O)-; and R10 is selected from:
    (a)H；(a) H;
    (b)环丙基、环丁基、环戊基、环己基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、氮杂环丁烷基、咪唑基、吗啉基、吡咯烷基、哌嗪基、
    Figure PCTCN2022119392-appb-100020
    Figure PCTCN2022119392-appb-100021
    并且其中每个所述环可各自独立任选被0、1、2或3个下列基团取代：OH、F、甲基、-CH 2OH、-C(＝O)OCH 3、-C(＝O)OC(CH 3) 3、NH 2、CN和氧代；优选为氧杂环丁烷基、环丙基；或     (b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidine base, piperazinyl,
    Figure PCTCN2022119392-appb-100020
    Figure PCTCN2022119392-appb-100021
    And wherein each of said rings can be independently and optionally substituted with 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH 2 OH, -C(=O)OCH 3 , -C( =O)OC(CH 3 ) 3 , NH 2 , CN and oxo; preferably oxetanyl, cyclopropyl; or
    (c)被0、1、2或3个OH、F、-C(＝O)OCH 3、-NH 2、-NH(CH 3)或-N(CH 3) 2取代的C 1-6烃基；优选为被 0、1、2或3个OH基团取代的C 1-6烃基；更优选为被1个OH基团取代的C 1-6烃基。 (c) C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH, F, -C(=O)OCH 3 , -NH 2 , -NH(CH 3 ) or -N(CH 3 ) 2 ; preferably a C 1-6 hydrocarbon group substituted by 0, 1, 2 or 3 OH groups; more preferably a C 1-6 hydrocarbon group substituted by 1 OH group.
  9. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中所述基团-Z-R 10为-N＝S(＝O)-(R 10) 2，其中两个R 10对可以与它们各自连接的硫原子组合以形成含有0、1、2或3个N原子和0、1或2个选自O和S的原子的饱和的或部分饱和的3元、4元、5元或6元单环；优选基团-Z-R 10选自：
    Figure PCTCN2022119392-appb-100022
    The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein The group -ZR 10 is -N=S(=O)-(R 10 ) 2 , wherein two pairs of R 10 can combine with their respective attached sulfur atoms to form a compound containing 0, 1, 2 or 3 N Atoms and 0, 1 or 2 atoms selected from O and S are saturated or partially saturated 3-membered, 4-membered, 5-membered or 6-membered monocyclic rings; preferably the group -ZR 10 is selected from:
    Figure PCTCN2022119392-appb-100022
  10. 如权利要求1-8中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 1为基团-Z-R 10，其中Z为-NHSO 2-或-SO 2NH-；并且R 10为氧杂环丁烷基、环丙基，或R 10为被0、1、2或3个OH基团取代的C 1-6烃基；优选，R 1为基团-Z-R 10，其中Z为-NHSO 2-或-SO 2NH-，并且R 10为-CH 2-CH 2-OH或-CH(CH 3)-CH 2-OH；更优选Z为-NHSO 2-，并且R 10为-CH 2-CH 2-OH。 The compound according to any one of claims 1-8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 1 is a group -ZR 10 , wherein Z is -NHSO 2 - or -SO 2 NH-; and R 10 is oxetanyl, cyclopropyl, or R 10 is substituted by 0, 1, 2 or 3 C 1-6 hydrocarbyl substituted by 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( CH3 )-CH2 - OH; more preferably Z is -NHSO2- , and R10 is -CH2- CH2 -OH.
  11. 如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为卤素或基团-Y-R 12，其中Y为化学键、-NH-、-NH-(CH 2) 0-4-或-O-(CH 2) 0-4-；并且R 12为含有0、1、2或3个N原子和0或1个选自O和S的原子的饱和的、部分饱和的或不饱和的3元、4元、5元、6元或7元单环或4元、5元、6元、7元、8元、9元、10元、11元或12元双环，其中所述单环和双环可各自独立任选被0、1、2或3个下列基团取代：F、Cl、Br、C 1-6烃基、C 1-4卤代烃基、-OH、-OC 1-4卤代烃基、CN、R 14和氧代；或R 12为C 1-6烃基，所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、-OH、-OC 1-4卤代烃基或CN。 The compound according to any one of claims 1-10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 2 is 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 a group containing 0 , 1, 2 or 3 N atoms and 0 or 1 saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic ring or 4 membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic rings, wherein the monocyclic and bicyclic rings can each independently be optionally represented by 0, 1, 2 or 3 of the following groups Group substitution: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OH, -OC 1-4 halogenated hydrocarbon group, CN, R 14 and oxo; or R 12 is C 1- 6 hydrocarbyl, which may be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -OH, -OC 1-4 halohydrocarbyl or CN.
  12. 如权利要求1-11中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为饱和5元或6元单环，其中每个所述环含有0、1或2个N原子和0或1个O原子，并且其中每个所述环被选自以下的0、1、2或3个基团取代：F、Cl、Br、C 1- 6烃基、C 1-4卤代烃基、-OH、-OC 1-4卤代烃基、CN、R 14和氧代。 The compound according to any one of claims 1-11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R is a saturated 5-membered or 6-membered monocyclic ring, wherein each said ring contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and wherein each said ring is selected from the following 0, 1 , 2 or 3 group substitutions: F, Cl, Br, C 1-6 hydrocarbon group, C 1-4 halogenated hydrocarbon group, -OH, -OC 1-4 halogenated hydrocarbon group, CN, R 14 and oxo .
  13. 如权利要求1-12中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为(a)卤素；(b)基团-Y-R 12，其中Y为化学键；并且R 12为吗啉基、哌啶基、氮杂环丁烷基、吡咯烷基、环丙基、环丁基、环戊基、环己基、哌嗪基、四氢呋喃基、
    Figure PCTCN2022119392-appb-100023
    Figure PCTCN2022119392-appb-100024
    Figure PCTCN2022119392-appb-100025
    其中每个所述环被选自以下的0、1、2或3个基团取代：F、Cl、Br、甲基、CF 3、-OH、-OCHF 2、CN和氧代；或(c)基团-Y-R 12，其中Y为-NH-、-O-、-O-(CH 2)-、-O-(CH 2)-(CH 2)-或-O-(CH 2)-(CH 2)-(CH 2)-，并且其中R 12为
    Figure PCTCN2022119392-appb-100026
    或R 12为C 1-6烃基，所述烃基可任选被0、1、2、3、4或5个下列基团取代：F、Cl、Br、甲基、CF3、-OH或CN。     The compound according to any one of claims 1-12 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 2 is (a) halogen; (b) a group -YR 12 , wherein Y is a chemical bond; and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl,
    Figure PCTCN2022119392-appb-100023
    Figure PCTCN2022119392-appb-100024
    Figure PCTCN2022119392-appb-100025
    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 )-, and wherein R 12 is
    Figure PCTCN2022119392-appb-100026
    Or R 12 is C 1-6 hydrocarbon group, which can be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF 3 , -OH or CN.
  14. 如权利要求1-13中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为吗啉基或哌啶基，所述吗啉基和哌啶基可任选被0、1、2或3个下列基团取代：F、Cl、Br、甲基、CF 3、-OH、-OCHF 2和CN。 The compound according to any one of claims 1-13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 2 is morpholinyl or piperidinyl, which may be optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF 3 , - OH, -OCHF 2 and CN.
  15. 如权利要求1-14中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为被1、2或3个氟基团取代的哌啶基。 The compound according to any one of claims 1-14 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 2 is piperidinyl substituted by 1, 2 or 3 fluoro groups.
  16. 如权利要求1-13中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为：
    Figure PCTCN2022119392-appb-100027
    The compound according to any one of claims 1-13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R2 is:
    Figure PCTCN2022119392-appb-100027
  17. 如权利要求1-14中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为被1、2或3个甲基基团取代的吗啉基。 The compound according to any one of claims 1-14 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.
  18. 如权利要求1-13中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 2为
    Figure PCTCN2022119392-appb-100028
    Figure PCTCN2022119392-appb-100029
    The compound according to any one of claims 1-13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R2 is
    Figure PCTCN2022119392-appb-100028
    Figure PCTCN2022119392-appb-100029
  19. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 10选自环丙基、环丁基、环戊基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基或1,3,4-氧杂噻嗪烷基。 The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinyl.
  20. 如权利要求1-19中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 3为H。 The compound according to any one of claims 1-19 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R3 is H.
  21. 如权利要求1-20中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 4选自(a)H；(b)被0、1、2或3个OH基团取代的C 1-6烃基；或(c)环丙基；或(d)F；R 4优选为H、F或甲基；R 4更优选为H。 The compound according to any one of claims 1-20 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R is selected from (a) H; (b) C 1-6 hydrocarbyl substituted by 0, 1, 2 or 3 OH groups; or (c) cyclopropyl; or (d) F; R is preferably H, F or methyl; R4 is more preferably H.
  22. 如权利要求1-21中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 5为H或F，优选为H。 The compound according to any one of claims 1-21 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 5 is H or F, preferably H.
  23. 如权利要求1-22中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 6为H或F，优选为H。 The compound according to any one of claims 1-22 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R6 is H or F, preferably H.
  24. 如权利要求1-23中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 7为H。 The compound according to any one of claims 1-23 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R7 is H.
  25. 如权利要求1-24中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中R 15为H或F，优选为H。 The compound according to any one of claims 1-24 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein R 15 is H or F, preferably H.
  26. 如权利要求1-25中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：The compound according to any one of claims 1-25 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
    Figure PCTCN2022119392-appb-100030
    Figure PCTCN2022119392-appb-100030
    Figure PCTCN2022119392-appb-100031
    Figure PCTCN2022119392-appb-100031
    Figure PCTCN2022119392-appb-100032
    Figure PCTCN2022119392-appb-100032
    Figure PCTCN2022119392-appb-100033
    Figure PCTCN2022119392-appb-100033
    Figure PCTCN2022119392-appb-100034
    Figure PCTCN2022119392-appb-100034
    Figure PCTCN2022119392-appb-100035
    Figure PCTCN2022119392-appb-100035
    Figure PCTCN2022119392-appb-100036
    Figure PCTCN2022119392-appb-100036
    Figure PCTCN2022119392-appb-100037
    Figure PCTCN2022119392-appb-100037
    Figure PCTCN2022119392-appb-100038
    Figure PCTCN2022119392-appb-100038
    Figure PCTCN2022119392-appb-100039
    Figure PCTCN2022119392-appb-100039
    Figure PCTCN2022119392-appb-100040
    Figure PCTCN2022119392-appb-100040
    Figure PCTCN2022119392-appb-100041
    Figure PCTCN2022119392-appb-100041
    Figure PCTCN2022119392-appb-100042
    Figure PCTCN2022119392-appb-100042
    Figure PCTCN2022119392-appb-100043
    Figure PCTCN2022119392-appb-100043
    Figure PCTCN2022119392-appb-100044
    Figure PCTCN2022119392-appb-100044
    Figure PCTCN2022119392-appb-100045
    Figure PCTCN2022119392-appb-100045
    Figure PCTCN2022119392-appb-100046
    Figure PCTCN2022119392-appb-100046
    Figure PCTCN2022119392-appb-100047
    Figure PCTCN2022119392-appb-100047
    Figure PCTCN2022119392-appb-100048
    Figure PCTCN2022119392-appb-100048
    Figure PCTCN2022119392-appb-100049
    Figure PCTCN2022119392-appb-100049
  27. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-26中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-26, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  28. 一种如权利要求1-26中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合 物或溶剂合物或如权利要求27所述的药物组合物在制备治疗由KIF18A蛋白介导的相关疾病药物中的用途。A compound as described in any one of claims 1-26, or each isomer thereof, each crystal form, a pharmaceutically acceptable salt, hydrate or solvate, or a drug as claimed in claim 27 Use of the composition in preparing medicines for treating related diseases mediated by KIF18A protein.
  29. 如权利要求28所述的用途，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。The use according to claim 28, wherein said disease is cancer, and said cancer is hematological cancer and solid tumor.
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