KIF18A inhibitors

Abstract

The present invention discloses KIF18A inhibitor.Specifically, the present invention relates to the compound of general formula (1), its preparation method, and the use of the compound of general formula (1) or its isomer, crystal, pharmaceutically acceptable salt, hydrate or solvate as KIF18A inhibitor in the preparation of antitumor agent. [Formula 1] TIFF2024542199000344.tif35168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202111399876.4, filed on November 19, 2022, Chinese Patent Application No. 202210225663.8, filed on March 9, 2022, and Chinese Patent Application No. 202210667619.2, filed on June 13, 2022, which are incorporated by reference in their entireties.

[0002] The present invention relates to the field of pharmaceutical chemistry, in particular to compounds having inhibitory activity against KIF18A protein, a method for preparing the same, and the use of such compounds in the preparation of antitumor agents. [Background technology]

[0003] Genomic instability is a common feature of most tumor cells. Most tumor cells exhibit abnormal gains or losses of chromosomes. Chromosomal instability in tumor cells leads to interactions between abnormal chromosomes and mitotic spindle microtubules, which causes chromosome segregation errors. Cells with chromosomal instability exhibit increased spindle microtubule polymerization and decreased spindle microtubule-centromere contact turnover compared to cells with normal chromosomes. Therefore, antimitotic therapies targeting the microtubule cytoskeleton may be particularly effective in cells with chromosomal instability.

[0004] Kinesins are a type of molecular motor that play an important role in cell division, intracellular vesicle and organelle transport. Mitotic kinesins play important roles in several aspects such as spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are classified into 14 subfamilies based on differences in the amino acid sequence of the motor domain, and the ATPase activity present in the motor domain allows the proteins to move unidirectionally along microtubules. The non-motor domain of these proteins is responsible for interacting with substrates, and various membrane organelles, signaling scaffold systems, and chromosomes serve as substrates for the non-motor domain to interact with. Kinesins obtain energy by ATP hydrolysis and move substrates along polarized microtubules. Therefore, kinesins are commonly referred to as "plus-end" or "minus-end" directional motors.

[0005] KIF18A protein belongs to the kinesin-8 subfamily. KIF18A protein is overexpressed in various types of cancer, including lung, ovarian, cervical, breast, pancreatic, prostate, colon, and bladder cancers. Studies have shown that KIF18A affects the dynamics of the plus ends of centromeric microtubules, controlling the correct positioning of chromosomes and spindle tension. In chromosomally unstable tumor cells, microtubule dynamics are abnormal, so such cells are particularly dependent on KIF18A protein to reduce spindle microtubule-centromere contact turnover and limit microtubule growth (Nat Commun. 2021, 12, 1213). Deletion of KIF18A protein from chromosomally unstable tumor cells leads to fragmentation of the cell's centrosomes and slow or halt progression of mitosis. However, these phenomena do not occur in cells with normal chromosomes. Thus, although KIF18A protein activity does not have a significant effect on the proliferation of normal cells, it is crucial for the proliferation of chromosomally unstable tumors. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Nat Commun.2021,12,1213 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, the development of KIF18A inhibitors represents a promising new approach against chromosomally unstable tumors. [Means for solving the problem]

[0008] (overview) The present invention provides a compound of general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In 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, X 5 -CR 15 = and X 4 -CR 4 = R 16 -C 3~8 Cycloalkyl, -OR 17 , -SR 18 , -NR 18 R 19 , or -NO2, X 5 -CR 15 = and X 4 If N, then R 16-OC 1~8 Hydrocarbyl, -C 3~8 Cycloalkyl, -OR 17 , -SR 18 , -NR 20 R 21 , or -NO2, X 5 If N, then R 16 -OC 1~8 Hydrocarbyl, -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 Of these, 4 or fewer are N. * teeth, [ka] indicates the position at which the molecule is bound to the end of R 17 -H, -C 1~8 Halohydrocarbyl, -C 3~8 Cycloalkyl, or -C 3~8 halocycloalkyl, wherein said -C 1~8 Halohydrocarbyl, said -C 3~8 cycloalkyl, or the -C 3~8 Halocycloalkyl is any of the following groups: H, halogen, and -C 1~4 optionally substituted with 0, 1, 2, or 3 of hydrocarbyl; R 18 and R 19 are each independently H, -C 1~8 Hydrocarbyl, -C 1~8 Halohydrocarbyl, -C 3~8Cycloalkyl, or -C 3~8 halocycloalkyl, wherein said -C 1~8 Hydrocarbyl, said -C 1~8 Halohydrocarbyl, said -C 3~8 cycloalkyl, or the -C 3~8 Halocycloalkyl is any of the following groups: H, halogen, and -C 1~4 optionally substituted with 0, 1, 2, or 3 of hydrocarbyl; R 20 and R 21 are each independently H, -C 1~8 Hydrocarbyl, -C 1~8 Halohydrocarbyl, -C 3~8 Cycloalkyl, or -C 3~8 halocycloalkyl, wherein said -C 1~8 Hydrocarbyl, said -C 1~8 Halohydrocarbyl, said -C 3~8 cycloalkyl, or the -C 3~8 Halocycloalkyl is selected from the following groups: H, halogen and -C 1~4 optionally substituted with 0, 1, 2, or 3 of hydrocarbyl, or R 20 and R 21 may be combined with the nitrogen atom to which they are respectively bonded 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 Hydrocarbyl-, -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)NR11 -, -C(=N-OH)-, or -NR 11 (C=O)- or a group -ZR 10 is -N=S(=O)-(R 10 )2, where the two R 10 may be combined with the sulfur atom to which they are respectively 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 a halogen or a group -YR 12 where Y is a chemical bond, -C 0~4 Hydrocarbyl-, -N(C 0~1 Hydrocarbyl)-C 0~4 Hydrocarbyl-, -C(=O)NR a R a (C 1~4 Hydrocarbyl)-, -OC 0~4 Hydrocarbyl-, -S-, -S(=O)-, -SO2-, -SO2NR 12 - or -S(=O)(=NH)-, R 3 H, halogen, C 1~8 Hydrocarbyl, or C 1~4 is a halohydrocarbyl, R 4 is H, halogen, R 4a , or R 4b and R 5 H, halogen, C 1~8 Alkyl, or C 1~4 is haloalkyl, R 6 H, halogen, C 1~8 Alkyl, C 1~4 Haloalkyl, -OH, -OR 6a -OR 6b and R 7 H, halogen, C 1~8 Hydrocarbyl, or C 1~4 is a halohydrocarbyl, R 8teeth, [ka] is selected from the group consisting of R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j , R 13k , and R 13l are each independently H, halogen, or R 13m , or R 13n or R 13a / R 13b , R 13c / R 13d , R 13e / R 13f , R 13g / R 13h , R 13i / R 13j , and R 13k / R 13l Each of the pairs of R 8 A saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring may be formed spiro-bonded to the ring, wherein said 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 said 3-, 4-, 5-, or 6-membered monocyclic ring contains no atoms selected from F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OR a , -OC 1~4 Halohydrocarbyl, CN, -NR a R a and oxo; R 9 is H or C 1~6 is a hydrocarbyl; R 10 , H, R 10a , R10b , or R 10c and R 11 , H, R 11a , or R 11b and R 12 is R 12a or R 12b and R 15 H, halogen, C 1~8 Hydrocarbyl, C 1~4 Halohydrocarbyl, -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, in each occurrence, 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, said monocyclic ring and said bicyclic ring each independently containing one of the following groups: F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OR a , -OC 1~4 Halohydrocarbyl, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2~6 Hydrocarbyl NRa R a , -OC 2~6 Hydrocarbyl 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 Hydrocarbyl NR a R a , -NR a C 2~6 Hydrocarbyl OR a , -C 1~6 Hydrocarbyl NR a R a , -C 1~6 Hydrocarbyl OR a , -C 1~6 Hydrocarbyl N(R a )C(=O)R b , -C 1~6 Hydrocarbyl OC(=O)R b , -C 1~6 HydrocarbylC(=O)NR a R a , -C 1~6 HydrocarbylC(=O)OR a , R 14 and 0, 1, 2, or 3 of oxo; R 4b , R 6b , R 10b, R 11b , R 12b , or R 13n In each case, C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, -R a , -OR a , -OC 1~4 optionally substituted with 0, 1, 2, 3, 4, or 5 of halohydrocarbyl, and CN; R 10c In each case, C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, -R a , -R c , -OR a , -OC 1~4 optionally substituted with 0, 1, 2, 3, 4 or 5 of halohydrocarbyl, and CN; R 14 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, in each occurrence, 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 each independently contain one of the following groups: F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OR a , -OC 1~4 Halohydrocarbyl, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2~6 Hydrocarbyl NR a R a , -OC 2~6Hydrocarbyl 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 Hydrocarbyl NR a R a , -NR a C 2~6 Hydrocarbyl OR a , -C 1~6 Hydrocarbyl NR a R a , -C 1~6 Hydrocarbyl OR a , -C 1~6 Hydrocarbyl N(R a )C(=O)R b , -C 1~6 Hydrocarbyl OC(=O)R b , -C 1~6 HydrocarbylC(=O)NR a R a , -C 1~6 HydrocarbylC(=O)OR a and 0, 1, 2 or 3 of oxo, R a is, in each occurrence, independently, H or R b and R bis, in each case independently, C 1~6 hydrocarbyl, phenyl, or benzyl, wherein said hydrocarbyl is selected from the following groups: halogen, -OH, -OC 1~4 Hydrocarbyl, -NH2, -NHC 1~4 Hydrocarbyl, -OC(=O)C 1~4 Hydrocarbyl, and -N(C 1~4 Hydrocarbyl)C 1~4 wherein the phenyl and the benzyl are each independently selected from the following groups: halogen, C 1~4 Hydrocarbyl, C 1~3 Halohydrocarbyl, -OH, -OC 1~4 Hydrocarbyl, -NH2, -NHC 1~4 Hydrocarbyl, -OC(=O)C 1~4 Hydrocarbyl, and -N(C 1~4 Hydrocarbyl)C 1~4 Optionally substituted with 0, 1, 2 or 3 of the hydrocarbyl: R c is, in each occurrence, independently: -OC(=O)C 1~5 and hydrocarbyl, wherein said hydrocarbyl is optionally substituted with one, two or three of the following groups: -OH and -NH.

[0009] In another preferred embodiment, the compound of general formula (1) has the following structure: [ka] where R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Hydrocarbyl, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 20 R 21 , or -NO2.

[0010] In another preferred embodiment, the compound of general formula (1) has the following structure: [ka] where R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Hydrocarbyl, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 20 R 21 , or -NO2.

[0011] In another preferred embodiment, the compound of general formula (1) has the following structure: [ka] where R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 18 R 19 , or -NO2.

[0012] In another preferred embodiment, in the general formula (1), R 16 -OH, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF2CF3, -OCF2Cl, -OCFCl2, [ka] -SH, -SCH3, -SCH2CH3, [ka] -SCF3, -SCH2CF3, -SCF2CF3, -SCF2Cl, -SCFCl2, [ka] -NH 2、 [ka] or -NO2, preferably -OCF3, -OCH2F, -OCHF2, [ka] -SCH3, -SCF3, -SCF2Cl, -SCFCl2, [ka] or -NO2, more preferably -OCF3, -OCH2F, -OCHF2, [ka] -SCH3, -SCF3, [ka] Or -NO2.

[0013] In another preferred embodiment, in the general formula (1), R 16 are -OCH3, -OCH2CH3, -OCH2CH2CH3, [ka] and preferably -OCH3.

[0014] In another preferred embodiment, in the general formula (1), R 9 is H, methyl or ethyl, preferably H.

[0015] In another preferred embodiment, 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 are each independently H, halogen, or C 1~6 Hydrocarbyl, or C 1~4 halohydrocarbyl, R 13a / R 13b R in the pair 13a and R 13b are combined with the carbon atoms to which they are respectively bonded to form R 8 A saturated 3-, 4-, or 5-membered monocyclic ring may be formed spiro-connected to the ring, said monocyclic ring containing 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; R 13a / R 13b R in the pair 13a and R13b are combined with the carbon atoms to which they are respectively bonded to form R 8 A cyclopropyl, cyclobutyl, or cyclopentyl ring may be formed spiro-linked to the ring.

[0016] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] and preferably [ka] It is.

[0017] In another preferred embodiment, in 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)-.

[0018] In another preferred embodiment, in the general formula (1), R 10 teeth, (a) H; (b)C 1~6 Hydrocarbyl, wherein said hydrocarbyl is optionally substituted with 0, 1, 2, or 3 of the following groups: F, Cl, Br, -OH, and -OCH3; 1~6 Hydrocarbyl; (c) a group, the group -ZR 10 But -N=S(=O)-(R 10 )2, then 2 R 10may be combined with the sulfur atom to which they are respectively 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, wherein the monocyclic ring is selected from F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -C 1~6 a hydrocarbyl group substituted with 0, 1, 2 or 3 groups selected from OH, -OH, -OCH3, -NH2, and oxo; and (d) C 1~6 Hydrocarbyl, wherein said C 1~6 The hydrocarbyl may be selected from the group: -OC(=O)C 1~5 wherein the C may be optionally substituted with one, two, or three hydrocarbyls. 1~5 The hydrocarbyl may be optionally substituted with one or two of the following groups: -OH and -NH2. 1~6 Hydrocarbyl is optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH and -OCH3; 1~6 Hydrocarbyl, is selected from.

[0019] In another preferred embodiment, in the general formula (1), R 1 is -CN or the group -ZR 10 where Z is a chemical bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; R 10 teeth, (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, [ka] (wherein each ring is optionally substituted, independently, with 0, 1, 2, or 3 of the following groups: OH, F, methyl, -CHOH, -C(=O)OCH, -C(=O)OC(CH), NH, CN, and oxo, with oxetanyl and cyclopropyl being preferred); (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 with 0, 1, 2 or 3 OH groups 1~6 Hydrocarbyl, more preferably C substituted with one OH group 1~6 Hydrocarbyl; and (d) C 1~6 Hydrocarbyl, 1~6 The hydrocarbyl may be selected from the following groups: [ka] may be optionally substituted with one, two or three of the C 1~6 The hydrocarbyl is optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, -OH and -OCH3; 1~6 Hydrocarbyl, is selected from.

[0020] In another preferred embodiment, in the general formula (1), the group -ZR 10 is -N=S(=O)-(R 10 )2, where the two R 10 may be combined with the sulfur atom to which they are respectively 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, preferably the group -ZR 10 teeth, [ka] is selected from.

[0021] In another preferred embodiment, in the general formula (1), R 1 is the group -ZR 10 where Z is -NHSO2- or -SO2NH-, and R 10 is oxetanyl or cyclopropyl, or R 10 is C substituted with 0, 1, 2 or 3 OH groups 1~6 or R 10 is C 1~6 Hydrocarbyl, wherein 1~6 Hydrocarbyl is selected from the following groups: [ka] may be optionally substituted with one, two or three of:

[0022] In another preferred embodiment, in the general formula (1), R 10 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: [ka] and the hydrocarbyl is preferably [ka] and Z is -NHSO2- or -SO2NH-, Z is preferably -NHSO2-.

[0023] In another preferred embodiment, in the general formula (1), R 10 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: [ka] and Z is -NHSO2- or -SO2NH-.

[0024] In another preferred embodiment, in the general formula (1), R 2 is a halogen or a 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 each independently contain one of the following groups: F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OH, -OC 1~4 Halohydrocarbyl, CN, R 14 and 0, 1, 2 or 3 of oxo, or R 12 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, -OH, -OC 1~4 It may be optionally substituted with 0, 1, 2, 3, 4, or 5 of halohydrocarbyl, and CN.

[0025] In another preferred embodiment, in the general formula (1), R 2 is a saturated 5- or 6-membered monocyclic ring, said ring containing 0, 1 or 2 N atoms and 0 or 1 O atom, said ring being free of F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OH, -OC 1~4 Halohydrocarbyl, CN, R 14 and oxo.

[0026] In another preferred embodiment, in the general formula (1), R 2 teeth, (a) halogen; (b) Group -YR 12 (wherein Y is a chemical bond; R 12 morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, [ka] wherein each ring is substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN, and oxo; or (c) Group -YR 12 (Wherein, Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2), and R 12 teeth, [ka] or R 12 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is optionally substituted with 0, 1, 2, 3, 4, or 5 of the following groups: F, Cl, Br, methyl, CF3, -OH, and CN; It is.

[0027] In another preferred embodiment, in the general formula (1), R 2 is morpholinyl or piperidinyl, wherein said morpholinyl and said piperidinyl are optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF3, -OH, -OCHF2, and CN.

[0028] In another preferred embodiment, in the general formula (1), R 2is piperidinyl substituted with one, two or three fluorine groups.

[0029] In another preferred embodiment, in the general formula (1), R 2 teeth, [ka] It is.

[0030] In another preferred embodiment, in the general formula (1), R 2 is morpholinyl substituted with one, two, or three methyl groups.

[0031] In another preferred embodiment, in the general formula (1), R 2 teeth, [ka] It is.

[0032] In another preferred embodiment, in the general formula (1), R 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, and 1,3,4-oxathiazinanyl.

[0033] In another preferred embodiment, in the general formula (1), R 3 is H.

[0034] In another preferred embodiment, in the general formula (1), R 4 teeth, (a) H; (b) C substituted with 0, 1, 2, or 3 OH groups 1~6 Hydrocarbyl; (c) cyclopropyl; and (d) F, Selected from R 4 is preferably H, F or methyl; R 4 is more preferably H.

[0035] In another preferred embodiment, in the general formula (1), R 5 is H or F, preferably H.

[0036] In another preferred embodiment, in the general formula (1), R 6 is H or F, preferably H.

[0037] In another preferred embodiment, in the general formula (1), R 7 is H.

[0038] In another preferred embodiment, in the general formula (1), R 15 is H or F, preferably H.

[0039] In another preferred embodiment, the general formula (1) is: [ka] where R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Hydrocarbyl, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 20 R 21 or -NO2, where R 2 , R 3 , R 10 , R 20 , and R 21 is defined as described above and illustrated in the specific examples.

[0040] In another preferred embodiment, the general formula (1) is: [ka] where R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 18 R 19 or -NO2, where R 2 , R 3 , R 10 , R 18 , and R 19 is defined as described above and illustrated in the specific examples.

[0041] In another preferred embodiment, the general formula (1) is: [ka] wherein R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Hydrocarbyl, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 20 R 21 , or -NO2, where L, R 10 , R 20 , and R21 is defined as described above and illustrated in the specific examples.

[0042] In another preferred embodiment, the general formula (1) is: [ka] wherein R 16 -C 3~6 Cycloalkyl, -OH, -OC 1~4 Halohydrocarbyl, -OC 3~6 Cycloalkyl, -OC 3~6 Halocycloalkyl, -SH, -SC 1~6 Hydrocarbyl, -SC 1~4 Halohydrocarbyl, -SC 3~6 Cycloalkyl, -SC 3~6 Halocycloalkyl, -NR 18 R 19 , or -NO2, where L, R 10 , R 18 , and R 19 is defined as described above and illustrated in the specific examples.

[0043] In various different embodiments of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] [ka]

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[0044] The present invention further aims to provide a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, diluent and / or excipient and, as an active ingredient, a compound of general formula (1) disclosed herein or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0045] The present invention further aims to provide the use of a compound of general formula (1) disclosed herein, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with KIF18A protein, wherein said disease is preferably cancer, and said cancer is a blood cancer or a solid cancer.

[0046] The present invention further contemplates providing a method for treating, regulating or preventing a disease associated with KIF18A protein, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) disclosed herein, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition described above.

[0047] The present inventors have, through the synthesis and careful study of various classes of novel compounds having KIF18A protein inhibitory activity, found that the compound of general formula (1) has surprisingly strong KIF18A protein inhibitory activity.

[0048] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0049] (Synthesis of Compounds) Methods for preparing the compounds disclosed herein are specifically described below, but are not intended to limit the invention in any way.

[0050] The above compounds may be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Additionally, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Missouri). The compounds described herein and other related compounds with various substituents may be synthesized using methods described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd Ed., (Wiley 1999). The general methods for preparing compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulas described herein.

[0051] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to the following description. In addition, the compounds of the present invention can be easily prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing the compounds described herein, wherein the compound of general formula (1) can be prepared according to the following general reaction schemes 1, 2, 3, or 4.

[0052] General reaction scheme 1

[0053] [ka]

[0054] Embodiments of compounds of general formula (1) may be prepared according to general reaction scheme 1, where R 1 , R 2 , R 3 , R 8 , R 16 , X 1 , X 2 , X 3 , X 4 and X 5 is as defined above, and W 1 represents fluorine, chlorine, bromine or iodine, H represents hydrogen, N represents nitrogen, R 1The reagent may be, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethyl-1-ol, or (11) cyclopropanethiol. As shown in General Reaction Scheme 1, compound 1-1 and compound 1-2 are subjected to an amidation reaction to produce compound 1-3, and compound 1-3 and R 1 Reaction with reagent 1-4 produces compound 1-5.

[0055] General reaction scheme 2

[0056] [ka]

[0057] Embodiments of compounds of general formula (1) may 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 , X 4 , and X 5 is as defined above, and W 1 represents fluorine, chlorine, bromine or iodine, H represents hydrogen, N represents nitrogen, R 1The reagent may be, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethyl-1-ol, or (11) cyclopropanethiol. As shown in General Reaction Scheme 2, compound 2-1 and compound 2-2 are subjected to an amidation reaction to produce compound 2-3, and compound 2-3 is reacted with R 1 Reaction with reagent 2-4 produces compound 2-5.

[0058] General reaction scheme 3

[0059] [ka]

[0060] Embodiments of compounds of general formula (1) may 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 is as defined above, and W 1 represents fluorine, chlorine, bromine or iodine, H represents hydrogen, N represents nitrogen, P 1 is an ester protecting group, R 1The reagents are, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethyl-1-ol, or (11) cyclopropanethiol. As shown in General Reaction Scheme 3, compound 3-1 and R 1 The compound 3-3 is reacted with a reagent 3-2 to produce a compound 3-3, and an ester group protecting group P is obtained from the compound 3-3. 1 is removed to produce compound 3-4, and compound 3-4 and compound 3-5 are subjected to an amidation reaction to produce compound 3-6.

[0061] General reaction scheme 4

[0062] [ka]

[0063] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 4, wherein R 1 , R 2 , R 3 , R 8 , R 16 , X 1 , X 2 , X 3 , X 4 , and X 5 is as defined above, and W 1 represents fluorine, chlorine, bromine or iodine, H represents hydrogen, N represents nitrogen, P 2 is an amino protecting group, R 1The reagents are, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethyl-1-ol, or (11) cyclopropanethiol. As shown in General Reaction Scheme 4, compound 4-1 and R 1 React with reagent 4-2 to produce compound 4-3, and then cleavage of the amino protecting group P from compound 4-3. 2 is removed to produce compound 4-4, and compound 4-4 and compound 4-5 are subjected to an amidation reaction to produce compound 4-6.

[0064] Further forms of the compound

[0065] As used herein, the term "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties of a compound. For example, when a substance is administered to an individual, the substance does not cause undesirable biological effects or adverse interactions with any of its components.

[0066] The term " pharmaceutically acceptable salt " refers to the form of a compound that does not cause significant irritation to the organism receiving the compound or does not eliminate the biological activity and properties of the compound.In certain embodiments, pharmaceutically acceptable salt is obtained by reacting the compound of general formula with an acid or base, wherein said acid or said base includes but is not limited to those described in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 1st Edition (Wiley, 2002).

[0067] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, compounds described herein may exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0068] In other specific examples, the compound of general formula (1) is prepared in various forms, including but not limited to amorphous, pulverized, and nanoparticle forms. In addition, the compound of formula (1) may be a polymorph, including crystalline forms. A polymorph comprises different lattice arrangements of the same elements of a compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystal system.

[0069] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0070] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 As another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and deuterated drugs generally have the advantages of reduced side effects, improved drug stability, enhanced efficacy, and extended in vivo half-life compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0071] Explanation of terms

[0072] Unless otherwise specified, the terms used herein, including those described in the specification and claims, are defined as follows. It should be noted that in this specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified. Conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used unless otherwise specified. In this specification, "or" or "and" means "and / or" unless otherwise specified.

[0073] Unless otherwise stated, "C α~β "Hydrocarbyl" means a hydrocarbyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, where α and β represent integers. The hydrocarbyls described in this section may also contain one or two double or triple bonds. The designation C0 hydrocarbyl represents a direct bond. 1~6 Examples of hydrocarbyls include: [ka] These include, but are not limited to:

[0074] Unless otherwise stated, "C α~β "Halohydrocarbyl" means a hydrocarbyl group as defined above in which any number (at least one) of the hydrogen atoms attached to the hydrocarbyl chain has been replaced with F, Cl, Br, or I.

[0075] Unless otherwise specified, "oxo" and "thio" refer to =O (eg, carbonyl) and =S (eg, thiocarbonyl), respectively.

[0076] Unless otherwise specified, "halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0077] Unless otherwise indicated, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via 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, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO and t- BuO.

[0078] Unless otherwise stated, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon ring system. The ring carbon atoms of the cycloalkyl can be optionally oxidized to form oxo or sulfide groups. The cycloalkyl further includes cycloalkylene. In some embodiments, the cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

[0079] Unless otherwise specified, "bicyclic ring" refers to a group characterized by two connected rings. Bicyclic rings may be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (ring atoms include, in addition to carbon atoms, one, two, or three heteroatoms, such as, for example, N, O, or S). The two rings may be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include: (a) spirocyclic compounds, in which the two rings share only one single atom (the spiroatom, usually a quaternary carbon); examples of spirocyclic compounds include: [ka] Spirocyclic compounds, including, but not limited to, (b) Fused bicyclic compounds, in which two rings share two adjacent atoms, i.e., the rings share a covalent bond, i.e., the bridgehead atoms are directly bonded (e.g., α-thujene and decalin), examples of fused bicyclic rings include the following: [ka] fused bicyclic compounds, including, but not limited to, (c) Bridged bicyclic compounds, in which two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom, for example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered as a pair of cyclopentane rings each sharing three of the five carbon atoms, examples of bridged bicyclic rings include the following: [ka] Bridged bicyclic compounds, including, but not limited to:

[0080] Unless otherwise specified, "carbocycle" or "carbocyclic", by itself or in combination with other terms, refers to "C α~β It represents a cyclic form of "hydrocarbyl." Examples of carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0081] 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 be found in the claims include the following: [ka] These include, but are not limited to:

[0082] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0083] "Saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogens, substituents that are not saturated at all with hydrogens, and substituents that are partially saturated with hydrogens.

[0084] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked, for example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0085] -N(C0 hydrocarbyl)-C 0~4 When the number of groups is zero, such as hydrocarbyl-, the linker group is -NH-C 0~4 It is meant to be hydrocarbyl-.

[0086] When the number of linker groups is 0, such as -(CH2)0-, it means that the linker group is a chemical bond.

[0087] Unless otherwise indicated, the absolute configuration of a stereocenter is represented by a solid wedge bond. [ka] and wedge-shaped dashed bond [ka] The relative configuration of the stereocenters is represented by a straight solid bond [ka] and straight dashed bond [ka] It is represented by the wavy line. [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0088] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0089] Specific pharmaceutical and medical terms

[0090] The term "acceptable" as used herein means that a formulation component or active ingredient does not have an excessive and deleterious effect on the general health of the treated subject.

[0091] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, can result from or relate to administration.

[0092] "Active ingredient" refers to compounds of general formula (1) and pharma- ceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. Possible asymmetric centers may exist depending on the properties of various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and 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.

[0093] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0094] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0095] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0096] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0097] therapeutic use

[0098] The present invention provides the use of the compound of general formula (1) or the pharmaceutical composition disclosed herein in inhibiting KIF18A protein, and thus in treating one or more disorders related to the activity of KIF18A protein.Thus, in certain embodiments, the present invention provides a method for treating a disorder mediated by KIF18A protein, comprising administering the compound disclosed herein or a pharmacologic composition thereof to a patient in need thereof.

[0099] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1).In some embodiments, the cancer is mediated by KIF18A protein.In other embodiments, the cancer is hematological or solid cancer, including but not limited to hematological malignancies (leukemia, lymphoma, and myeloma, including multiple myeloma, myelodysplastic syndrome, and myeloproliferative familial syndrome), and solid tumors (carcinomas such as prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, renal cancer, ovarian cancer, and soft tissue cancer, osteosarcoma, and stromal tumors).

[0100] Route of administration

[0101] The compound of the present invention and its pharmaceutically acceptable salts can be prepared into various formulations containing a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salts and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious adverse effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0102] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use and have sufficient purity and low toxicity. "Compatibility" means that the components of the composition can be mixed with the compounds of the present invention without significantly reducing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0103] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0105] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0106] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0107] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0108] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0109] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous 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.

[0110] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required as required.

[0111] The compound of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, and the dosage is a pharma- ceutical effective dose. For a 60 kg human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage will take into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0112] The features described in the present invention or the features described above in the embodiments can be combined in any combination. All features disclosed herein can be used in any composition, and the various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise specified, the features disclosed herein are merely generic examples of equivalent or similar features.

[0113] (Detailed Description) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference only and describe specific examples. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0114] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was expressed by volume.

[0115] The following abbreviations are used in the present invention: (Boc)2O is di-tert-butyl dicarbonate; BOPCl is bis(2-oxo-3-oxazolidinyl)phosphinic chloride; CDCl3 is deuterated chloroform; Cs2CO3 is cesium carbonate; CuI is cuprous iodide; EtOAc is ethyl acetate; Hexane is n-hexane; HPLC is high performance liquid chromatography; MeCN is acetonitrile; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIPEA is diisopropylethylamine; 1,4-Dioxane is 1,4-dichloroethane; oxane;DMF is N,N-dimethylformamide;DMAP is 4-(dimethylamino)pyridine;DMSO is dimethylsulfoxide;h is hour;HATU is N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-methylene]-N-methylmethanaminium hexafluorophosphate-N-oxide;IPA is isopropanol;min is minute;K2CO3 is potassium carbonate;KOAc is potassium acetate;K3PO4 is potassium phosphate;LiBH4 is lithium borohydride;min is minute;MeOH is Methanol; MS is mass spectrometry; NMR is nuclear magnetic resonance; Pd / C is palladium on carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); PE is petroleum ether; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenylyl)]palladium(II) methanesulfonate; Sarcosine is sarcosine; TFA is tris(diphenylphosphine)palladium(II) methanesulfonate; Fluoroacetic acid; TMSCl is trimethylchlorosilane; T3P is 1-propanephosphonic anhydride; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; X-Phos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; TLC is thin layer chromatography; XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0116] Example 1: Synthesis of Compound 1

[0117] [ka]

[0118] Step 1: Synthesis of compound int_1-3

[0119] [ka]

[0120] 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 mixture was heated to 80° C. and incubated for 24 h until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (1.2 g, yield: 91.6%). ESI-MS m / z: 258 [M+H] + .

[0121] Step 2: Synthesis of compounds int_1-5

[0122] [ka]

[0123] int_1-4 (15 g, 56.3 mmol) was dissolved in methanol (150 mL) and concentrated sulfuric acid (2.5 mL) was added. The mixture was heated to 80° C. and incubated for 4 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, then saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a white solid (14 g, yield: 89%). This solid was used directly in the next reaction. ESI-MS m / z: 281 [M+H] + .

[0124] Step 3: Synthesis of compounds int_1-7

[0125] [ka]

[0126] 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 and incubated for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography (SiO2, EtOAc:Hexane = 1:1) to obtain the desired product (16.3 g, yield: 88%). ESI-MS m / z: 372 [M+H] + .

[0127] Step 4: Synthesis of compounds int_1-8

[0128] [ka]

[0129] Int_1-7 (16.3 g, 43.9 mmol) was dissolved in a mixture of methanol (100 mL) and water (10 mL), and lithium hydroxide (2.1 g, 87.8 mmol) was added at room temperature. The mixture was stirred at room temperature for 6 hours until LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product (17 g). The crude product was used directly in the next reaction. ESI-MS m / z: 358 [M+H] + .

[0130] Step 5: Synthesis of compounds int_1-9

[0131] [ka]

[0132] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give a solid. This 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 was stirred at 40 °C for 10 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAC=100:1) to give a solid (1.4 g, yield: 76.1%). ESI-MS m / z: 597 [M+H] + .

[0133] Step 6: Synthesis of Compound 1

[0134] [ka]

[0135] 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 mixture was purged with argon three times, and then int_1-9 (1.4 g, 2.347 mmol) was added. Under an argon atmosphere, the reaction was heated to 90 °C and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography (SiO2, EtOAc:Hexane=1:1) to give a solid (1 g, yield: 71.8%). 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 9.0, 2.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 3.74 (t, J = 6.5 Hz, 2H), 3.32 (d, J = 6.5 Hz, 2H), 3.14 (t, J = 5.5 Hz, 4H), 2.95 (t, J = 5.2 Hz, 4H), 2.11 (tq, J = 14.6, 8.9, 7.2 Hz, 4H), 1.50 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 594 [M+H] + .

[0136] Example 2: Synthesis of Compound 2

[0137] [ka]

[0138] Step 1: Synthesis of compound int_2-2

[0139] [ka]

[0140] 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 and incubated for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (300 mg, yield: 99%). ESI-MS m / z: 238 [M+H] + .

[0141] Step 2: Synthesis of compound int_2-3

[0142] [ka]

[0143] 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 was stirred at 80 °C for 10 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (60 mg, yield: 24.6%). ESI-MS m / z: 577 [M+H] + .

[0144] Step 3: Synthesis of compound 2

[0145] [ka]

[0146] 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 mixture was purged with argon three times, and then int_2-3 (60 mg, 0.1 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a solid (20 mg, yield: 34.9%). 1 H NMR (400 MHz, Chloroform-d) δ 12.95 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.35 (s, 1H), 7.22 - 7.16 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.97 - 3.82 (m, 3H), 3.35 (d, J = 5.4 Hz, 2H), 3.16 (t, J = 10.5 Hz, 2H), 3.07 (q, J = 7.6, 6.5 Hz, 4H), 3.04 - 2.96 (m, 1H), 2.70 (t, J = 10.9 Hz, 2H), 1.66 (s, 4H), 1.21 (d, J = 6.2 Hz, 3H), 0.45 (s, 4H). ESI-MS m / z: 574 [M+H] + .

[0147] Example 3: Synthesis of Compound 3

[0148] [ka]

[0149] Step 1: Synthesis of compound int_3-2

[0150] [ka]

[0151] 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 and incubated for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (280 mg, yield: 92%). ESI-MS m / z: 238 [M+H] + .

[0152] Step 2: Synthesis of compound int_3-3

[0153] [ka]

[0154] 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 was stirred at 80 °C for 10 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (119 mg, yield: 48.9%). ESI-MS m / z: 577 [M+H] + .

[0155] Step 3: Synthesis of compound 3

[0156] [ka]

[0157] 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 mixture was purged with argon three times, and then int_3-3 (119 mg, 0.207 mmol) was added. Under an argon atmosphere, the reaction was heated to 90 °C and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a solid (50 mg, yield: 42.3%). 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 9.0, 2.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 3.85 (dd, J = 11.4, 2.6 Hz, 1H), 3.79 - 3.60 (m, 4H), 3.07 (dd, J = 29.4, 12.0 Hz, 2H), 2.95 (t, J = 5.3 Hz, 4H), 2.90 - 2.78 (m, 1H), 2.59 (dd, J = 11.9, 9.8 Hz, 1H), 1.52 (d, J = 4.7 Hz, 4H), 1.10 (d, J = 6.2 Hz, 3H), 0.33 (s, 4H). ESI-MS m / z: 574 [M+H] + .

[0158] Example 4: Synthesis of Compound 4

[0159] [ka]

[0160] Step 1: Synthesis of compound int_4-2

[0161] [ka]

[0162] 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 salt, 310 mg, 2.562 mmol) were added. The mixture was heated to 80 °C and incubated for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (300 mg, yield: 100%). ESI-MS m / z: 230 [M+H] + .

[0163] Step 2: Synthesis of compound int_4-3

[0164] [ka]

[0165] 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 was stirred at 80 °C for 10 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (130 mg, yield: 52.6%). ESI-MS m / z: 569 [M+H] + .

[0166] Step 3: Synthesis of compound 4

[0167] [ka]

[0168] 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 mixture was purged with argon three times, and then int_4-3 (70 mg, 0.123 mmol) was added. Under an argon atmosphere, the reaction was heated to 90 °C and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (54 mg, yield: 77.1%). 1 H NMR (400 MHz, Chloroform-d) δ 12.85 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.69 (s, 1H), 7.34 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.84 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 11.9 Hz, 4H), 4.16 (s, 2H), 3.34 (t, J = 5.3 Hz, 2H), 3.08 (t, J = 5.3 Hz, 4H), 1.63 (s, 4H), 0.45 (s, 4H). ESI-MS m / z: 566 [M+H] + .

[0169] Example 5: Synthesis of Compound 6

[0170] [ka]

[0171] Step 1: Synthesis of compound int_6-2

[0172] [ka]

[0173] 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 salt, 171 mg, 1.281 mmol) were added. The mixture was heated to 80 °C and incubated for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (290 mg, yield: 97.0%). ESI-MS m / z: 234 [M+H] + .

[0174] Step 2: Synthesis of compound int_6-3

[0175] [ka]

[0176] 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 was stirred at 80 °C for 16 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (70 mg, yield: 43.8%). ESI-MS m / z: 573 [M+H]+ .

[0177] Step 3: Synthesis of compound 6

[0178] [ka]

[0179] 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 mixture was purged with argon three times, and then int_6-3 (70 mg, 0.122 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (45 mg, yield: 64.7%). 1 H NMR (400 MHz, Chloroform-d) δ 12.71 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.90 - 7.76 (m, 2H), 7.33 (s, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.85 - 6.71 (m, 1H), 4.14 (t, J = 5.0 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 5.1 Hz, 2H), 3.16 (s, 2H), 3.07 (d, J = 5.5 Hz, 4H), 1.90 (t, J = 6.7 Hz, 2H), 1.65 (s, 4H), 0.62 (d, J = 5.3 Hz, 4H), 0.43 (s, 4H). ESI-MS m / z: 570 [M+H] + .

[0180] Example 6: Synthesis of Compound 7

[0181] [ka]

[0182] Step 1: Synthesis of compound int_7-2

[0183] [ka]

[0184] int_7-1 (372 mg, 5.17 mmol) was dissolved in DMF (30 mL) and NaH (820 mg, 20.5 mmol, 60% purity) was added at 0° C. under nitrogen atmosphere. The reaction was incubated at 0° C. for 1 h under nitrogen atmosphere, and then int_1-1 (400 mg, 2.564 mmol) was added. The mixture was heated to 80° C. and incubated for 24 h until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (170 mg, yield: 32%). ESI-MS m / z: 209 [M+H] + .

[0185] Step 2: Synthesis of compound int_7-3

[0186] [ka]

[0187] int_1-8 (129 mg, 0.361 mmol) was dissolved in DCM (2 mL) and oxalyl chloride (1 mL) 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. int_7-2 (50 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (100 mg) was slowly added under ice bath. The reaction solution was incubated at room temperature for 1 hour and the prepared acyl chloride product was added to the reaction solution. The reaction solution was incubated at 40 °C for 5 hours until LC-MS showed the reaction was complete. The reaction solution was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled 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%). ESI-MS m / z: 548 [M+H] + .

[0188] Step 3: Synthesis of compound 7

[0189] [ka]

[0190] 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 mixture was purged with argon three times, and then int_7-3 (77 mg, 0.14 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (44 mg, yield: 57%). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 9.1, 2.1 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.1 Hz, 1H), 4.79 (t, J = 7.2 Hz, 1H), 3.74 (t, J = 6.6 Hz, 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 = 5.0 Hz, 4H), 0.32 (s, 4H). ESI-MS m / z: 545 [M+H] + .

[0191] Example 7: Synthesis of Compound 65

[0192]

change

[0193] ステップ1:Synthesis of compound int_65-2

[0194]

change

[0195] Int_1-8 (100 mg, 0.279 mmol) was dissolved in DCM (8 mL) and oxalyl chloride (1 mL) was added. The reaction was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product. Int_65-1 (72 mg, 0.279 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (60 mg) was slowly added under ice bath. The reaction was incubated at room temperature for 1 h and the prepared acyl chloride product was added to the reaction. The reaction was incubated at 40° C. for 12 h until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled 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%). ESI-MS m / z: 598 [M+H] + .

[0196] Step 2: Synthesis of compound 65

[0197] [ka]

[0198] 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 mixture was purged with argon three times, and then int_65-2 (130 mg, 0.217 mmol) was added. The reaction was heated to 90° C. under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (10 mg, yield: 7.7%). 1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.50 (t, J = 5.7 Hz, 4H), 3.33 (s, 2H), 2.99 (t, J = 5.2 Hz, 4H), 2.12 (d, J = 8.1 Hz, 4H), 1.86 - 1.48 (m, 4H), 0.40 (s, 4H). ESI-MS m / z: 595 [M+H] + .

[0199] Example 8: Synthesis of Compound 97

[0200]

change

[0201] ステップ1:Synthesis of compound int_97-2

[0202]

change

[0203] int_97-1 (100 mg, 0.375 mmol) was dissolved in DCM (8 mL) and oxalyl chloride (1 mL) was added. The reaction was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product. int_1-3 (96 mg, 0.375 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (60 mg) was slowly added under ice bath. The reaction was incubated at room temperature for 1 hour and the prepared acyl chloride product was added to the reaction. The reaction was incubated at 40° C. for 12 hours until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled 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%). ESI-MS m / z: 506 [M+H] + .

[0204] Step 2: Synthesis of compound 97

[0205] [ka]

[0206] 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) and the mixture was purged with argon three times. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (10 mg, yield: 6.7%). 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.99 (d, J = 9.2 Hz, 2H), 7.72 (s, 1H), 7.41 (d, J = 8.8 Hz, 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). ESI-MS m / z: 595 [M+H] + .

[0207] Example 9: Synthesis of Compound 129

[0208]

change

[0209] ステップ1:Synthesis of compound int_129-1

[0210]

change

[0211] int_97-1 (100 mg, 0.375 mmol) was dissolved in DCM (8 mL) and oxalyl chloride (1 mL) was added. The reaction was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product. int_65-1 (96 mg, 0.375 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (60 mg) was added slowly under ice bath. The reaction was incubated at room temperature for 1 hour and the prepared acyl chloride product was added to the reaction. The reaction was incubated at 40° C. for 12 hours until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled 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%). ESI-MS m / z: 507 [M+H] + .

[0212] Step 2: Synthesis of compound 129

[0213] [ka]

[0214] 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) and the mixture was purged with argon three times. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (20 mg, yield: 12.2%). 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.57 (s, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 6.33 (s, 1H), 4.80 (s, 1H), 3.65 (t, J = 7.0 Hz, 2H), 3.48 (t, J = 5.7 Hz, 4H), 3.17 - 3.12 (m, 2H), 2.93 (t, J = 5.2 Hz, 4H), 2.08 (d, J = 14.6 Hz, 4H), 1.65 (s, 4H), 0.35 (s, 4H). ESI-MS m / z: 596 [M+H] + .

[0215] Example 10: Synthesis of Compound 161

[0216] [ka]

[0217] Step 1: Synthesis of compound int_161-3

[0218] [ka]

[0219] 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 was stirred at 60° C. for 4 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (150 mg, yield: 78%). ESI-MS m / z: 550 [M+H] + .

[0220] Step 2: Synthesis of compound 161

[0221] [ka]

[0222] 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 mixture was purged with argon three times, and then int_161-3 (70 mg, 0.127 mmol) was added. The reaction was heated to 130 °C in a microwave under argon atmosphere and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (22 mg, 19% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 3.74 (t, J = 6.7 Hz, 2H), 3.64 (t, J = 5.8 Hz, 4H), 3.21 (t, J = 6.7 Hz, 2H), 2.83 (t, J = 5.3 Hz, 4H), 2.25 - 2.13 (m, 4H), 1.53 (s, 4H), 0.37 (s, 4H). ESI-MS m / z: 595 [M+H] + .

[0223] Example 11: Synthesis of Compound 257

[0224] [ka]

[0225] Step 1: Synthesis of compound int_257-2

[0226] [ka]

[0227] int_257-1 (25 g, 107 mmol) was dissolved in dioxane (400 mL) and int_1-2 (20 g, 161 mmol), Pd2(dba)3 (5 g, 5.4 mmol), xantphos (3 g, 5.4 mmol), and Cs2CO3 (104 g, 321 mmol) were added. Under nitrogen atmosphere, the mixture was heated to 100 °C and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to obtain the desired product (5.5 g, yield: 19%). ESI-MS m / z: 274 [M+H] + .

[0228] Step 2: Synthesis of compound int_257-3

[0229] [ka]

[0230] 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 was purged with hydrogen three times. The reaction was incubated at 60° C. for 16 h under hydrogen atmosphere until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (4.2 g, yield: 86%). The crude product was used directly in the next reaction. ESI-MS m / z: 244 [M+H] + .

[0231] Step 3: Synthesis of compound int_257-4

[0232] [ka]

[0233] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0234] int_257-3 (0.7 g, 3.4 mmol) was dissolved in tetrahydrofuran (40 mL) and NaH (720 mg, 18 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (1.2 g, yield: 71%). ESI-MS m / z: 583 [M+H] + .

[0235] Step 4: Synthesis of compound 257

[0236] [ka]

[0237] 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 mixture was purged with argon three times, and then int_1-10 (0.43 g, 3.4 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography (SiO2, n-hexane / ethyl acetate = 1:1) to give a solid (0.77 g, yield: 77%). 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.16 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.6, 2.1 Hz, 1H), 4.93 (s, 1H), 3.81 (s, 3H), 3.76 (t, J = 6.5 Hz, 2H), 3.52 (t, J = 5.6 Hz, 4H), 3.35 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 5.4 Hz, 4H), 2.09 (td, J = 14.1, 6.7 Hz, 4H), 1.72 (s, 4H), 0.38 (s, 4H). ESI-MS m / z: 580 [M+H] + .

[0238] Example 12: Synthesis of Compound 258

[0239] [ka]

[0240] Step 1: Synthesis of compound int_258-1

[0241] [ka]

[0242] 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. Under nitrogen atmosphere, the mixture was heated to 100 °C and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to obtain the desired product (780 mg, yield: 71.8%). ESI-MS m / z: 254 [M+H] + .

[0243] Step 2: Synthesis of compound int_258-2

[0244] [ka]

[0245] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (550 mg, yield: 80%). The crude product was used directly in the next reaction. ESI-MS m / z: 224 [M+H] + .

[0246] Step 3: Synthesis of compound int_258-3

[0247] [ka]

[0248] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0249] int_258-2 (120 mg, 0.532 mmol) was dissolved in tetrahydrofuran (10 mL), and NaH (72 mg, 1.8 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (250 mg, yield: 82.7%). ESI-MS m / z: 563 [M+H] + .

[0250] Step 4: Synthesis of compound 258

[0251] [ka]

[0252] 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 mixture was purged with argon three times, and then int_1-10 (111 mg, 0.888 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (150 mg, yield: 60.4%). 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.6, 2.1 Hz, 1H), 3.86 - 3.72 (m, 6H), 3.65 (td, J = 11.7, 3.0 Hz, 2H), 2.95 (d, J = 5.4 Hz, 4H), 2.76 (td, J = 12.3, 3.3 Hz, 1H), 2.51 (d, J = 12.9 Hz, 2H), 1.71 (s, 4H), 1.12 (d, J = 6.2 Hz, 3H), 0.36 (s, 4H). ESI-MS m / z: 560 [M+H] + .

[0253] Example 13: Synthesis of Compound 259

[0254] [ka]

[0255] Step 1: Synthesis of compound int_259-1

[0256] [ka]

[0257] 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. Under nitrogen atmosphere, the mixture was heated to 100 °C and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to obtain the desired product (750 mg, yield: 69.4%). ESI-MS m / z: 254 [M+H] + .

[0258] Step 2: Synthesis of compound int_259-2

[0259] [ka]

[0260] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (560 mg, yield: 84.7%). The crude product was used directly in the next reaction. ESI-MS m / z: 224 [M+H] + .

[0261] Step 3: Synthesis of compound int_259-3

[0262] [ka]

[0263] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0264] int_259-2 (200 mg, 0.893 mmol) was dissolved in tetrahydrofuran (10 mL), and NaH (170 mg, 4.465 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (340 mg, yield: 67.7%). ESI-MS m / z: 563 [M+H] + .

[0265] Step 4: Synthesis of compound 259

[0266] [ka]

[0267] 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 mixture was purged with argon three times, and then int_1-10 (151 mg, 1.210 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (150 mg, yield: 44.4%). ESI-MS m / z: 560 [M+H] + .

[0268] Example 14: Synthesis of Compound 260

[0269] [ka]

[0270] Step 1: Synthesis of compound int_260-1

[0271] [ka]

[0272] 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 mixture was heated to 100 °C under nitrogen atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the 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, filtered, and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (80 mg, yield: 36.7%). ESI-MS m / z: 246 [M+H] + .

[0273] Step 2: Synthesis of compound int_260-2

[0274] [ka]

[0275] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (60 mg, yield: 89.5%). The crude product was used directly in the next reaction. ESI-MS m / z: 216 [M+H] + .

[0276] Step 3: Synthesis of compound int_260-3

[0277] [ka]

[0278] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0279] int_260-2 (60 mg, 0.279 mmol) was dissolved in tetrahydrofuran (5 mL), and NaH (100 mg, 4.166 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (80 mg, yield: 51.9%). ESI-MS m / z: 555 [M+H] + .

[0280] Step 4: Synthesis of compound 260

[0281] [ka]

[0282] 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 mixture was purged with argon three times, and then int_1-10 (36 mg, 0.289 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (40 mg, yield: 50.6%). 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.6, 2.1 Hz, 1H), 4.40 (t, J = 12.6 Hz, 4H), 3.74 (d, J = 3.4 Hz, 5H), 3.33 (m, 2H), 2.94 (t, J = 5.5 Hz, 4H), 1.94-1.58 (m, 4H), 0.37 (s, 4H). ESI-MS m / z: 552 [M+H] + .

[0283] Example 15: Synthesis of Compound 261

[0284] [ka]

[0285] Step 1: Synthesis of compound int_261-2

[0286] [ka]

[0287] int_261-1 (300 mg, 2.618 mmol) was dissolved in DMF (30 mL) and NaH (208 mg, 5.2 mmol, 60% purity) was added at 0° C. under nitrogen atmosphere. The reaction solution was reacted at 0° C. for 1 h under nitrogen atmosphere, and then int_257-1 (610 mg, 2.618 mmol) was added. The mixture was heated to 80° C. and incubated for 24 h until LC-MS showed the reaction was complete. The reaction solution was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (500 mg, yield: 71.8%). ESI-MS m / z: 267 [M+H] + .

[0288] Step 2: Synthesis of compound int_261-3

[0289] [ka]

[0290] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (410 mg, yield: 92.3%). The crude product was used directly in the next reaction. ESI-MS m / z: 237 [M+H] + .

[0291] Step 3: Synthesis of compound int_261-4

[0292] [ka]

[0293] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0294] int_261-3 (450 mg, 1.910 mmol) was dissolved in tetrahydrofuran (10 mL), and NaH (366 mg, 9.550 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (500 mg, yield: 45.9%). ESI-MS m / z: 576 [M+H] + .

[0295] Step 4: Synthesis of compound 261

[0296] [ka]

[0297] 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 mixture was purged with argon three times, and then int_1-10 (44 mg, 0.348 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (25 mg, yield: 25.3%). 1H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.40-7.27 (m, 2H), 7.14 (dd, J = 8.6, 2.2 Hz, 1H), 4.58 (t, J = 6.3 Hz, 2H), 3.94 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.36 (t, J = 6.2 Hz, 2H), 3.07 (t, J = 5.3 Hz, 4H), 2.75 (qt, J = 10.9, 6.3 Hz, 2H), 1.79 (s, 4H), 0.42 (s, 4H). ESI-MS m / z: 573 [M+H] + .

[0298] Example 16: Synthesis of Compound 262

[0299]

change

[0300] ステップ1:Synthesis of compound int_262-1

[0301]

change

[0302] 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 mixture was heated to 100 °C under nitrogen atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (320 mg, yield: 68.6%). ESI-MS m / z: 250 [M+H] + .

[0303] Step 2: Synthesis of compound int_262-2

[0304] [ka]

[0305] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (165 mg, yield: 57.8%). The crude product was used directly in the next reaction. ESI-MS m / z: 220 [M+H] + .

[0306] Step 3: Synthesis of compound int_262-3

[0307] [ka]

[0308] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product. int_262-2 (165 mg, 0.752 mmol) was dissolved in tetrahydrofuran (5 mL), and NaH (150 mg, 3.76 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=5:1) to obtain a solid (170 mg, yield: 40.4%). ESI-MS m / z: 559 [M+H] + .

[0309] Step 4: Synthesis of compound 262

[0310] [ka]

[0311] 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 mixture was purged with argon three times, and then int_1-10 (76 mg, 0.608 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (120 mg, yield: 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.6, 2.1 Hz, 1H), 3.74 (dt, J = 7.0, 3.6 Hz, 4H), 3.70 (s, 3H), 3.47 (s, 2H), 2.93 (d, J = 5.2 Hz, 4H), 1.79 (s, 6H), 0.57 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 556 [M+H] + .

[0312] Example 17: Synthesis of Compound 263

[0313]

change

[0314] ステップ1:Synthesis of compound int_263-1

[0315]

change

[0316] int_7-1 (460 mg, 1.974 mmol) was dissolved in DMF (20 mL) and NaH (510 mg, 3.948 mmol, 60% purity) was added at 0° C. under nitrogen atmosphere. The reaction was incubated at 0° C. for 1 h under nitrogen atmosphere, and then int_257-1 (1.5 g, 1.974 mmol) was added. The mixture was heated to 80° C. and incubated for 24 h until LC-MS showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (300 mg, yield: 67.9%). ESI-MS m / z: 225 [M+H] + .

[0317] Step 2: Synthesis of compound int_263-2

[0318] [ka]

[0319] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 12 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (255 mg, yield: 98%). The crude product was used directly in the next reaction. ESI-MS m / z: 195 [M+H] + .

[0320] Step 3: Synthesis of compound int_262-3

[0321] [ka]

[0322] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0323] int_263-2 (300 mg, 1.546 mmol) was dissolved in tetrahydrofuran (10 mL), and NaH (180 mg, 4.5 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction 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%). ESI-MS m / z: 534 [M+H] + .

[0324] Step 4: Synthesis of compound 263

[0325] [ka]

[0326] 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 mixture was purged with argon three times, and then int_1-10 (70 mg, 0.562 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (55 mg, yield: 36.9%). 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.6, 2.1 Hz, 1H), 5.31-5.19 (m, 1H), 3.74 (d, J = 4.5 Hz, 5H), 2.96 (t, J = 5.3 Hz, 4H), 2.48-2.39 (m, 2H), 2.08 (dtd, J = 12.5, 10.0, 8.0 Hz, 2H), 1.80-1.53 ​​(m, 6H), 0.41 (s, 4H). ESI-MS m / z: 531 [M+H] + .

[0327] Example 18: Synthesis of Compound 273

[0328]

change

[0329] ステップ1:Synthesis of compound int_273-2

[0330]

change

[0331] 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 incubated at room temperature for 24 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 30:1) to obtain the desired product (6.9 g, yield: 99%). ESI-MS m / z: 309 [M+H] + .

[0332] Step 2: Synthesis of compound int_273-3

[0333] [ka]

[0334] 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 salt, 4.8 g, 32.5 mmol) were added. The mixture was heated to 100 °C and incubated for 16 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 30:1) to obtain the desired product (6.1 g, yield: 92%). ESI-MS m / z: 400 [M+H] + .

[0335] Step 3: Synthesis of compound int_273-5

[0336] [ka]

[0337] int_273-3 (6.1 g, 15.3 mmol) was dissolved in dioxane (40 mL) and benzyl mercaptan (5.7 g, 45.9 mmol), Pd2(dba)3 (2 g, 2.2 mmol), xantphos (2 g, 3.6 mmol) and DIPEA (7.9 g, 61.2 mmol) were added. The mixture was heated to 100 °C under nitrogen atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction 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, filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain the desired product (6.7 g, yield: 97%). ESI-MS m / z: 444 [M+H] + .

[0338] Step 4: Synthesis of compound int_273-6

[0339] [ka]

[0340] int_273-5 (16.3 g, 43.9 mmol) was dissolved in a mixed solvent of acetonitrile / water / acetic acid (40 mL / 1 mL / 0.5 mL) and dichlorohydantoin (3.4 g, 17.3 mmol) was added under ice bath. The mixture was stirred at 0° C. under nitrogen atmosphere and reacted for 0.5 h until LC-MS showed the reaction was complete. The reaction solution was diluted with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product. The crude product was dissolved in a mixed solution of acetonitrile and tetrahydrofuran (30 mL / 10 mL) and glycine methyl ester hydrochloride (5.4 g, 43 mmol) and potassium carbonate (12 g, 87 mmol) were added. The mixture was stirred at room temperature for 1 h until LC-MS showed 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 3:1) to obtain the desired product (3.2 g, yield: 80%). ESI-MS m / z: 473 [M+H] + .

[0341] Step 5: Synthesis of compound int_273-7

[0342] [ka]

[0343] 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 was purged with hydrogen three times. The reaction was incubated at 50° C. for 16 h under hydrogen atmosphere until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (2.5 g, yield: 96%). The crude product was used directly in the next reaction. ESI-MS m / z: 383 [M+H] + .

[0344] Step 6: Synthesis of compound int_273-8

[0345] [ka]

[0346] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent to give 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 added slowly under ice bath. The mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction 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, filtered and distilled under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the desired product (250 mg, yield: 31%). 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.36 (s, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 7.82-7.75 (m, 2H), 7.66 (dd, J = 8.2, 1.7 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 2H), 3.52 (d, J = 6.3 Hz, 4H), 3.49 (s, 3H), 3.39 (d, J = 6.7 Hz, 2H), 3.03 (t, J = 5.4 Hz, 4H), 2.06 (t, J = 5.1 Hz, 2H), 1.70 (s, 4H), 0.36 (s, 4H). ESI-MS m / z: 608 [M+H] + .

[0347] Step 7: Synthesis of compound 273

[0348] [ka]

[0349] int_273-8 (230 mg, 0.38 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (5 mL / 5 mL), and sodium borohydride (43 mg, 1.1 mmol) and lithium chloride (48 mg, 1.1 mmol) were added slowly under ice bath. The reaction was incubated at room temperature for 3 hours until LC-MS showed the reaction was complete. The reaction was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (210 mg, yield: 95%). 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 7.79 (dd, J = 5.1, 3.4 Hz, 2H), 7.67 (dd, J = 8.2, 1.7 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 4.73 (s, 1H), 3.80 (s, 3H), 3.51 (t, J = 5.7 Hz, 4H), 3.42-3.36 (m, 2H), 3.03 (t, J = 5.3 Hz, 4H), 2.81 (t, J = 6.2 Hz, 2H), 2.05 (q, J = 11.2, 8.5 Hz, 4H), 1.70 (m, 4H), 0.36 (s, 4H). ESI-MS m / z: 580 [M+H] + .

[0350] Example 19: Synthesis of Compound 321

[0351] [ka]

[0352] Step 1: Synthesis of compound int_321-2

[0353] [ka]

[0354] 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 incubated at 100 °C for 3 h under argon atmosphere until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product (1.5 g, yield: 100%). ESI-MS m / z: 311 [M+H] + .

[0355] Step 2: Synthesis of compound int_321-3

[0356] [ka]

[0357] int_321-2 (1.5 g, 4.82 mmol) was dissolved in methanol (50 mL) and 20 mL of acetic acid was added. The mixture was stirred under ice bath for 10 min, and zinc powder (1.5 g, 24.10 mmol) was added in small portions. The reaction was warmed to room temperature and incubated for 1 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. 100 mL of water was added to the crude product, and the aqueous phase was extracted with dichloromethane (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product (1 g, yield: 77%). ESI-MS m / z: 281 [M+H] + .

[0358] Step 3: Synthesis of compound int_321-5

[0359] [ka]

[0360] int_321-4 (5 g, 21.55 mmol) was suspended in methanol (100 mL) and trimethylchlorosilane (7 g, 64.65 mmol) was added. The reaction was allowed to react at room temperature for 4 h and gradually clarified until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (5.2 g, yield: 98%). ESI-MS m / z: 246 [M+H] + .

[0361] Step 4: Synthesis of compound int_321-6

[0362] [ka]

[0363] int_321-5 (5 g, 16.2 mmol) was dissolved in 1,4-dioxane (100 mL) and cesium carbonate (20 g, 63.4 mmol), Pd2(dba)3 (1.9 g, 2.11 mmol), and Xantphos (1.2 g, 2.11 mmol) were added. Under an argon atmosphere, the mixture was heated to 100 °C and incubated for 18 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 10:1) to obtain the desired product (4.3 g, yield: 71%). ESI-MS m / z: 287 [M+H] + .

[0364] Step 5: Synthesis of compound int_321-7

[0365] [ka]

[0366] int_273-6 (4.3 g, 15.02 mmol) was dissolved in methanol (50 mL) and NaOH (2 M, 20 mL) was added with stirring at room temperature. The reaction was incubated at room temperature for 4 hours until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a solid. Water (100 mL) was added to the solid. The aqueous phase was extracted with dichloromethane (50 mL x 2) and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (2 g, yield: 58%). ESI-MS m / z: 273 [M+H] + .

[0367] Step 6: Synthesis of compound int_321-8

[0368] [ka]

[0369] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product. int_321-3 (2.1 g, 7.37 mmol) was dissolved in tetrahydrofuran (50 mL) and sodium hydride (2.9 g, 73.7 mmol, 60% purity) was slowly added under ice bath. The reaction was reacted at room temperature for 1 h and the prepared acyl chloride product was added to the reaction. The reaction was incubated at 40 °C for 5 h until LC-MS showed the reaction was complete. The reaction was diluted with water (100 mL) and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to obtain the desired product (3.7 g, yield: 95%). ESI-MS m / z: 535 [M+H] + .

[0370] Step 7: Synthesis of compound 321

[0371] [ka]

[0372] 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 mixture was purged with argon three times before int_1-10 (266 mg, 1.87 mmol) was added. The reaction was heated to 130 °C in a microwave under argon atmosphere and incubated for 3.5 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (260 mg, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.39 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.7, 2.4 Hz, 1H), 3.90 (s, 3H), 3.71 (t, J = 6.7 Hz, 2H), 3.56 (t, J = 5.5 Hz, 4H), 3.18 (t, J = 6.7 Hz, 2H), 2.78 (t, J = 5.3 Hz, 4H), 2.13 (tt, J = 13.7, 5.6 Hz, 4H), 1.52 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 580 [M+H] + .

[0373] Example 20: Synthesis of compound 337

[0374]

change

[0375] ステップ1:Synthesis of compound int_337-1

[0376]

change

[0377] 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 mixture was heated to 100 °C under nitrogen atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction 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, filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (1.7 g, yield: 74.9%). ESI-MS m / z: 355 [M+H] + .

[0378] Step 2: Synthesis of compound int_337-2

[0379] [ka]

[0380] int_337-1 (360 mg, 1.02 mmol) was dissolved in a mixed solvent of acetonitrile / water / acetic acid (30 mL / 1 mL / 1 mL), and dichlorohydantoin (402 mg, 2.04 mmol) was added under ice bath. The mixture was stirred at 0° C. under nitrogen atmosphere and reacted for 0.5 h until LC-MS showed the reaction was complete. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was dissolved in a mixed solution of acetonitrile and tetrahydrofuran (30 mL / 10 mL), and glycine methyl ester hydrochloride (1 g, 7.96 mmol) and potassium carbonate (3.3 g, 24 mmol) were added. The mixture was stirred at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product, which was subjected to column chromatography to obtain the desired product (100 mg, yield: 25.6%). ESI-MS m / z: 384 [M+H] + .

[0381] Step 3: Synthesis of compound int_337-3

[0382] [ka]

[0383] 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 was purged with hydrogen three times. The reaction was incubated at room temperature under hydrogen atmosphere for 16 hours until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product (90 mg, yield: 97.8%). The crude product was used directly in the next reaction. ESI-MS m / z: 354 [M+H] + .

[0384] Step 4: Synthesis of compound int_337-4

[0385] [ka]

[0386] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent to obtain the acyl chloride product. int_337-3 (140 mg, 0.396 mmol) was dissolved in tetrahydrofuran (10 mL) and sodium hydride (56 mg, 1.4 mmol, 60% purity) was slowly added under ice bath. The reaction was incubated at room temperature for 1 h to react, and then the prepared acyl chloride product was added to the reaction. The reaction was incubated at 40 °C for 5 h to react until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled 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%). ESI-MS m / z: 608 [M+H] + .

[0387] Step 5: Synthesis of compound 337

[0388] [ka]

[0389] int_337-4 (100 mg, 0.165 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (5 mL / 5 mL), and sodium borohydride (38 mg, 1 mmol) and lithium chloride (42 mg, 1 mmol) were added slowly under ice bath. The reaction was incubated at room temperature for 3 hours until LC-MS showed the reaction was complete. The reaction was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (82 mg, yield: 85.8%). 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.69 (d, J = 6.5 Hz, 1H), 3.91 (s, 3H), 3.58 (d, J = 6.5 Hz, 4H), 2.81 (dt, J = 37.8, 5.6 Hz, 6H), 2.15 (d, J = 7.6 Hz,4H), 1.55 (s, 4H), 0.35 (s, 4H). ESI-MS m / z: 580 [M+H] + .

[0390] Example 21: Synthesis of Compound 353

[0391] [ka]

[0392] Step 1: Synthesis of compound int_353-2

[0393] [ka]

[0394] 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 solution was stirred at room temperature for 2 hours, then concentrated under reduced pressure to remove the solvent and obtain the acyl chloride product. int_353-1 (44 mg, 0.185 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (50 mg, 1.25 mmol, 60% purity) was slowly added under ice bath. The reaction solution was incubated at room temperature for 1 hour, and the prepared acyl chloride product was added to the reaction solution. The reaction solution was incubated at room temperature for 5 hours until LC-MS showed the reaction was complete. The reaction solution 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, filtered, and distilled 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%). ESI-MS m / z: 492 [M+H] + .

[0395] Step 2: Synthesis of compound 353

[0396] [ka]

[0397] 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 mixture was purged with argon three times, and then int_1-10 (97.2 mg, 0.78 mmol) was added. The reaction was heated to 110° C. under argon atmosphere and incubated for 12 hours until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (56 mg, yield: 27%). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.66 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 6.35 (s, 1H), 3.89 (s, 3H), 3.64 (t, J = 6.6 Hz, 2H), 3.54 (d, J = 3.1 Hz, 4H), 3.09 (t, J = 6.6 Hz, 2H), 2.78 (d, J = 5.5 Hz, 4H), 2.19-2.03 (m, 4H), 1.47 (s, 4H), 0.30 (s, 4H). ESI-MS m / z: 581 [M+H] + .

[0398] Example 22: Synthesis of Compound 369

[0399]

change

[0400] ステップ1:Synthesis of compound int_369-2

[0401]

change

[0402] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and 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 ice bath. The reaction was incubated at 40 °C for 12 h until LC-MS showed the reaction was complete. The reaction 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, filtered, and distilled 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.38 (s, 1H), 8.29 (t, J = 6.1 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.85 (d, J = 5.8 Hz, 2H), 3.56 (d, J = 11.2 Hz, 6H), 3.31 (s, 2H), 2.99 (t, J = 5.2 Hz, 3H), 2.21-1.95 (m, 4H), 1.53 (t, J = 5.3 Hz, 4H), 0.34 (s, 4H). ESI-MS m / z: 609 [M+H] + .

[0403] Step 2: Synthesis of compound 369

[0404] [ka]

[0405] int_369-2 (70 mg, 0.115 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (5 mL / 5 mL), and sodium borohydride (38 mg, 1 mmol) and lithium chloride (42 mg, 1 mmol) were added slowly under ice bath. The reaction was incubated at room temperature for 3 hours until LC-MS showed the reaction was complete. The reaction was diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (9 mg, yield: 12.9%). 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.40 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 9.2 Hz, 2H), 7.50 (d, J = 8.3 Hz, 1H), 4.63 (t, J = 5.6 Hz,1H), 3.92 (s, 3H), 3.57 (t, J = 5.6 Hz, 4H), 3.44-3.34 (m, 2H), 2.97 (dt, J = 26.4, 6.1 Hz, 6H), 2.27-2.04 (m, 4H), 1.53 (t, J = 5.2 Hz, 4H), 0.34 (s, 4H). ESI-MS m / z: 581 [M+H] + .

[0406] Example 23: Synthesis of Compound 385

[0407] [ka]

[0408] Step 1: Synthesis of compound int_385-2

[0409] [ka]

[0410] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0411] int_385-1 (70 mg, 0.28 mmol) was dissolved in tetrahydrofuran (40 mL), and NaH (67 mg, 1.68 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=8:1) to obtain a solid (140 mg, yield: 87%). ESI-MS m / z: 600 [M+H] + .

[0412] Step 2: Synthesis of compound 385

[0413] [ka]

[0414] 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 mixture was purged with argon three times, and then int_1-10 (58 mg, 0.46 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (77 mg, yield: 56.2%). 1H NMR (400 MHz, Chloroform-d) δ 12.45 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.75-7.70 (m, 1H), 7.33 (s, 1H), 7.20-7.16 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02 (t, J = 9.3 Hz, 1H), 5.80 (s, 1H), 5.66 (s, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.37-3.29 (m, 2H), 3.23 (t, J = 5.6 Hz, 4H), 3.07 (s, 4H), 2.14 (tt, J = 13.1, 5.4 Hz, 4H), 1.62 (s, 4H), 0.43 (s, 4H). ESI-MS m / z: 597 [M+H] + .

[0415] Example 24: Synthesis of Compound 577

[0416] [ka]

[0417] Step 1: Synthesis of compound int_577-2

[0418] [ka]

[0419] int_1-8 (138 mg, 0.387 mmol) was dissolved in DCM (50 mL) and int_577-1 (100 mg, 0.387 mmol), HATU (294 mg, 0.774 mmol) and DIPEA (193.8 mg, 1.5 mmol) in DMF (10 mL) were added. The reaction was warmed to 60° C. under nitrogen atmosphere and stirred for 2 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (130 mg, yield: 56%). ESI-MS m / z: 598 [M+H] + .

[0420] Step 2: Synthesis of compound 577

[0421] [ka]

[0422] 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 mixture was purged with argon three times, and then int_1-10 (54 mg, 0.435 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (80 mg, yield: 62%). 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.5, 2.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.5, 2.0 Hz, 1H), 3.74 (t, J = 6.5 Hz, 2H), 3.27 (d, J = 6.6 Hz, 2H), 3.01 (t, J = 5.6 Hz, 4H), 2.94 (t, J = 5.3 Hz, 4H), 2.39 (s, 3H), 2.10 (dt, J = 14.3, 7.9 Hz, 4H), 1.53 (s, 4H), 0.34 (s, 4H). ESI-MS m / z: 595 [M+H] + .

[0423] Example 25: Synthesis of Compound 641

[0424] [ka]

[0425] Step 1: Synthesis of compound int_641-2

[0426] [ka]

[0427] int_1-8 (100 mg, 0.29 mmol) was dissolved in DCM (50 mL) and int_641-1 (100 mg, 0.29 mmol), HATU (220 mg, 0.585 mmol) and DIPEA (193.8 mg, 1.5 mmol) in DMF (8 mL) were added. The reaction was stirred at room temperature under nitrogen atmosphere for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (110 mg, yield: 55.2%). ESI-MS m / z: 681 [M+H] + .

[0428] Step 2: Synthesis of compound int_641-3

[0429] [ka]

[0430] 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 mixture was purged with argon three times before int_1-10 (60 mg, 0.47 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a solid (110 mg, yield: 69.1%). ESI-MS m / z: 678 [M+H] + .

[0431] Step 3: Synthesis of compound 641

[0432] [ka]

[0433] int_641-3 (110 mg, 0.162 mmol) was dissolved in methanol / hydrochloric acid (4N, 15 mL) and the reaction was incubated at room temperature for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated on a rotary evaporator and purified by column chromatography to give a solid (60 mg, yield: 64.5%). 1H NMR (400 MHz, Chloroform-d) δ 12.26 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J = 3.0 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 4.09 (t, J = 5.1 Hz, 2H), 3.30 (t, J = 5.1 Hz, 2H), 3.07-2.98 (m, 8H), 2.87 (s, 3H), 2.12 (ddt, J = 16.7, 11.5, 5.6 Hz, 4H), 1.62 (s, 4H), 0.40 (s, 4H). ESI-MS m / z: 578 [M+H] + .

[0434] Example 26: Synthesis of Compound 643

[0435] [ka]

[0436] Step 1: Synthesis of compound int_643-2

[0437] [ka]

[0438] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0439] int_643-1 (800 mg, 3.3 mmol) was dissolved in tetrahydrofuran (50 mL) and triethylamine (666 mg, 6.6 mmol) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was stirred at room temperature for 6 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=7:1) to obtain a solid (1.1 g, yield: 57.8%). ESI-MS m / z: 682 [M+H] + .

[0440] Step 2: Synthesis of compound int_643-3

[0441] [ka]

[0442] 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 xantphos (27 mg, 0.056 mmol) were dissolved in 1,4-dioxane (40 mL) and int_1-10 (473 mg, 3.78 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (550 mg, yield: 50.45%). ESI-MS m / z: 679 [M+H] + .

[0443] Step 3: Synthesis of compound 643

[0444] [ka]

[0445] Int_643-3 (100 mg, 0.147 mmol) was dissolved in methanol / hydrochloric acid (4N, 15 mL) and the reaction was allowed to react at room temperature for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated on a rotary evaporator and purified by column chromatography to give a solid (57 mg, yield: 67%). 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.6, 2.1 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.98 (q, J = 5.2 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 3.12 (t, J = 5.7 Hz, 4H), 2.94 (d, J = 5.2 Hz, 4H), 2.71 (d, J = 5.1 Hz, 3H), 2.16 (tt, J = 11.8, 5.2 Hz, 4H), 1.73 (s, 4H), 0.35 (s, 4H). ESI-MS m / z: 579 [M+H] + .

[0446] Example 27: Synthesis of Compound 645

[0447] [ka]

[0448] Step 1: Synthesis of compound int_645-2

[0449] [ka]

[0450] 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 was incubated at 25 °C for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 5:1) to obtain the desired product (10 g, yield: 68.6%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 2.8, 9.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 1.54-1.46 (m, 9H).

[0451] Step 2: Synthesis of compound int_645-4

[0452] [ka]

[0453] 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 mixture was purged with nitrogen three times and heated to 100 °C. The mixture was incubated under nitrogen atmosphere for 2 h until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. Water (300 mL) was added to the crude product and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 3:1) to obtain the desired product (6 g, yield: 44.6%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.14-8.07 (m, 1H), 8.06-8.00 (m, 1H), 7.98 (d, J = 2.5 Hz, 1H), 2.97 (br t, J = 5.4 Hz, 4H), 2.31-2.13 (m, 4H), 1.53-1.50 (m, 9H).

[0454] Step 3: Synthesis of compound int_645-5

[0455] [ka]

[0456] Int_645-4 (3.60 g, 10.1 mmol) was dissolved in DCM (20 mL) and HCl / EtOAc solution (4 M, 2.52 mL) was added. The reaction was incubated at 25° C. for 16 hours until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product (2.4 g, yield: 81.1%). The crude product was used directly in the next reaction. 1 H NMR (400 MHz, DMSO-d6) δ = 7.82 (dd, J = 2.6, 8.9 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 2.92 (br s, 4H), 2.28-2.11 (m, 4H).

[0457] Step 4: Synthesis of compound int_645-6

[0458] [ka]

[0459] int_645-5 (2.40 g, 8.17 mmol) was dissolved in DMF (20 mL) and 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 at 0 °C under nitrogen atmosphere. After the addition, the reaction was warmed to room temperature and incubated for another 16 h until LC-MS showed the reaction was complete. 30 mL of ice water was added to the reaction and the mixture was stirred for another 0.5 h. Then, water (300 mL) was added and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 3:1) to obtain the desired product (2 g, yield: 83.7%). 1 H NMR (400 MHz, DMSO-d6) δ = 7.86 (dd, J = 2.7, 9.0 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 3.10 (br d, J = 7.2 Hz, 4H), 2.99 (s, 6H), 2.26-2.09 (m, 4H).

[0460] Step 5: Synthesis of compound int_645-7

[0461] [ka]

[0462] 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 was purged with hydrogen three times. The reaction was incubated at 25° C. for 16 h under hydrogen atmosphere until LC-MS showed the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol=10:1) to give a solid (0.85 g, yield: 46.6%). 1 H NMR (400 MHz, DMSO-d6) δ = 6.65 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.18 (dd, J = 2.4, 8.3 Hz, 1H), 4.60 (s, 2H), 3.12 (br s, 4H), 2.63 (s, 6H), 2.19-1.99 (m, 4H).

[0463] Step 6: Synthesis of compound int_645-8

[0464] [ka]

[0465] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0466] int_645-7 (760 mg, 3 mmol) was dissolved in tetrahydrofuran (40 mL), and NaH (720 mg, 18 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=15:1) to obtain a solid (1.75 g, yield: 98.3%). ESI-MS m / z: 595 [M+H] + .

[0467] Step 7: Synthesis of compound 645

[0468] [ka]

[0469] 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 mixture was purged with argon three times, and then int_1-10 (553 mg, 4.42 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography (SiO2, dichloromethane / methanol = 100:1) to give a solid (580 mg, yield: 33.2%). 1 H NMR (400 MHz, Chloroform-d) δ 12.36 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.12 (s, 2H), 3.30 (dt, J = 12.2, 5.1 Hz, 6H), 3.06 (t, J = 5.4 Hz, 4H), 2.82 (s, 6H), 2.12 (d, J = 15.2 Hz, 4H), 1.65 (s, 4H), 0.41 (s, 4H). ESI-MS m / z: 592 [M+H] + .

[0470] Example 28: Synthesis of Compound 653

[0471] [ka]

[0472] Step 1: Synthesis of compound int_653-2

[0473] [ka]

[0474] int_1-8 (140 mg, 0.396 mmol) was dissolved in DCM (50 mL) and int_653-1 (100 mg, 0.396 mmol), HATU (300 mg, 0.792 mmol), and DIPEA (206.8 mg, 1.6 mmol) in DMF (8 mL) were added. The reaction was stirred at room temperature under nitrogen for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (90 mg, yield: 38.4%). ESI-MS m / z: 592 [M+H] + .

[0475] Step 2: Synthesis of compound 653

[0476] [ka]

[0477] 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 mixture was purged with argon three times, and then int_1-10 (38 mg, 0.304 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (25 mg, yield: 55%). 1H NMR (400 MHz, Chloroform-d) δ 12.40 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.02 (d, J = 9.7 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.13 (s, 2H), 3.32 (d, J = 5.7 Hz, 2H), 3.19 (d, J = 5.8 Hz, 4H), 3.06 (d, J = 5.9 Hz, 4H), 2.70 (s, 1H), 2.16 (dd, J = 18.3, 10.7 Hz, 4H), 1.62 (s, 4H), 1.01-0.95 (m, 2H), 0.71 (dd, J = 5.6, 1.8 Hz, 2H), 0.41 (s, 4H). ESI-MS m / z: 589 [M+H] + .

[0478] Example 29: Synthesis of Compound 655

[0479] [ka]

[0480] Step 1: Synthesis of compound int_655-2

[0481] [ka]

[0482] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0483] int_655-1 (150 mg, 0.507 mmol) was dissolved in tetrahydrofuran (5 mL), and NaH (300 mg, 7.5 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (320 mg, yield: 99%). ESI-MS m / z: 636 [M+H] + .

[0484] Step 2: Synthesis of compound 655

[0485] [ka]

[0486] 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 mixture was purged with argon three times, and then int_1-10 (138 mg, 1.1 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (250 mg, yield: 72%). 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 7.30 (dd, J = 8.7, 1.4 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.5, 2.1 Hz, 1H), 3.74 (t, J = 6.6 Hz, 2H), 3.29 (m, 2H), 3.13 (t, J = 5.6 Hz, 4H), 2.95 (t, J = 5.3 Hz, 4H), 2.09 (p, J = 8.1 Hz, 4H), 1.52 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 633 [M+H] + .

[0487] Example 30: Synthesis of Compound 661

[0488] [ka]

[0489] Step 1: Synthesis of compound 661

[0490] [ka]

[0491] 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 incubated at room temperature for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (0.7 g, yield: 70%). 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 8.7, 2.1 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 3.78 (s, 3H), 3.56 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 5.5 Hz, 4H), 2.94 (t, J = 5.2 Hz, 4H), 2.05 (dt, J = 16.4, 6.8 Hz, 4H), 1.87 (s, 3H), 1.71 (m, 4H), 0.35 (s, 4H). ESI-MS m / z: 622 [M+H] + .

[0492] Example 31: Synthesis of Compound 663

[0493] [ka]

[0494] Step 1: Synthesis of compound 663

[0495] [ka]

[0496] 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 incubated at room temperature for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (1.05 g, yield: 93.7%). 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.43 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.7, 2.1 Hz, 1H), 4.31 (t, J = 5.5 Hz, 2H), 3.79 (s, 3H), 3.59 (t, J = 5.6 Hz, 2H), 3.50 (t, J = 5.7 Hz, 4H), 2.94 (t, J = 5.3 Hz, 4H), 2.38 (p, J = 7.0 Hz, 1H), 2.07 (q, J = 9.6, 6.0 Hz, 4H), 1.73 (m, 4H), 0.98 (d, J = 7.0 Hz, 6H), 0.35 (s, 4H). ESI-MS m / z: 650 [M+H] + .

[0497] Example 32: Synthesis of Compound 669

[0498]

change

[0499] ステップ1:Synthesis of compound 669

[0500]

change

[0501] 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 incubated at room temperature for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to obtain the desired product (233 mg, yield: 48%). 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.73 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.56 (s, 4H), 3.41 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 5.3 Hz, 4H), 2.12 (d, J = 15.3 Hz, 4H), 1.95 (s, 3H), 1.53 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 622 [M+H] + .

[0502] Example 33: Synthesis of Compound 714

[0503] [ka]

[0504] Step 1: Synthesis of compound int_714-2

[0505] [ka]

[0506] 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 incubated at room temperature for 16 h until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, ethyl acetate / methanol = 1:1) to obtain the desired product (1.16 g, yield: 86.3%). 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.08 (t, J = 8.6 Hz, 2H), 4.35 (s, 2H), 3.79 (m, 4H), 3.54 (s, 2H), 3.49 (d, J = 5.9 Hz, 4H), 2.95 (s, 4H), 2.20-1.94 (m, 4H), 1.89-1.82 (m, 5H), 1.33 (s, 9H), 0.74 (dd, J = 6.8, 4.7 Hz, 5H), 0.35 (s, 4H). ESI-MS m / z: 779 [M+H] + .

[0507] Step 2: Synthesis of compound 714

[0508] [ka]

[0509] int_714-2 (1.16 g, 1.49 mmol) was dissolved in HCl / dioxane solution (4 M, 11.6 mL), and the mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, and the crude product was added with saturated aqueous NaHCO3 (15 mL) to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (20 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give the desired product (300 mg, yield: 29.6%). 1 H NMR: (400 MHz, DMSO-d6) δ 12.81 (s, 1H), δ 8.05 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.09 (dd, J = 8.6, 2.1 Hz, 1H), 4.37 (t, J = 5.7 Hz, 2H), 3.81 (s, 3H), 3.64-3.55 (m, 2H), 3.54-3.41 (m, 4H), 3.05 (d, J = 5.3 Hz, 1H), 2.97 (br s, 4H), 2.15-2.02 (m, 4H), 1.93-1.52 (m, 5H), δ 0.81 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H), 0.37 (s, 4H). ESI-MS m / z: 679 [M+H] + .

[0510] Example 34: Synthesis of Compound 727

[0511] [ka]

[0512] Step 1: Synthesis of compound int_727-1

[0513] [ka]

[0514] 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 incubated at room temperature for 4 hours until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 5:1 → 1:1) to obtain the desired product (1.1 g, yield: 62.9%). ESI-MS m / z: 779 [M+H] + .

[0515] Step 2: Synthesis of compound 727

[0516] [ka]

[0517] int_727-1 (550 mg, 0.71 mmol) was dissolved in HCl / dioxane solution (4 M, 11 mL), and the mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, and saturated aqueous 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 × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give the product. The product was further purified by preparative HPLC (column: Phenomenex C18 250 × 50 mm × 10 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 43%-73%, 8 min) to give the desired product (291 mg, yield: 58.8%). 1H NMR: (400 MHz, DMSO-d6) δ 10.44-10.34 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.06-6.96 (m, 1H), 4.35 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 3.65-3.54 (m, 4H), 3.07 (br d, J = 5.3 Hz, 1H), 2.82 (br t, J = 4.9 Hz, 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). ESI-MS m / z: 679 [M+H] + .

[0518] Example 35: Synthesis of Compound 740

[0519]

change

[0520] ステップ1:Synthesis of compound int_740-1

[0521]

change

[0522] 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 incubated at room temperature for 4 hours until LC-MS showed the reaction was complete. The reaction was filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the desired product (1 g, yield: 65.8%). ESI-MS m / z: 779 [M+H] + .

[0523] Step 2: Synthesis of compound 740

[0524] [ka]

[0525] int_740-1 (800 mg, 1.03 mmol) was dissolved in HCl / dioxane solution (4 M, 11 mL), and the mixture was incubated at room temperature for 1 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, and the crude product was added with saturated aqueous NaHCO3 solution (8 mL) to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (8 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give the desired product (310 mg, yield: 44.3%). 1H NMR: (400 MHz, Chloroform-d) δ 12.53 (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, 3H), 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). ESI-MS m / z: 679 [M+H] + .

[0526] Example 36: Synthesis of Compound 825

[0527] [ka]

[0528] Step 1: Synthesis of compound int_825-2

[0529] [ka]

[0530] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0531] int_825-1 (75 mg, 0.266 mmol) was dissolved in tetrahydrofuran (6 mL), and NaH (100 mg, 2.5 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=10:1) to obtain a solid (59 mg, yield: 35.7%). ESI-MS m / z: 622 [M+H] + .

[0532] Step 2: Synthesis of compound 825

[0533] [ka]

[0534] 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 mixture was purged with argon three times before int_1-10 (24 mg, 0.189 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated by rotary evaporation, and purified by column chromatography to give a solid (7 mg, yield: 12.1%). 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.31-7.14 (m, 2H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 3.38 (t, J = 5.6 Hz, 4H), 3.31 (t, J = 6.5 Hz, 2H), 3.06 (d, J = 5.9 Hz, 4H), 2.95 (d, J = 5.4 Hz, 4H), 2.10 (tt, J = 13.1, 5.5 Hz, 4H), 1.93-1.50 (m, 8H), 0.36 (s, 4H). ESI-MS m / z: 619 [M+H] + .

[0535] Example 37: Synthesis of Compound 826

[0536] [ka]

[0537] Step 1: Synthesis of compound int_826-2

[0538] [ka]

[0539] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0540] int_826-1 (170 mg, 0.605 mmol) was dissolved in tetrahydrofuran (10 mL), and NaH (170 mg, 4.25 mmol, 60% purity) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=10:1) to obtain a solid (190 mg, yield: 58.1%). ESI-MS m / z: 547 [M+H] + .

[0541] Step 2: Synthesis of compound 826

[0542] [ka]

[0543] 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 mixture was purged with argon three times, and then int_1-10 (65 mg, 0.518 mmol) was added. The reaction was heated to 130° C. under argon atmosphere and incubated for 3 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (51 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 3.72 (t, J = 6.8 Hz, 2H), 3.18 (q, J = 7.0 Hz, 6H), 2.88 (s, 6H), 2.82 (t, J = 5.3 Hz, 4H), 2.21-2.10 (m, 4H), 1.51 (s, 4H), 0.34 (s, 4H). ESI-MS m / z: 592 [M+H] + .

[0544] Example 38: Synthesis of Compound 828

[0545] [ka]

[0546] Step 1: Synthesis of compound int_828-2

[0547] [ka]

[0548] int_1-8 (356 mg, 1 mmol) was dissolved in DCM (50 mL) and int_828-1 (340 mg, 1 mmol), HATU (760 mg, 2 mmol) and TEA (304 mg, 3 mmol) in DMF (8 mL) were added. The reaction was stirred at room temperature under nitrogen atmosphere for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give a solid (500 mg, yield: 83.6%). ESI-MS m / z: 681 [M+H] + .

[0549] Step 2: Synthesis of compound int_828-3

[0550] [ka]

[0551] 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 mixture was purged with argon three times, and then int_1-10 (60 mg, 0.47 mmol) was added. The reaction was heated to 90 °C under argon atmosphere and incubated for 12 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (140 mg, yield: 70.3%). ESI-MS m / z: 678 [M+H] + .

[0552] Step 3: Synthesis of compound 828

[0553] [ka]

[0554] int_828-3 (80 mg, 0.118 mmol) was dissolved in methanol / hydrochloric acid (4N, 10 mL) and the reaction was incubated at room temperature for 12 h until LC-MS showed the reaction was complete. The reaction was concentrated on a rotary evaporator and purified by column chromatography to give a solid (50 mg, yield: 73.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.41 (s, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.6, 2.0 Hz, 1H), 3.84 (s, 2H), 3.71 (t, J = 6.6 Hz, 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). ESI-MS m / z: 578 [M+H] + .

[0555] Example 39: Synthesis of Compound 829

[0556] [ka]

[0557] Step 1: Synthesis of compound int_829-2

[0558] [ka]

[0559] 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 was stirred at room temperature for 2 h and then concentrated under reduced pressure to remove the solvent and give the acyl chloride product.

[0560] int_829-1 (100 mg, 0.411 mmol) was dissolved in tetrahydrofuran (10 mL), and NAH (80 mg, 2 mmol, purity 60%) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h, and then the previously prepared acyl chloride was added at room temperature. The reaction was warmed to 40° C. and stirred for 10 h until LC-MS showed the reaction was complete. The reaction was quenched by adding methanol under ice bath, and the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, n-hexane / ethyl acetate=6:1) to obtain a solid (90 mg, yield: 44.5%). ESI-MS m / z: 492 [M+H] + .

[0561] Step 2: Synthesis of compound 829

[0562] [ka]

[0563] 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) and the mixture was purged with argon three times. The reaction was heated to 95 °C under argon atmosphere and incubated for 16 h until LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated on a rotary evaporator, and purified by column chromatography to give a solid (50 mg, yield: 50.5%). 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.18 (s, 2H), 3.78 (s, 3H), 3.51 (d, J = 5.8 Hz, 4H), 3.12 (t, J = 5.4 Hz, 4H), 2.05 (tt, J = 13.7, 5.4 Hz, 4H), 1.64 (d, J = 5.7 Hz, 4H), 1.22 (s, 6H), 0.33 (s, 4H). ESI-MS m / z: 545 [M+H] + .

[0564] Using various starting materials and following the above synthesis methods, 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, and 830–837 in Table 1 were obtained.

[0565] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

[0566] [Table 2-1] [Table 2-2]

[0567] Biological Example 1: In vitro assay of compounds of the present invention for inhibiting the enzymatic activity of KIF18A

[0568] KIF18A enzyme assay: The enzymatic activity of KIF18A after treatment with compounds was measured by an assay of microtubule-stimulated ATPase activity. ADP generated from the ATPase reaction was measured in this assay. Compounds were serially diluted 2-fold in DMSO over a range of 22 concentration points. Recombinant human KIF18A (1-467His tag) protein was expressed using the baculovirus system. The concentrations of KIF18A protein, microtubules, and ATP in the reaction were optimized for a standardized homogeneous enzyme assay using the ADP-Glo ​​Kinase / ATPase Assay Kit. Reaction buffer [(15 mM Tris, pH 7.5), 10 mM MgCl2, 0.01% Pluronic F-68, 1 μM paclitaxel, 30 μg / mL pig microtubules] was prepared. Compounds and KIF18A protein (30 nM) were added to the prepared reaction buffer, and the reaction mixture was incubated at room temperature for 15 min, followed by the addition of ATP (Km, 75 μM). The resulting reaction mixture was incubated at room temperature for another 15 min. 5 μL of ADP-Glo ​​reagent was mixed with 2.5 μL of the reaction mixture, and the resulting mixture was incubated at room temperature for 40 min. 10 μL of ADP-Glo ​​detection reagent was added, and the mixture was incubated at room temperature for 40 min. Luminescence was read using a microplate reader and compared with the DMSO group to determine the inhibition rate and IC of the compounds. 50 The values ​​were calculated and the results are shown in Table 3 below.

[0569] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0570] As can be seen from the data in Table 3, the compounds of the present invention have good inhibitory activity against the enzyme activity of KIF18A.

[0571] Biological Example 2: In vitro antiproliferative activity of compounds of the invention against HT-29 cells HT-29 cells were seeded in 384-well plates at 3000 cells / well. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting from 5 μM were added. Cell viability was assessed 72 hours after administration by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and expressed as IC 50 The values ​​were also calculated and the results are shown in Table 4 below.

[0572] [Table 4]

[0573] The reference compound AMG650 is compound 4 in WO2020132648A1.

[0574] [ka]

[0575] As can be seen from the data in Table 4, some of the compounds of the present invention have stronger antiproliferative activity against HT-29 cells compared to AMG650.

[0576] Biological Example 3: In vitro antiproliferative activity of compounds of the invention against HCT116 cells HCT116 cells were seeded in 384-well plates at 3000 cells / well. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting from 5 μM were added. Cell viability was evaluated 72 hours after administration by measuring intracellular ATP content. The inhibition rate of viable cells by the compounds was calculated compared to the DMSO group and expressed as IC 50 The values ​​were also calculated and the results are shown in Table 5 below.

[0577] [Table 5]

[0578] As can be seen from the data in Table 5, neither the compounds of the present invention nor AMG650 have antiproliferative activity against HCT116 cells.

[0579] Biological Example 4: In Vivo Pharmacodynamic Studies - Mouse HT29 Subcutaneous Xenograft Tumor Model BALB / c nude mice were injected with 5 × 10 6 HT29 cells were inoculated subcutaneously. 3 After growing to 100 mm, the mice were randomly divided into the following groups and administered intragastrically once a day: 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 a week and at the end of treatment. The tumor growth inhibition rate of the compound was calculated according to the following formula: tumor growth inhibition rate (TGI) = 1 - (tumor volume of the treatment group on day 28 - tumor volume of the treatment group on day 1) / (tumor volume of the vehicle control group on day 28 - tumor volume of the treatment group on day 1). The results are shown in Table 6.

[0580] [Table 6]

[0581] As can be seen from Table 6, the compounds of the present invention can inhibit tumor growth at a dose of 80 mg / kg in a subcutaneous xenograft tumor model in HT29-bearing mice, and compound 714, compound 727, and compound 740 showed stronger inhibitory effects on HT29 mouse subcutaneous xenograft tumors compared with AMG650.

[0582] Biological Example 5: Histone H3 Ser10 phosphorylation assay in HT29 cells (immunofluorescence assay) HT29 cells were seeded at 8000 cells / well in a 96-well plate (Fisher 160376). The following day, serially diluted compounds were added. Six hours after compound addition, cells were washed once with 1×PBS, fixed with 4% PFA for 15 min, washed three times with 1×PBS, and permeabilized with 0.02% Triton-X100 for 10 min. Blocking buffer was then added for 15-30 min, and primary antibody (Phospho-Histone H3(Ser10)(D7N8E) XP® Rabbit mAb #53348) diluted 1:3000 was added. Plates were left at 4°C overnight. The following day, cells were washed three times with 1×PBS, and secondary antibody (Fluorescein(FITC)-conjugated Affinipure Goat Anti-Rabbit IgG(H+L)) diluted 1:1000 was added. The cells were incubated in the dark for 1-2 hours and washed three times with 1x PBS. Nuclei were stained with DAPI, and after staining, images were taken using an MD ImageXpress Pico personal high-content imaging analysis system. The ratio of phosphorylation (FITC / DAPI) at H3 Ser10 site in HT29 cells was quantified. To evaluate the effect of compounds on the mitotic phase of HT29 cells, the EC 50 The values ​​were calculated and the results are shown in Table 7 below.

[0583] [Table 7]

[0584] As can be seen from Table 7, the compounds of the present invention have relatively strong activity in inducing phosphorylation at the H3 Ser10 site in HT-29 cells, and compared to AMG650, the compounds of the present invention have stronger activity in inducing phosphorylation at the H3 Ser10 site.

[0585] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 1】 (In general formula (1), X １ is -CR ５ = or N, X ２ is -CR ６ = or N, X ３ is -CR ７ = or N, X ４ is -CR ４ = or N, X ５ is -CR １５ = or N, X ５ Ga-CR １５ = and X ４ Ga-CR ４ If =, R １６ is -C ３－８ cycloalkyl, —OR １７ , -SR １８ , -NR １８ R １９ , or -NO ２ and X ５ Ga-CR １５ = and X ４ If N, then R １６ Ha-O-C １～８ Hydrocarbyl, -C ３－８ cycloalkyl, —OR １７ , -SR １８ , -NR ２０ R ２１ , or -NO ２ and X ５ If N, then R １６ is -O-C １～８ Hydrocarbyl, -C ３～８ cycloalkyl, —OR １７ , -SR １８ , -NR ２０ R ２１ , or -NO ２ and L is —(C═O)—NR ９ - ＊ or -NR ９ -(C=O)- ＊ and X １ , X ２ , X ３ , X ４ , and X ５ 4 or less of the ＊ teeth, 【Chemistry 2】 indicates the position at which the molecule binds to the end of R １７ is H, -C １～８ Halohydrocarbyl, -C ３～８ cycloalkyl, or —C ３～８ halocycloalkyl, wherein said —C １～８ halohydrocarbyl, said -C ３～８ cycloalkyl, or the aforementioned —C ３～８ Halocycloalkyl is selected from the following groups: H, halogen, and —C １～４ optionally substituted with 0, 1, 2, or 3 of the hydrocarbyl; R １８ and R １９ are each independently H, —C １～８ Hydrocarbyl, -C １～８ Halohydrocarbyl, -C ３～８ cycloalkyl, or —C ３～８ halocycloalkyl, wherein said —C １～８ Hydrocarbyl, said -C １～８ halohydrocarbyl, said -C ３～８ cycloalkyl, or the aforementioned —C ３～８ Halocycloalkyl is selected from the following groups: H, halogen, and —C １～４ optionally substituted with 0, 1, 2, or 3 of the hydrocarbyl; R ２０ and R ２１ are each independently H, —C １～８ Hydrocarbyl, -C １～８ Halohydrocarbyl, -C ３～８ cycloalkyl, or —C ３～８ halocycloalkyl, wherein said —C １～８ Hydrocarbyl, the aforementioned -C １～８ halohydrocarbyl, said -C ３～８ cycloalkyl, or the aforementioned —C ３～８ Halocycloalkyl is selected from the following groups: H, halogen, and —C １～４ optionally substituted with 0, 1, 2, or 3 of hydrocarbyl, or R ２０ and R ２１ may be combined with the nitrogen atom to which they are respectively bonded 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 is -CN or -Z-R １０ where Z is a chemical bond, -C ０～４ Hydrocarbyl-, -NR １１ -, -NR １１ SO ２ -, -SO ２ NR １１ -, -NR １１ -S(=O)(=NH)-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -C ０～４ Hydrocarbyl-O-, -(C=O)-, -(C=O)NR １１ -, -C(=N-OH)-, or -NR １１ (C═O)— or a group —Z—R １０ is -N=S(=O)-(R １０ ) ２ where two R １０ may be combined with the sulfur atoms to which they are respectively bonded 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 a halogen or a group -Y-R １２ where Y is a chemical bond, -C ０～４ Hydrocarbyl-, -N(C ０～１ Hydrocarbyl)-C ０～４ Hydrocarbyl-, —C(═O)NR ａ R ａ (C １～４ Hydrocarbyl)-, —O—C ０～４ Hydrocarbyl-, -S-, -S(=O)-, -SO ２ -, -SO ２ NR １２ - or -S(=O)(=NH)-, R ３ is H, halogen, C １～８ Hydrocarbyl, or C １～４ is a halohydrocarbyl, R ４ is H, halogen, R ４ａ , or R ４ｂ and R ５ is H, halogen, C １～８ Alkyl, or C １～４ is haloalkyl, R ６ is H, halogen, C １～８ Alkyl, C １～４ Haloalkyl, —OH, —O—R ６ａ , or -O-R ６ｂ and R ７ is H, halogen, C １～８ Hydrocarbyl, or C １～４ is a halohydrocarbyl, R ８ teeth, 【Transformation 3】 is selected from the group consisting of R １３ａ , R １３ｂ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ , R １３ｉ , R １３ｊ , R １３ｋ , and R １３ｌ are each independently H, halogen, or R １３ｍ , or R １３ｎ or R １３ａ / R １３ｂ , R １３ｃ / R １３ｄ , R １３ｅ / R １３ｆ , R １３ｇ / R １３ｈ , R １３ｉ / R １３ｊ , and R １３ｋ / R １３ｌ Each pair of R, together with the carbon atom to which it is respectively attached, independently represents R ８ spiro-bonded to the ring may form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring, wherein said 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, the 3-, 4-, 5-, or 6-membered monocyclic ring is selected from the group consisting of F, Cl, Br, C １～６ Hydrocarbyl, C １～４ halohydrocarbyl, —OR ａ , -OC １～４ Halohydrocarbyl, CN, -NR ａ R ａ and oxo; R ９ is H or C １～６ is a hydrocarbyl, R １０ is H, R １０ａ , R １０ｂ , or R １０ｃ and R １１ is H, R １１ａ , or R １１ｂ and R １２ is R １２ａ or R １２ｂ and R １５ is H, halogen, C １～８ Hydrocarbyl, C １～４ Halohydrocarbyl, —O—C １～８ Hydrocarbyl, or -O-R 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, in each occurrence, 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, said monocyclic ring and said bicyclic ring each independently containing one of the following groups: F, Cl, Br, C １～６ Hydrocarbyl, C １～４ halohydrocarbyl, —OR ａ , -OC １～４ Halohydrocarbyl, CN, —C(═O)R ｂ , -C(=O)OR ａ , —C(═O)NR ａ R ａ , -C(=NR ａ ) NR ａ R ａ , -OC(=O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２～６ Hydrocarbyl NR ａ R ａ , -OC ２～６ Hydrocarbyl OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR ａ R ａ , -NR ａ R ａ , -N(R ａ ) C(=O)R ｂ , -N(R ａ ) C(=O) OR ｂ , -N(R ａ )C(=O)NR ａ R ａ , -N(R ａ ) C(=NR ａ ) NR ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C ２～６ Hydrocarbyl NR ａ R ａ , -NR ａ C ２～６ Hydrocarbyl OR ａ , -C １～６ Hydrocarbyl NR ａ R ａ , -C １～６ Hydrocarbyl OR ａ , -C １～６ Hydrocarbyl N(R ａ ) C(=O)R ｂ , -C １～６ Hydrocarbyl OC(=O)R ｂ , -C １～６ HydrocarbylC(=O)NR ａ R ａ , -C １～６ Hydrocarbyl C(=O)OR ａ , R １４ and 0, 1, 2, or 3 oxo, R ４ｂ , R ６ｂ , R １０ｂ , R １１ｂ , R １２ｂ , or R １３ｎ In each case, C １～６ hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, —R ａ , -OR ａ , -OC １～４ optionally substituted with 0, 1, 2, 3, 4, or 5 of halohydrocarbyl, and CN; R １０ｃ In each case, C １～６ hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, —R ａ , -R ｃ , -OR ａ , -OC １～４ optionally substituted with 0, 1, 2, 3, 4 or 5 of halohydrocarbyl, and CN; R １４ is, in each occurrence, 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 or 1 atom selected from O and S, wherein said monocyclic ring and said bicyclic ring each independently contain one of the following groups: F, Cl, Br, C １～６ Hydrocarbyl, C １～４ halohydrocarbyl, —OR ａ , -OC １～４ Halohydrocarbyl, CN, —C(═O)R ｂ , -C(=O)OR ａ , —C(═O)NR ａ R ａ , -C(=NR ａ ) NR ａ R ａ , -OC(=O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２～６ Hydrocarbyl NR ａ R ａ , -OC ２～６ Hydrocarbyl OR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR ａ R ａ , -NR ａ R ａ , -N(R ａ ) C(=O)R ｂ , -N(R ａ ) C(=O) OR ｂ , -N(R ａ )C(=O)NR ａ R ａ , -N(R ａ ) C(=NR ａ ) NR ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ , -NR ａ C ２～６ Hydrocarbyl NR ａ R ａ , -NR ａ C ２～６ Hydrocarbyl OR ａ , -C １～６ Hydrocarbyl NR ａ R ａ , -C １～６ Hydrocarbyl OR ａ , -C １～６ Hydrocarbyl N(R ａ ) C(=O)R ｂ , -C １～６ Hydrocarbyl OC(=O)R ｂ , -C １～６ HydrocarbylC(=O)NR ａ R ａ , -C １～６ Hydrocarbyl C(=O)OR ａ and 0, 1, 2 or 3 oxo, R ａ is, in each occurrence, independently H or R ｂ and R ｂ is, in each occurrence independently, C １～６ hydrocarbyl, phenyl, or benzyl, wherein said hydrocarbyl is selected from the following groups: halogen, —OH, —OC １～４ Hydrocarbyl, —NH ２ , -NHC １～４ Hydrocarbyl, —OC(═O)C １～４ Hydrocarbyl, and —N(C １～４ Hydrocarbyl) C １～４ The phenyl and the benzyl may each independently be substituted with 0, 1, 2, or 3 of the following groups: halogen, C １～４ Hydrocarbyl, C １～３ Halohydrocarbyl, —OH, —OC １～４ Hydrocarbyl, —NH ２ , -NHC １～４ Hydrocarbyl, —OC(═O)C １～４ Hydrocarbyl, and —N(C １～４ Hydrocarbyl) C １～４ Optionally substituted with 0, 1, 2 or 3 of the hydrocarbyl: R ｃ is, in each occurrence, independently -OC(=O)C １～５ hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: -OH and -NH ２ may be optionally substituted with one, two or three of

2. The general formula (1) has the following structure: 【Chemistry 4】 (In the formula, R １６ But, -C ３～６ Cycloalkyl, —OH, —O—C １～４ Hydrocarbyl, —O—C １～４ Halohydrocarbyl, —O—C ３～６ Cycloalkyl, —O—C ３～６ Halocycloalkyl, —SH, —S—C １～６ Hydrocarbyl, -S-C １～４ Halohydrocarbyl, —S—C ３～６ Cycloalkyl, —S—C ３～６ Halocycloalkyl, —NR ２０ R ２１ , or -NO ２ ), or 【Transformation 5】 wherein R 16 is —C 3-6 cycloalkyl, —OH, —O—C 1-4 hydrocarbyl, —O—C 1-4 halohydrocarbyl, —O—C 3-6 cycloalkyl, —O—C 3-6 halocycloalkyl, —SH, —S—C 1-6 hydrocarbyl, —S—C 1-4 halohydrocarbyl, —S—C 3-6 cycloalkyl, —S—C 3-6 halocycloalkyl, —NR 20 R 21 , or —NO 2 ; or 【Transformation 6】 10. The compound of claim 1, having the formula: wherein R 16 is —C 3-6 cycloalkyl, —OH, —O—C 1-4 halohydrocarbyl, —O—C 3-6 cycloalkyl, —O—C 3-6 halocycloalkyl, —SH, —S—C 1-6 hydrocarbyl, —S—C 1-4 halohydrocarbyl, —S—C 3-6 cycloalkyl, —S—C 3-6 halocycloalkyl, —NR 18 R 19 , or —NO 2 , or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

3. In general formula (1), R １６ -OH, -OCF ３ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ２ CF ３ , -OCF ２ Cl, -OCFC1 ２ , 【Transformation 7】 -SH、-SCH ３ 、-SCH ２ CH ３ 、 【Transformation 8】 -SCF ３ 、-SCH ２ CF ３ 、-SCF ２ CF ３ 、-SCF ２ Cl、-SCFCl ２ 、 【Chemistry 9】 -NH ２、 【Chemistry 10】 or - NO ２ and preferably -OCF ３ , -OCH ２ F, -OCHF ２ , 【Chemistry 11】 -SCH ３ 、-SCF ３ 、-SCF ２ Cl、-SCFCl ２ 、 【Chemistry 12】 or - NO ２ and more preferably, -OCF ３ , -OCH ２ F, -OCHF ２ , 【Chemistry 13】 -SCH ３ 、-SCF ３ 、 【Chemistry 14】 or - NO ２ 2. The compound of claim 1, wherein:

4. R １６ Yes, -OCH ３ ,-OCH ２ CH ３ ,-OCH ２ CH ２ CH ３ 、 【Chemistry 15】 and Preferably, —OCH ３ and In the general formula (1), R 9 is H, methyl or ethyl, preferably H, and In general formula (1), R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j , R 13k and R 13l are each independently H, halogen, C 1-6 hydrocarbyl or C 1-4 halohydrocarbyl, and R 13a and R 13b in the pair R 13a / R 13b may combine with the carbon atoms respectively bonded thereto to form a saturated 3-, 4- or 5-membered monocyclic ring spiro-bonded to the R 8 ring, wherein said monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and preferably R 13c , R 13d , R 13e , R 13f, R 13g, R 13h, R 13i, R 13j, R 13k, and R 13l are each independently H, methyl, or ethyl, and R 13a and R 13b in the pair R 13a / R 13b may combine with the carbon atoms to which they are respectively bonded to form a cyclopropyl, cyclobutyl, or cyclopentyl ring spiro-bonded to the R 8 ring, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

5. In the general formula (1), the structural unit: 【Chemistry 16】 teeth, 【Chemistry 17】 and preferably [Chemistry 18] 2. The compound of claim 1, wherein:

6. In the general formula (1), Z is a chemical bond, —NH—, —NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; In addition, in the general formula (1), R 10 is (a) H; (b) C 1-6 hydrocarbyl, wherein said hydrocarbyl is optionally substituted with 0, 1, 2, or 3 of the following groups: F, Cl, Br, —OH, and —OCH 3 ; (c) the group -Z-R 10 when the group is -N═S(═O)—(R 10 ) 2 , two R 10 s may combine with the sulfur atoms to which they are each bonded 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, wherein the monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, C 1-6 hydrocarbyl, C 1-4 halohydrocarbyl, —C 1-6 hydrocarbylOH, —OH, —OCH 3 , —NH 2 , and oxo; and (d) C 1-6 hydrocarbyl, wherein said C 1-6 hydrocarbyl is optionally substituted with one, two, or three of the following groups: —OC(═O)C 1-5 hydrocarbyl, said C 1-5 hydrocarbyl is optionally substituted with one or two of the following groups: —OH and —NH 2 , and said C 1-6 hydrocarbyl is optionally substituted with zero, one, two, or three of the following groups: F, Cl, Br, —OH, and —OCH 3 ; 2. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, selected from:

7. In general formula (1), R １ is —CN or a group —Z—R １０ where Z is a chemical bond, -NH-, -NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, and R １０ but, (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, 【Chemistry 19】 wherein the rings each independently contain one of the following groups: OH, F, methyl, —CH ２ OH, -C(=O)OCH ３ , -C(=O)OC(CH ３ ) ３ , N.H. ２ , CN, and oxo, with oxetanyl and cyclopropyl being preferred; (c) 0, 1, 2 or 3 of OH, F, -C(=O)OCH ３ , -NH ２ , -NH(CH ３ ) or -N(CH ３ ) ２ C substituted with １～６ Hydrocarbyl, preferably C substituted with 0, 1, 2 or 3 OH groups １～６ Hydrocarbyl, more preferably C substituted with one OH group １～６ hydrocarbyl; and (d) C １～６ Hydrocarbyl, wherein said C １～６ The hydrocarbyl may be selected from the following groups: 【Chemistry 20】 and optionally substituted with one, two or three of the C １～６ Hydrocarbyl is selected from the following groups: F, Cl, Br, —OH and —OCH ３ C １～６ Hydrocarbyl, or In general formula (1), the group -Z-R 10 is -N=S(=O)-(R 10 ) 2 , wherein two R 10 s may be combined with the sulfur atoms respectively bonded thereto 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 is 【Chemistry 21】 or In general formula (1), R 1 is a group -Z-R 10 , where Z is -NHSO 2 - or -SO 2 NH-, and R 10 is oxetanyl or cyclopropyl, or R 10 is C 1-6 hydrocarbyl substituted with 0, 1, 2 or 3 OH groups, or R 10 is C 1-6 hydrocarbyl, where said C 1-6 hydrocarbyl is one of the following groups: 【Chemistry 22】 2. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with one, two or three of:

8. In general formula (1), R １０ But C １～６ hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: 【Chemistry 23】 and the hydrocarbyl is preferably optionally substituted with 0, 1, 2 or 3 of 【Chemistry 24】 and Z is substituted with -NHSO ２ -or-SO ２ NH—, and Z is preferably —NHSO ２ -or- In the general formula (1), R 10 is selected from C 1-6 hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: 【Chemistry 25】 and Z is -NHSO 2 - or -SO 2 NH-, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. In general formula (1), R ２ is a halogen or a group -Y-R １２ where Y is a chemical bond, -NH-, -NH-(CH ２ ) ０～４ -, or -O-(CH ２ ) 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 said monocyclic ring and said bicyclic ring each independently contain one of the following groups: F, Cl, Br, C １～６ Hydrocarbyl, C １～４ Halohydrocarbyl, —OH, —OC １～４ Halohydrocarbyl, CN, R １４ and 0, 1, 2 or 3 of oxo, or R １２ is C １～６ hydrocarbyl, wherein said hydrocarbyl is selected from the following groups: F, Cl, Br, —OH, —OC １～４ 2. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with 0, 1, 2, 3, 4, or 5 of halohydrocarbyl, and CN.

10. In general formula (1), R ２ is a saturated 5- or 6-membered monocyclic ring, wherein said ring contains 0, 1 or 2 N atoms and 0 or 1 O atoms, and said ring is selected from the group consisting of F, Cl, Br, C １～６ Hydrocarbyl, C １～４ Halohydrocarbyl, —OH, —OC １～４ Halohydrocarbyl, CN, R １４ and oxo, In the general formula (1), R 2 is (a) halogen; (b) the group -Y-R 12 , wherein Y is a chemical bond and R 12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, 【Chemistry 26】 wherein each ring is substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF 3 , —OH, —OCHF 2 , CN, and oxo; or (c) the group -Y-R 12 , wherein Y is -NH-, -O-, -O-(CH 2 )-, -O-(CH 2 )-(CH 2 )-, or -O-(CH 2 )-(CH 2 )-(CH 2 )-; and R 12 is 【Chemistry 27】 or R 12 is C 1-6 hydrocarbyl, wherein said hydrocarbyl is optionally substituted with 0, 1, 2, 3, 4, or 5 of the following groups: F, Cl, Br, methyl, CF 3 , —OH, and CN. That is, In the general formula (1), R 2 is morpholinyl or piperidinyl, wherein the morpholinyl and the piperidinyl may be optionally substituted with 0, 1, 2 or 3 of the following groups: F, Cl, Br, methyl, CF 3 , —OH, —OCHF 2 , and CN; In the general formula (1), R 2 is piperidinyl substituted with 1, 2 or 3 fluorine groups; In the general formula (1), R 2 is 【Chemistry 28】 That is, In the general formula (1), R 2 is morpholinyl substituted with 1, 2, or 3 methyl groups, or In the general formula (1), R 2 is 【Chemistry 29】 2. The compound of claim 1, wherein:

11. In general formula (1), R １０ is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, and 1,3,4-oxathiazinanyl, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. In general formula (1), R ３ is H, In the general formula (1), R 4 is (a) H; (b) C 1-6 hydrocarbyl substituted with 0, 1, 2, or 3 OH groups; (c) cyclopropyl; and (d) F, wherein R 4 is preferably H, F, or methyl, and R 4 is more preferably H; In the general formula (1), R 5 is H or F, preferably H. In the general formula (1), R 6 is H or F, preferably H. In the general formula (1), R 7 is H, or The compound according to claim 1, wherein in general formula (1), R 15 is H or F, preferably H, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

13. The compound has the following structure: 【Chemistry 30-1】 【Chemistry 30-2】 【Transformation 30-3】 【Chemistry 30-4】 【Transformation 30-5】 【Transformation 30-6】 【Transformation 30-7】 【Transformation 30-8】 【Chemistry 30-9】 [Transformation 30-10] 【Chemistry 30-11】 【Transformation 30-12】 【Transformation 30-13】 【Chemistry 30-14】 [Transformation 30-15] 【Transformation 30-16】 【Chemistry 30-17】 [Chemistry 30-18] 【Chemistry 30-19】 [Transformation 30-20] 【Chemistry 30-21】 【Chemistry 30-22】 [Chemistry 30-23] [Chemistry 30-24] [Chemistry 30-25] [Chemistry 30-26] 【Chemistry 31】 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, having one of the following formulas:

14. 14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 13, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

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