Pharmaceutical composition for cancer treatment

Abstract

The invention discloses a pharmaceutical composition for cancer treatment. In particular to a composition consisting of a KIF18A inhibitor and a compound for inhibiting protein activity, and the compound for inhibiting protein activity is preferably a compound for inhibiting PLK1 protein activity or a compound for inhibiting Aurora B protein activity.

Description

A pharmaceutical composition for treating cancer

[0001] This application claims priority to Chinese patent application No. 202211530468.2, filed on November 30, 2022, and Chinese patent application No. 202310767807.7, filed on June 27, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a pharmaceutical composition for cancer treatment, in particular to a pharmaceutical composition of a KIF18A inhibitor and a compound that inhibits protein activity, and use of the pharmaceutical composition in preparing cancer treatment drugs. Background Art

[0003] Genomic instability is a common feature of most tumor cells. Most tumor cells have abnormal chromosome gains or losses. Chromosome instability in tumor cells can lead to abnormal chromosome interactions with spindle microtubules, resulting in chromosome segregation errors. Compared with cells carrying normal chromosomes, cells with unstable chromosomes will produce increased microtubule polymerization and weakened dynamic alternation of spindle microtubules and kinetochores (Turn over). Therefore, anti-mitotic therapy targeting the microtubule skeleton may be particularly effective for cells with chromosomal instability.

[0004] Kinesins are a type of molecular motor that play an important role in cell division and the transport of intracellular vesicles and organelles. Kinesins play an important role in many aspects, including spindle assembly, chromosome segregation, centrosome separation and dynamics. Based on the differences in the amino acid sequence of the motor domain, human kinesins are divided into 14 subtypes. The ATPase activity of its motor domain promotes unidirectional movement of kinesins along microtubules, and the non-motor domain is responsible for interacting with substrates including membranous organelles, signal transduction scaffolding systems and chromosomes. Kinesins obtain energy through ATP hydrolysis, thereby moving substrates along microtubules. Depending on the direction of movement of kinesins on microtubules, kinesins are called "plus-end" or "minus-end" directional motors.

[0005] The KIF18A protein belongs to the kinesin-8 subtype. The KIF18A protein is overexpressed in many types of cancer, such as lung cancer, ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, prostate cancer, colon cancer, and bladder cancer. Studies have shown that KIF18A plays an important role in cell division. On the one hand, KIF18A regulates the elongation of the plus end of the centromere microtubules (the end bound to the chromosome), thereby controlling the correct chromosome positioning and spindle tension. In tumor cells with chromosomal instability, abnormal microtubule movement makes these cells particularly dependent on the KIF18A protein to reduce the contact conversion between spindle microtubules and kinetochores and limit microtubule growth (Nat Commun. 2021, 12, 1213). On the other hand, KIF18A maintains the integrity of the centrioles. When the KIF18A protein is missing in tumor cells with chromosomal instability, the centrosome of the cell becomes fragmented, which causes the mitotic process to slow down or terminate. Compared with normal cells, chromosomally unstable tumors are particularly sensitive to the loss of KIF18A, suggesting that the development of KIF18A inhibitors is a new and potential approach to combat tumors with chromosomal instability.

[0006] Summary of the Invention

[0007] The present invention provides a pharmaceutical composition for treating cancer, comprising a KIF18A inhibitor and a compound that inhibits protein activity.

[0008] In another preferred embodiment, the compound that inhibits protein activity is a compound that inhibits PLK1 protein activity or a compound that inhibits Aurora B protein activity.

[0009] In another preferred embodiment, the cancer treatment is inducing cancer cell death.

[0010] In another preferred embodiment, the cancer treatment is anti-cancer cell proliferation.

[0011] In another preferred embodiment, the cancer is a cancer characterized by chromosomal instability.

[0012] In another preferred embodiment, the cancer is a cancer characterized by aneuploidy.

[0013] In another preferred embodiment, the cancer is a cancer characterized by whole genome duplication.

[0014] In another preferred embodiment, the cancer is a cancer characterized by chromosomal instability and aneuploidy.

[0015] In another preferred embodiment, the cancer is a cancer characterized by chromosomal instability and whole genome duplication.

[0016] In another preferred embodiment, the cancer is a cancer characterized by aneuploidy and whole genome duplication.

[0017] In another preferred embodiment, the cancer is a cancer characterized by chromosomal instability, aneuploidy and whole genome duplication.

[0018] In another preferred embodiment, the cancer is a solid tumor or a blood cancer.

[0019] In another preferred embodiment, the cancer includes but is not limited to uterine cancer, bladder cancer, prostate cancer, breast cancer, lung cancer, intestinal cancer, pancreatic cancer, kidney cancer, ovarian cancer, soft tissue cancer, osteosarcoma or stromal tumor.

[0020] In another preferred embodiment, the compound that inhibits the activity of PLK1 protein includes a PLK1 inhibitor and a PLK1 degrader.

[0021] In another preferred embodiment, the PLK1 inhibitor is a dihydropteridinone compound, a pyridopyrimidine compound, an aminopyrimidine compound, a substituted thiazolidinone compound, a pteridine compound, a dihydroimidazo[l,5-f]pteridine compound, a benzyl styryl sulfone compound, a stilbene compound, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0022] In another preferred embodiment, the PLK1 inhibitor is

[0023] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0024] In another preferred embodiment, the PLK1 inhibitor is TKM-080301, (poly d, l-lactide-polyethylene glycol-poly d, l-lactide)-loaded black phosphorus nanosheets (black phosphorus nanosheets incorporated with poly(d, l-lactide)-poly(ethylene glycol)-poly(d, l-lactide), BP@PLEL hydrogel) or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.

[0025] In another preferred embodiment, the PLK1 degrader is

[0026] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0027] In another preferred embodiment, the compound that inhibits the activity of Aurora B protein includes Aurora B inhibitors and Aurora B degraders.

[0028] In another preferred embodiment, the Aurora B inhibitor is

[0029] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0030] In another preferred embodiment, the KIF18A inhibitor is a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0031] In the general formula (1):

[0032] X 1 -CR 5 = or N;

[0033] X 2 -CR 6 = or N;

[0034] X 3 -CR 7 = or N;

[0035] X 4 -CR 4 = or N;

[0036] X 5 -CR 15 = or N;

[0037] When X 5 -CR 15 = and X 4 -CR 4 = when R 16 -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 18 R 19 or -NO2;

[0038] When X 5 -CR 15 = and X 4 When N, R 16 For-OC 1-8 Hydrocarbon, -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 20 R 21 or -NO2;

[0039] When X 5 When N, R 16 For-OC 1-8 Hydrocarbon, -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 20 R 21 or -NO2;

[0040] L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 、X 2 、X 3 、X 4 and X 5 Among them, no more than 4 are N;

[0041] * represents the connection end;

[0042] R 17 H, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein the -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 Hydrocarbon group.

[0043] R 18and R 19 Each independently represents H, -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein the -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 Hydrocarbon group.

[0044] R 20 and R 21 Each independently represents H, -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein the -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 Hydrocarbyl; or R 20 and R 21 can combine with the nitrogen atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

[0045] R 1 -CN or -ZR 10 , where Z is a chemical bond, -C 0-4 Hydrocarbon-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C 0-4 Hydrocarbyl-O-, -(C=O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

[0046] R 2 is halogen or group -YR 12 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a R a (C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR 12 - or -S(=O)(=NH)-;

[0047] R 3 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups;

[0048] R 4 H, halogen, R 4a or R 4b ;

[0049] R 5 H, halogen, C 1-8 Alkyl or C 1-4 alkyl halide;

[0050] R 6 H, halogen, C 1-8 Alkyl, C 1-4 Haloalkyl, -OH, -OR 6a OR 6b ;

[0051] R 7 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups;

[0052] R 8 Selected from the group consisting of:

[0053] R 13a 、R 13b 、R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R13j 、R 13k and R 13l are independently H, halogen, R 13m or R 13n ; or R 13a and R 13b Yes, R 13c and R 13d Yes, R 13e and R 13f Yes, R 13g and R 13h Yes, R 13i and R 13j Right or R 13k and R 13l Each of the pairs can independently form a spiro-linked carbon atom to which they are attached. 8 a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, CN, -NR a R a or oxo;

[0054] R 9 H or C 1-6 hydrocarbon group;

[0055] R 10 H, R 10a 、R 10b or R 10c ;

[0056] R 11 H, R 11a or R 11b ;

[0057] R 12 R 12a or R 12b ;

[0058] R 15 H, halogen, C 1-8 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OC 1-8 Hydrocarbyl or -OR 15a , where R 15ais a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0059] R 4a 、R 6a 、R 10a 、R 11a 、R 12a or R 13m is independently selected from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 、R 14 and oxo;

[0060] R 4b 、R 6b 、R 10b 、R 11b 、R 12b or R 13n is independently selected in each case from: C 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN;

[0061] R 10c is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-R c 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN;

[0062] R 14is independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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;

[0063] R a is independently H or R b ;

[0064] R b In each case, independently C 1-6 Hydrocarbyl, phenyl or benzyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 and wherein the phenyl and benzyl groups are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, C 1-4 Hydrocarbon, C 1-3 Halogenated hydrocarbons, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 a hydrocarbon group; and

[0065] R c is independently at each occurrence -OC(=O)C 1-5 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: -OH or -NH2.

[0066] In another preferred embodiment, the compound of general formula (1) has the following structure:

[0067] where R 16 -C 3-6 Cycloalkyl, -OH, -OC1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 Or -NO2.

[0068] In another preferred embodiment, the compound of general formula (1) has the following structure:

[0069] where R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 Or -NO2.

[0070] In another preferred embodiment, the compound of general formula (1) has the following structure:

[0071] where R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 18 R 19 Or -NO2.

[0072] In another preferred embodiment, wherein in the general formula (1), R 16 For -OH, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF2CF3, -OCF2Cl, -OCFCl2, -SH, -SCH3, -SCH2CH3, -SCF3, -SCH2CF3, -SCF2CF3, -SCF2Cl, -SCFCl2, -NH2, Or -NO2; preferably -OCF3, -OCH2F, -OCHF2, -SCH3, -SCF3, -SCF2Cl, -SCFCl2, Or -NO2; More preferably -OCF3, -OCH2F, -OCHF2, -SCH3, -SCF3, Or -NO2.

[0073] In another preferred embodiment, wherein in the general formula (1), R 16 -OCH3, -OCH2CH3, -OCH2CH2CH3, Preferred is -OCH3.

[0074] In another preferred embodiment, wherein in the general formula (1), R 9 is H, methyl or ethyl, preferably H.

[0075] In another preferred embodiment, wherein in the general formula (1), R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each is independently H, halogen, C 1-6 Hydrocarbon or C 1-4 halogenated hydrocarbon group; and R 13a and R 13b R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 a saturated 3-, 4-, or 5-membered monocyclic ring; wherein the ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; preferably, R 13c 、R13d 、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 R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 cyclopropyl, cyclobutyl or cyclopentyl ring.

[0076] In another preferred embodiment, wherein the structural unit for: Preferably

[0077] In another preferred embodiment, in the general formula (1), Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-.

[0078] In another preferred embodiment, wherein in the general formula (1), R 10 Selected from (a) H; or (b) C 1-6 a hydrocarbon group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3; or (c) when the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can be combined with the sulfur atom to which they are attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl OH, -OH, -OCH3, -NH2 or oxo; or (d) C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbon group may be optionally substituted with 1, 2 or 3 of the following groups: -OC(=O)C 1-5 Hydrocarbyl, wherein the C 1-5The hydrocarbon group may be optionally substituted with 1 or 2 of the following groups: -OH or -NH2; and the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

[0079] In another preferred embodiment, wherein in the general formula (1), R 1 is -CN or -ZR 10 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and R 10 Selected from:

[0080] (a)H;

[0081] (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, and wherein each of the rings may be independently optionally substituted by 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN and oxo; preferably oxetane, cyclopropyl;

[0082] (c) C substituted with 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 Hydrocarbyl; preferably C substituted by 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; more preferably C substituted by 1 OH group 1-6 a hydrocarbon group; or

[0083] (d)C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: And the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

[0084] In another preferred embodiment, wherein the general formula (1) wherein the group -ZR 10 -N=S(=O)-(R 10 )2, where two R 10The sulphur atoms to which they are attached may combine to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; preferably the group -ZR 10 Selected from:

[0085] In another preferred embodiment, wherein in the general formula (1), R 1 -ZR 10 , wherein Z is -NHSO2- or -SO2NH-; and R 10 is oxetane, cyclopropyl, or R 10 is C substituted with 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; or R 10 C 1-6 Hydrocarbyl, wherein the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups:

[0086] In another preferred embodiment, wherein in the general formula (1), R 10 Selected from C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: Preferably Z is -NHSO2- or -SO2NH-; Z is preferably -NHSO2-.

[0087] In another preferred embodiment, wherein in the general formula (1), R 10 Selected from C 1-6 A hydrocarbon group, which may be optionally substituted with 1, 2 or 3 of the following groups: Z is -NHSO2- or -SO2NH-.

[0088] In another preferred embodiment, wherein in the general formula (1), R 2 is halogen or group -YR 12 , where Y is a chemical bond, -NH-, -NH-(CH2) 0-4 -or-O-(CH2) 0-4 -; and R 12is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo; or R 12 C 1-6 Hydrocarbyl, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

[0089] In another preferred embodiment, wherein in the general formula (1), R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and wherein each of said rings is substituted with 0, 1, 2 or 3 groups selected from:

[0090] F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

[0091] In another preferred embodiment, wherein in the general formula (1), R 2 is (a) halogen; (b) group -YR 12 , where Y is a chemical bond; and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN and oxo; or (c) a group -YR 12 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-, and wherein R 12 for or R 12 C 1-6A hydrocarbyl group, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF3, -OH or CN.

[0092] In another preferred embodiment, wherein in the general formula (1), R 2 is morpholinyl or piperidinyl, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF3, -OH, -OCHF2 and CN.

[0093] In another preferred embodiment, wherein in the general formula (1), R 2 is piperidinyl substituted by 1, 2 or 3 fluoro groups.

[0094] In another preferred embodiment, wherein in the general formula (1), R 2 for:

[0095] In another preferred embodiment, wherein in the general formula (1), R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.

[0096] In another preferred embodiment, wherein in the general formula (1), R 2 for

[0097] In another preferred embodiment, wherein in the general formula (1), R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinyl.

[0098] In another preferred embodiment, wherein in the general formula (1), R 3 For H.

[0099] In another preferred embodiment, wherein in the general formula (1), R 4 selected from (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl; or (c) cyclopropyl; or (d) F; R 4 Preferably H, F or methyl; R 4 More preferably, it is H.

[0100] In another preferred embodiment, wherein in the general formula (1), R 5 is H or F, preferably H.

[0101] In another preferred embodiment, wherein in the general formula (1), R 6 is H or F, preferably H.

[0102] In another preferred embodiment, wherein in the general formula (1), R 7 For H.

[0103] In another preferred embodiment, wherein in the general formula (1), R 15 is H or F, preferably H.

[0104] In another preferred embodiment, the general formula (1) has the following structure:

[0105] R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 or -NO2, R 2 、R 3 、R 10 、R 20 and R 21 The definitions of are as described above and are illustrated in the specific embodiments.

[0106] In another preferred embodiment, the general formula (1) has the following structure:

[0107] R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 18 R 19 or -NO2, R 2 、R 3 、R 10 、R 18 and R 19 The definitions of are as described above and are illustrated in the specific embodiments.

[0108] In another preferred embodiment, the general formula (1) has the following structure:

[0109] R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 or -NO2, L, R 10 、R 20 and R 21 The definitions of are as described above and are illustrated in the specific embodiments.

[0110] In another preferred embodiment, the general formula (1) has the following structure:

[0111] R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 18 R 19 or -NO2, L, R 10 、R 18 and R 19 The definitions of are as described above and are illustrated in the specific embodiments.

[0112] In another specific embodiment, the compound has one of the following structures:

[0113] In another preferred embodiment, the KIF18A inhibitor is a compound represented by the general formula (5) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0114] In general formula (5):

[0115] X 1 -CR 5 = or N;

[0116] X 2 -CR 6 = or N;

[0117] X 3 -CR 7 = or N;

[0118] X 4 -CR 4 =;

[0119] X 5 -CR 15 =;

[0120] R 16 C 1-8 hydrocarbon group;

[0121] L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 、X 2 、X 3 、X 4 and X 5 Among them, no more than 4 are N;

[0122] * represents the connection end;

[0123] R 1 -CN or -ZR 10 , where Z is a chemical bond, -C 0-4 Hydrocarbon-, -NR11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C 0-4 Hydrocarbyl-O-, -(C=O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S;

[0124] R 2 is halogen or group -YR 12 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a R a (C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR 12 - or -S(=O)(=NH)-;

[0125] R 3 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups;

[0126] R 4 H, halogen, R 4a or R 4b ;

[0127] R 5 H, halogen, C 1-8 Alkyl or C 1-4 alkyl halide;

[0128] R 6 H, halogen, C 1-8 Alkyl, C 1-4 Haloalkyl, -OH, -OR 6a OR 6b ;

[0129] R 7H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups;

[0130] R 8 Selected from the group consisting of:

[0131] 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 independently H, halogen, R 13m or R 13n ; or R 13a and R 13b Yes, R 13c and R 13d Yes, R 13e and R 13f Yes, R 13g and R 13h Yes, R 13i and R 13j Right or R 13k and R 13l Each of the pairs can independently form a spiro-linked carbon atom to which they are attached. 8 a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, CN, -NR a R a or oxo;

[0132] R 9 H or C 1-6 hydrocarbon group;

[0133] R 10 H, R 10a 、R 10b or R 10c ;

[0134] R 11H, R 11a or R 11b ;

[0135] R 12 R 12a or R 12b ;

[0136] R 15 H, halogen, C 1-8 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OC 1-8 Hydrocarbyl or -OR 15a , where R 15a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0137] R 4a 、R 6a 、R 10a 、R 11a 、R 12a or R 13m is independently selected from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NRa 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 、R 14 and oxo;

[0138] R 4b 、R 6b 、R 10b 、R 11b 、R 12b or R 13n is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN;

[0139] R 10c is independently selected in each case from:1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-R c 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN;

[0140] R 14 is independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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;

[0141] R a is independently H or R b ;

[0142] R b In each case, independently C 1-6 Hydrocarbyl, phenyl or benzyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 and wherein the phenyl and benzyl groups are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, C 1-4 Hydrocarbon, C 1-3 Halogenated hydrocarbons, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 a hydrocarbon group; and

[0143] R c is independently at each occurrence -OC(=O)C 1-5Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: -OH or -NH2.

[0144] In another preferred embodiment, the general formula (5) has the following structure:

[0145] where R 16 C 1-4 Hydrocarbon group.

[0146] In another preferred embodiment, wherein in the general formula (5), R 16 for Preferably

[0147] In another preferred embodiment, wherein in the general formula (5), R 9 is H, methyl or ethyl, preferably H.

[0148] In another preferred embodiment, wherein in the general formula (5), R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each is independently H, halogen, C 1-6 Hydrocarbon or C 1-4 halogenated hydrocarbon group; and R 13a and R 13b R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 a saturated 3-, 4-, or 5-membered monocyclic ring; wherein the 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 R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8cyclopropyl, cyclobutyl or cyclopentyl ring.

[0149] In another preferred embodiment, wherein in the general formula (5), the structural unit for: Preferably

[0150] In another preferred embodiment, in the general formula (5), Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-.

[0151] In another preferred embodiment, wherein in the general formula (5), R 10 Selected from (a) H; or (b) C 1-6 a hydrocarbon group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3; or (c) when the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can be combined with the sulfur atom to which they are attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl OH, -OH, -OCH3, -NH2 or oxo; or (d) C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbon group may be optionally substituted with 1, 2 or 3 of the following groups: -OC(=O)C 1-5 Hydrocarbyl, wherein the C 1-5 The hydrocarbon group may be optionally substituted with 1 or 2 of the following groups: -OH or -NH2; and the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

[0152] In another preferred embodiment, wherein in the general formula (5), R 1 is -CN or -ZR 10 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and R10 Selected from:

[0153] (a)H;

[0154] (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, and wherein each of the rings may be independently optionally substituted by 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN and oxo; preferably oxetane, cyclopropyl;

[0155] (c) C substituted with 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 Hydrocarbyl; preferably C substituted by 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; more preferably C substituted by 1 OH group 1-6 a hydrocarbon group; or

[0156] (d)C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: And the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

[0157] In another preferred embodiment, wherein the general formula (5) wherein the group -ZR 10 -N=S(=O)-(R 10 )2, where two R 10 The sulphur atoms to which they are attached may combine to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; preferably the group -ZR 10 Selected from:

[0158] In another preferred embodiment, wherein in the general formula (5), R 1 -ZR 10 , wherein Z is -NHSO2- or -SO2NH-; and R 10 is oxetane, cyclopropyl, or R 10is C substituted with 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; or R 10 C 1-6 Hydrocarbyl, wherein the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups:

[0159] In another preferred embodiment, wherein in the general formula (5), R 10 Selected from C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: Preferably Z is -NHSO2- or -SO2NH-; Z is preferably -NHSO2-.

[0160] In another preferred embodiment, wherein in the general formula (5), R 10 Selected from C 1-6 A hydrocarbon group, which may be optionally substituted with 1, 2 or 3 of the following groups: Z is -NHSO2- or -SO2NH-.

[0161] In another preferred embodiment, wherein in the general formula (5), R 2 is halogen or group -YR 12 , where Y is a chemical bond, -NH-, -NH-(CH2) 0-4 -or-O-(CH2) 0-4 -; and R 12 is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo; or R 12 C 1-6 Hydrocarbyl, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

[0162] In another preferred embodiment, wherein in the general formula (5), R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and wherein each of said rings is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

[0163] In another preferred embodiment, wherein in the general formula (5), R 2 is (a) halogen; (b) group -YR 12 , where Y is a chemical bond; and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN and oxo; or (c) a group -YR 12 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-, and wherein R 12 for or R 12 C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF3, -OH or CN.

[0164] In another preferred embodiment, wherein in the general formula (5), R 2 is morpholinyl or piperidinyl, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF3, -OH, -OCHF2 and CN.

[0165] In another preferred embodiment, wherein in the general formula (5), R 2 is piperidinyl substituted by 1, 2 or 3 fluoro groups.

[0166] In another preferred embodiment, wherein in the general formula (5), R 2 for:

[0167] In another preferred embodiment, wherein in the general formula (5), R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.

[0168] In another preferred embodiment, wherein in the general formula (5), R 2 for

[0169] In another preferred embodiment, wherein in the general formula (5), R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinyl.

[0170] In another preferred embodiment, wherein in the general formula (5), R 3 For H.

[0171] In another preferred embodiment, wherein in the general formula (5), R 4 selected from (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl; or (c) cyclopropyl; or (d) F; R 4 Preferably H, F or methyl; R 4 More preferably, it is H.

[0172] In another preferred embodiment, wherein in the general formula (5), R 5 is H or F, preferably H.

[0173] In another preferred embodiment, wherein in the general formula (5), R 6 is H or F, preferably H.

[0174] In another preferred embodiment, wherein in the general formula (5), R 7 For H.

[0175] In another preferred embodiment, wherein in the general formula (5), R 15 is H or F, preferably H.

[0176] In various embodiments of the present invention, the compound of formula (5) has one of the following structures:

[0177] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2020132648 / US2020239441:

[0178] where X 1 、R x 、R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 and R 9 The definition of is as described in WO2020132648 / US2020239441. Preferably or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0179] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2020132649 / US2022056015:

[0180] Among them, L, X 1 、X 2 、X 3 、X 4 、R x 、R 1 、R 2 、R 4 and R 5 The definition of is as described in WO2020132649 / US2022056015. Preferably

[0181] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0182] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2020132651 / US2022073504:

[0183] where X 1 、R x 、R 1 、R 2 、R 3 、R 4 、R5 、R 7 、R 8 and R 9 The definition of is as described in WO2020132651 / US2022073504. Preferably

[0184] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0185] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2020132653 / US2022002311:

[0186] Among them, L, X 1 、X 2 、X 3 、X 4 、R x 、R 1 、R 2 、R 4 and R 5 The definition of is as described in WO2020132653 / US2022002311. Preferably

[0187] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0188] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2021026098 / US2022289724:

[0189] Among them, L, R x 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , R7, R 8 and R 9 The definition of is as described in WO2021026098 / US2022289724. Preferably

[0190] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0191] In another preferred embodiment, the KIF1Aa inhibitor has a structure as shown in formula (1) in WO2021026099:

[0192] Among them, L, R x 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 The definition of is as described in WO2021026099. Preferably

[0193] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0194] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2021026100 / US2022372018:

[0195] Among them, L, X 1 、X 2 、X 3 、R x 、R 2 、R 5 、R 6 、R 7 、R 8 and R 9 The definition of is as described in WO2021026100 / US2022372018. Preferably

[0196] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0197] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2021026101 / US2022281843:

[0198] Among them, L, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、R x 、R 1、R 2 、R 4 and R 5 The definition of is as described in WO2021026101 / US2022281843. Preferably

[0199] or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0200] In another preferred embodiment, the KIF18A inhibitor is or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0201] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2022268230:

[0202] Among them, A, B, L, X 1 、X 2 、X 3 and X 4 The definition of is as described in WO2022268230. Preferably

[0203] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (1) in WO2023028564 / US2023147507:

[0204] Among them, A, B, Y1, Y2, Y3, Y4, R B and m are as defined in WO2023028564 / US2023147507.

[0205] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in Formula V in WO2023198209A1:

[0206] Among them, A, B, R X 、R 1 、R 3 、X 4 、X 5 、X 6 and m are as defined in WO2023198209A1.

[0207] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in WO2023212240A1:

[0208] Among them, A and B 1 、B 2 、R 3 、R 4 , X, Y, Z, V and W are as defined in WO2023212240A1.

[0209] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in CN202211486927:

[0210] Among them, A, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 and L are as defined in CN202211486927. Preferably

[0211] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in CN202310220736:

[0212] where R 1 、R 2 、R 3 The definitions of m and n are as described in CN202310220736.

[0213] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in WO2023217230A1:

[0214] where R 1 、R 2 、W 1 、W 2 , L 1 , L 2 、Cy 1 、Cy 2and Z are as defined in WO2023217230A1.

[0215] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in WO2023217232A1:

[0216] where R 1 、R 2 、W 1 、W 2 , L 1 , L 2 、Cy 1 、Cy 2 and Z are as defined in WO2023217232A1.

[0217] In another preferred embodiment, the KIF18A inhibitor has a structure as shown in the general formula (I) in WO2023217233A1:

[0218] Among them, A, R 1 、W 1 、W 2 、W 3 , L 1 , L 2 、Cy 1 、Cy 2 and Z are as defined in WO2023217233A1.

[0219] Through research in related fields, the inventors unexpectedly discovered that KIF18A inhibitors and PLK1 inhibitors or degraders, as well as KIF18A inhibitors and AuroraB inhibitors or degraders, all have synergistic effects in treating diseases. These combinations exhibit significantly greater activity than when used alone. The diseases described are preferably cancers, including hematological cancers and solid tumors.

[0220] In another preferred embodiment, the pharmaceutical composition comprises 0.0001-100000 nM of a KIF18A inhibitor and 0.0001-100000 nM of a PLK1 inhibitor;

[0221] The concentration of KIF18A inhibitor is preferably 0.0001-50000 nM, 0.0001-25000 nM, 0.0001-12500 nM, 0.0001-6250 nM, 0.0001-5000 nM, 0.0001-3125 nM, 0.0001-1562 nM, 0.0001-1000 nM, 0.0001-781 nM, 0.0001-400 nM, 0.64-400 nM;

[0222] The concentration of the PLK1 inhibitor is preferably 0.0001-50000 nM, 0.0001-25000 nM, 0.0001-12500 nM, 0.0001-6250 nM, 0.0001-3125 nM, 0.0001-1562 nM, 0.0001-1000 nM, 0.0001-781 nM, 0.0001-500 nM, 0.0001-400 nM, 0.0001-100 nM, 0.0001-50 nM, 0.0001-25 nM, 0.0001-10 nM, 1.6-1000 nM, 1.6-200 nM, 1.6-40 nM, 3.125-50 nM.

[0223] The KIF18A inhibitor is preferably a compound of the general formula (1), more preferably compound 257 in the general formula (1); the KIF18A inhibitor is preferably AMG560; the PLK1 inhibitor is preferably Plogosertib, TAK960, Volasertib, Rigosertib, BI2536, Onvansertib, GSK461364, MLN0905, Ro3280; the PLK1 inhibitor is preferably Plogosertib; the PLK1 inhibitor is preferably TAK960; the PLK1 inhibitor is preferably Volasertib; the PLK1 inhibitor is preferably Rigosertib; the PLK1 inhibitor is preferably BI2536; the PLK1 inhibitor is preferably Onvansertib; the PLK1 inhibitor is preferably GSK461364; the PLK1 inhibitor is preferably MLN0905; the PLK1 inhibitor is preferably Ro3280.

[0224] Preferably, the pharmaceutical composition comprises 0.0001-50000 nM of a KIF18A inhibitor and 0.0001-100000 nM of a PLK1 inhibitor;

[0225] Preferably, the pharmaceutical composition comprises 0.0001-100000 nM of a KIF18A inhibitor and 0.0001-50000 nM of a PLK1 inhibitor;

[0226] Preferably, the pharmaceutical composition comprises 0.0001-50000 nM of a KIF18A inhibitor and 0.0001-50000 nM of a PLK1 inhibitor;

[0227] Preferably, the pharmaceutical composition comprises 0.0001-50000 nM of a KIF18A inhibitor and 0.0001-25000 nM of a PLK1 inhibitor;

[0228] Preferably, the pharmaceutical composition comprises 0.0001-25000 nM of a KIF18A inhibitor and 0.0001-50000 nM of a PLK1 inhibitor;

[0229] Preferably, the pharmaceutical composition comprises 0.0001-25000 nM of a KIF18A inhibitor and 0.0001-25000 nM of a PLK1 inhibitor;

[0230] Preferably, the pharmaceutical composition comprises 0.0001-12500 nM of a KIF18A inhibitor and 0.0001-25000 nM of a PLK1 inhibitor;

[0231] Preferably, the pharmaceutical composition comprises 0.0001-25000 nM of a KIF18A inhibitor and 0.0001-12500 nM of a PLK1 inhibitor;

[0232] Preferably, the pharmaceutical composition comprises 0.0001-12500 nM of a KIF18A inhibitor and 0.0001-12500 nM of a PLK1 inhibitor;

[0233] Preferably, the pharmaceutical composition comprises 0.0001-12500 nM of a KIF18A inhibitor and 0.0001-6250 nM of a PLK1 inhibitor;

[0234] Preferably, the pharmaceutical composition comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-12500 nM of a PLK1 inhibitor;

[0235] Preferably, the pharmaceutical composition comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-6250 nM of a PLK1 inhibitor;

[0236] Preferably, the pharmaceutical composition comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-6250 nM of a PLK1 inhibitor;

[0237] Preferably, the pharmaceutical composition comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor;

[0238] Preferably, the pharmaceutical composition comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor;

[0239] Preferably, the pharmaceutical composition comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor;

[0240] Preferably, the pharmaceutical composition comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor;

[0241] Preferably, the pharmaceutical composition comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor;

[0242] Preferably, the pharmaceutical composition comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor;

[0243] Preferably, the pharmaceutical composition comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor;

[0244] Preferably, the pharmaceutical composition comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor;

[0245] Preferably, the pharmaceutical composition comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-400 nM of a PLK1 inhibitor;

[0246] Preferably, the pharmaceutical composition comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor;

[0247] Preferably, the pharmaceutical composition comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-400 nM of a PLK1 inhibitor;

[0248] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor;

[0249] Preferably, the pharmaceutical composition comprises 0.0001-1000 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor;

[0250] Preferably, the pharmaceutical composition comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor;

[0251] Preferably, the pharmaceutical composition comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-50 nM of a PLK1 inhibitor;

[0252] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-1000 nM of Plogosertib;

[0253] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-200 nM of Plogosertib;

[0254] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-40 nM of Plogosertib;

[0255] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-1000 nM of Plogosertib;

[0256] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-200 nM of Plogosertib;

[0257] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-40 nM of Plogosertib;

[0258] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-1000 nM Plogosertib;

[0259] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-200 nM Plogosertib;

[0260] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-40 nM Plogosertib;

[0261] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-1000 nM of TAK960;

[0262] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-200 nM of TAK960;

[0263] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 1.6-40 nM of TAK960;

[0264] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-1000 nM of TAK960;

[0265] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-200 nM of TAK960;

[0266] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-40 nM of TAK960;

[0267] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-1000 nM TAK960;

[0268] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-200 nM TAK960;

[0269] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 1.6-40 nM TAK960;

[0270] Preferably, the pharmaceutical composition comprises 0.64-400 nM of the compound of formula (1) and 3.125-50 nM of Volasertib;

[0271] Preferably, the pharmaceutical composition comprises 0.64-400 nM of compound 257 of formula (1) and 3.125-50 nM of Volasertib;

[0272] Preferably, the pharmaceutical composition comprises 0.64-400 nM AMG650 and 3.125-50 nM Volasertib;

[0273] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of Rigosertib;

[0274] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of Rigosertib;

[0275] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-10 nM of BI2536;

[0276] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-10 nM of BI2536;

[0277] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of Volasertib;

[0278] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of Volasertib;

[0279] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-1000 nM of Onvansertib;

[0280] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-500 nM of Onvansertib;

[0281] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of Onvansertib;

[0282] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of Onvansertib;

[0283] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-1000 nM of Onvansertib;

[0284] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-500 nM of Onvansertib;

[0285] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of Onvansertib;

[0286] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of Onvansertib;

[0287] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-1000 nM of GSK461364;

[0288] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-500 nM of GSK461364;

[0289] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of GSK461364;

[0290] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-10 nM of GSK461364;

[0291] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-1000 nM of GSK461364;

[0292] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-500 nM of GSK461364;

[0293] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of GSK461364;

[0294] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-10 nM of GSK461364;

[0295] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-1000 nM of MLN0905;

[0296] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-500 nM of MLN0905;

[0297] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of MLN0905;

[0298] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of MLN0905;

[0299] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-1000 nM of MLN0905;

[0300] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-500 nM of MLN0905;

[0301] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of MLN0905;

[0302] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of MLN0905;

[0303] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of Ro3280;

[0304] Preferably, the pharmaceutical composition comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of Ro3280. BRIEF DESCRIPTION OF THE DRAWINGS

[0305] FIG1 is a matrix diagram showing the inhibitory effect of compound 257 of Biological Example 19 of the present invention in combination with CYC140 (Plogosertib) on HT29 cell proliferation;

[0306] FIG2 is a matrix diagram showing the inhibitory effect of compound 257 of Biological Example 19 of the present invention in combination with TAK-960 on HT29 cell proliferation;

[0307] FIG3 is a matrix diagram showing the inhibitory effect of AMG650 in combination with CYC140 (Plogosertib) on HT29 cell proliferation in Biological Example 19 of the present invention;

[0308] FIG4 is a matrix diagram showing the inhibitory effect of AMG650 and TAK-960 combined with each other on HT29 cell proliferation in Biological Example 19 of the present invention;

[0309] FIG5 is a Bliss independence model matrix diagram of the synergistic effect of compound 257 of Biological Example 19 of the present invention in combination with CYC140 (Plogosertib) on the inhibition of HT29 cell proliferation;

[0310] FIG6 is a Bliss independence model matrix diagram of the synergistic effect of compound 257 of Biological Example 19 of the present invention in combination with TAK-960 on the inhibition of HT29 cell proliferation;

[0311] FIG7 is a Bliss independence model matrix diagram of the synergistic effect of AMG650 and CYC140 (Plogosertib) combined with CYC140 (Plogosertib) on the inhibition of HT29 cell proliferation in Biological Example 19 of the present invention;

[0312] FIG8 is a Bliss independence model matrix diagram of the synergistic effect of AMG650 and TAK-960 combined with the inhibition of HT29 cell proliferation in Biological Example 19 of the present invention;

[0313] FIG9 is a matrix diagram showing the inhibitory effect of compound 257 of Biological Example 21 of the present invention in combination with Volasertib on SK-OV-3 cell proliferation;

[0314] FIG10 is a matrix diagram showing the inhibitory effect of AMG650 in combination with Volasertib on SK-OV-3 cell proliferation in Biological Example 21 of the present invention;

[0315] FIG11 is a Bliss independence model matrix diagram of the synergistic effect of compound 257 of biological example 21 of the present invention in combination with Volasertib on the inhibition of SK-OV-3 cell proliferation;

[0316] FIG12 is a Bliss independence model matrix diagram of the synergistic effect of AMG650 in combination with Volasertib on the inhibition of SK-OV-3 cell proliferation in Biological Example 21 of the present invention;

[0317] FIG13 is a matrix diagram showing the inhibitory effect of compound 257 of Biological Example 22 of the present invention in combination with Volasertib on HT29 cell proliferation;

[0318] FIG14 is a matrix diagram showing the inhibitory effect of AMG650 in combination with Volasertib on HT29 cell proliferation in Biological Example 22 of the present invention;

[0319] FIG15 is a Bliss independence model matrix diagram of the synergistic effect of compound 257 of biological example 22 of the present invention in combination with Volasertib on the inhibition of HT29 cell proliferation;

[0320] FIG16 is a Bliss independence model matrix diagram of the synergistic effect of AMG650 in combination with Volasertib on the inhibition of HT29 cell proliferation in Biological Example 22 of the present invention.

[0321] Synthesis of compounds

[0322] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0323] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using 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), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0324] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, the amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. On the one hand, the present invention also provides a method for preparing the compound of the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction schemes 1-4:

[0325] General reaction scheme 1

[0326] An embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein R 1 、R 2 、R 3 、R 8 、R 16 、X 1 、X 2 、X 3 、X 4 and X 5 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-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethane-1-ol or (11) cyclopropanethiol. As shown in the general reaction scheme 1, compound 1-1 and compound 1-2 undergo amidation reaction to produce compound 1-3, and compound 1-3 reacts with R 1 Reagents 1-4 react to produce compound 1-5.

[0327] General reaction scheme 2

[0328] An embodiment of the compound of formula (1) can be prepared according to general reaction scheme 2, wherein R 1 、R 2 、R 3 、R 8 、R 16 、X 1 、X 2 、X 3 、X4 and X 5 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-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (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 produce compound 2-3, and compound 2-3 reacts with R 1 Reagent 2-4 reacts to produce compound 2-5.

[0329] General reaction scheme 3

[0330] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 3, wherein R 1 、R 2 、R 3 、R 8 、R 16 、X 1 、X 2 、X 3 、X 4 and X 5 As defined above; W 1 represents fluorine, chlorine, bromine or iodine; H represents hydrogen; N represents nitrogen; P 1 is a protecting group for an ester group; 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-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethan-1-ol or (11) cyclopropanethiol. As shown in the general reaction scheme 3, compound 3-1 is reacted with R 1 Reagent 3-2 reacts to generate compound 3-3, and compound 3-3 removes the ester protecting group P 1 Compound 3-4 is obtained, and compound 3-4 and compound 3-5 undergo amidation reaction to generate compound 3-6.

[0331] General reaction scheme 4

[0332] Embodiments of compounds of 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 As defined above; W 1 represents fluorine, chlorine, bromine or iodine; H represents hydrogen; N represents nitrogen; P 2 is a protecting group for an amine group; 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-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethan-1-ol or (11) cyclopropanethiol. As shown in the general reaction scheme 4, compound 4-1 is reacted with R 1 Reagent 4-2 reacts to generate compound 4-3, and compound 4-3 removes the amino protecting group P 2 Compound 4-4 is obtained, and compound 4-4 and compound 4-5 undergo amidation reaction to generate compound 4-6.

[0333] Further forms of compounds

[0334] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0335] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0336] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0337] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0338] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0339] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0340] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0341] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0342] the term

[0343] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0344] Unless otherwise specified, “C α-β "Hydrocarbyl" means a hydrocarbon group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, where α and β represent integers. The hydrocarbon groups described in this section may also contain one or two double bonds or triple bonds. The designation of C0 hydrocarbon group indicates a direct bond. C 1-6 Examples of hydrocarbyl groups include, but are not limited to, the following:

[0345] Unless otherwise specified, “C α-β "Haloalkyl" means an alkyl as defined above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.

[0346] Unless otherwise specified, "oxo" and "thioxo" mean =0 (eg, carbonyl) and =S (eg, thiocarbonyl), respectively.

[0347] Unless otherwise specified, "halo" or "halogen" means a halogen atom selected from F, Cl, Br and I.

[0348] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0349] Unless otherwise specified, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon ring system. The ring carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or sulfide group. Cycloalkyl also includes cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, etc.

[0350] Unless otherwise specified, "bicyclic" means a group having two connected rings. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2, or 3 heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic rings (e.g., tetralin). Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom (spiro atom, which is typically a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0351] (b) Fused bicyclic compounds, where the two rings share two adjacent atoms. That is, the rings share a covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic rings include, but are not limited to:

[0352] 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 considered a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

[0353] Unless otherwise specified, "carbocycle" or "carbocyclic" means, by itself or in combination with other terms, a ring comprising "C α-β Examples of carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0354] Unless otherwise specified, "heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may appear in the claims include, but are not limited to, the following:

[0355] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0356] "Saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.

[0357] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0358] When the number of a group is 0, such as -N(C0 hydrocarbon)-C 0-4 Hydrocarbyl-, indicating that the connecting group is -NH-C 0-4 Hydrocarbyl-.

[0359] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a chemical bond.

[0360] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0361] Unless otherwise stated, Indicates a single bond or a double bond.

[0362] Specific pharmaceutical and medical terms

[0363] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0364] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0365] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0366] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0367] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0368] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being 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 determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0369] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0370] Therapeutic uses

[0371] The present invention provides methods of treating diseases, including but not limited to cancer, using the pharmaceutical compositions of the present invention.

[0372] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions. In other embodiments, the cancer is a blood cancer and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

[0373] Route of administration

[0374] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0375] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0376] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0377] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0378] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0379] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0380] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0381] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0382] 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 excipients include water, ethanol, polyols and suitable mixtures thereof.

[0383] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0384] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0385] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0386] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0387] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0388] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; BOPCl represents bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride; CDCl3 represents deuterated chloroform; Cs2CO3 represents cesium carbonate; CuI represents cuprous iodide; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCE represents 1,2-dichloroethane; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; 1,4-Diox ane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; hr represents hour; HATU represents N-[(dimethylamino)-1H-1,2,3-triazole-[4,5-b]pyridine-1-methylene]-N-methylmethanium hexafluorophosphate-N-oxide; IPA represents isopropyl alcohol; min represents minute; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; K3PO4 represents potassium phosphate; LiB H4 represents lithium borohydride; min represents minutes; MeOH represents methanol; MS represents mass spectrometry; NMR represents nuclear magnetic resonance; Pd / C represents palladium on carbon; Pd(PPh3)4 represents tetrakistriphenylphosphine palladium; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); PE represents petroleum ether; RuPhos-Pd-G3 represents (2-dicyclohexylphosphino-2′6′-diisopropoxy-11′-biphenyl)[2-(2′-amino-11′-biphenyl)]palladium(II) methanesulfonate; Sarcos Ine stands for sarcosine; TFA stands for trifluoroacetic acid; TMSCl stands for trimethylsilyl chloride; T3P stands for 1-propylphosphonic anhydride; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; X-Phos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; TLC stands for thin layer chromatography; XPhos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0389] Example 1 Synthesis of Compound 1

[0390] Step 1: Synthesis of compound int_1-3

[0391] Int_1-1 (800 mg, 5.124 mmol) was dissolved in DMSO (10 mL), and potassium carbonate (1.41 g, 10.249 mmol) and int_1-2 (1.24 g, 10.249 mmol) were added. The reaction mixture was heated to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the desired product (1.2 g, yield: 91.6%).

[0392] ESI-MS m / z:258[M+H] + .

[0393] Step 2: Synthesis of compound int_1-5

[0394] Int_1-4 (15 g, 56.3 mmol) was dissolved in methanol (150 mL), concentrated sulfuric acid (2.5 mL) was added, and the mixture was heated to 80°C for 4 hours. LC-MS monitoring indicated the reaction was 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 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 was used directly in the next reaction.

[0395] ESI-MS m / z:281[M+H] + .

[0396] Step 3: Synthesis of compound int_1-7

[0397] Int_1-5 (14 g, 49.9 mmol) was dissolved in DMSO (100 mL), and cesium carbonate (23.4 g, 71.7 mmol) and int_1-6 (6.98 g, 62.8 mmol) were added. The mixture was heated to 90°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (500 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane = 1:1) to obtain the desired product (16.3 g, yield: 88%).

[0398] ESI-MS m / z:372[M+H] + .

[0399] Step 4: Synthesis of compound int_1-8

[0400] Dissolve int_1-7 (16.3 g, 43.9 mmol) in a mixture of methanol (100 ml) and water (10 ml). Add lithium hydroxide (2.1 g, 87.8 mmol) at room temperature and stir for 6 hours. LC-MS monitoring indicates the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain a crude product (17 g). The crude product can be used directly in the next reaction.

[0401] ESI-MS m / z:358[M+H] + .

[0402] Step 5: Synthesis of compound int_1-9

[0403] Int_1-8 (1.1 g, 3.08 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (888.4 mg, 7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to yield a solid. The solid was dissolved in DCM (10 mL), and int_1-3 (792 mg, 3.08 mmol) and pyridine (730 mg, 9.24 mmol) were added. The reaction mixture was stirred at 40°C for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAC = 100:1) to yield a solid (1.4 g, yield: 76.1%).

[0404] ESI-MS m / z:597[M+H] + .

[0405] Step 6: Synthesis of Compound 1

[0406] Int_1-10 (291 mg, 2.374 mmol), sarcosine (209.1 mg, 2.348 mmol), cuprous iodide (227 mg, 1.174 mmol), and potassium phosphate (1.5 g, 7.041 mmol) were dissolved in DMF (20 mL). The atmosphere was replaced with argon three times, and int_1-9 (1.4 g, 2.347 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography (SiO2, EtOAc:Hexane = 1:1) to obtain a solid (1 g, yield: 71.8%).

[0407] 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.03(d,J=9.0Hz,1H),7.78(d,J=8.5Hz,1H),7.75 (d,J=2.1Hz,1H),7.49(dd,J=9.0,2.1Hz,1H),7.14(d,J=2.1Hz,1H),7.01(dd,J=8.5,2.1Hz,1H),3.74(t,J=6.5Hz,2H),3.3 2(d,J=6.5Hz,2H),3.14(t,J=5.5Hz,4H),2.95(t,J=5.2Hz,4H),2.11(tq,J=14.6,8.9,7.2Hz,4H),1.50(s,4H),0.33(s,4H).

[0408] ESI-MS m / z:594[M+H] + .

[0409] Example 2 Synthesis of Compound 2

[0410] Step 1: Synthesis of compound int_2-2

[0411] Int_1-1 (200 mg, 1.281 mmol) was dissolved in DMSO (5 mL), and potassium carbonate (354 mg, 2.562 mmol) and int_2-1 (259 mg, 2.562 mmol) were added. The mixture was heated to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (300 mg, 99% yield).

[0412] ESI-MS m / z:238[M+H] + .

[0413] Step 2: Synthesis of compound int_2-3

[0414] Int_1-8 (151 mg, 0.422 mmol) was dissolved in DMF (4 mL), and HATU (240 mg, 0.632 mmol), DIPEA (163 mg, 1.264 mmol), and int_2-2 (100 mg, 0.422 mmol) were added. The reaction mixture was stirred at 80°C for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (60 mg, yield: 24.6%).

[0415] ESI-MS m / z:577[M+H] + .

[0416] Step 3: Synthesis of compound 2

[0417] Int_1-10 (20 mg, 0.15 mmol), (1S,2S)-N,N-dimethylcyclohexane (7 mg, 0.05 mmol), cuprous iodide (10 mg, 0.05 mmol), and potassium phosphate (63 mg, 0.3 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_2-3 (60 mg, 0.1 mmol) was added. Under argon protection, the reaction solution was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (20 mg, yield: 34.9%).

[0418] 1 H NMR(400MHz,Chloroform-d)δ12.95(s,1H),8.21(d,J=8.1Hz,1H),8.00(d,J=8.9Hz,1H),7.83(d,J=2.3Hz,1H),7.35(s,1H),7.22–7.16(m,1H),7 .08(d,J=8.0Hz,1H),4.15(s,2H),3.97–3.82(m,3H),3.35(d,J=5.4Hz,2 H),3.16(t,J=10.5Hz,2H),3.07(q,J=7.6,6.5Hz,4H),3.04–2.96(m,1H), 2.70(t,J=10.9Hz,2H),1.66(s,4H),1.21(d,J=6.2Hz,3H),0.45(s,4H).

[0419] ESI-MS m / z:574[M+H] + .

[0420] Example 3 Synthesis of Compound 3

[0421] Step 1: Synthesis of compound int_3-2

[0422] Int_1-1 (200 mg, 1.281 mmol) was dissolved in DMSO (10 mL), and potassium carbonate (354 mg, 2.562 mmol) and int_3-1 (259 mg, 2.562 mmol) were added. The mixture was heated to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography to yield the desired product (280 mg, 92% yield).

[0423] ESI-MS m / z:238[M+H] + .

[0424] Step 2: Synthesis of compound int_3-3

[0425] Int_1-8 (151 mg, 0.422 mmol) was dissolved in DMF (4 mL), and HATU (240 mg, 0.632 mmol), DIPEA (163 mg, 1.264 mmol), and int_3-2 (100 mg, 0.422 mmol) were added. The reaction mixture was stirred at 80°C for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (119 mg, yield: 48.9%).

[0426] ESI-MS m / z:577[M+H] + .

[0427] Step 3: Synthesis of compound 3

[0428] Int_1-10 (39 mg, 0.310 mmol), (1S,2S)-N,N-dimethylcyclohexane (15 mg, 0.103 mmol), cuprous iodide (20 mg, 0.103 mmol), and potassium phosphate (132 mg, 0.620 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_3-3 (119 mg, 0.207 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (50 mg, yield: 42.3%).

[0429] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),7.99(d,J=9.0Hz,1H),7.80(d,J=8.5Hz,1H),7.65(d,J=2.2H z,1H),7.47(dd,J=9.0,2.1Hz,1H),7.14(d,J=2.1Hz,1H),7.01(dd,J=8.5,2.0Hz,1H),3.85(dd,J= 11.4, 2.6Hz, 1H), 3.79–3.60 (m, 4H), 3.07 (dd, J=29.4, 12.0Hz, 2H), 2.95 (t, J=5.3Hz, 4H), 2.90–2. 78(m,1H),2.59(dd,J=11.9,9.8Hz,1H),1.52(d,J=4.7Hz,4H),1.10(d,J=6.2Hz,3H),0.33(s,4H).

[0430] ESI-MS m / z:574[M+H] + .

[0431] Example 4 Synthesis of Compound 4

[0432] Step 1: Synthesis of compound int_4-2

[0433] Int_1-1 (200 mg, 1.281 mmol) was dissolved in DMSO (5 mL), and potassium carbonate (710 mg, 5.124 mmol) and int_4-1 (hydrochloride, 310 mg, 2.562 mmol) were added. The mixture was heated to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (300 mg, 100% yield).

[0434] ESI-MS m / z:230[M+H] + .

[0435] Step 2: Synthesis of compound int_4-3

[0436] Int_1-8 (156 mg, 0.436 mmol) was dissolved in DMF (3 mL), and HATU (342 mg, 0.872 mmol), DIPEA (165 mg, 1.308 mmol), and int_4-2 (100 mg, 0.436 mmol) were added. The reaction mixture was stirred at 80°C for 10 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (130 mg, yield: 52.6%).

[0437] ESI-MS m / z:569[M+H] + .

[0438] Step 3: Synthesis of compound 4

[0439] Int_1-10 (16 mg, 0.123 mmol), (1S,2S)-N,N-dimethylcyclohexane (9 mg, 0.062 mmol), cuprous iodide (12 mg, 0.062 mmol), and potassium phosphate (80 mg, 0.369 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_4-3 (70 mg, 0.123 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (54 mg, yield: 77.1%).

[0440] 1 H NMR(400MHz,Chloroform-d)δ12.85(s,1H),8.20(d,J=8.2Hz,1H),8.02(d,J=9.0Hz,1H),7.69(s,1H),7.34(s,1H),7.07(d,J=8.4Hz,1H),6. 96 (s, 1H), 6.84 (d, J = 9.0Hz, 1H), 4.39 (t, J = 11.9Hz, 4H), 4.16 (s, 2H), 3.34 (t, J = 5.3Hz, 2H), 3.08 (t, J = 5.3Hz, 4H), 1.63 (s, 4H), 0.45 (s, 4H).

[0441] ESI-MS m / z:566[M+H] + .

[0442] Example 5 Synthesis of Compound 6

[0443] Step 1: Synthesis of compound int_6-2

[0444] Int_1-1 (200 mg, 1.281 mmol) was dissolved in DMSO (5 mL), and potassium carbonate (710 mg, 5.124 mmol) and int_6-1 (hydrochloride, 171 mg, 1.281 mmol) were added. The mixture was heated to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then subjected to column chromatography to obtain the desired product (290 mg, yield: 97.0%).

[0445] ESI-MS m / z:234[M+H] + .

[0446] Step 2: Synthesis of compound int_6-3

[0447] Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (3 mL), and HATU (342 mg, 0.872 mmol), DIPEA (165 mg, 1.308 mmol), and int_6-2 (65 mg, 0.28 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (70 mg, yield: 43.8%).

[0448] ESI-MS m / z:573[M+H] + .

[0449] Step 3: Synthesis of compound 6

[0450] Int_1-10 (16 mg, 0.123 mmol), (1S,2S)-N,N-dimethylcyclohexane (9 mg, 0.062 mmol), cuprous iodide (12 mg, 0.062 mmol), and potassium phosphate (80 mg, 0.369 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_6-3 (70 mg, 0.122 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (45 mg, yield: 64.7%).

[0451] 1H NMR(400MHz,Chloroform-d)δ12.71(s,1H),8.20(d,J=8.3Hz,1H),7.90–7.76( m,2H),7.33(s,1H),7.06(d,J=8.3Hz,2H),6.85–6.71(m,1H),4.14(t,J=5.0Hz ,2H),3.46(t,J=6.6Hz,2H),3.34(t,J=5.1Hz,2H),3.16(s,2H),3.07(d,J=5.5 Hz, 4H), 1.90 (t, J = 6.7Hz, 2H), 1.65 (s, 4H), 0.62 (d, J = 5.3Hz, 4H), 0.43 (s, 4H).

[0452] ESI-MS m / z:570[M+H] + .

[0453] Example 6 Synthesis of Compound 7

[0454] Step 1: Synthesis of compound int_7-2

[0455] Int_7-1 (372 mg, 5.17 mmol) was dissolved in DMF (30 mL). NaH (820 mg, 20.5 mmol, 60% purity) was added at 0°C under nitrogen. The reaction mixture was allowed to react at 0°C under nitrogen for 1 hour. Int_1-1 (400 mg, 2.564 mmol) was then added and the temperature was raised to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography to yield the desired product (170 mg, 32% yield).

[0456] ESI-MS m / z:209[M+H] + .

[0457] Step 2: Synthesis of compound int_7-3

[0458] Int_1-8 (129 mg, 0.361 mmol) was dissolved in DCM (2 mL), and oxalyl chloride (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_7-2 (50 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (100 mg) was slowly added under ice-cooling. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (77 mg, yield: 59%).

[0459] ESI-MS m / z:548[M+H] + .

[0460] Step 3: Synthesis of compound 7

[0461] Int_1-10 (36 mg, 0.29 mmol), (1S,2S)-N,N-dimethylcyclohexane (10 mg, 0.021 mmol), cuprous iodide (14 mg, 0.07 mmol), and potassium phosphate (90 mg, 0.42 mmol) were dissolved in DMF (7 mL). The atmosphere was replaced with argon three times, and int_7-3 (77 mg, 0.14 mmol) was added. Under argon protection, the reaction solution was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (44 mg, yield: 57%).

[0462] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.99(d,J=8.9Hz,1H),7.76(d,J=8.5Hz,1H ),7.58(d,J=2.1Hz,1H),7.47(dd,J=9.1,2.1Hz,1H),7.12(d,J=2.1Hz,1H),7.00( dd,J=8.5,2.1Hz,1H),4.79(t,J=7.2Hz,1H),3.74(t,J=6.6Hz,2H),2.95(t,J=5.2 Hz, 4H), 2.22–2.04 (m, 2H), 1.91–1.61 (m, 2H), 1.49 (t, J = 5.0Hz, 4H), 0.32 (s, 4H).

[0463] ESI-MS m / z:545[M+H]+ .

[0464] Example 7 Synthesis of Compound 65

[0465] Step 1: Synthesis of compound int_65-2

[0466] Int_1-8 (100 mg, 0.279 mmol) was dissolved in DCM (8 mL), and oxalyl chloride (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_65-1 (72 mg, 0.279 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (60 mg) was slowly added under ice-cooling. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (130 mg, yield: 78%).

[0467] ESI-MS m / z:598[M+H] + .

[0468] Step 2: Synthesis of compound 65

[0469] Int_1-10 (40 mg, 0.325 mmol), (1S,2S)-N,N-dimethylcyclohexane (15 mg, 0.108 mmol), cuprous iodide (20 mg, 0.108 mmol), and potassium phosphate (138 mg, 0.651 mmol) were dissolved in DMF (10 mL). The atmosphere was replaced with argon three times, and int_65-2 (130 mg, 0.217 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (10 mg, yield: 7.7%).

[0470] 1H NMR (400MHz, DMSO-d6) δ13.70(s,1H),8.44(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.86(d,J=8.9Hz,1H),7.24(d,J=2.1Hz,1H),7.10(dd,J=8.7,2 .1Hz,1H),3.75(t,J=6.5Hz,2H),3.50(t,J=5.7Hz,4H),3.33(s,2H),2.9 9(t,J=5.2Hz,4H),2.12(d,J=8.1Hz,4H),1.86–1.48(m,4H),0.40(s,4H).

[0471] ESI-MS m / z:595[M+H] + .

[0472] Example 8 Synthesis of Compound 97

[0473] Step 1: Synthesis of compound int_97-2

[0474] Int_97-1 (100 mg, 0.375 mmol) was dissolved in DCM (8 mL), and oxalyl chloride (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_1-3 (96 mg, 0.375 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (60 mg) was slowly added under ice-cooling. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (128 mg, yield: 68.1%).

[0475] ESI-MS m / z:506[M+H] + .

[0476] Step 2: Synthesis of compound 97

[0477] Int_1-10 (52 mg, 0.414 mmol), cesium carbonate (135 mg, 0.414 mmol), Pd2(dba)3 (12 mg, 0.0138 mmol), XantPhos (19 mg, 0.033 mmol), and int_97-2 (128 mg, 0.253 mmol) were dissolved in dioxane (10 mL). The atmosphere was replaced with argon three times. Under argon protection, the reaction solution was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (10 mg, yield: 6.7%).

[0478] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),7.99(d,J=9.2Hz,2H),7.72(s,1H),7.41(d,J=8.8Hz,1H),6.53(d,J=7.8 Hz, 1H), 3.74 (t, J = 6.9 Hz, 2H), 3.11 (dd, J = 13.5, 6.6 Hz, 8H), 2.09 (d, J = 15.1 Hz, 4H), 1.37 (m, 4H), 0.28 (s, 4H).

[0479] ESI-MS m / z:595[M+H] + .

[0480] Example 9 Synthesis of Compound 129

[0481] Step 1: Synthesis of compound int_129-1

[0482] Int_97-1 (100 mg, 0.375 mmol) was dissolved in DCM (8 mL), and oxalyl chloride (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_65-1 (96 mg, 0.375 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (60 mg) was slowly added under an ice bath. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (140 mg, yield: 74.4%).

[0483] ESI-MS m / z:507[M+H] + .

[0484] Step 2: Synthesis of compound 129

[0485] Int_1-10 (52 mg, 0.414 mmol), cesium carbonate (135 mg, 0.414 mmol), Pd2(dba)3 (12 mg, 0.0138 mmol), XantPhos (19 mg, 0.033 mmol), and int_129-1 (140 mg, 0.276 mmol) were dissolved in dioxane (10 mL). The atmosphere was replaced with argon three times. Under argon protection, the reaction solution was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (20 mg, yield: 12.2%).

[0486] 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.57(s,1H),8.39(d,J=9.0Hz,1H),7.82(d,J=8.9Hz,1H),6.33(s,1H),4.80(s,1H),3.65(t ,J=7.0Hz,2H),3.48(t,J=5.7Hz,4H),3.17–3.12(m,2H),2.93(t,J=5.2Hz,4H),2.08(d,J=14.6Hz,4H),1.65(s,4H),0.35(s,4H).

[0487] ESI-MS m / z:596[M+H] + .

[0488] Example 10 Synthesis of Compound 161

[0489] Step 1: Synthesis of compound int_161-3

[0490] Int_161-1 (100 mg, 0.348 mmol) was dissolved in DMF (4 mL), and HATU (264 mg, 0.696 mmol), DIPEA (163 mg, 1.264 mmol), and int_161-2 (98 mg, 0.348 mmol) were added. The reaction mixture was stirred at 60°C for 4 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (150 mg, yield: 78%).

[0491] ESI-MS m / z:550[M+H] + .

[0492] Step 2: Synthesis of compound 161

[0493] Int_1-10 (24 mg, 0.191 mmol), sarcosine (6 mg, 0.064 mmol), cuprous iodide (12 mg, 0.062 mmol), and potassium phosphate (80 mg, 0.369 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_161-3 (70 mg, 0.127 mmol) was added. Under argon protection, the reaction solution was microwave-heated at 130°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (22 mg, yield: 19%).

[0494] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.54(d,J=8.2Hz,1H),8.32(d,J=8.8Hz,1H),7.72(d,J=8.2Hz,1H),7.19(d,J=2.4Hz,1H),7.02(dd,J=8.8,2 .4Hz,1H),3.74(t,J=6.7Hz,2H),3.64(t,J=5.8Hz,4H),3.21(t,J=6.7Hz ,2H),2.83(t,J=5.3Hz,4H),2.25–2.13(m,4H),1.53(s,4H),0.37(s,4H).

[0495] ESI-MS m / z:595[M+H] + .

[0496] Example 11 Synthesis of Compound 257

[0497] Step 1: Synthesis of compound int_257-2

[0498] Int_257-1 (25 g, 107 mmol) was dissolved in dioxane (400 mL), and int_1-2 (20 g, 161 mmol), Pd(dba) (5 g, 5.4 mmol), Xantphos (3 g, 5.4 mmol), and CsCO (104 g, 321 mmol) were added. The reaction mixture was heated to 100°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was diluted with water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO, n-hexane / ethyl acetate = 5:1) to obtain the desired product (5.5 g, yield: 19%).

[0499] ESI-MS m / z:274[M+H] + .

[0500] Step 2: Synthesis of compound int_257-3

[0501] Int_257-2 (5.5 g, 20 mmol) was dissolved in methanol (100 mL), and Pd / C (2.00 g, 10% purity) was added. The reaction system was purged with hydrogen three times, and the reaction mixture was allowed to react at 60°C under a hydrogen atmosphere for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (4.2 g, 86% yield). The crude product was used directly in the next reaction.

[0502] ESI-MS m / z:244[M+H] + .

[0503] Step 3: Synthesis of compound int_257-4

[0504] Int_1-8 (1.2 g, 3.36 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (888.4 mg, 7 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0505] Int_257-3 (0.7 g, 3.4 mmol) was dissolved in tetrahydrofuran (40 mL). Under nitrogen, NaH (720 mg, 18 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (1.2 g, yield: 71%).

[0506] ESI-MS m / z:583[M+H] + .

[0507] Step 4: Synthesis of compound 257

[0508] Int_257-4 (1 g, 1.7 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (122 mg, 0.85 mmol), cuprous iodide (164 mg, 0.85 mmol), and potassium phosphate (1.1 g, 5.1 mmol) were dissolved in DMF (20 mL). The atmosphere was replaced with argon three times, and int_1-10 (0.43 g, 3.4 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography (SiO2, hexane / ethyl acetate = 1:1) to obtain a solid (0.77 g, yield: 77%).

[0509] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),10.16(s,1H),8.06(d,J=8.6Hz,1H),7.81(d,J= 8.5Hz,1H),7.36(d,J=8.6Hz,1H),7.25(d,J=2.2Hz,1H),7.11(dd,J=8.6,2.1Hz,1H), 4.93(s,1H),3.81(s,3H),3.76(t,J=6.5Hz,2H),3.52(t,J=5.6Hz,4H),3.35(t,J=6.5 Hz, 2H), 2.97 (t, J = 5.4Hz, 4H), 2.09 (td, J = 14.1, 6.7Hz, 4H), 1.72 (s, 4H), 0.38 (s, 4H).

[0510] ESI-MS m / z:580[M+H] + .

[0511] Example 12 Synthesis of Compound 258

[0512] Step 1: Synthesis of compound int_258-1

[0513] Int_257-1 (1 g, 4.29 mmol) was dissolved in dioxane (30 mL), and int_2-1 (480 mg, 4.72 mmol), Ruphos-Pd-G3 (360 mg, 0.429 mmol), and Cs2CO3 (2.8 g, 8.58 mmol) were added. The reaction mixture was heated to 100°C under nitrogen for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain the desired product (780 mg, yield: 71.8%).

[0514] ESI-MS m / z:254[M+H] + .

[0515] Step 2: Synthesis of compound int_258-2

[0516] Int_258-1 (780 mg, 3.08 mmol) was dissolved in methanol (20 mL), and Pd / C (200 mg, 10% purity) was added. The reaction system was replaced with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (550 mg, 80% yield). The crude product was used directly in the next reaction.

[0517] ESI-MS m / z:224[M+H] + .

[0518] Step 3: Synthesis of compound int_258-3

[0519] Int_1-8 (190 mg, 0.532 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (888.4 mg, 7 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0520] Int_258-2 (120 mg, 0.532 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (72 mg, 1.8 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice-cooling, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (250 mg, yield: 82.7%).

[0521] ESI-MS m / z:563[M+H] + .

[0522] Step 4: Synthesis of compound 258

[0523] Int_258-3 (250 mg, 0.444 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (32 mg, 0.222 mmol), cuprous iodide (42 mg, 0.222 mmol), and potassium phosphate (282 mg, 1.332 mmol) were dissolved in DMF (20 mL). The atmosphere was replaced with argon three times, and int_1-10 (111 mg, 0.888 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (150 mg, yield: 60.4%).

[0524] 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),8.05(d,J=8.6Hz,1H),7.78(d,J=8.4Hz,1H) ,7.31(d,J=8.5Hz,1H),7.24(d,J=2.1Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),3.86–3. 72(m,6H),3.65(td,J=11.7,3.0Hz,2H),2.95(d,J=5.4Hz,4H),2.76(td,J=12.3,3 .3Hz,1H),2.51(d,J=12.9Hz,2H),1.71(s,4H),1.12(d,J=6.2Hz,3H),0.36(s,4H).

[0525] ESI-MS m / z:560[M+H] + .

[0526] Example 13 Synthesis of Compound 259

[0527] Step 1: Synthesis of compound int_259-1

[0528] Int_257-1 (1 g, 4.29 mmol) was dissolved in dioxane (30 mL), and int_3-1 (480 mg, 4.72 mmol), Ruphos-Pd-G3 (360 mg, 0.429 mmol), and Cs2CO3 (2.7 g, 8.38 mmol) were added. The reaction was heated to 100°C under nitrogen for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain the desired product (750 mg, yield: 69.4%).

[0529] ESI-MS m / z:254[M+H] + .

[0530] Step 2: Synthesis of compound int_259-2

[0531] Int_259-1 (750 mg, 2.964 mmol) was dissolved in methanol (20 mL), and Pd / C (200 mg, 10% purity) was added. The reaction system was purged with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (560 mg, yield: 84.7%). The crude product was used directly in the next reaction.

[0532] ESI-MS m / z:224[M+H] + .

[0533] Step 3: Synthesis of compound int_259-3

[0534] Int_1-8 (335 mg, 0.938 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (888.4 mg, 7 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0535] Int_259-2 (200 mg, 0.893 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (170 mg, 4.465 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the previously prepared acyl chloride was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (340 mg, yield: 67.7%).

[0536] ESI-MS m / z:563[M+H] + .

[0537] Step 4: Synthesis of compound 259

[0538] Int_259-3 (340 mg, 0.604 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (44 mg, 0.302 mmol), cuprous iodide (58 mg, 0.302 mmol), and potassium phosphate (384 mg, 1.810 mmol) were dissolved in DMF (15 mL). The atmosphere was replaced with argon three times, and int_1-10 (151 mg, 1.210 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (150 mg, yield: 44.4%).

[0539] ESI-MS m / z:560[M+H] + .

[0540] Example 14 Synthesis of Compound 260

[0541] Step 1: Synthesis of compound int_260-1

[0542] Int_257-1 (200 mg, 0.858 mmol) was dissolved in dioxane (15 mL), and int_4-1 (hydrochloride, 167 mg, 1.287 mmol), Pd2(dba)3 (78 mg, 0.086 mmol), Xantphos (49 mg, 0.086 mmol), and Cs2CO3 (839 mg, 2.575 mmol) were added. The reaction mixture was heated to 100°C under nitrogen for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then subjected to column chromatography to obtain the desired product (80 mg, yield: 36.7%).

[0543] ESI-MS m / z:246[M+H] + .

[0544] Step 2: Synthesis of compound int_260-2

[0545] Int_260-1 (80 mg, 0.858 mmol) was dissolved in methanol (10 mL), and Pd / C (20 mg, 10% purity) was added. The reaction system was purged with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (60 mg, yield: 89.5%). The crude product was used directly in the next reaction.

[0546] ESI-MS m / z:216[M+H] + .

[0547] Step 3: Synthesis of compound int_260-3

[0548] Int_1-8 (95 mg, 0.266 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (380.7 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0549] Int_260-2 (60 mg, 0.279 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen, NaH (100 mg, 4.166 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (80 mg, yield: 51.9%).

[0550] ESI-MS m / z:555[M+H] + .

[0551] Step 4: Synthesis of compound 260

[0552] Int_260-3 (80 mg, 0.144 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.072 mmol), cuprous iodide (14 mg, 0.072 mmol), and potassium phosphate (92 mg, 0.433 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_1-10 (36 mg, 0.289 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (40 mg, yield: 50.6%).

[0553] 1 H NMR (400MHz, DMSO-d6) δ13.03(s,1H),8.04(d,J=8.6Hz,1H),7.67(d,J=8.4Hz,1H),7.28(d,J=8.5Hz,1H),7.23(d,J=2.1Hz,1H),7.09(d d,J=8.6,2.1Hz,1H),4.40(t,J=12.6Hz,4H),3.74(d,J=3.4Hz,5H),3.33(m,2H),2.94(t,J=5.5Hz,4H),1.94–1.58(m,4H),0.37(s,4H).

[0554] ESI-MS m / z:552[M+H] + .

[0555] Example 15 Synthesis of Compound 261

[0556] Step 1: Synthesis of compound int_261-2

[0557] Int_261-1 (300 mg, 2.618 mmol) was dissolved in DMF (30 mL). NaH (208 mg, 5.2 mmol, 60% purity) was added at 0°C under nitrogen. The reaction mixture was allowed to react at 0°C under nitrogen for 1 hour. Int_257-1 (610 mg, 2.618 mmol) was then added and the temperature was raised to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then subjected to column chromatography to yield the desired product (500 mg, yield: 71.8%).

[0558] ESI-MS m / z:267[M+H] + .

[0559] Step 2: Synthesis of compound int_261-3

[0560] Int_261-2 (500 mg, 1.880 mmol) was dissolved in methanol (20 mL), and Pd / C (50 mg, 10% purity) was added. The reaction system was purged with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (410 mg, yield: 92.3%). The crude product was used directly in the next reaction.

[0561] ESI-MS m / z:237[M+H] + .

[0562] Step 3: Synthesis of compound int_261-4

[0563] Int_1-8 (682 mg, 1.910 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (482 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0564] Int_261-3 (450 mg, 1.910 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (366 mg, 9.550 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (500 mg, yield: 45.9%).

[0565] ESI-MS m / z:576[M+H] + .

[0566] Step 4: Synthesis of compound 261

[0567] Int_261-4 (100 mg, 0.174 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.087 mmol), cuprous iodide (17 mg, 0.087 mmol), and potassium phosphate (111 mg, 0.523 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_1-10 (44 mg, 0.348 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (25 mg, yield: 25.3%).

[0568] 1 H NMR (400MHz, Methanol-d4) δ8.11(d,J=8.6Hz,1H),7.86(d,J=8.4Hz,1H),7.40–7.27(m,2H),7.14(dd,J=8.6,2.2Hz,1H),4.58(t,J=6.3Hz,2 H), 3.94 (t, J = 6.2Hz, 2H), 3.84 (s, 3H), 3.36 (t, J = 6.2Hz, 2H), 3.07 (t, J = 5.3Hz, 4H), 2.75 (qt, J = 10.9, 6.3Hz, 2H), 1.79 (s, 4H), 0.42 (s, 4H).

[0569] ESI-MS m / z:573[M+H] + .

[0570] Example 16 Synthesis of Compound 262

[0571] Step 1: Synthesis of compound int_262-1

[0572] Int_257-1 (348 mg, 1.5 mmol) was dissolved in dioxane (15 mL), and int_6-1 (hydrochloride, 200 mg, 1.5 mmol), Ruphos-Pd-G3 (125 mg, 0.15 mmol), and Cs2CO3 (977 mg, 3 mmol) were added. The reaction was heated to 100°C under nitrogen for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (320 mg, yield: 68.6%).

[0573] ESI-MS m / z:250[M+H] +

[0574] Step 2: Synthesis of compound int_262-2

[0575] Int_262-1 (320 mg, 1.28 mmol) was dissolved in methanol (20 mL), and Pd / C (30 mg, 10% purity) was added. The reaction system was replaced with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (165 mg, yield: 57.8%). The crude product was used directly in the next reaction.

[0576] ESI-MS m / z:220[M+H] +

[0577] Step 3: Synthesis of compound int_262-3

[0578] Int_1-8 (270 mg, 0.752 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (380.7 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0579] Int_262-2 (165 mg, 0.752 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen, NaH (150 mg, 3.76 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to obtain a solid (170 mg, yield: 40.4%).

[0580] ESI-MS m / z:559[M+H] + .

[0581] Step 4: Synthesis of compound 262

[0582] Int_262-3 (170 mg, 0.304 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (22 mg, 0.152 mmol), cuprous iodide (29 mg, 0.152 mmol), and potassium phosphate (193 mg, 912 mmol) were dissolved in DMF (10 mL). The atmosphere was replaced with argon three times, and int_1-10 (76 mg, 0.608 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (120 mg, yield: 71%).

[0583] 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.04(d,J=8.6Hz,1H),7.48(d,J=8.3Hz,1H),7.22(d,J=2.2Hz,1H),7.15(d,J=8.4Hz,1H),7.08(dd ,J=8.6,2.1Hz,1H),3.74(dt,J=7.0,3.6Hz,4H),3.70(s,3H),3.47(s,2H),2.93(d,J=5.2Hz,4H),1.79(s,6H),0.57(s,4H),0.33(s,4H).

[0584] ESI-MS m / z:556[M+H] + .

[0585] Example 17 Synthesis of Compound 263

[0586] Step 1: Synthesis of compound int_263-1

[0587] Int_7-1 (460 mg, 1.974 mmol) was dissolved in DMF (20 mL). NaH (510 mg, 3.948 mmol, 60% purity) was added at 0°C under nitrogen. The reaction mixture was incubated at 0°C for 1 hour under nitrogen. Int_257-1 (1.5 g, 1.974 mmol) was then added and the temperature was raised to 80°C for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography to yield the desired product (300 mg, yield: 67.9%).

[0588] ESI-MS m / z:225[M+H] + .

[0589] Step 2: Synthesis of compound int_263-2

[0590] Int_263-1 (300 mg, 1.339 mmol) was dissolved in methanol (30 mL), and Pd / C (30 mg, 10% purity) was added. The reaction system was replaced with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (255 mg, 98% yield). The crude product was used directly in the next reaction.

[0591] ESI-MS m / z:195[M+H] + .

[0592] Step 3: Synthesis of compound int_263-3

[0593] Int_1-8 (552 mg, 1.546 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (482 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0594] Int_263-2 (300 mg, 1.546 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (180 mg, 4.5 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice-cooling, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (510 mg, yield: 63.8%).

[0595] ESI-MS m / z:534[M+H] + .

[0596] Step 4: Synthesis of compound 263

[0597] Int_263-3 (150 mg, 0.281 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.141 mmol), cuprous iodide (27 mg, 0.141 mmol), and potassium phosphate (180 mg, 0.843 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_1-10 (70 mg, 0.562 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (55 mg, yield: 36.9%).

[0598] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),8.04(d,J=8.6Hz,1H),7.81(d,J=8.4Hz ,1H),7.34(d,J=8.6Hz,1H),7.24(d,J=2.1Hz,1H),7.09(dd,J=8.6,2.1Hz,1H ),5.31–5.19(m,1H),3.74(d,J=4.5Hz,5H),2.96(t,J=5.3Hz,4H),2.48–2.39 (m,2H),2.08(dtd,J=12.5,10.0,8.0Hz,2H),1.80–1.53(m,6H),0.41(s,4H).

[0599] ESI-MS m / z:531[M+H] + .

[0600] Example 18 Synthesis of Compound 273

[0601] Step 1: Synthesis of compound int_273-2

[0602] Int_273-1 (5 g, 22.8 mmol) was dissolved in DMF (50 mL), and sodium carbonate (4.9 g, 46.2 mmol) and benzyl bromide (5.9 g, 34.5 mmol) were added. The mixture was allowed to react at room temperature for 24 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (200 mL), and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 30:1) to obtain the desired product (6.9 g, yield: 99%).

[0603] ESI-MS m / z:309[M+H] + .

[0604] Step 2: Synthesis of compound int_273-3

[0605] Int_273-2 (5 g, 16.2 mmol) was dissolved in DMSO (20 mL), and DIPEA (6.3 g, 48.8 mmol) and int_1-6 (hydrochloride, 4.8 g, 32.5 mmol) were added. The reaction mixture was heated to 100°C and allowed to react for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 30:1) to obtain the desired product (6.1 g, yield: 92%).

[0606] ESI-MS m / z:400[M+H] + .

[0607] Step 3: Synthesis of compound int_273-5

[0608] Int_273-3 (6.1 g, 15.3 mmol) was dissolved in dioxane (40 mL), followed by the addition of benzyl mercaptan (5.7 g, 45.9 mmol), Pd(dba) (2 g, 2.2 mmol), Xantphos (2 g, 3.6 mmol), and DIPEA (7.9 g, 61.2 mmol). The reaction mixture was heated to 100°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO, n-hexane / ethyl acetate = 10:1) to afford the desired product (6.7 g, yield: 97%).

[0609] ESI-MS m / z:444[M+H] + .

[0610] Step 4: Synthesis of compound int_273-6

[0611] Int_273-5 (16.3 g, 43.9 mmol) was dissolved in a mixture of acetonitrile / water / acetic acid (40 mL / 1 mL / 0.5 mL). Dichlorohydantoin (3.4 g, 17.3 mmol) was added under ice-cooling. The mixture was stirred at 0°C under nitrogen for 0.5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was dissolved in a mixture of acetonitrile and tetrahydrofuran (30 mL / 10 mL), glycine methyl hydrochloride (5.4 g, 43 mmol) and potassium carbonate (12 g, 87 mmol) were added, and the mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 3:1) to obtain the desired product (3.2 g, yield: 80%).

[0612] ESI-MS m / z:473[M+H] + .

[0613] Step 5: Synthesis of compound int_273-7

[0614] Int_273-6 (3.2 g, 6.8 mmol) was dissolved in methanol (30 mL), and Pd / C (1.00 g, 10% purity) and 5 drops of acetic acid were added. The reaction system was replaced with hydrogen three times, and the reaction solution was allowed to react at 50°C under a hydrogen atmosphere for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (2.5 g, yield: 96%). The crude product was used directly in the next reaction.

[0615] ESI-MS m / z:383[M+H] + .

[0616] Step 6: Synthesis of compound int_273-8

[0617] Int_273-7 (0.5 g, 1.3 mmol) was dissolved in DCM (15 mL), and oxalyl chloride (888 mg, 7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. The acyl chloride was dissolved in tetrahydrofuran (20 mL), and int_257-3 (318 mg, 1.3 mmol) and triethylamine (1.3 g, 13 mmol) were slowly added under an ice bath. The reaction was allowed to react at room temperature for 1 hour, and LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (250 mg, yield: 31%).

[0618] 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.36(s,1H),8.23(d,J=8.2Hz,1H),7 .82–7.75(m,2H),7.66(dd,J=8.2,1.7Hz,1H),7.37(d,J=8.6Hz,1H),3.80( s,3H),3.76(s,2H),3.52(d,J=6.3Hz,4H),3.49(s,3H),3.39(d,J=6.7Hz,2 H), 3.03 (t, J = 5.4Hz, 4H), 2.06 (t, J = 5.1Hz, 2H), 1.70 (s, 4H), 0.36 (s, 4H).

[0619] ESI-MS m / z:608[M+H] + .

[0620] Step 7: Synthesis of compound 273

[0621] Int_273-8 (230 mg, 0.38 mmol) was dissolved in a mixture of methanol and tetrahydrofuran (5 mL / 5 mL). Sodium borohydride (43 mg, 1.1 mmol) and lithium chloride (48 mg, 1.1 mmol) were slowly added under an ice bath. The reaction mixture was allowed to react at room temperature for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (210 mg, 95% yield).

[0622] 1H NMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 8.23 ​​(d, J = 8.2Hz, 1H), 7.79 (dd, J = 5.1 ,3.4Hz,2H),7.67(dd,J=8.2,1.7Hz,1H),7.37(d,J=8.6Hz,1H),4.73(s,1H), 3.80(s,3H),3.51(t,J=5.7Hz,4H),3.42–3.36(m,2H),3.03(t,J=5.3Hz,4H), 2.81(t,J=6.2Hz,2H), 2.05(q,J=11.2,8.5Hz,4H), 1.70(m,4H),0.36(s,4H).

[0623] ESI-MS m / z:580[M+H] + .

[0624] Example 19 Synthesis of Compound 321

[0625] Step 1: Synthesis of compound int_321-2

[0626] Int_321-1 (1 g, 4.55 mmol) was dissolved in DMF (20 mL), and int_1-6 (670 mg, 4.55 mmol) and potassium carbonate (1.8 g, 13.64 mmol) were added. The mixture was reacted at 100°C for 3 hours under argon. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure, and 100 mL of water was added. The aqueous phase was extracted with ethyl acetate (200 mL x 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 (1.5 g, yield: 100%).

[0627] ESI-MS m / z:311[M+H] + .

[0628] Step 2: Synthesis of compound int_321-3

[0629] Dissolve int_321-2 (1.5 g, 4.82 mmol) in methanol (50 mL), add 20 mL of acetic acid, and stir on an ice bath for 10 minutes. Then, add zinc powder (1.5 g, 24.10 mmol) in small portions. Warm the reaction mixture to room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. Filter the reaction mixture to obtain a filtrate, which is then concentrated under reduced pressure to yield the crude product. Add 100 mL of water to the crude product, extract the aqueous phase with dichloromethane (200 mL x 3), and dry the organic phase over anhydrous sodium sulfate. Filter the organic phase and evaporate under reduced pressure to yield the crude product (1 g, yield: 77%).

[0630] ESI-MS m / z:281[M+H] + .

[0631] Step 3: Synthesis of compound int_321-5

[0632] Int_321-4 (5 g, 21.55 mmol) was suspended in methanol (100 mL) and trimethylsilyl chloride (7 g, 64.65 mmol) was added. The reaction mixture was allowed to react at room temperature for 4 hours, during which time the solution gradually became clear. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product (5.2 g, 98% yield).

[0633] ESI-MS m / z:246[M+H] + .

[0634] Step 4: Synthesis of compound int_321-6

[0635] Int_321-5 (5 g, 16.2 mmol) was dissolved in 1,4-dioxane (100 mL), and cesium carbonate (20 g, 63.4 mmol), Pd(dba) (1.9 g, 2.11 mmol), and Xantphos (1.2 g, 2.11 mmol) were added. Under argon, the mixture was heated to 100°C and allowed to react for 18 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (300 mL), and the aqueous phase was extracted with dichloromethane (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO, n-hexane / ethyl acetate = 10:1) to obtain the desired product (4.3 g, yield: 71%).

[0636] ESI-MS m / z:287[M+H] + .

[0637] Step 5: Synthesis of compound int_321-7

[0638] Int_273-6 (4.3 g, 15.02 mmol) was dissolved in methanol (50 mL). NaOH (2 M, 20 mL) was added with stirring at room temperature. The reaction mixture was allowed to react at room temperature for 4 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a solid. Water (100 mL) was added to the solid, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The aqueous phase was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the desired product (2 g, yield: 58%).

[0639] ESI-MS m / z:273[M+H] + .

[0640] Step 6: Synthesis of compound int_321-8

[0641] Int_321-7 (2 g, 7.37 mmol) was dissolved in DCM (100 mL), and oxalyl chloride (1.4 g, 11 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_321-3 (2.1 g, 7.37 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydroxide (2.9 g, 73.7 mmol, 60% purity) was slowly added under ice-cooling. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to give the desired product (3.7 g, yield: 95%).

[0642] ESI-MS m / z:535[M+H] + .

[0643] Step 7: Synthesis of compound 321

[0644] Int_321-8 (500 mg, 0.94 mmol), N,N-dimethylglycine (66 mg, 0.47 mmol), cuprous iodide (89 mg, 0.47 mmol), and potassium phosphate (596 mg, 2.8 mmol) were dissolved in DMF (20 mL). The atmosphere was replaced with argon three times, and int_1-10 (266 mg, 1.87 mmol) was added. Under argon protection, the reaction mixture was heated to 130°C in a microwave oven for 3.5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (260 mg, 48% yield).

[0645] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.39(s,1H),8.30(d,J=8.8Hz,1H),7.76(d, J=8.2Hz,1H),7.47(d,J=8.3Hz,1H),7.14(d,J=2.4Hz,1H),6.97(dd,J=8.7,2.4Hz ,1H),3.90(s,3H),3.71(t,J=6.7Hz,2H),3.56(t,J=5.5Hz,4H),3.18(t,J=6.7Hz, 2H), 2.78(t,J=5.3Hz,4H), 2.13(tt,J=13.7,5.6Hz,4H), 1.52(s,4H), 0.33(s,4H).

[0646] ESI-MS m / z:580[M+H] + .

[0647] Example 20 Synthesis of Compound 337

[0648] Step 1: Synthesis of compound int_337-1

[0649] Int_321-2 (2 g, 6.43 mmol) was dissolved in dioxane (30 mL), and benzyl mercaptan (2.4 g, 19.28 mmol), Pd2(dba)3 (300 mg, 0.33 mmol), Xantphos (300 mg, 0.54 mmol), and DIPEA (3.3 g, 25.72 mmol) were added. The reaction mixture was heated to 100°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography to yield the desired product (1.7 g, yield: 74.9%).

[0650] ESI-MS m / z:355[M+H] + .

[0651] Step 2: Synthesis of compound int_337-2

[0652] Int_337-1 (360 mg, 1.02 mmol) was dissolved in a mixture of acetonitrile / water / acetic acid (30 mL / 1 mL / 1 mL). Dichlorohydantoin (402 mg, 2.04 mmol) was added under ice-cooling. The mixture was stirred at 0°C under nitrogen for 0.5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was dissolved in a mixture of acetonitrile and tetrahydrofuran (30 mL / 10 mL), glycine methyl hydrochloride (1 g, 7.96 mmol) and potassium carbonate (3.3 g, 24 mmol) were added, and the mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL x 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 target product (100 mg, yield: 25.6%).

[0653] ESI-MS m / z:384[M+H] + .

[0654] Step 3: Synthesis of compound int_337-3

[0655] Int_337-2 (100 mg, 0.261 mmol) was dissolved in methanol (10 mL), and Pd / C (30 mg, 10% purity) and 5 drops of acetic acid were added. The reaction system was replaced with hydrogen three times, and the reaction solution was allowed to react at room temperature under a hydrogen atmosphere for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (90 mg, yield: 97.8%). The crude product was used directly in the next reaction.

[0656] ESI-MS m / z:354[M+H] + .

[0657] Step 4: Synthesis of compound int_337-4

[0658] Int_321-7 (220 mg, 0.809 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (1 g, 8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_337-3 (140 mg, 0.396 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (56 mg, 1.4 mmol, 60% purity) was slowly added under ice-cooling. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at 40°C for 5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (100 mg, yield: 41.7%).

[0659] ESI-MS m / z:608[M+H] + .

[0660] Step 5: Synthesis of compound 337

[0661] Int_337-4 (100 mg, 0.165 mmol) was dissolved in a mixture of methanol and tetrahydrofuran (5 mL / 5 mL). Sodium borohydride (38 mg, 1 mmol) and lithium chloride (42 mg, 1 mmol) were slowly added under an ice bath. The reaction mixture was allowed to react at room temperature for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (82 mg, yield: 85.8%).

[0662] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.58(d,J=8.6Hz,1H),7.81(d,J=8.2Hz,1H),7.68(s,1H),7.58(d,J=8.7Hz,1H),7.49(d,J=8.8Hz,1H ), 4.69 (d, J = 6.5Hz, 1H), 3.91 (s, 3H), 3.58 (d, J = 6.5Hz, 4H), 2.81 (dt, J = 37.8, 5.6Hz, 6H), 2.15 (d, J = 7.6Hz, 4H), 1.55 (s, 4H), 0.35 (s, 4H).

[0663] ESI-MS m / z:580[M+H] + .

[0664] Example 21 Synthesis of Compound 353

[0665] Step 1: Synthesis of compound int_353-2

[0666] Int_321-7 (50 mg, 0.184 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (12 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_353-1 (44 mg, 0.185 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydroxide (50 mg, 1.25 mmol, 60% purity) was slowly added under an ice bath. The reaction mixture was allowed to react at room temperature for 1 hour. The prepared acyl chloride product was then added to the reaction mixture, and the reaction mixture was allowed to react at room temperature for 5 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (50 mg, yield: 55%).

[0667] ESI-MS m / z:492[M+H] + .

[0668] Step 2: Synthesis of compound 353

[0669] Int_353-2 (190 mg, 0.39 mmol), cesium carbonate (129.8 mg, 1.16 mmol), Pd2(dba)3 (95 mg, 0.218 mmol), and Xantphos (95 mg, 0.346 mmol) were dissolved in 1,4-dioxane (10 mL). The atmosphere was replaced with argon three times, and int_1-10 (97.2 mg, 0.78 mmol) was added. Under argon, the reaction mixture was heated to 110°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (56 mg, yield: 27%).

[0670] 1H NMR (400MHz, DMSO-d6) δ9.75(s,1H),8.66(s,1H),7.72(d,J=8.2Hz,1H),7.45(d,J=8.3Hz,1H),6.35(s,1H),3.89(s,3H),3.64(t ,J=6.6Hz,2H),3.54(d,J=3.1Hz,4H),3.09(t,J=6.6Hz,2H),2.78(d,J=5.5Hz,4H),2.19–2.03(m,4H),1.47(s,4H),0.30(s,4H).

[0671] ESI-MS m / z:581[M+H] + .

[0672] Example 22 Synthesis of Compound 369

[0673] Step 1: Synthesis of compound int_369-2

[0674] Int_321-7 (27 mg, 0.1 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (12 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated under reduced pressure to obtain the acyl chloride product. Int_369-1 (37 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (202 mg, 2 mmol) and the prepared acyl chloride product were slowly added under an ice bath. The reaction mixture was allowed to react at 40°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (2 mg, yield: 3.3%).

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.38(s,1H),8.29(t,J=6.1Hz,1H),7.80(d,J=8.2Hz,1H),7.63(s,1H),7.50(d,J=8.3Hz,1H),3.92(s, 3H), 3.85 (d, J = 5.8Hz, 2H), 3.56 (d, J = 11.2Hz, 6H), 3.31 (s, 2H), 2.99 (t, J = 5.2Hz, 3H), 2.21–1.95 (m, 4H), 1.53 (t, J = 5.3Hz, 4H), 0.34 (s, 4H).

[0676] ESI-MS m / z:609[M+H]+ .

[0677] Step 2: Synthesis of compound 369

[0678] Int_369-2 (70 mg, 0.115 mmol) was dissolved in a mixture of methanol and tetrahydrofuran (5 mL / 5 mL). Sodium borohydride (38 mg, 1 mmol) and lithium chloride (42 mg, 1 mmol) were slowly added under an ice bath. The reaction mixture was allowed to react at room temperature for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield the desired product (9 mg, yield: 12.9%).

[0679] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.40(s,1H),7.80(d,J=8.2Hz,1H),7.67(d,J=9.2Hz,2H),7.50(d,J=8.3Hz,1H),4.63(t,J=5.6Hz,1H) ,3.92(s,3H),3.57(t,J=5.6Hz,4H),3.44–3.34(m,2H),2.97(dt,J=26.4,6.1Hz,6H),2.27–2.04(m,4H),1.53(t,J=5.2Hz,4H),0.34(s,4H).

[0680] ESI-MS m / z:581[M+H] + .

[0681] Example 23 Synthesis of Compound 385

[0682] Step 1: Synthesis of compound int_385-2

[0683] Int_1-8 (150 mg, 0.42 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (507 mg, 4 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0684] Int_385-1 (70 mg, 0.28 mmol) was dissolved in tetrahydrofuran (40 mL). Under nitrogen, NaH (67 mg, 1.68 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 8:1) to obtain a solid (140 mg, yield: 87%).

[0685] ESI-MS m / z:600[M+H] + .

[0686] Step 2: Synthesis of compound 385

[0687] Int_385-2 (140 mg, 0.23 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (16 mg, 0.115 mmol), cuprous iodide (22 mg, 0.115 mmol), and potassium phosphate (146 mg, 0.69 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_1-10 (58 mg, 0.46 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (77 mg, yield: 56.2%).

[0688] 1 H NMR(400MHz,Chloroform-d)δ12.45(s,1H),8.20(d,J=8.3Hz,1H),7.75–7.70(m ,1H),7.33(s,1H),7.20–7.16(m,1H),7.12(d,J=8.6Hz,1H),7.02(t,J=9.3Hz,1H ),5.80(s,1H),5.66(s,1H),4.13(d,J=5.7Hz,2H),3.37–3.29(m,2H),3.23(t,J= 5.6Hz, 4H), 3.07 (s, 4H), 2.14 (tt, J = 13.1, 5.4Hz, 4H), 1.62 (s, 4H), 0.43 (s, 4H).

[0689] ESI-MS m / z:597[M+H] + .

[0690] Example 24 Synthesis of Compound 577

[0691] Step 1: Synthesis of compound int_577-2

[0692] Int_1-8 (138 mg, 0.387 mmol) was dissolved in DCM (50 mL). Int_577-1 (100 mg, 0.387 mmol), HATU (294 mg, 0.774 mmol), and DIPEA (193.8 mg, 1.5 mmol) were added and dissolved in DMF (10 mL). Under nitrogen, the reaction mixture was heated to 60°C and stirred for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (130 mg, yield: 56%).

[0693] ESI-MS m / z:598[M+H] + .

[0694] Step 2: Synthesis of compound 577

[0695] Int_577-2 (130 mg, 0.217 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (9 mg, 0.065 mmol), cuprous iodide (12 mg, 0.065 mmol), and potassium phosphate (138 mg, 0.653 mmol) were dissolved in DMF (10 mL). The atmosphere was replaced with argon three times, and int_1-10 (54 mg, 0.435 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (80 mg, yield: 62%).

[0696] 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),7.80(d,J=8.5Hz,1H),7.63(d,J=2.2Hz,1H),7. 48(dd,J=8.5,2.1Hz,1H),7.17(d,J=8.6Hz,1H),7.12(d,J=2.1Hz,1H),6.99(dd,J=8.5 ,2.0Hz,1H),3.74(t,J=6.5Hz,2H),3.27(d,J=6.6Hz,2H),3.01(t,J=5.6Hz,4H),2.94 (t,J=5.3Hz,4H),2.39(s,3H),2.10(dt,J=14.3,7.9Hz,4H),1.53(s,4H),0.34(s,4H).

[0697] ESI-MS m / z:595[M+H] + .

[0698] Example 25 Synthesis of Compound 641

[0699] Step 1: Synthesis of compound int_641-2

[0700] Int_1-8 (100 mg, 0.29 mmol) was dissolved in DCM (50 mL). Int_641-1 (100 mg, 0.29 mmol), HATU (220 mg, 0.585 mmol), and DIPEA (193.8 mg, 1.5 mmol) were dissolved in DMF (8 mL). The reaction mixture was stirred at room temperature for 12 hours under nitrogen. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (110 mg, yield: 55.2%).

[0701] ESI-MS m / z:681[M+H] + .

[0702] Step 2: Synthesis of compound 641-3

[0703] Int_641-2 (160 mg, 0.235 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (17 mg, 0.117 mmol), cuprous iodide (22 mg, 0.117 mmol), and potassium phosphate (150 mg, 0.705 mmol) were dissolved in DMF (10 mL). The atmosphere was replaced with argon three times, and int_1-10 (60 mg, 0.47 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (110 mg, yield: 69.1%).

[0704] ESI-MS m / z:678[M+H] + .

[0705] Step 3: Synthesis of compound 641

[0706] Int_641-3 (110 mg, 0.162 mmol) was dissolved in methanol / hydrochloric acid (4 N, 15 mL) and the reaction mixture was allowed to react at room temperature for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was dried and purified by column chromatography to obtain a solid (60 mg, yield: 64.5%).

[0707] 1 H NMR(400MHz,Chloroform-d)δ12.26(s,1H),8.11(d,J=8.4Hz,1H),7.63(d,J= 2.3Hz,1H),7.34(s,1H),7.25(d,J=3.0Hz,1H),6.99(d,J=8.3Hz,1H),6.63(d ,J=8.6Hz,1H),4.09(t,J=5.1Hz,2H),3.30(t,J=5.1Hz,2H),3.07–2.98(m,8H ), 2.87 (s, 3H), 2.12 (ddt, J = 16.7, 11.5, 5.6Hz, 4H), 1.62 (s, 4H), 0.40 (s, 4H).

[0708] ESI-MS m / z:578[M+H] + .

[0709] Example 26 Synthesis of Compound 643

[0710] Step 1: Synthesis of compound int_643-2

[0711] Int_1-8 (1.17 g, 3.3 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (1.9 g, 15 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0712] Int_643-1 (800 mg, 3.3 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen, triethylamine (666 mg, 6.6 mmol) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature, and the reaction mixture was stirred at room temperature for 6 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 7:1) to obtain a solid (1.1 g, yield: 57.8%).

[0713] ESI-MS m / z:682[M+H] + .

[0714] Step 2: Synthesis of compound 643-3

[0715] Int_643-2 (1.1 g, 1.89 mmol), cesium carbonate (921 mg, 2.83 mmol), Pd2(dba)3 (35 mg, 0.037 mmol), and X-Phos (27 mg, 0.056 mmol) were dissolved in 1,4-dioxane (40 mL). Int_1-10 (473 mg, 3.78 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (550 mg, yield: 50.45%).

[0716] ESI-MS m / z:679[M+H] + .

[0717] Step 3: Synthesis of compound 643

[0718] Int_643-3 (100 mg, 0.147 mmol) was dissolved in methanol / hydrochloric acid (4 N, 15 mL) and the reaction mixture was allowed to react at room temperature for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was dried and purified by column chromatography to obtain a solid (57 mg, yield: 67%).

[0719] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.02(d,J=8.6Hz,1H),7.86(d,J=8.4Hz,1H),7.21(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),6.91(d,J =8.6Hz,1H),4.98(q,J=5.2Hz,1H),3.73(t,J=6.5Hz,2H),3.12(t,J=5.7Hz,4H),2.94(d,J=5.2Hz,4H),2.71(d,J=5.1Hz,3H),2.16(tt,J=11.8, 5.2Hz,4H),1.73(s,4H),0.35(s,4H).

[0720] ESI-MS m / z:579[M+H] + .

[0721] Example 27 Synthesis of Compound 645

[0722] Step 1: Synthesis of compound int_645-2

[0723] Int_645-1 (10.0 g, 37.8 mmol) was dissolved in DCM (20 mL), and Boc2O (8.27 g, 37.8 mmol, 8.70 mL), TEA (4.98 g, 49.2 mmol, 6.85 mL), and DMAP (231 mg, 1.89 mmol) were added. The reaction mixture was allowed to react at 25°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1) to afford the desired product (10 g, yield: 68.6%).

[0724] 1 H NMR (400MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.58 (d, J = 2.8Hz, 1H), 8.22 (dd, J = 2.8, 9.0Hz, 1H), 7.82 (d, J = 9.0Hz, 1H), 1.54-1.46 (m, 9H).

[0725] Step 2: Synthesis of compound int_645-4

[0726] Int_645-2 (10.00 g, 27.4 mmol), int_645-3 (6.65 g, 54.9 mmol), RuPhos Pd G3 (2.30 g, 2.75 mmol), and Cs2CO3 (26.8 g, 82.4 mmol) were dissolved in toluene (50 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 2 hours under a nitrogen atmosphere. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was added to water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 3:1) to obtain the desired product (6 g, yield: 44.6%).

[0727] 1 H NMR (400MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.14-8.07 (m, 1H), 8.06-8.00 (m, 1H), 7.98 (d, J = 2.5Hz, 1H), 2.97 (br t,J=5.4Hz,4H),2.31-2.13(m,4H),1.53-1.50(m,9H).

[0728] Step 3: Synthesis of compound int_645-5

[0729] Int_645-4 (3.60 g, 10.1 mmol) was dissolved in DCM (20 mL) and HCl / EtOAc solution (4 M, 2.52 mL). The reaction mixture was allowed to react at 25°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a crude product (2.4 g, yield: 81.1%), which was used directly in the next reaction.

[0730] 1 H NMR (400MHz, DMSO-d6) δ = 7.82 (dd, J = 2.6, 8.9Hz, 1H), 7.74 (d, J = 2.5Hz, 1H), 6.75 (d, J = 8.9Hz, 1H), 2.92 (br s, 4H), 2.28-2.11 (m, 4H).

[0731] Step 4: Synthesis of compound int_645-6

[0732] Int_645-5 (2.40 g, 8.17 mmol) was dissolved in DMF (20 mL). NaH (1.63 g, 40.86 mmol, 60% purity, 5.00 eq) and MeI (5.80 g, 40.9 mmol, 2.54 mL, 5.00 eq) were added to the reaction mixture at 0°C under nitrogen. After addition, the reaction mixture was warmed to room temperature and allowed to react for 16 hours. LC-MS monitoring indicated the reaction was complete. 30 mL of ice water was added to the reaction mixture, and stirring was continued for 0.5 hours. Water (300 mL) was then added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were filtered and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO2, hexane / ethyl acetate = 3:1) to afford the desired product (2 g, yield: 83.7%).

[0733] 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (dd, J = 2.7, 9.0Hz, 1H), 7.70 (d, J = 2.6Hz, 1H), 6.98 (d, J = 9.1Hz, 1H), 3.10 (br d,J=7.2Hz,4H),2.99(s,6H),2.26-2.09(m,4H).

[0734] Step 5: Synthesis of compound int_645-7

[0735] Int_645-6 (2.00 g, 7.01 mmol) was dissolved in methanol (20 mL), and Pd / C (1.00 g, 7.01 mmol, 10% purity) was added. The reaction system was purged with hydrogen three times, and the reaction mixture was allowed to react at 25°C under a hydrogen atmosphere for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol = 10:1) to obtain a solid (0.85 g, yield: 46.6%).

[0736] 1 H NMR (400MHz, DMSO-d6) δ = 6.65 (d, J = 8.3Hz, 1H), 6.23 (d, J = 2.3Hz, 1H), 6.18 (dd, J = 2.4, 8.3Hz, 1H), 4.60 (s, 2H), 3.12 (br s,4H),2.63(s,6H),2.19-1.99(m,4H).

[0737] Step 6: Synthesis of compound int_645-8

[0738] Int_1-8 (1.2 g, 3.36 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (888.4 mg, 7 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0739] Int_645-7 (760 mg, 3 mmol) was dissolved in tetrahydrofuran (40 mL). Under nitrogen, NaH (720 mg, 18 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 15:1) to obtain a solid (1.75 g, yield: 98.3%).

[0740] ESI-MS m / z:595[M+H] + .

[0741] Step 7: Synthesis of compound 645

[0742] Int_645-8 (1.75 g, 2.95 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (210 mg, 1.475 mmol), cuprous iodide (281 mg, 1.475 mmol), and potassium phosphate (1.879 g, 8.85 mmol) were dissolved in DMF (50 mL). The atmosphere was replaced with argon three times. Int_1-10 (553 mg, 4.42 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography (SiO2, dichloromethane / methanol = 100:1) to afford a solid (580 mg, yield: 33.2%).

[0743] 1 H NMR(400MHz,Chloroform-d)δ12.36(s,1H),8.18(d,J=8.3Hz,1H),7.52(s,1H),7.33(s,1H),7.13(s,1H),7.02(d,J=8.2Hz,1H),6.93(d,J= 8.4Hz,1H),4.12(s,2H),3.30(dt,J=12.2,5.1Hz,6H),3.06(t,J=5.4Hz,4H),2.82(s,6H),2.12(d,J=15.2Hz,4H),1.65(s,4H),0.41(s,4H).

[0744] ESI-MS m / z:592[M+H] + .

[0745] Example 28 Synthesis of Compound 653

[0746] Step 1: Synthesis of compound int_653-2

[0747] Int_1-8 (140 mg, 0.396 mmol) was dissolved in DCM (50 mL). Int_653-1 (100 mg, 0.396 mmol), HATU (300 mg, 0.792 mmol), and DIPEA (206.8 mg, 1.6 mmol) dissolved in DMF (8 mL) were added. Under nitrogen, the reaction mixture was stirred at room temperature for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (90 mg, yield: 38.4%).

[0748] ESI-MS m / z:592[M+H] + .

[0749] Step 2: Synthesis of compound 653

[0750] Int_653-2 (90 mg, 0.152 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.076 mmol), cuprous iodide (14 mg, 0.076 mmol), and potassium phosphate (96 mg, 0.456 mmol) were dissolved in DMF (8 mL). The atmosphere was replaced with argon three times, and int_1-10 (38 mg, 0.304 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (25 mg, 55% yield).

[0751] 1 H NMR(400MHz,Chloroform-d)δ12.40(s,1H),8.19(d,J=8.3Hz,1H),7.67(s,1H),7.32(s ,1H),7.24(s,1H),7.02(d,J=9.7Hz,1H),6.80(d,J=8.4Hz,1H),4.13(s,2H),3.32(d,J= 5.7Hz,2H),3.19(d,J=5.8Hz,4H),3.06(d,J=5.9Hz,4H),2.70(s,1H),2.16(dd,J=18.3 ,10.7Hz,4H),1.62(s,4H),1.01–0.95(m,2H),0.71(dd,J=5.6,1.8Hz,2H),0.41(s,4H).

[0752] ESI-MS m / z:589[M+H] + .

[0753] Example 29 Synthesis of Compound 655

[0754] Step 1: Synthesis of compound int_655-2

[0755] Int_1-8 (216.8 mg, 0.607 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (761.4 mg, 6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0756] Int_655-1 (150 mg, 0.507 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen, NaH (300 mg, 7.5 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice-cooling, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (320 mg, 99% yield).

[0757] ESI-MS m / z:636[M+H] + .

[0758] Step 2: Synthesis of compound 655

[0759] Int_655-2 (350 mg, 0.55 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (39 mg, 0.27 mmol), cuprous iodide (53 mg, 0.28 mmol), and potassium phosphate (351 mg, 1.66 mmol) were dissolved in DMF (7 mL). The atmosphere was replaced with argon three times, and int_1-10 (138 mg, 1.1 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (250 mg, 72% yield).

[0760] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),7.79(d,J=8.5Hz,1H),7.65(d,J=2.5Hz,1 H),7.43(dd,J=8.8,2.4Hz,1H),7.30(dd,J=8.7,1.4Hz,1H),7.13(d,J=2.1Hz,1H ),7.00(dd,J=8.5,2.1Hz,1H),3.74(t,J=6.6Hz,2H),3.29(m,2H),3.13(t,J=5. 6Hz, 4H), 2.95 (t, J = 5.3Hz, 4H), 2.09 (p, J = 8.1Hz, 4H), 1.52 (s, 4H), 0.33 (s, 4H).

[0761] ESI-MS m / z:633[M+H] + .

[0762] Example 30 Synthesis of Compound 661

[0763] Step 1: Synthesis of compound 661

[0764] Compound 257 (1 g, 1.7 mmol) was dissolved in dichloromethane (20 mL), and acetic anhydride (176 mg, 1.7 mmol), pyridine (273 mg, 3.5 mmol), and DMAP (11 mg, 0.09 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to afford the desired product (0.7 g, 70% yield).

[0765] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),8.03(d,J=8.6Hz,1H),7.79(d,J=8.5Hz,1H) ,7.34(d,J=8.6Hz,1H),7.20(d,J=2.2Hz,1H),7.06(dd,J=8.7,2.1Hz,1H),4.27(t ,J=5.7Hz,2H),3.78(s,3H),3.56(t,J=5.7Hz,2H),3.49(t,J=5.5Hz,4H),2.94(t, J=5.2Hz, 4H), 2.05 (dt, J=16.4, 6.8Hz, 4H), 1.87 (s, 3H), 1.71 (m, 4H), 0.35 (s, 4H).

[0766] ESI-MS m / z:622[M+H] + .

[0767] Example 31 Synthesis of Compound 663

[0768] Step 1: Synthesis of compound 663

[0769] 257 (1 g, 1.7 mmol) was dissolved in dichloromethane (20 mL), and isobutyric anhydride (273 mg, 1.72 mmol), pyridine (273 mg, 3.5 mmol), and DMAP (11 mg, 0.09 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to afford the desired product (1.05 g, 93.7% yield).

[0770] 1H NMR (400MHz, DMSO-d6) δ12.79(s,1H),10.43(s,1H),8.04(d,J=8.6Hz,1H),7.79(d,J=8.5Hz, 1H),7.34(d,J=8.6Hz,1H),7.19(d,J=2.2Hz,1H),7.08(dd,J=8.7,2.1Hz,1H),4.31(t,J=5.5H z,2H),3.79(s,3H),3.59(t,J=5.6Hz,2H),3.50(t,J=5.7Hz,4H),2.94(t,J=5.3Hz,4H),2.38 (p, J=7.0Hz, 1H), 2.07 (q, J=9.6, 6.0Hz, 4H), 1.73 (m, 4H), 0.98 (d, J=7.0Hz, 6H), 0.35 (s, 4H).

[0771] ESI-MS m / z:650[M+H] + .

[0772] Example 32 Synthesis of Compound 669

[0773] Step 1: Synthesis of compound 669

[0774] 321 (455 mg, 0.784 mmol) was dissolved in dichloromethane (14 mL), and acetic anhydride (80 mg, 0.784 mmol), pyridine (125 mg, 1.58 mmol), and DMAP (5.2 mg, 0.04 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to afford the desired product (233 mg, 48% yield).

[0775] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.73(s,1H),8.31(d,J=8.8Hz,1H),7.76(d ,J=8.2Hz,1H),7.48(d,J=8.3Hz,1H),7.13(d,J=2.4Hz,1H),6.97(dd,J=8.8,2.4H z,1H),4.27(t,J=6.0Hz,2H),3.90(s,3H),3.56(s,4H),3.41(t,J=6.0Hz,2H),2.7 9(d,J=5.3Hz,4H),2.12(d,J=15.3Hz,4H),1.95(s,3H),1.53(s,4H),0.33(s,4H).

[0776] ESI-MS m / z:622[M+H] + .

[0777] Example 33 Synthesis of Compound 714

[0778] Step 1: Synthesis of compound int_714-2

[0779] 257 (1 g, 1.73 mmol) was dissolved in tetrahydrofuran (20 mL), and int_714-1 (1.87 g, 8.63 mmol), BOPCl (1.10 g, 4.31 mmol), 3-nitro-4H-1,2,4-triazole (491.94 mg, 4.31 mmol), and DIPEA (1.11 g, 8.63 mmol, 1.50 mL) were added. The mixture was allowed to react at room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (SiO2, ethyl acetate / methanol = 1:1) to afford the desired product (1.16 g, yield: 86.3%).

[0780] 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),8.03(d,J=8.6Hz,1H),7.79(d,J=8.5Hz ,1H),7.34(d,J=8.7Hz,1H),7.20(s,1H),7.08(t,J=8.6Hz,2H),4.35(s,2H), 3.79(m,4H),3.54(s,2H),3.49(d,J=5.9Hz,4H),2.95(s,4H),2.20–1.94(m,4 H), 1.89-1.82 (m, 5H), 1.33 (s, 9H), 0.74 (dd, J = 6.8, 4.7Hz, 5H), 0.35 (s, 4H).

[0781] ESI-MS m / z:779[M+H] + .

[0782] Step 2: Synthesis of compound 714

[0783] Int_714-2 (1.16 g, 1.49 mmol) was dissolved in 4M HCl / dioxane solution (11.6 mL) and allowed to react at room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. Saturated NaHCO₃ solution (15 mL) was added to the crude product to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate. The organic phases were filtered and distilled under reduced pressure to obtain the desired product (300 mg, yield: 29.6%).

[0784] 1 HNMR: (400MHz, DMSO-d6)δ12.81(s,1H),δ8.05(d,J=8.6Hz,1H),7.82(d,J=8.5Hz,1H),7.37(d,J=8.6Hz,1H),7.21(d,J=2.2Hz,1H), 7.09(dd,J=8.6,2.1Hz,1H),4.37(t,J=5.7Hz,2H),3.81(s,3H),3.64-3.55(m,2H),3.54-3.41(m,4H),3.05(d,J=5.3Hz,1H),2.97(br s, 4H), 2.15-2.02 (m, 4H), 1.93-1.52 (m, 5H), δ0.81 (d, J = 6.8Hz, 3H), 0.75 (d, J = 6.8Hz, 3H), 0.37 (s, 4H).

[0785] ESI-MS m / z:679[M+H] + .

[0786] Example 34 Synthesis of Compound 727

[0787] Step 1: Synthesis of compound int_727-1

[0788] 321 (1.3 g, 2.25 mmol) was dissolved in tetrahydrofuran (100 mL), and int_714-1 (2.4 g, 11.22 mmol), BOPCl (1.4 g, 5.61 mmol), 3-nitro-4H-1,2,4-triazole (640 mg, 5.61 mmol), and DIPEA (646.25 mg, 5 mmol) were added. The mixture was allowed to react at room temperature for 4 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 5:1 to 1:1) to obtain the desired product (1.1 g, yield: 62.9%).

[0789] ESI-MS m / z:779[M+H] + .

[0790] Step 2: Synthesis of Compound 727

[0791] Int_727-1 (550 mg, 0.71 mmol) was dissolved in 4M HCl / dioxane solution (11 mL) and allowed to react at room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. Saturated NaHCO₃ solution (6 mL) was added to the crude product to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (6 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The organic phases were filtered and distilled under reduced pressure to obtain the product. The product was further purified by prep-HPLC (column: Phenomenex C₁₈ 250*50mm*10µm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 43%-73%, 8 min.) to obtain the desired product (291 mg, yield: 58.8%).

[0792] 1 H NMR: (400MHz, DMSO-d6) δ10.44-10.34(m,1H),8.34(d,J=8.8Hz,1H),7.79(d,J=8.1Hz,1H),7.50(d,J=8.4Hz, 1H),7.15(d,J=2.4Hz,1H),7.06-6.96(m,1H),4.35(t,J=6.0Hz,2H),3.93(s,3H),3.65-3.54(m,4H),3.07(br d,J=5.3Hz,1H),2.82(br t,J=4.9Hz,4H),2.22-2.10(m,4H),1.85-1.71(m,1H),1.67-1.42(m,4H),0.88-0.73(m,6H),0.35(s,4H).

[0793] ESI-MS m / z:679[M+H] + .

[0794] Example 35 Synthesis of Compound 740

[0795] Step 1: Synthesis of compound int_740-1

[0796] 273 (1.3 g, 2.25 mmol) was dissolved in tetrahydrofuran (100 mL), and int_714-1 (2.4 g, 11.22 mmol), BOPCl (1.4 g, 5.61 mmol), 3-nitro-4H-1,2,4-triazole (640 mg, 5.61 mmol), and DIPEA (646.25 mg, 5 mmol) were added. The mixture was allowed to react at room temperature for 4 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the desired product (1 g, yield: 65.8%).

[0797] ESI-MS m / z:779[M+H] + .

[0798] Step 2: Synthesis of Compound 740

[0799] Int_740-1 (800 mg, 1.03 mmol) was dissolved in 4M HCl / dioxane solution (11 mL) and allowed to react at room temperature for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. Saturated NaHCO₃ solution (8 mL) was added to the crude product to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (8 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The organic phases were filtered and distilled under reduced pressure to obtain the desired product (310 mg, yield: 44.3%).

[0800] 1 H NMR: (400MHz, Chloroform-d) δ12.53(s,1H),8.36–8.34(m,1H),7.85–7.80(m,1H) ),7.73(s,1H),7.66–7.64(m,1H),7.11–7.04(m,1H),4.21-4.10(m,2H),4.13(s,3 H),3.52-3.35(m,4H),3.25-3.20(m,1H),3.20-3.10(m,2H),3.05(m,4H),2.12-2 .10(m,4H),1.90-1.71(m,1H),1.75-1.42(m,4H),0.75-0.85(m,6H),0.34(s,4H).

[0801] ESI-MS m / z:679[M+H] + .

[0802] Example 36 Synthesis of Compound 825

[0803] Step 1: Synthesis of compound int_825-2

[0804] Int_1-8 (95 mg, 0.266 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (380 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0805] Int_825-1 (75 mg, 0.266 mmol) was dissolved in tetrahydrofuran (6 mL). Under nitrogen, NaH (100 mg, 2.5 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 10:1) to obtain a solid (59 mg, yield: 35.7%).

[0806] ESI-MS m / z:622[M+H] +

[0807] Step 2: Synthesis of Compound 825

[0808] Int_825-2 (59 mg, 0.095 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.047 mmol), cuprous iodide (10 mg, 0.047 mmol), and potassium phosphate (60 mg, 0.285 mmol) were dissolved in DMF (5 mL). The atmosphere was replaced with argon three times, and int_1-10 (24 mg, 0.189 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (7 mg, yield: 12.1%).

[0809] 1H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.03(d,J=8.6Hz,1H),7.79(d,J=8.4H z,1H),7.31–7.14(m,2H),7.07(dd,J=8.6,2.1Hz,1H),3.73(t,J=6.5Hz,2H) ,3.38(t,J=5.6Hz,4H),3.31(t,J=6.5Hz,2H),3.06(d,J=5.9Hz,4H),2.95(d ,J=5.4Hz,4H),2.10(tt,J=13.1,5.5Hz,4H),1.93–1.50(m,8H),0.36(s,4H).

[0810] ESI-MS m / z:619[M+H] + .

[0811] Example 37 Synthesis of Compound 826

[0812] Step 1: Synthesis of compound int_826-2

[0813] Int_321-3 (187.6 mg, 0.605 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (760 mg, 6 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0814] Int_826-1 (170 mg, 0.605 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (170 mg, 4.25 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 10:1) to obtain a solid (190 mg, yield: 58.1%).

[0815] ESI-MS m / z:547[M+H] + .

[0816] Step 2: Synthesis of Compound 826

[0817] Int_826-2 (190 mg, 0.345 mmol), N,N-dimethylglycine (25 mg, 0.173 mmol), cuprous iodide (33 mg, 0.173 mmol), and potassium phosphate (219 mg, 1.035 mmol) were dissolved in DMF (4 mL). The atmosphere was replaced with argon three times, and int_1-10 (65 mg, 0.518 mmol) was added. Under argon, the reaction mixture was heated to 130°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (51 mg, 25% yield).

[0818] 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.06(d,J=8.7Hz,1H),7.55(dd,J=8.4,2 .1Hz,1H),7.48(d,J=2.2Hz,1H),7.11(d,J=2.4Hz,1H),7.01(d,J=8.4Hz,1H) ,6.95(dd,J=8.7,2.4Hz,1H),3.72(t,J=6.8Hz,2H),3.18(q,J=7.0Hz,6H),2. 88(s,6H),2.82(t,J=5.3Hz,4H),2.21–2.10(m,4H),1.51(s,4H),0.34(s,4H).

[0819] ESI-MS m / z:592[M+H] + .

[0820] Example 38 Synthesis of Compound 828

[0821] Step 1: Synthesis of compound int_828-2

[0822] Int_1-8 (356 mg, 1 mmol) was dissolved in DCM (50 mL). Int_828-1 (340 mg, 1 mmol), HATU (760 mg, 2 mmol), and TEA (304 mg, 3 mmol) were dissolved in DMF (8 mL). The reaction mixture was stirred at room temperature for 12 hours under nitrogen. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (500 mg, yield: 83.6%).

[0823] ESI-MS m / z:681[M+H] + .

[0824] Step 2: Synthesis of compound 828-3

[0825] Int_828-2 (200 mg, 0.29 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.145 mmol), cuprous iodide (30 mg, 0.145 mmol), and potassium phosphate (180 mg, 0.87 mmol) were dissolved in DMF (8 mL). The atmosphere was replaced with argon three times, and int_1-10 (60 mg, 0.47 mmol) was added. Under argon, the reaction mixture was heated to 90°C for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (140 mg, yield: 70.3%).

[0826] ESI-MS m / z:678[M+H] + .

[0827] Step 3: Synthesis of Compound 828

[0828] Int_828-3 (80 mg, 0.118 mmol) was dissolved in methanol / hydrochloric acid (4 N, 10 mL) and the reaction mixture was allowed to react at room temperature for 12 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was dried and purified by column chromatography to obtain a solid (50 mg, yield: 73.5%).

[0829] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),7.76(d,J=8.6Hz,1H),7.60(d,J=2.0Hz,1H),7.48(dd,J =8.3,2.0Hz,1H),7.41(s,1H),7.00(d,J=2.1Hz,1H),6.86(dd,J=8.6,2.0Hz,1H),3.84(s,2H), 3.71(t,J=6.6Hz,2H),3.18–3.10(m,2H),2.94(dt,J=11.8,5.5Hz,8H),2.19–2.07(m,4H),1.54(s,4H),0.34(s,4H).

[0830] ESI-MS m / z:578[M+H] + .

[0831] Example 39 Synthesis of Compound 829

[0832] Step 1: Synthesis of compound int_829-2

[0833] Int_257-3 (100 mg, 0.374 mmol) was dissolved in DCM (10 mL), and oxalyl chloride (380 mg, 3 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product.

[0834] Int_829-1 (100 mg, 0.411 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, NaH (80 mg, 2 mmol, 60% purity) was added. After stirring at room temperature for 0.5 hours, the acid chloride prepared above was added at room temperature. The reaction mixture was heated to 40°C and stirred for 10 hours. LC-MS monitoring indicated the reaction was complete. Methanol was added to quench the reaction under ice, and the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate = 6:1) to obtain a solid (90 mg, yield: 44.5%).

[0835] ESI-MS m / z:492[M+H] + .

[0836] Step 2: Synthesis of Compound 829

[0837] Int_829-2 (90 mg, 0.183 mmol), int_829-3 (33 mg, 0.366 mmol), cesium carbonate (90 mg, 0.274 mmol), Pd2(dba)3 (17 mg, 0.0183 mmol), and XantPhos (10 mg, 0.0183 mmol) were dissolved in 1,4-dioxane (8 mL). The atmosphere was replaced with argon three times. Under argon protection, the reaction solution was heated to 95°C for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, dried by spin drying, and purified by column chromatography to obtain a solid (50 mg, yield: 50.5%).

[0838] 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.24(d,J=8.4Hz,1H),7.73(d,J=8.4Hz,1H),7.34(d,J=8.6Hz,1H),6.68(d,J=8.4Hz,1H),4.18(s,2H ), 3.78 (s, 3H), 3.51 (d, J = 5.8Hz, 4H), 3.12 (t, J = 5.4Hz, 4H), 2.05 (tt, J = 13.7, 5.4Hz, 4H), 1.64 (d, J = 5.7Hz, 4H), 1.22 (s, 6H), 0.33 (s, 4H).

[0839] ESI-MS m / z:545[M+H]+ .

[0840] Using the above synthesis method and different raw materials, the target compounds 5, 8-64, 66-96, 98-128, 130-160, 162-256, 264-272, 274-320, 322-336, 338-352, 354-368, 370-384, 386-576, 578-640, 642, 644, 646-652, 654, 656-660, 662, 664-668, 670-713, 715-726, 728-739, 741-824, 827, 830-837 in Table 1 can be obtained.

[0841] Table 1

[0842] Table 2 NMR data of some compounds in Table 1

[0843] Biological Example 1 In vitro antiproliferative activity of the compounds of the present invention on HT-29 cells

[0844] 3000 HT-29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or a compound with a maximum concentration of 5 μM and a 1:5 serial dilution was then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 3 below.

[0845] Table 3 Antiproliferative activity of the compounds of the present invention on HT-29 cells (IC 50 ,nM)

[0846] The reference compound AMG650 is compound 4 in WO2020132648A1.

[0847] From the data in Table 3, it can be seen that some compounds of the present invention have stronger anti-proliferative activity against HT-29 cells than AMG650.

[0848] Biological Example 2 In vitro antiproliferative activity of the compounds of the present invention on HCT116 cells

[0849] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or a compound with a maximum concentration of 5 μM and a 1:5 serial dilution was then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 4 below.

[0850] Table 4 Antiproliferative activity of the compounds of the present invention on HCT116 cells (IC 50 ,nM)

[0851] From the data in Table 4, it can be seen that the compound of the present invention and AMG650 have no anti-proliferative activity against HCT116 cells.

[0852] Biological Example 3 In vivo efficacy study - mouse HT29 subcutaneous transplant tumor model

[0853] BALB / c nude mice were subcutaneously inoculated with 5x10 6 HT29 cells, wait until the tumor grows to 100-150 mm 3After randomization, the animals were divided into groups and administered orally once daily: Group 1: vehicle control group; Group 2: compound 661 (80 mg / kg); Group 3: compound 669 (80 mg / kg); Group 4: compound 677 (80 mg / kg); Group 5: compound 714 (80 mg / kg); Group 6: compound 727 (80 mg / kg); Group 7: compound 740 (80 mg / kg); and Group 8: AMG650 (80 mg / kg). Tumor volumes were measured twice weekly and at the end of dosing. Tumor growth inhibition rates (TGI) were calculated as 1 - (tumor volume of the dosing group on day 28 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 28 - tumor volume of the dosing group on day 1). The results are shown in Table 5.

[0854] Table 5 Growth inhibition rate of HT29 subcutaneous transplanted tumor in mice

[0855] As shown in Table 5, the compounds of the present invention were able to inhibit tumor growth in a HT29 mouse subcutaneous xenograft tumor model at a dose of 80 mg / kg. Furthermore, Compounds 714, 727, and 740 showed a stronger inhibitory effect on HT29 mouse subcutaneous xenograft tumors than AMG650.

[0856] Biological Example 4 Phosphorylation Determination of Histone H3 Ser10 Site in HT29 Cells (Immunofluorescence Method)

[0857] HT29 cells were seeded in 96-well plates (Fisher 160376) with 8,000 cells per well. The next day, serially diluted compounds were added. Six hours after compound addition, the cells were washed once with 1X PBS, fixed with 4% PFA for 15 minutes, washed three times with 1X PBS, and permeabilized with 0.02% Triton-X100 for 10 minutes. The cells were then blocked with blocking buffer for 15–30 minutes. The primary antibody (Phospho-Histone H3 (Ser10)) was added at a concentration of 1:3000, and the plates were incubated at 4°C overnight. The next day, the cells were washed three times with 1X PBS, and the secondary antibody (Fluorescein (FITC)-conjugated Affinipure Goat Anti-Rabbit IgG (H+L)) was added at a concentration of 1:1000. The cells were incubated in the dark for 1–2 hours and washed three times with 1X PBS. Cell nuclei were then stained with DAPI. Quantify the phosphorylation ratio (FITC / DAPI) of H3 Ser10 in HT29 cells. Evaluate the effect of compounds on Phospho-Histone H3 and calculate the compound EC 50 The results are shown in Table 6 below.

[0858] Table 6 Phosphorylation induction of H3 Ser10 site in HT29 cells by the compounds of the present invention (EC 50 ,nM)

[0859] As shown in Table 6, the compounds of the present invention have a strong inducing activity on the phosphorylation of H3 Ser10 site in HT-29 cells, and compared with AMG650, the compounds of the present invention have a stronger inducing activity on the phosphorylation of H3 Ser10 site than AMG650.

[0860] Biological Example 5 Effect of the Compound of the Present Invention Combined with a PLK1 Inhibitor on the Activity of HT29 Cells

[0861] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 7 below.

[0862] Table 7 Inhibitory activity of compound 257 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0863] As can be seen from the data in Table 7, compared with the compound 257 alone, the compound 257 combined with the PLK1 inhibitor has a stronger inhibitory effect on HT-29 cells.

[0864] Biological Example 6 Effect of the Compound of the Present Invention Combined with a PLK1 Inhibitor on the Activity of HCT116 Cells

[0865] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 8 below.

[0866] Table 8 Inhibitory activity of compound 257 of the present invention in combination with PLK1 inhibitor on HCT116 cells (IC 50 ,nM)

[0867] As can be seen from the data in Table 8, the compound 257 of the present invention alone has no anti-proliferative activity against HCT116 cells, and the combination of compound 257 and PLK1 inhibitor has no obvious combined effect on the activity of HCT116 cells.

[0868] Biological Example 7 Effect of the Compound of the Present Invention or AMG650 Combined with a PLK1 Inhibitor on the Activity of HT29 Cells

[0869] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257 or AMG650, diluted 1:5 at a maximum concentration of 400 nM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC2 was calculated. 50 The results are shown in Table 9 below.

[0870] Table 9 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0871] As can be seen from the data in Table 9, compared with the present invention compound 257 alone or AMG650 alone, the combination of compound 257 or AMG650 with a PLK1 inhibitor has a stronger inhibitory effect on HT-29 cells.

[0872] Biological Example 8 Effect of the Compound of the Present Invention or AMG650 Combined with a PLK1 Inhibitor on the Activity of HCT116 Cells

[0873] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257 or AMG650, diluted 1:5 at a maximum concentration of 10 μM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 10 below.

[0874] Table 10 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on HCT116 cells (IC 50 ,nM)

[0875] As can be seen from the data in Table 10, the compound 257 or AMG650 alone has no anti-proliferative activity against HCT116 cells, and the combination of compound 257 or AMG650 with a PLK1 inhibitor has no obvious effect on the activity of HCT116 cells.

[0876] Biological Example 9 Effect of the Compound of the Present Invention Combined with a PLK1 Inhibitor on the Activity of HT29 Cells

[0877] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 400 nM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 The results are shown in Table 11 below.

[0878] Table 11 Inhibitory activity of compound 257 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0879] As can be seen from the data in Table 11, compared with the compound 257 alone, the compound 257 combined with the PLK1 inhibitor has a stronger inhibitory effect on HT-29 cells.

[0880] Biological Example 10 Effect of the Compound of the Present Invention Combined with a PLK1 Inhibitor on the Activity of HCT116 Cells

[0881] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 400 nM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 12 below.

[0882] Table 12 Inhibitory activity of compound 257 of the present invention in combination with PLK1 inhibitor on HCT116 cells (IC 50 ,nM)

[0883] As can be seen from the data in Table 12, the compound 257 of the present invention alone has no anti-proliferative activity against HCT116 cells, and the combination of compound 257 and PLK1 inhibitor has no obvious combined effect on the activity of HCT116 cells.

[0884] Biological Example 11 Effect of the Compound of the Present Invention Combined with an Aurora B Inhibitor on the Activity of HT29 Cells

[0885] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of Aurora B inhibitor were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 The results are shown in Table 13 below.

[0886] Table 13 Inhibitory activity of compound 257 of the present invention in combination with Aurora B inhibitor on HT29 cells (IC 50 ,nM)

[0887] As can be seen from the data in Table 13, compared with the compound 257 of the present invention alone, the compound 257 combined with the Aurora B inhibitor has a stronger inhibitory effect on HT-29 cells.

[0888] Biological Example 12 Effect of the Compound of the Present Invention Combined with an Aurora B Inhibitor on the Activity of HCT116 Cells

[0889] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of Aurora B inhibitor were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 The results are shown in Table 14 below.

[0890] Table 14 Inhibitory activity of compound 257 of the present invention in combination with Aurora B inhibitor on HCT116 cells (IC 50 ,nM)

[0891] As can be seen from the data in Table 14, the compound 257 of the present invention alone has no anti-proliferative activity against HCT116 cells, and the combination of compound 257 and Aurora B inhibitor has no obvious effect on the activity of HCT116 cells.

[0892] Biological Example 13 In Vivo Efficacy Study of Combination Drugs - Mouse HT29 Subcutaneous Transplant Tumor Model

[0893] BALB / c nude mice were subcutaneously inoculated with 5x10 6 HT29 cells, wait until the tumor grows to 100-150 mm 3The patients were randomly divided into groups and then given oral administration: Group 1: vehicle control group; Group 2: compound 714; Group 3: AMG650; Group 4: compound 714 + Rigosertib; Group 5: compound 714 + BI 2536; Group 6: compound 714 + Volasertib; Group 7: compound 714 + Onvansertib; Group 8: compound 714 + GSK461364; Group 9: compound 714 + MLN0905; Group 10: compound 714 + Ro3280; Group 11: AMG650 + Rigosertib; Group 12: AMG650 + BI 2536; Group 13: AMG650+Volasertib; Group 14: AMG650+Onvansertib; Group 15: AMG650+GSK461364; Group 16: AMG650+MLN0905; Group 17: AMG650+Ro3280; Group 18: Compound 714+SP96; Group 19: Compound 714+Barasertib; Group 20: AMG650+SP96; Group 21: AMG650+Barasertib; Group 22: Rigosertib; Group 23: BI 2536; Group 24: Volasertib; Group 25: Onvansertib; Group 26: GSK461364; Group 27: MLN0905; Group 28: Ro3280; Group 29: SP96; Group 30: Barasertib, once a day. Tumor volume was measured twice a week and at the end of dosing. The tumor growth inhibition rate of the compound was calculated as follows: tumor growth inhibition rate (TGI) = 1-(tumor volume of the dosing group on day 28 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 28 - tumor volume of the vehicle control group on day 1).

[0894] Biological Example 14 In vivo efficacy study of combined drug therapy - mouse HT29 subcutaneous transplant tumor model

[0895] BALB / c nude mice were subcutaneously inoculated with 5x10 6 HT29 cells, wait until the tumor grows to 100-150 mm 3After randomization, the patients were divided into groups and given oral administration once daily for 14 consecutive days. On day 15, all groups stopped receiving the drug, and tumor growth was observed until day 21. Tumor volume was measured twice weekly and at the end of the treatment. The tumor growth inhibition rate of the compound was calculated according to tumor growth inhibition rate (TGI) = 1-(tumor volume of the dosing group on day 15 / 21-tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 15 / 21-tumor volume of the vehicle control group on day 1).

[0896] Table 15 Growth inhibition rate of mouse HT29 subcutaneous transplanted tumor

[0897] As shown in Table 15, Compound 714 or AMG650 of the present invention inhibited tumor growth in a subcutaneous xenograft model of HT29 mice, while the PLK1 inhibitor Onvasertib showed weaker efficacy. The combination of Compound 714 or AMG650 with the PLK1 inhibitor Onvasertib demonstrated a stronger tumor inhibitory effect than either 714, AMG650, or Onvasertib alone. Furthermore, after discontinuation of the drug on day 14, the efficacy of the combination group was more sustained than that of the single-agent group.

[0898] Biological Example 15 Effect of the Compound of the Present Invention Combined with a PLK1 Degrader on the Activity of HT29 Cells

[0899] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of PLK1 degraders were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC2 was calculated. 50 value.

[0900] Biological Example 16 Effect of the Compound of the Present Invention Combined with a PLK1 Degrader on the Activity of HCT116 Cells

[0901] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257, diluted 1:5 at a maximum concentration of 5 μM, and the indicated concentrations of PLK1 degraders were then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 value.

[0902] Biological Example 17 Effect of the Compound of the Present Invention Combined with PLK1 siRNA on the Activity of HT29 Cells

[0903] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight before being transfected with the indicated concentrations of PLK1 siRNA. Twenty-four hours later, DMSO or compound 257, with a maximum concentration of 5 μM and a 1:5 dilution series, were added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 value.

[0904] Biological Example 18 Effect of the Compound of the Present Invention Combined with PLK1 siRNA on the Activity of HCT116 Cells

[0905] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight before being transfected with the indicated concentrations of PLK1 siRNA. Twenty-four hours later, DMSO or compound 257, diluted 1:5 with a maximum concentration of 5 μM, was added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 value.

[0906] Biological Example 19 Effects of the Compounds of the Present Invention, AMG650, or Compound A Combined with PLK1 Inhibitors on the Activity of HT29 Cells

[0907] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or a 1:5 serial dilution of Compound 257, AMG650, or Compound A, with a maximum concentration of 400 nM, and the indicated concentrations of a PLK1 inhibitor were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compounds compared to the DMSO group was calculated (see Figures 1, 2, 3, and 4), and the IC values ​​were calculated based on this. 50 The results are shown in Tables 16 and 17 below. The BLISS independence model was used to analyze the interactions between the drugs, and the results are shown in Figures 5, 6, 7, and 8.

[0908] Table 16 Inhibitory activity of compound 257, AMG650 or Compound A combined with PLK1 inhibitor on HT29 cells

[0909] Table 17 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0910] As shown in Tables 16 and 17, as well as Figures 1, 2, 3, 4, 5, 6, 7, and 8, the combination of Compound 257, AMG650, or Compound A with a PLK1 inhibitor exhibited a stronger inhibitory effect on HT-29 cells than Compound 257 alone, AMG650, or Compound A alone. Compound A is Compound 134 described in patent WO2023028564A1.

[0911] Biological Example 20 Effect of the Compound of the Present Invention, AMG650 or Compound A Combined with a PLK1 Inhibitor on the Activity of HCT116 Cells

[0912] 3000 HCT116 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or a 1:5 dilution series of Compound 257, AMG650, or Compound A, with a maximum concentration of 400 nM, and the indicated concentrations of a PLK1 inhibitor were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compound compared to the DMSO group was calculated, and the IC2 was calculated. 50 The results are shown in Table 18 below.

[0913] Table 18 Inhibitory activity of compound 257, AMG650 or Compound A in combination with PLK1 inhibitor on HCT116 cells (IC 50 ,nM)

[0914] As can be seen from the data in Table 18, Compound 257, AMG650, or Compound A alone do not have antiproliferative activity against HCT116 cells. The combination of Compound 257, AMG650, or Compound A with a PLK1 inhibitor has no significant effect on HCT116 cell viability. Compound A is Compound 134 described in patent WO2023028564A1.

[0915] Biological Example 21 Effect of the Compound of the Present Invention or AMG650 Combined with a PLK1 Inhibitor on the Activity of SK-OV-3 Cells

[0916] 3000 SK-OV-3 cells were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257 or AMG650, diluted 1:5 at a maximum concentration of 400 nM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compounds compared to the DMSO group was calculated (see Figures 9 and 10), and the IC was calculated based on this percentage. 50 The results are shown in Tables 19 and 20 below. The BLISS independence model was used to analyze the interactions between the drugs, and the results are shown in Figures 11 and 12.

[0917] Table 19 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on SK-OV-3 cells (IC 50 ,nM)

[0918] Table 20 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on SK-OV-3 cells (IC 50 ,nM)

[0919] It can be seen from the data in Table 19, Table 20 and Figures 9, 10, 11 and 12 that compared with the compound 257 of the present invention alone or AMG650 alone, the combination of compound 257 or AMG650 with a PLK1 inhibitor has a stronger inhibitory effect on SK-OV-3 cells.

[0920] Biological Example 22 Effect of the Compound of the Present Invention or AMG650 Combined with a PLK1 Inhibitor on the Activity of HT29 Cells

[0921] 3000 HT29 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound 257 or AMG650, diluted 1:5 at a maximum concentration of 400 nM, and the indicated concentrations of PLK1 inhibitors were then added. Cell survival was assessed 168 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition achieved by the compounds compared to the DMSO group was calculated (see Figures 13 and 14), and the IC was calculated based on this percentage. 50 The results are shown in Tables 21 and 22 below. The BLISS independence model was used to analyze the interactions between the drugs, and the results are shown in Figures 15 and 16.

[0922] Table 21 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0923] Table 22 Inhibitory activity of compound 257 or AMG650 of the present invention in combination with PLK1 inhibitor on HT29 cells (IC 50 ,nM)

[0924] From the data in Table 21, Table 22 and Figures 13, 14, 15 and 16, it can be seen that compared with the compound 257 of the present invention alone or AMG650 alone, the combination of compound 257 or AMG650 with a PLK1 inhibitor has a stronger inhibitory effect on HT-29 cells.

[0925] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A pharmaceutical composition for cancer treatment, characterized in that: Includes a KIF18A inhibitor and a compound that inhibits protein activity. 2 . The pharmaceutical composition according to claim 1 , wherein the compound that inhibits protein activity is a compound that inhibits PLK1 protein activity or a compound that inhibits Aurora B protein activity.

3. The pharmaceutical composition of claim 1, wherein the cancer treatment is inducing cancer cell death.

4. The pharmaceutical composition of claim 1, wherein the cancer treatment is anti-cancer cell proliferation. The pharmaceutical composition according to claim 1 , wherein the cancer is a cancer characterized by chromosomal instability. The pharmaceutical composition of claim 1 , wherein the cancer is a cancer characterized by aneuploidy.

7. The pharmaceutical composition of claim 1, wherein the cancer is a cancer characterized by whole genome duplication.

8. The pharmaceutical composition according to claim 1, wherein the cancer is a cancer characterized by chromosomal instability and aneuploidy.

9. The pharmaceutical composition of claim 1, wherein the cancer is a cancer characterized by chromosomal instability and whole genome duplication.

10. The pharmaceutical composition of claim 1, wherein the cancer is a cancer characterized by aneuploidy and whole genome duplication.

11. The pharmaceutical composition according to claim 1, wherein the cancer is a cancer characterized by chromosomal instability, aneuploidy and whole genome duplication.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the cancer is a solid tumor or a blood cancer.

13. The pharmaceutical composition of claim 12, wherein the cancer includes but is not limited to uterine cancer, bladder cancer, prostate cancer, breast cancer, lung cancer, intestinal cancer, pancreatic cancer, kidney cancer, ovarian cancer, soft tissue cancer, osteosarcoma or stromal tumor.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the compound that inhibits the activity of PLK1 protein comprises a PLK1 inhibitor and a PLK1 degrader.

15. The pharmaceutical composition of claim 14, wherein the PLK1 inhibitor is a dihydropteridinone compound, a pyridopyrimidine compound, an aminopyrimidine compound, a substituted thiazolidinone compound, a pteridine compound, a dihydroimidazo[l,5-f]pteridine compound, a benzyl styryl sulfone compound, a stilbene compound, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

16. The pharmaceutical composition of claim 15, wherein the PLK1 inhibitor is or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

17. The pharmaceutical composition according to claim 15, wherein the PLK1 inhibitor is TKM-080301, (poly d, l-lactide-polyethylene glycol-poly d, l-lactide)-loaded black phosphorus nanosheets (black phosphorus nanosheets incorporated with poly(d, l-lactide)-poly(ethylene glycol)-poly(d, l-lactide), BP@PLEL hydrogel) or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.

18. The pharmaceutical composition according to claim 14, wherein the PLK1 degrader is or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

19. The pharmaceutical composition according to any one of claims 1 to 13, wherein the compound that inhibits the activity of Aurora B protein comprises an Aurora B inhibitor and an Aurora B degrader. The Aurora B inhibitor is preferably or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the KIF18A inhibitor is a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): X 1 -CR 5 = or N; X 2 -CR 6 = or N; X 3 -CR 7 = or N; X 4 -CR 4 = or N; X 5 -CR 15 = or N; When X 5 -CR 15 = and X 4 -CR 4 = when R 16 -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 18 R 19 or -NO2; When X 5 -CR 15 = and X 4 When N, R 16 For-OC 1-8 Hydrocarbon, -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 20 R 21 or -NO2; When X 5 When N, R 16 For-OC 1-8 Hydrocarbon, -C 3-8 Cycloalkyl, -OR 17 、-SR 18 、-NR 20 R 21 or -NO2; L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 、X 2 、X 3 、X 4 and X 5 Among them, no more than 4 are N; * represents the connection end; R 17 H, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein the -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 hydrocarbon group; R 18 and R 19 Each independently represents H, -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 hydrocarbon group; R 20 and R 21 Each independently represents H, -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 Halogenated cycloalkyl, wherein the -C 1-8 Hydrocarbon, -C 1-8 Halogenated hydrocarbon, -C 3-8 Cycloalkyl or -C 3-8 The halocycloalkyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: H, halogen or -C 1-4 Hydrocarbyl; or R 20 and R 21 can combine with the nitrogen atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 1 -CN or -ZR 10 , where Z is a chemical bond, -C 0-4 Hydrocarbon-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C 0-4 Hydrocarbyl-O-, -(C=O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 2 is halogen or group -YR 12 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a R a (C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR 12 - or -S(=O)(=NH)-; R 3 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups; R 4 H, halogen, R 4a or R 4b ; R 5 H, halogen, C 1-8 Alkyl or C 1-4 alkyl halide; R 6 H, halogen, C 1-8 Alkyl, C 1-4 Haloalkyl, -OH, -OR 6a OR 6b ; R 7 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups; R 8 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 independently H, halogen, R 13m or R 13n ; or R 13a and R 13b Yes, R 13c and R 13d Yes, R 13e and R 13f Yes, R 13g and R 13h Yes, R 13i and R 13j Right or R 13k and R 13l Each of the pairs can independently form a spiro-linked carbon atom to which they are attached. 8 a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, CN, -NR a R a or oxo; R 9 H or C 1-6 hydrocarbon group; R 10 H, R 10a 、R 10b or R 10c ; R 11 H, R 11a or R 11b ; R 12 R 12a or R 12b ; R 15 H, halogen, C 1-8 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OC 1-8 Hydrocarbyl or -OR 15a , where R 15a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 4a 、R 6a 、R 10a 、R 11a 、R 12a or R 13m is independently selected from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 、R 14 and oxo; R 4b 、R 6b 、R 10b 、R 11b 、R 12b or R 13n is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN; R 10c is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-R c 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN; R 14 is independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 is independently H or R b ; R b In each case, independently C 1-6 Hydrocarbyl, phenyl or benzyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 and wherein the phenyl and benzyl groups are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, C 1-4 Hydrocarbon, C 1-3 Halogenated hydrocarbons, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 hydrocarbon group; And R c is independently at each occurrence -OC(=O)C 1-5 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: -OH or -NH2.

21. The pharmaceutical composition of claim 20, wherein the compound of formula (1) has the following structure: where R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 Or -NO2.

22. The pharmaceutical composition of claim 20, wherein the compound of formula (1) has the following structure: where R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Hydrocarbon, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 20 R 21 Or -NO2.

23. The pharmaceutical composition according to claim 20, wherein the compound of formula (1) has the following structure: where R 16 -C 3-6 Cycloalkyl, -OH, -OC 1-4 Halogenated hydrocarbon, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -SH, -SC 1-6 Hydrocarbon, -SC 1-4 Halogenated hydrocarbon, -SC 3-6 Cycloalkyl, -SC 3-6 Halogenated cycloalkyl, -NR 18 R 19 Or -NO2.

24. The pharmaceutical composition according to any one of claims 20 to 23, wherein in the general formula (1), R 16 For -OH, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF2CF3, -OCF2Cl, -OCFCl2, -SH, -SCH3, -SCH2CH3, -SCF3, -SCH2CF3, -SCF2CF3, -SCF2Cl, -SCFCl2, -NH2, Or -NO2; preferably -OCF3, -OCH2F, -OCHF2, -SCH3, -SCF3, -SCF2Cl, -SCFCl2, Or -NO2; More preferably -OCF3, -OCH2F, -OCHF2, -SCH3, -SCF3, Or -NO2.

25. The pharmaceutical composition according to any one of claims 20 to 22, wherein in the general formula (1), R 16 -OCH3, -OCH2CH3, -OCH2CH2CH3, Preferred is -OCH3.

26. The pharmaceutical composition according to any one of claims 20 to 25, wherein in the general formula (1), R 9 is H, methyl or ethyl, preferably H.

27. The pharmaceutical composition according to claim 20, wherein in the general formula (1), R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each is independently H, halogen, C 1-6 Hydrocarbon or C 1-4 halogenated hydrocarbon group; and R 13a and R 13b R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 a saturated 3-, 4-, or 5-membered monocyclic ring; wherein the 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 R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 cyclopropyl, cyclobutyl or cyclopentyl ring.

28. The pharmaceutical composition according to any one of claims 20 to 27, wherein in the general formula (1), the structural unit for: Preferably 29. The pharmaceutical composition according to any one of claims 20 to 28, wherein in the general formula (1), Z is a chemical bond, -NH-, -NHSO2-, -SONH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-.

30. The pharmaceutical composition according to any one of claims 20 to 29, wherein in the general formula (1), R 10 Selected from (a) H; or (b) C 1- 6 hydrocarbon groups, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3; or (c) when the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can be combined with the sulfur atom to which they are attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl OH, -OH, -OCH3, -NH2 or oxo; or (d) C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbon group may be optionally substituted with 1, 2 or 3 of the following groups: -OC(=O)C 1-5 Hydrocarbyl, wherein the C 1-5 The hydrocarbon group may be optionally substituted with 1 or 2 of the following groups: -OH or -NH2; and the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

31. The pharmaceutical composition according to any one of claims 20 to 30, wherein in the general formula (1), R 1 -CN or -ZR 10 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and R 10 Selected from: (a)H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, and wherein each of the rings may be independently optionally substituted by 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN and oxo; preferably oxetane, cyclopropyl; (c) C substituted with 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 Hydrocarbyl; preferably C substituted by 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; more preferably C substituted by 1 OH group 1-6 a hydrocarbon group; or (d)C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: And the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

32. The pharmaceutical composition according to any one of claims 20 to 31, wherein in the general formula (1), the group -ZR 10 -N=S(=O)-(R 10 )2, where two R 10 The sulphur atoms to which they are attached may combine to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; preferably the group -ZR 10 Selected from:

33. The pharmaceutical composition according to any one of claims 20 to 31, wherein in the general formula (1), R 1 -ZR 10 , wherein Z is -NHSO2- or -SO2NH-; and R 10 is oxetane, cyclopropyl, or R 10 is C substituted with 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; or R 10 C 1-6 Hydrocarbyl, wherein the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups:

34. The pharmaceutical composition according to any one of claims 20 to 29, wherein in the general formula (1), R 10 Selected from C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: Preferably Z is -NHSO2- or -SO2NH-; Z is preferably -NHSO2-.

35. The pharmaceutical composition according to any one of claims 20 to 29, wherein in the general formula (1), R 10 Selected from C 1-6 A hydrocarbon group, which may be optionally substituted with 1, 2 or 3 of the following groups: Z is -NHSO2- or -SO2NH-.

36. The pharmaceutical composition according to any one of claims 20 to 35, wherein in the general formula (1), R 2 is halogen or group -YR 12 , where Y is a chemical bond, -NH-, -NH-(CH2) 0-4 -or-O-(CH2) 0-4 -; and R 12 is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo; or R 12 C 1-6 Hydrocarbyl, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

37. The pharmaceutical composition according to any one of claims 20 to 36, wherein in the general formula (1), R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and wherein each of said rings is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

38. The pharmaceutical composition according to any one of claims 20 to 37, wherein in the general formula (1), R 2 is (a) halogen; (b) group -YR 12 , where Y is a chemical bond; and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN and oxo; or (c) a group -YR 12 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-, and wherein R 12 for or R 12 C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF3, -OH or CN.

39. The pharmaceutical composition according to any one of claims 20 to 38, wherein in the general formula (1), R 2 is morpholinyl or piperidinyl, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF3, -OH, -OCHF2 and CN.

40. The pharmaceutical composition according to any one of claims 20 to 39, wherein in the general formula (1), R 2 is piperidinyl substituted by 1, 2 or 3 fluoro groups.

41. The pharmaceutical composition according to any one of claims 20 to 38, wherein in the general formula (1), R 2 for:

42. The pharmaceutical composition according to any one of claims 20 to 39, wherein in the general formula (1), R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.

43. The pharmaceutical composition according to any one of claims 20 to 38, wherein in the general formula (1), R 2 for 44. The pharmaceutical composition according to any one of claims 20 to 40, wherein in the general formula (1), R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinyl.

45. The pharmaceutical composition according to any one of claims 20 to 44, wherein in the general formula (1), R 3 For H.

46. ​​The pharmaceutical composition according to any one of claims 20 to 45, wherein in the general formula (1), R 4 selected from (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl; or (c) cyclopropyl; or (d) F; R 4 Preferably H, F or methyl; R 4 More preferably, it is H.

47. The pharmaceutical composition according to any one of claims 20 to 46, wherein in the general formula (1), R 5 is H or F, preferably H.

48. The pharmaceutical composition according to any one of claims 20 to 47, wherein in the general formula (1), R 6 is H or F, preferably H.

49. The pharmaceutical composition according to any one of claims 20 to 48, wherein in the general formula (1), R 7 For H.

50. The pharmaceutical composition according to any one of claims 20 to 49, wherein in the general formula (1), R 15 is H or F, preferably H.

51. The pharmaceutical composition of any one of claims 20-50, wherein the compound has one of the following structures:

52. The pharmaceutical composition according to any one of claims 1 to 19, wherein the KIF18A inhibitor is a compound represented by general formula (5) or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates: In general formula (5): X 1 -CR 5 = or N; X 2 -CR 6 = or N; X 3 -CR 7 = or N; X 4 -CR 4 =; X 5 -CR 15 =; R 16 C 1-8 hydrocarbon group; L is -(C=O)-NR 9 -* or -NR 9 -(C=O)-*; and X 1 、X 2 、X 3 、X 4 and X 5 Among them, no more than 4 are N; * represents the connection end; R 1 -CN or -ZR 10 , where Z is a chemical bond, -C 0-4 Hydrocarbon-, -NR 11 -、-NR 11 SO2-、-SO2NR 11 -、-NR 11 -S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -C 0-4 Hydrocarbyl-O-, -(C=O)-, -(C=O)NR 11 -, -C(=N-OH)- or -NR 11 (C=O)-; or the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can combine with the sulfur atom to which they are attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 2 is halogen or group -YR 12 , where Y is a chemical bond, -C 0-4 Hydrocarbyl-, -N(C 0-1 Hydrocarbon)-C 0-4 Hydrocarbyl-, -C(=O)NR a R a (C 1-4 Hydrocarbon)-、-OC 0-4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR 12 - or -S(=O)(=NH)-; R 3 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups; R 4 H, halogen, R 4a or R 4b ; R 5 H, halogen, C 1-8 Alkyl or C 1-4 alkyl halide; R 6 H, halogen, C 1-8 Alkyl, C 1-4 Haloalkyl, -OH, -OR 6a OR 6b ; R 7 H, halogen, C 1-8 Hydrocarbon or C 1-4 halogenated hydrocarbon groups; R 8 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 independently H, halogen, R 13m or R 13n ; or R 13a and R 13b Yes, R 13c and R 13d Yes, R 13e and R 13f Yes, R 13g and R 13h Yes, R 13i and R 13j Right or R 13k and R 13l Each of the pairs can independently form a spiro-linked carbon atom to which they are attached. 8 a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, CN, -NR a R a or oxo; R 9 H or C 1-6 hydrocarbon group; R 10 H, R 10a 、R 10b or R 10c ; R 11 H, R 11a or R 11b ; R 12 R 12a or R 12b ; R 15 H, halogen, C 1-8 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OC 1-8 Hydrocarbyl or -OR 15a , where R 15a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 4a 、R 6a 、R 10a 、R 11a 、R 12a or R 13m is independently selected from: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 、R 14 and oxo; R 4b 、R 6b 、R 10b 、R 11b 、R 12b or R 13n is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -R a 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN; R 10c is independently selected in each case from: 1-6 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted by 0, 1, 2, 3, 4 or 5 of the following Group substitution: F, Cl, Br, -R a 、-R c 、-OR a 、-OC 1-4 Halogenated hydrocarbons and CN; R 14 is independently selected from the group consisting of: a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -OR a 、-OC 1-4 Halogenated hydrocarbon, 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 Hydrocarbon NR a R a 、-OC 2-6 Hydrocarbon OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR 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)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2-6 Hydrocarbon NR a R a 、-NR a C 2-6 Hydrocarbon OR a 、-C 1-6 Hydrocarbon NR a R a 、-C 1-6 Hydrocarbon 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 is independently H or R b ; R b In each case, independently C 1-6 Hydrocarbyl, phenyl or benzyl, wherein the hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 and wherein the phenyl and benzyl groups are each independently optionally substituted with 0, 1, 2 or 3 of the following groups: halogen, C 1-4 Hydrocarbon, C 1-3 Halogenated hydrocarbons, -OH, -OC 1-4 Hydrocarbon, -NH2, -NHC 1-4 Hydrocarbyl, -OC(=O)C 1-4 Hydrocarbyl or -N(C 1-4 Hydrocarbon) C 1-4 a hydrocarbon group; and R c is independently at each occurrence -OC(=O)C 1-5 Hydrocarbyl, wherein the hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: -OH or -NH2.

53. The pharmaceutical composition of claim 52, wherein the general formula (5) has the following structure: where R 16 C 1-4 Hydrocarbon group.

54. The pharmaceutical composition of claim 52 or 53, wherein in the general formula (5), R 16 for Preferably 55. The pharmaceutical composition according to any one of claims 52 to 54, wherein in the general formula (5), R 9 is H, methyl or ethyl, preferably H.

56. The pharmaceutical composition of claim 52, wherein in the general formula (5), R 13c 、R 13d 、R 13e 、R 13f 、R 13g 、R 13h 、R 13i 、R 13j 、R 13k and R 13l Each is independently H, halogen, C 1-6 Hydrocarbon or C 1-4 halogenated hydrocarbon group; and R 13a and R 13b R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 a saturated 3-, 4-, or 5-membered monocyclic ring; wherein the 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 R in the center 13a and R 13b The carbon atoms to which they are attached can combine to form a spiral to R 8 cyclopropyl, cyclobutyl or cyclopentyl ring.

57. The pharmaceutical composition according to any one of claims 52 to 56, wherein in the general formula (5), the structural unit for: Preferably 58. The pharmaceutical composition of any one of claims 52 to 57, wherein in the general formula (5), Z is a chemical bond, -NH-, -NHSO2-, -SONH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-.

59. The pharmaceutical composition according to any one of claims 52 to 58, wherein in the general formula (5), R 10 Selected from (a) H; or (b) C 1-6 a hydrocarbon group, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3; or (c) when the group -ZR 10 -N=S(=O)-(R 10 )2, wherein the two R 10 can be combined with the sulfur atom to which they are attached to form a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbon, -C 1-6 Hydrocarbyl OH, -OH, -OCH3, -NH2 or oxo; or (d) C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbon group may be optionally substituted with 1, 2 or 3 of the following groups: -OC(=O)C 1-5 Hydrocarbyl, wherein the C 1-5 The hydrocarbon group may be optionally substituted with 1 or 2 of the following groups: -OH or -NH2; and the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

60. The pharmaceutical composition according to any one of claims 52 to 59, wherein in the general formula (5), R 1 -CN or -ZR 10 , wherein Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and R 10 Selected from: (a)H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, and wherein each of the rings may be independently optionally substituted by 0, 1, 2 or 3 of the following groups: OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN and oxo; preferably oxetane, cyclopropyl; (c) C substituted with 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 Hydrocarbyl; preferably C substituted by 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; more preferably C substituted by 1 OH group 1-6 a hydrocarbon group; or (d)C 1-6 Hydrocarbyl, the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups: And the C 1-6 The hydrocarbyl group may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH or -OCH3.

61. The pharmaceutical composition of any one of claims 52 to 60, wherein in the general formula (5), the group -ZR 10 -N=S(=O)-(R 10 )2, where two R 10 The sulphur atoms to which they are attached may combine to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; preferably the group -ZR 10 Selected from:

62. The pharmaceutical composition according to any one of claims 52 to 60, wherein in the general formula (5), R 1 -ZR 10 , wherein Z is -NHSO2- or -SO2NH-; and R 10 is oxetane, cyclopropyl, or R 10 is C substituted with 0, 1, 2 or 3 OH groups 1-6 Hydrocarbyl; or R 10 C 1-6 Hydrocarbyl, wherein the C 1-6 The hydrocarbyl group may be optionally substituted with 1, 2 or 3 of the following groups:

63. The pharmaceutical composition according to any one of claims 52 to 58, wherein in the general formula (5), R 10 Selected from C 1- 6 hydrocarbon groups, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: Preferably Z is -NHSO2- or -SO2NH-; Z is preferably -NHSO2-.

64. The pharmaceutical composition according to any one of claims 52 to 58, wherein in the general formula (5), R 10 Selected from C 1-6 A hydrocarbon group, which may be optionally substituted with 1, 2 or 3 of the following groups: Z is -NHSO2- or -SO2NH-.

65. The pharmaceutical composition according to any one of claims 52 to 64, wherein in the general formula (5), R 2 is halogen or group -YR 12 , where Y is a chemical bond, -NH-, -NH-(CH2) 0-4 -or-O-(CH2) 0-4 -; and R 12 is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently optionally substituted by 0, 1, 2 or 3 of the following groups: F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo; or R 12 C 1-6 Hydrocarbyl, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, -OH, -OC 1-4 Halogenated hydrocarbon or CN.

66. The pharmaceutical composition according to any one of claims 52 to 65, wherein in the general formula (5), R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and wherein each of said rings is substituted by 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, C 1-6 Hydrocarbon, C 1-4 Halogenated hydrocarbons, -OH, -OC 1-4 Halogenated hydrocarbon, CN, R 14 and oxo.

67. The pharmaceutical composition according to any one of claims 52 to 66, wherein in the general formula (5), R 2 is (a) halogen; (b) group -YR 12 , where Y is a chemical bond; and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, wherein each of said rings is substituted with 0, 1, 2 or 3 groups selected from the group consisting of F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN and oxo; or (c) a group -YR 12 , wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-, and wherein R 12 for or R 12 C 1-6 A hydrocarbyl group, which may be optionally substituted with 0, 1, 2, 3, 4 or 5 of the following groups: F, Cl, Br, methyl, CF3, -OH or CN.

68. The pharmaceutical composition according to any one of claims 52 to 67, wherein in the general formula (5), R 2 is morpholinyl or piperidinyl, which may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF3, -OH, -OCHF2 and CN.

69. The pharmaceutical composition according to any one of claims 52 to 68, wherein in the general formula (5), R 2 is piperidinyl substituted by 1, 2 or 3 fluoro groups.

70. The pharmaceutical composition according to any one of claims 52 to 67, wherein in the general formula (5), R 2 for:

71. The pharmaceutical composition of any one of claims 52 to 68, wherein in the general formula (5), R 2 is morpholinyl substituted by 1, 2 or 3 methyl groups.

72. The pharmaceutical composition of any one of claims 52-67, wherein in the general formula (5), R 2 for 73. The pharmaceutical composition according to any one of claims 52 to 59, wherein in the general formula (5), R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinyl.

74. The pharmaceutical composition of any one of claims 52-73, wherein in the general formula (5), R 3 For H.

75. The pharmaceutical composition of any one of claims 52-74, wherein in the general formula (5), R 4 selected from (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl; or (c) cyclopropyl; or (d) F; R 4 Preferably H, F or methyl; R 4 More preferably, it is H.

76. The pharmaceutical composition of any one of claims 52-75, wherein in the general formula (5), R 5 is H or F, preferably H.

77. The pharmaceutical composition of any one of claims 52-76, wherein in the general formula (5), R 6 is H or F, preferably H.

78. The pharmaceutical composition of any one of claims 52-77, wherein in the general formula (5), R 7 For H.

79. The pharmaceutical composition of any one of claims 52-78, wherein in the general formula (5), R 15 is H or F, preferably H.

80. The pharmaceutical composition of any one of claims 52-79, wherein the compound has one of the following structures:

81. The pharmaceutical composition of any one of claims 1 to 19, wherein the KIF18A inhibitor is or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

82. The pharmaceutical composition of any one of claims 1 to 19, wherein the KIF18A inhibitor is or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

83. The pharmaceutical composition according to any one of claims 1 to 82, wherein Contains 0.0001-100000nM KIF18A inhibitor and 0.0001-100000nM PLK1 inhibitor; Preferably, it comprises 0.0001-50000 nM of KIF18A inhibitor and 0.0001-100000 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-100000 nM of KIF18A inhibitor and 0.0001-50000 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-50000 nM of KIF18A inhibitor and 0.0001-50000 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-50000 nM of KIF18A inhibitor and 0.0001-25000 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-25000 nM of KIF18A inhibitor and 0.0001-50000 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-25000 nM of a KIF18A inhibitor and 0.0001-25000 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-12500 nM of a KIF18A inhibitor and 0.0001-25000 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-25000 nM of KIF18A inhibitor and 0.0001-12500 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-12500 nM of a KIF18A inhibitor and 0.0001-12500 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-12500 nM of KIF18A inhibitor and 0.0001-6250 nM of PLK1 inhibitor; Preferably, it comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-12500 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-6250 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-6250 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-6250 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-3125 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-3125 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-1562 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-1562 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-781 nM of a KIF18A inhibitor and 0.0001-400 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-781 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-400 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-5000 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-1000 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-1000 nM of a PLK1 inhibitor; Preferably, it comprises 0.0001-400 nM of a KIF18A inhibitor and 0.0001-50 nM of a PLK1 inhibitor; Preferably, it comprises 0.64-400 nM of the compound of formula (1) and 1.6-1000 nM of Plogosertib; Preferably, it contains 0.64-400nM of the compound of formula (1) and 1.6-200nM of Plogosertib; Preferably, it comprises 0.64-400 nM of the compound of formula (1) and 1.6-40 nM of Plogosertib; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-1000 nM of Plogosertib; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-200 nM of Plogosertib; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-40 nM of Plogosertib; Preferably, comprising 0.64-400 nM AMG650 and 1.6-1000 nM Plogosertib; Preferably, comprising 0.64-400 nM AMG650 and 1.6-200 nM Plogosertib; Preferably, comprising 0.64-400 nM AMG650 and 1.6-40 nM Plogosertib; Preferably, it comprises 0.64-400 nM of the compound of formula (1) and 1.6-1000 nM of TAK960; Preferably, it comprises 0.64-400 nM of the compound of formula (1) and 1.6-200 nM of TAK960; Preferably, it comprises 0.64-400 nM of the compound of formula (1) and 1.6-40 nM of TAK960; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-1000 nM of TAK960; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-200 nM of TAK960; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 1.6-40 nM of TAK960; Preferably, it comprises 0.64-400nM AMG650 and 1.6-1000nM TAK960; Preferably, it comprises 0.64-400nM AMG650 and 1.6-200nM TAK960; Preferably, it contains 0.64-400nM AMG650 and 1.6-40nM TAK960; Preferably, it contains 0.64-400nM of the compound of formula (1) and 3.125-50nM of Volasertib; Preferably, it comprises 0.64-400 nM of compound 257 of formula (1) and 3.125-50 nM of Volasertib; Preferably, comprising 0.64-400 nM AMG650 and 3.125-50 nM Volasertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of Rigosertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of Rigosertib; Preferably, it contains 0.0001-5000nM of the compound of formula (1) and 0.0001-10nM of BI2536; Preferably, it contains 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-10 nM of BI2536; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of Volasertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of Volasertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-1000 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-500 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-25 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of the general formula (1) and 0.0001-1000 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of the general formula (1) and 0.0001-500 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of the general formula (1) and 0.0001-100 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of Onvansertib; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-1000 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-500 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-100 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of the compound of formula (1) and 0.0001-10 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-1000 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-500 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-100 nM of GSK461364; Preferably, it comprises 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-10 nM of GSK461364; Preferably, it comprises 0.0001-5000nM of the compound of formula (1) and 0.0001-1000nM of MLN0905; Preferably, it comprises 0.0001-5000nM of the compound of formula (1) and 0.0001-500nM of MLN0905; Preferably, it contains 0.0001-5000nM of the compound of formula (1) and 0.0001-100nM of MLN0905; Preferably, it contains 0.0001-5000nM of the compound of formula (1) and 0.0001-25nM of MLN0905; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-1000 nM of MLN0905; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-500 nM of MLN0905; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-100 nM of MLN0905; Preferably, it comprises 0.0001-5000 nM of compound 257 of formula (1) and 0.0001-25 nM of MLN0905; Preferably, it contains 0.0001-5000nM of the compound of formula (1) and 0.0001-25nM of Ro3280; Preferably, it contains 0.0001-5000 nM of compound 257 of general formula (1) and 0.0001-25 nM of Ro3280.

84. Use of a pharmaceutical composition comprising a KIF18A inhibitor and a compound that inhibits protein activity in the preparation of a drug for treating cancer.

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