KIF18A inhibitors

Abstract

The present invention discloses a group of KIF18A inhibitors.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] TIFF2025508192000232.tif31168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202210266719.4, filed on March 17, 2022, which is incorporated by reference in its entirety herein.

[0002] The present invention relates to the field of pharmaceutical chemistry, in particular to a group of compounds having inhibitory activity against KIF18A protein, a preparation method thereof, and the use of said group of 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" directed 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. Research has 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 is 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 slows or stops mitotic progression. 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. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, the development of KIF18A inhibitors represents a promising new approach against chromosomally unstable tumors. [Means for solving the problem]

[0007] (overview) The present invention provides a compound represented by formula (1), or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof, or a 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, Ring A is a 7- to 10-membered cycloalkylene, a 7- to 10-membered heterocycloalkylene, a 7- to 10-membered heteroarylene, or a 10-membered arylene, wherein the 7- to 10-membered cycloalkylene, the 7- to 10-membered heterocycloalkylene, the 7- to 10-membered heteroarylene, or the 10-membered arylene is H, a halogen, -C 1~4 Hydrocarbyl, -C 1~4 Halohydrocarbyl, or -OC 1~4 optionally substituted with 0, 1, 2, or 3 groups selected from hydrocarbyl; L is -(C=O)-NR 3 - **** or -NR 3 -(C=O)- **** and **** teeth, [ka] represents a bond to the end of R 1 -CN or -ZR 10 where Z is a chemical bond, -C 0~4 Hydrocarbylene-, -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 Hydrocarbylene-O- ** , -(C=O)-, -(C=O)NR 11 -, -C(=N-OH)-, or -NR 11 (C=O)- ** or a group -ZR 10 is -N=S(=O)-(R 10 ) 2 where the two R 10may 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; ** is R 10 represents a bond to the end, R 2 is a halogen or a group -YR 12 where Y is a chemical bond, -C 0~4 Hydrocarbylene-, -N(C 0~1 Hydrocarbyl)-C 0~4 Hydrocarbylene- *** , -C(=O)NR a (C 1~4 Hydrocarbyl)- *** , -OC 0~4 Hydrocarbylene- *** , -S-, -S(=O)-, -SO 2 -, -SO 2 NR 12 - *** , or -S(=O)(=NH)- *** and *** is R 12 represents a bond to the end, R 3 is H or C 1~6 is a hydrocarbyl; 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 8 teeth, [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 the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and the 3-, 4-, 5-, or 6-membered monocyclic ring further contains no 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 10 , H, R 10a , R 10b , or R 10c and R 11 , H, R 11a , or R 11b and R 12 is R12a or R 12b and R 6a , R 10a , R 11a , R 12a , or R 13m is independently selected from a saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently selected from 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(=NRa )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 HydrocarbylC(=O)OR a , R 4 and oxo, R 6b , R 10b , R 11b , R 12b , or R 13n In each case, C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from F, Cl, Br, -R a , -OR a , -OC 1~4 optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from halohydrocarbyl, and CN; R 10c In each case, C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from F, Cl, Br, -Ra , -R c , -OR a , -OC 1~4 halohydrocarbyl, and CN; R 4 is independently selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently selected from 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(Ra )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 HydrocarbylC(=O)OR a and oxo, R a is, in each occurrence, independently, H or R b and R b is, in each case independently, C 1~6 hydrocarbyl, phenyl, or benzyl, wherein said hydrocarbyl is halogen, -OH, -OC 1~4 Hydrocarbyl, -NH 2 , -NHC 1~4 Hydrocarbyl, -OC(=O)C 1~4 Hydrocarbyl, or -N(C 1~4 Hydrocarbyl)C 1~4hydrocarbyl, wherein the phenyl and the benzyl are each independently selected from 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, or -N(C 1~4 Hydrocarbyl)C 1~4 and optionally substituted with 0, 1, 2 or 3 groups selected from hydrocarbyl: R c is, in each occurrence, independently: -OC(=O)C 1~5 hydrocarbyl, wherein said hydrocarbyl is -OH or -NH 2 Optionally, one, two or three of the groups may be substituted.

[0008] In another preferred embodiment, the general formula (1) has the following structure: [ka] has.

[0009] In another preferred embodiment, in the general formula (1), ring A is a 9- to 10-membered cycloalkylene, a 9- to 10-membered heterocycloalkylene, a 9- to 10-membered heteroarylene, or a 10-membered arylene, wherein the 9- to 10-membered cycloalkylene, the 9- to 10-membered heterocycloalkylene, the 9- to 10-membered heteroarylene, or the 10-membered arylene is H, F, Cl, Br, -C 1~4 Hydrocarbyl, -C 1~4 Halohydrocarbyl, or -OC 1~4 It may be optionally substituted with 0, 1, 2, or 3 groups selected from hydrocarbyl.

[0010] In another preferred embodiment, in the general formula (1), ring A is [ka] where: * represents a bond to the L terminal, and the above groups are H, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -OCH 3 , or -OCH 2 CH 3 and optionally substituted with 0, 1, 2, or 3 groups selected from

[0011] In another preferred embodiment, in the general formula (1), ring A is [ka] where: * represents a bond to the L terminal, and the above groups are H, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -OCH 3 , or -OCH 2 CH 3 and optionally substituted with 0, 1, 2, or 3 groups selected from

[0012] In another preferred embodiment, in the general formula (1), R 3 is H, methyl, or ethyl, preferably H.

[0013] 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 13lare 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-bonded 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 R 13b 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.

[0014] In another preferred embodiment, in the general formula (1), the structural unit: [ka] teeth, [ka] and preferably [ka] It is.

[0015] In another preferred embodiment, in the general formula (1), Z is a chemical bond, -NH-, or -NHSO. 2-, -SO 2 NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-.

[0016] In another preferred embodiment, in the general formula (1), R 10 teeth, (a) H; or (b)C 1~6 Hydrocarbyl, wherein the hydrocarbyl is F, Cl, Br, -OH or -OCH 3 C 1~6 Hydrocarbyl; (c) a group, the group -ZR 10 But -N=S(=O)-(R 10 ) 2 If, then, the two R 10 may 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 the group consisting of F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -C 1~6 Hydrocarbylene OH, -OH, -OCH 3 , -NH 2 or oxo; or (d) C 1~6 Hydrocarbyl, wherein said C 1~6 The hydrocarbyl is -OC(=O)C 1~5 hydrocarbyl, wherein the C 1~5 The hydrocarbyl is -OH or -NH 2 and optionally substituted with one or two groups selected from the group consisting of C 1~6 Hydrocarbyl is F, Cl, Br, -OH or -OCH3 C 1~6 Hydrocarbyl, is selected from.

[0017] 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-, -NHSO 2 -, -SO 2 NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(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 independently OH, F, methyl, -CH 2 OH, -C(=O)OCH 3 , -C(=O)OC(CH 3 ) 3 , N.H. 2 , CN, and oxo), preferably oxetanyl or cyclopropyl; (c) 0, 1, 2 or 3 OH, F, -C(=O)OCH 3 , -NH 2 , -NH(CH 3 ) or -N(CH 3 ) 2 C replaced 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; or (d) C 1~6Hydrocarbyl, 1~6 The hydrocarbyl is [ka] and optionally substituted with one, two or three groups selected from the group consisting of 1~6 Hydrocarbyl is F, Cl, Br, -OH or -OCH 3 C 1~6 Hydrocarbyl, is selected from.

[0018] 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.

[0019] In another preferred embodiment, in the general formula (1), R 1 is the group -ZR 10 where Z is -NHSO 2 -OR-SO 2 NH-;R 10 is oxetanyl or cyclopropyl, or R 10 is C substituted with 0, 1, 2 or 3 OH groups 1~6 Hydrocarbyl or R 10 is C 1~6 Hydrocarbyl, wherein said C 1~6 The hydrocarbyl is [ka] It may be optionally substituted with 1, 2 or 3 groups selected from:

[0020] In another preferred embodiment, in the general formula (1), R 10 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from [ka] , preferably [ka] Z is optionally substituted with 0, 1, 2 or 3 groups selected from -NHSO 2 -OR-SO 2 NH- and Z is preferably -NHSO 2 -It is.

[0021] In another preferred embodiment, in the general formula (1), R 10 is C 1~6 hydrocarbyl, wherein said hydrocarbyl is selected from [ka] and Z is optionally substituted with one, two or three groups selected from the group consisting of -NHSO 2 -OR-SO 2 It is NH-.

[0022] 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-(CH 2 ) 0~4 - or -O-(CH 2 ) 0~4 - and R 12is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, wherein the monocyclic ring and the bicyclic ring are each independently selected from F, Cl, Br, C 1~6 Hydrocarbyl, C 1~4 Halohydrocarbyl, -OH, -OC 1~4 Halohydrocarbyl, CN, R 14 and oxo, or R 12 is C 1~6 Hydrocarbyl, wherein the hydrocarbyl is F, Cl, Br, -OH, -OC 1~4 It may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from halohydrocarbyl, or CN.

[0023] In another preferred embodiment, in the general formula (1), R 2 is a saturated 5- or 6-membered monocyclic ring, each of which contains 0, 1 or 2 N atoms and 0 or 1 O atom, each of which 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.

[0024] 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 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, [ka] where each ring is F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 , CN, and oxo; or (c) Group -YR 12 (Wherein, Y is -NH-, -O-, -O-(CH 2 )-, -O-(CH 2 )-(CH 2 )-, or -O-(CH 2 )-(CH 2 )-(CH 2 ) and R 12 teeth, [ka] or R 12 is C 1~6 hydrocarbyl, wherein the hydrocarbyl is F, Cl, Br, methyl, CF 3 , -OH, or CN), It is.

[0025] In another preferred embodiment, in the general formula (1), R 2 is morpholinyl or piperidinyl, wherein said morpholinyl and said piperidinyl are F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 and CN.

[0026] In another preferred embodiment, in the general formula (1), R 2 is piperidinyl substituted with one, two or three fluorine groups.

[0027] In another preferred embodiment, in the general formula (1), R 2 teeth, [ka] It is.

[0028] In another preferred embodiment, in the general formula (1), R 2 is morpholinyl substituted with one, two, or three methyl 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 10 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, and 1,3,4-oxathiazinanyl.

[0031] In another preferred embodiment, in the general formula (1), R 5 is H or F, preferably H.

[0032] In another preferred embodiment, in the general formula (1), R 6 is H or F, preferably H.

[0033] In another preferred embodiment, in the general formula (1), R 7 is H.

[0034] In various different embodiments of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] has one of the following:

[0035] In various different embodiments of the present invention, the compound of general formula (1) also has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] has one of the following:

[0036] Another object of the present invention is to provide a pharmaceutical composition containing a pharma- ceutically acceptable carrier, diluent and / or excipient, and, as an active ingredient, the compound of general formula (1) of the present invention or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof.

[0037] The present invention further aims to provide use of a compound of general formula (1) of the present invention, or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with the KIF18A protein.

[0038] The present invention further contemplates providing a method for treating, regulating or preventing a related disease mediated by KIF18A protein, comprising administering a therapeutically effective amount of a compound of general formula (1) of the present invention, or an isomer thereof, a crystal thereof, a pharma- ceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or the above-mentioned pharmaceutical composition to a subject.

[0039] 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.

[0040] 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.

[0041] (Synthesis of Compounds) Methods for preparing the compound of the general formula (1) of the present invention are specifically described below, but these specific methods do not limit the present invention in any way.

[0042] The compounds of general formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Furthermore, the solvents, temperatures and other reaction conditions described herein may be varied. The starting materials for the synthesis of the compounds may be obtained synthetically or commercially available. The compounds described herein and other related compounds with different substituents are 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 may be modified by using appropriate reagents and conditions to introduce different groups into the molecular formulas described herein.

[0043] 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 temperatures, and reaction times, 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 a compound of general formula (1), wherein the compound of general formula (1) can be prepared according to the following general reaction schemes 1, 2, 3, or 4.

[0044] General reaction scheme 1

[0045] [ka]

[0046] Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, where R 1 , R 2 , ring A, R 8 , X 1 , X 2 and X 3 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-aminoethan-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.

[0047] General reaction scheme 2

[0048] [ka]

[0049] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 2, wherein R 1 , R 2 , ring A, R 8 , X 1 , X 2 and X 3 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-aminoethan-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.

[0050] General reaction scheme 3

[0051] [ka]

[0052] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 3, wherein R 1 , R 2 , ring A, R 8 , X 1 , X 2 , and X 3 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-aminoethan-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.

[0053] General reaction scheme 4

[0054] [ka]

[0055] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 4, wherein R 1 , R 2 , ring A, R 8 , X 1 , X 2 , and X 3 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-aminoethan-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.

[0056] Further forms of the compound 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.

[0057] 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).

[0058] 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.

[0059] 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 crystalline form.

[0060] 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.

[0061] 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.

[0062] Explanation of terms 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.

[0063] 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. 0 The hydrocarbyl notation represents a direct bond. 1~6 Examples of hydrocarbyls include: [ka] These include, but are not limited to:

[0064] 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.

[0065] Unless otherwise specified, "oxo" and "thio" refer to =O (eg, carbonyl) and =S (eg, thiocarbonyl), respectively.

[0066] Unless otherwise specified, "halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0067] Unless otherwise noted, "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 is OCH 3 , OCF 3 , CHF 2 O, C.F. 3 CH 2 O. i- PrO, n- PrO, i- BuO, n- BuO and t- BuO.

[0068] Unless otherwise stated, "cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon ring system. The ring carbon atoms of the cycloalkyl may 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, [ka] These include, but are not limited to:

[0069] Unless otherwise specified, "aryl" refers to an aromatic hydrocarbon group that is monocyclic or polycyclic. For example, a monocyclic aryl ring can be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0070] Unless otherwise noted, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, phenanthrylene, and the like.

[0071] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), said heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl include pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [ka] These include, but are not limited to:

[0072] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0073] Unless otherwise stated, "heterocycloalkyl" refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus, which may optionally include one or more alkenylenes as part of the ring structure. Partially unsaturated heterocycloalkyls may be referred to as "heterocycloalkenyls" when the heterocycloalkyl contains at least one double bond, and "heterocycloalkynyls" when the heterocycloalkyl contains at least one triple bond. Heterocycloalkyls may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused or bridged rings). In some embodiments, heterocycloalkyls are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl contains 0-3 double bonds. In some embodiments, a heterocycloalkyl contains 0-2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also called partially unsaturated heterocycles) that have one or more aromatic rings fused (i.e., sharing bonds) to the heterocycloalkyl ring, e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyls that contain fused aromatic rings may be bonded through any ring atom, including the ring atoms of the fused aromatic rings.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl,. [ka] These include, but are not limited to:

[0074] Unless otherwise indicated, "heterocycloalkylidene" means a divalent heterocycloalkyl group as defined above.

[0075] Unless otherwise stated, "bicyclic ring" refers to a group characterized by two connected rings. The bicyclic ring 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 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:

[0076] 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.

[0077] 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:

[0078] "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.

[0079] "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.

[0080] 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.

[0081] N(C 0 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-.

[0082] -(CH 2 ) 0 When the number of linker groups is 0, such as -, it means that the linker group is a chemical bond.

[0083] 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.

[0084] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0085] Specific pharmaceutical and medical terms 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.

[0086] 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.

[0087] "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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] therapeutic use The present invention provides the use of the compound of general formula (1) or pharmaceutical composition of the present invention in inhibiting KIF18A protein, and thus in treating one or more disorders related to the activity of KIF18A protein.Accordingly, in certain embodiments, the present invention provides a method for treating a disorder mediated by KIF18A protein, the method comprising administering the compound of the present invention or a pharmacologic composition thereof to a patient in need thereof.

[0093] In some embodiments, a method for treating cancer is provided, comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general structural formula (1) to an individual in need thereof.In some embodiments, the cancer is mediated by KIF18A protein.In other embodiments, the cancer is the hematological cancer and solid cancer, preferably a chromosomally unstable tumor, including but not limited to hematological malignancies (leukemia, lymphoma, and myeloma, including multiple myeloma, myelodysplastic syndrome, and myeloproliferative familial syndrome), solid tumors (carcinomas such as prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, and soft tissue cancer, osteosarcoma, and stromal tumors).Leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases are preferred. In another embodiment, the cancer is colon cancer, ovarian cancer, breast cancer, uterine cancer, cervical cancer, fallopian tube cancer, peritoneal cancer, lung cancer, liver cancer, head and neck cancer, pancreatic cancer, prostate cancer, oral cancer, esophageal cancer, and cancer metastasis of these cancers.In another embodiment, the breast cancer is preferably triple-negative breast cancer.In another embodiment, the ovarian cancer is preferably high-grade ovarian cancer, more preferably platinum-resistant high-grade ovarian cancer, more preferably platinum-resistant high-grade serous ovarian cancer.In another embodiment, the peritoneal cancer is preferably primary peritoneal cancer.In another embodiment, the uterine cancer is preferably serous endometrial cancer.

[0094] Route of administration 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.

[0095] "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.

[0096] The compounds of the present invention can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] (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.

[0107] 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. The following abbreviations are used in the present invention. (Boc) 2O is di-tert-butyl dicarbonate; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene; BOPCl is bis(2-oxo-3-oxazolidinyl)phosphinic chloride; t-BuONa is sodium tert-butoxide; CDCl 3 is deuterated chloroform; Cs 2 CO 3 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-dioxane; 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; K 2 CO 3 is potassium carbonate; KOAc is potassium acetate; K 3 PO 4 is potassium phosphate; LiBH 4 is lithium borohydride; min is minutes; MeOH is methanol; MS is mass spectrometry; NMR is nuclear magnetic resonance; Pd / C is palladium on carbon; Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium; Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium(0); Pd(OAc) 2 is palladium acetate; PE is petroleum ether; RuPhos-Pd-G 3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-11'-biphenylyl)]palladium(II) methanesulfonate; Sarcosine is sarcosine; TFA is trifluoroacetic acid; T 3P stands for 1-propanephosphonic anhydride; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TLC stands for thin layer chromatography; and XPhos stands for 2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl.

[0108] Example 1: Synthesis of Compound 1

[0109] [ka]

[0110] Step 1: Synthesis of compound int_1-2 [ka]

[0111] int_1-1 (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 reacted for 4 h, and LC-MS monitoring 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 as is in the next step. ESI-MS m / z: 281 [M+H] +

[0112] Step 2: Synthesis of compounds int_1-4 [ka]

[0113] int_1-2 (14 g, 49.9 mmol) was dissolved in DMSO (100 mL) and cesium carbonate (23.4 g, 71.7 mmol) and int_1-3 (6.98 g, 62.8 mmol) were added. The mixture was heated to 90 °C and reacted for 24 h, and LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (500 mL) 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 (SiO 2 , ethyl acetate:hexane=1:1) to obtain the desired product (16.3 g, yield: 88%). ESI-MS m / z: 372 [M+H] + .

[0114] Step 3: Synthesis of compounds int_1-5 [ka]

[0115] Int_1-4 (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 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (17 g). The crude product was used directly in the next step. ESI-MS m / z: 358 [M+H] + .

[0116] Step 4: Synthesis of compounds int_1-7 [ka]

[0117] int_1-5 (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_1-6 (783.2 mg, 3.08 mmol) and pyridine (730 mg, 9.24 mmol) were added. The reaction was stirred at 40° C. for 10 h. LC-MS monitoring 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 (SiO 2 , PE:EtOAc=100:1) to give a solid (1.3 g, yield: 71.4%). ESI-MS m / z: 594 [M+H] + .

[0118] Step 5: Synthesis of Compound 1 [ka]

[0119] int_1-8 (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 solution was purged with argon three times and int_1-7 (1.3 g, 2.19 mmol) was added. Under an argon atmosphere, the reaction was heated to 90 °C and reacted for 3 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography (SiO 2 , ethyl acetate:hexane=1:1) to give a solid (1 g, yield: 77.5%). 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.06 - 6.95 (m, 2H), 4.51 (t, J = 8.7 Hz, 2H), 3.73 (t, J = 6.6 Hz, 2H), 3.23 - 3.08 (m, 6H), 2.94 (t, J = 5.1 Hz, 4H), 2.15 - 1.96 (m, 4H), 1.53 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 591 [M+H] + .

[0120] Example 2: Synthesis of Compound 65

[0121]

change

[0122] ステップ1:Synthesis of compound int_65-2

[0123]

change

[0124] int_65-1 (17.6 g, 101 mmol) was dissolved in THF (200 mL) and n-BuLi (2.5 M, 60.8 mL) was slowly added dropwise at -78 °C under nitrogen atmosphere. After the reaction was reacted at -78 °C for 0.5 h, ethylene oxide (22.3 g, 506 mmol, 25.3 mL) was added dropwise to the reaction at -78 °C and the reaction was reacted at -78 °C for 1 h, then slowly heated to room temperature and reacted for another 1.5 h. LC-MS monitoring showed the reaction was complete. Saturated ammonium chloride solution (200 mL) was added to the reaction to quench the reaction. 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 (16 g, yield: 72.5%). The crude product was used as is in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 8.09 (d, J=4.9 Hz, 1H), 7.37 (d, J=4.9 Hz, 1H), 5.16 - 5.06 (m, 2H), 4.79 (t, J=5.3 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.57 - 3.53 (m, 3H), 2.86 (t, J=6.7 Hz, 2H).

[0125] Step 2: Synthesis of compound int_65-3

[0126] [ka]

[0127] int_65-2 (16.0 g, 73.5 mmol) was dissolved in methanol (200 mL) and hydrochloric acid solution (12 M, 30.6 mL) was added at 0° C. The mixture was heated to 25° C. and reacted for 3 h, and LC-MS monitoring showed the reaction was complete. At 0° C., 1N NaOH was added to the reaction to adjust the pH to 7. The aqueous phase was extracted with ethyl acetate (300 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product (10 g, yield: 78.3%). The crude product was used as is in the next step. 1 H NMR (400MHz, DMSO-d6) δ = 8.09 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 4.9 Hz, 1H), 5.16 - 5.06 (m, 2H), 4.79 (t, J = 5.3 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.57 - 3.53 (m, 3H), 2.86 (t, J = 6.7 Hz, 2H).

[0128] Step 3: Synthesis of compound int_65-4

[0129] [ka]

[0130] Int_1-4 (9.50 g, 54.7 mmol) was dissolved in a mixed solvent of THF (200 mL) and water (50 mL), and the I 2 (13.8 g, 54.7 mmol, 11.0 mL) and K 2 CO 3 (15.1 g, 109 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 h. LC-MS monitoring showed the reaction was complete. 100 mL of water was added to the reaction. 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 purified by column chromatography (SiO 2 , PE:EtOAc=1:1) to give a solid (13 g, yield: 79.3%). 1 H NMR (400MHz, DMSO-d6) δ = 10.10 (s, 1H), 7.58 (s, 1H), 3.63 (t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H).

[0131] Step 4: Synthesis of compound int_65-5

[0132] [ka]

[0133] int_65-4 (7.10 g, 23.7 mmol) and PPh 3 (9.33 g, 35.5 mmol) was dissolved in THF (100 mL) and DIAD (7.19 g, 35.5 mmol, 6.91 mL) was added dropwise slowly under nitrogen atmosphere at 0° C. The reaction was heated to 70° C. and stirred for 1 h. LC-MS monitoring showed the reaction was complete. 100 mL of water was added to the reaction. 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 purified by column chromatography (SiO 2 , PE:ethyl acetate=3:1) to obtain a solid (11 g, yield: 65.9%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.42 (s, 1H), 4.64 (t, J = 8.9 Hz, 2H), 3.31 - 3.19 (m, 2H).

[0134] Step 5: Synthesis of compound int_65-7

[0135] [ka]

[0136] int_65-5 (1.19 g, 4.26 mmol) and int_65-6 (5.16 g, 42.6 mmol) were mixed and the reaction was heated to 140 °C and stirred under nitrogen atmosphere for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (30 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 (SiO 2 , EtOAc:Hexane=5:1) to give the desired product (0.35 g, yield: 22.4%). 1H NMR (400MHz, CHLOROFORM-d) δ = 7.08 (s, 1H), 4.58 (t, J = 8.9 Hz, 2H), 3.77 - 3.68 (m, 4H), 3.15 (t, J = 8.9 Hz, 2H), 2.03 - 1.89 (m, 4H).

[0137] Step 6: Synthesis of compound int_65-8

[0138] [ka]

[0139] int_65-7(0.35g, 955μmol), NH 2 Boc (223 mg, 1.91 mmol), RuPhos Pd G3 (79.9 mg, 95.5 μmol), K 3 PO 4 (405 mg, 1.91 mmol) was dissolved in 1,4-dioxane (5 mL) and the reaction was heated to 80° C. and stirred under nitrogen atmosphere for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give the crude product (0.2 g, yield: 58.8%). This crude product was used directly in the next step. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.08 (s, 1H), 4.58 (t, J = 8.9 Hz, 2H), 3.77 - 3.68 (m, 4H), 3.15 (t, J = 8.9 Hz, 2H), 2.03 - 1.89 (m, 4H).

[0140] Step 7: Synthesis of compound int_65-9

[0141] [ka]

[0142] int_65-8 (0.20 g, 562 μmol) was dissolved in dichloromethane (5 mL) and hydrochloric acid / dioxane solution (4 M, 5 mL) was added at 0° C. The mixture was heated to 25° C. and reacted for 2 h, and LC-MS monitoring showed the reaction was complete. Ammonia water was added to the reaction solution and the pH was adjusted to 9 at 0° C. The aqueous phase was extracted with ethyl acetate (30 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 purified by column chromatography (SiO 2 , PE:EtOAc=1:1) to give a solid (108 mg, yield: 75.1%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 5.89 (s, 1H), 4.40 (t, J = 8.7 Hz, 2H), 3.64 - 3.54 (m, 4H), 2.99 (t, J = 8.6 Hz, 2H), 2.03 - 1.86 (m, 4H).

[0143] Step 8: Synthesis of compound int_65-10

[0144] [ka]

[0145] int_1-5 (70 mg, 0.196 mmol) was dissolved in DCM (3 mL) and oxalyl chloride (253.8 mg, 2 mmol) was added. The reaction was stirred at room temperature for 2 h, then concentrated under reduced pressure to remove the solvent and obtain an acyl chloride solid. int_65-9 (50 mg, 0.196 mmol) was dissolved in THF (5 mL) and sodium hydride (30 mg, 0.75 mmol, 60% purity) was added at 0° C. under nitrogen atmosphere. The reaction was heated to room temperature and reacted for 1 h, after which the reaction was cooled to 0° C. The acyl chloride prepared above was slowly added to the reaction, and the reaction was heated to 45° C. and stirred for 12 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (92 mg, yield: 79%). ESI-MS m / z: 595 [M+H] + .

[0146] Step 9: Synthesis of compound 65

[0147] [ka]

[0148] int_1-8 (39 mg, 0.309 mmol), dimethylcyclohexane-1,2-diamine (11 mg, 0.077 mmol), cuprous iodide (15 mg, 0.077 mmol), and potassium phosphate (98 mg, 0.464 mmol) were dissolved in DMF (5 mL). The solution was purged with argon three times, and int_65-10 (92 mg, 0.155 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (50 mg, yield: 55%). 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 3.73 (t, J = 6.5 Hz, 2H), 3.66 (t, J = 5.8 Hz, 4H), 3.17 (t, J = 8.8 Hz, 2H), 2.94 (t, J = 5.3 Hz, 4H), 2.16 - 1.93 (m, 4H), 1.69 (s, 4H), 0.36 (s, 4H). ESI-MS m / z: 592 [M+H] + .

[0149] Example 3: Synthesis of Compound 129

[0150] [ka]

[0151] Step 1: Synthesis of compound int_129-2

[0152] [ka]

[0153] int_129-1 (28.7 g, 131 mmol) was dissolved in acetonitrile (50 mL) and treated with potassium acetate (29.1 g, 296 mmol), ICl (21.4 g, 131 mmol, 6.71 mL) and CH 3 COOH (60 mL) was added. The mixture was heated to 50° C. and reacted for 42 h, TLC monitoring showed the reaction was complete. 500 mL of water was added to the reaction. The aqueous phase was extracted with ethyl acetate (500 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a white solid (42 g, yield: 92.8%). This solid was used as it was in the next step.

[0154] Step 2: Synthesis of compound int_129-4

[0155] [ka]

[0156] int_129-2 (37.0 g, 107 mmol) was dissolved in acetonitrile (500 mL) and mixed with int_129-3 (11.1 g, 112 mmol), CuI (409 mg, 2.15 mmol), TEA (21.8 g, 215 mmol), and Pd(PPh 3 ) 2 Cl 2(755 mg, 1.08 mmol) was added. The reaction was reacted at 20° C. for 3 h under nitrogen atmosphere, then heated to 80° C. and reacted for 8 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (500 mL) and the aqueous phase was extracted with ethyl acetate (500 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 (SiO 2 The mixture was purified with EtOAc:hexane (1:10→3:1) to give the desired product (12 g, yield: 35.5%). 1 H NMR: (400 MHz, CHLOROFORM-d) δ 8.19 (d, J = 17.4 Hz, 2H), 6.91 (s, 1H), 0.19 (s, 9H).

[0157] Step 3: Synthesis of compound int_129-6

[0158] [ka]

[0159] int_129-4 (11 g, 35.0 mmol) was dissolved in methylbenzene (300 mL), and int_129-5 (4.40 g, 36.3 mmol), BINAP (4.36 g, 7.00 mmol), t-BuONa (6.73 g, 70.0 mmol), and Pd(OAc) were added. 2 (785 mg, 3.50 mmol) was added at room temperature. The reaction was heated to 110° C. and stirred under nitrogen atmosphere for 16 h. LC-MS monitoring showed the reaction was complete. Methylbenzene was removed under reduced pressure and the reaction was diluted with water (200 mL). The aqueous phase was extracted with ethyl acetate (200 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 purified by column chromatography (SiO 2 The mixture was purified with EtOAc:hexane (1:10→3:1) to give the desired product (6.4 g, yield: 64.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (d, J = 2.0 Hz, 1H), 7.71 - 7.46 (m, 2H), 6.84 (d, J = 2.1 Hz, 1H), 3.54 - 3.47 (m, 2H), 3.45 - 3.44 (m, 1H), 3.56 - 3.36 (m, 1H), 2.20 - 2.09 (m, 4H). ESI-MS m / z: 283 [M+H] + .

[0160] Step 4: Synthesis of compound int_129-7

[0161] [ka]

[0162] int_129-6 (4.50 g, 15.9 mmol) was dissolved in ethanol (50 mL) and Fe (8.90 g, 159 mmol) and ammonium chloride solution (8.53 g, 159 mmol, 3.5 M) were added at room temperature. The reaction was heated to 70° C. and stirred under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product (3 g, yield: 74.6%). The crude product was used directly in the next step. ESI-MS m / z: 253 [M+H] + .

[0163] Step 5: Synthesis of compound int_129-8

[0164] [ka]

[0165] int_1-5 (3.50 g, 9.80 mmol) was dissolved in DCM (50 mL) and HATU (6.71 g, 17.6 mmol) and DIPEA (4.56 g, 35.3 mmol) were added. The reaction was stirred at room temperature for 0.5 h and int_129-7 (4.20 g, 11.76 mmol) was added. The reaction was heated to 50° C. and stirred for 16 h. LC-MS monitoring 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 (SiO 2 , PE:EtOAC=10:1→3:1) to obtain a solid (5 g, yield: 71.9%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 12.32 (s, 1H), 8.03 - 7.86 (m, 1H), 7.72 - 7.47 (m, 4H), 7.18 (d, J = 10.6 Hz, 2H), 6.70 (d, J = 1.4 Hz, 1H), 5.23 (s, 2H), 3.47 (br t, J = 5.3 Hz, 4H), 3.02 (br t, J = 5.0 Hz, 4H), 2.31 - 2.02 (m, 4H), 1.75 - 1.45 (m, 5H). ESI-MS m / z: 592 [M+H] + .

[0166] Step 6: Synthesis of compound 129

[0167] [ka]

[0168] int_1-8 (1.03 g, 8.24 mmol), dimethylcyclohexane-1,2-diamine (781 mg, 5.50 mmol), cuprous iodide (1.05 g, 5.50 mmol), and Cs 2 CO 3(3.58 g, 11.0 mmol) was dissolved in DMF (70 mL). The solution was purged with argon three times and int_129-8 (3.25 g, 5.50 mmol) was added. The reaction was heated to 110° C. and reacted under argon for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature and concentrated to dryness on a rotary evaporator and purified by column chromatography (SiO 2 , DCM:MeOH=10:1→1:1) to give a solid (1.5 g, yield: 46.4%). 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 2H), 7.94 (d, J = 2.1 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.14 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 3.74 (t, J = 6.6 Hz, 2H), 3.44 (t, J = 5.7 Hz, 4H), 3.29 (d, J = 6.6 Hz, 2H), 2.96 (t, J = 5.2 Hz, 4H), 2.24 - 2.07 (m, 4H), 1.55 (s, 4H), 0.33 (s, 4H). ESI-MS m / z: 589 [M+H] + .

[0169] Example 4: Synthesis of Compound 385

[0170] [ka]

[0171] Step 1: Synthesis of compound int_385-2

[0172] [ka]

[0173] int_385-1 (5.00 g, 20.7 mmol) was dissolved in DMF (50 mL), and t-BuOK (2.44 g, 21.8 mmol) was added under a nitrogen atmosphere at 0° C. After 0.5 h of reaction, CH 3 I (5.41 g, 37.3 mmol, 98% purity) was added at 0° C. The reaction was heated to 25° C. and reacted for 1 h, and TLC monitoring showed the reaction was complete. 50 mL of water was added to the reaction to precipitate. The mixture was filtered to obtain a filter cake, which was washed with water (100 mL×2) and dried to obtain a yellow solid (5 g, crude product). This solid was used as is in the next step. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 4.14 (s, 3 H) 6.59 (d, J = 3.25 Hz, 1 H) 7.08 (d, J = 3.25 Hz, 1 H) 8.19 (d, J = 2.13 Hz, 1 H) 8.40 (d, J = 2.13 Hz, 1 H).

[0174] Step 2: Synthesis of compound int_385-4

[0175] [ka]

[0176] Int_385-2 (4.80 g, 18.8 mmol) was dissolved in methylbenzene (50 mL), and RuPhos Pd G3 (1.57 g, 1.88 mmol), Cs 2 CO 3 (12.3 g, 37.6 mmol), int_385-3 (4.56 g, 37.6 mmol) were added. The reaction was heated to 100° C. and reacted under nitrogen atmosphere for 16 h, TLC monitoring showed the reaction was complete. The reaction was diluted with water (100 mL) 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 (SiO 2The mixture was purified with EtOAc:hexane (1:30→1:3) to give the desired product (3.4 g, yield: 61.2%).

[0177] Step 3: Synthesis of compound int_385-5

[0178] [ka]

[0179] int_385-4 (3.40 g, 11.5 mmol) was dissolved in ethanol (35 mL) and Fe (6.43 g, 115 mmol, 10.0 equiv.) and ammonium chloride solution (6.16 g, 115 mmol, 3.4 M) were added at room temperature. The reaction was stirred at 70 °C for 0.5 h. TLC monitoring 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 give the crude product (3.7 g). The crude product was used directly in the next step. 1 H NMR: (400 MHz, CHLOROFORM-d) δ 6.82 (d, J = 2.9 Hz, 1H), 6.75 (s, 1H), 6.46 (s, 1H), 6.22 (d, J = 2.9 Hz, 1H), 3.98 (s, 3H), 3.18 (br d, J = 10.9 Hz, 2H), 2.96 - 2.89 (m, 2H), 2.19 - 2.01 (m, 6H).

[0180] Step 4: Synthesis of compound int_385-6

[0181] [ka]

[0182] int_1-5 (3.50 g, 9.80 mmol) was dissolved in DCM (50 mL) and HATU (5.59 g, 14.7 mmol) and DIPEA (3.80 g, 29.4 mmol) were added. The reaction was stirred at room temperature for 0.5 h and int_385-5 (2.60 g, 9.80 mmol) was added. The reaction was heated to 50° C. and stirred for 16 h. LC-MS monitoring 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 (SiO 2 , PE:EtOAc=1:0→3:1) to give a solid (1.25 g, yield: 21.1%). ESI-MS m / z: 605 [M+H] + .

[0183] Step 5: Synthesis of compound 385

[0184] [ka]

[0185] int_385-6 (1.25 g, 2.07 mmol), dimethylcyclohexane-1,2-diamine (29.4 mg, 206 μmol), cuprous iodide (393 mg, 2.07 mmol), and Cs 2 CO 3 (1.35 g, 4.14 mmol) was dissolved in DMF (25 mL). The solution was purged with argon three times and int_1-8 (388 mg, 3.10 mmol) was added. The reaction was heated to 90° C. and reacted under argon for 3 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature and concentrated to dryness on a rotary evaporator and purified by column chromatography (SiO 2 The residue was purified with EtOAc:hexane (1:20→1:1) to give a solid (0.53 g, yield: 42.8%). 1H NMR: (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.06 (s, 1H), 7.94 - 7.85 (m, 2H), 7.22 - 7.20 (m, 1H), 7.19 (d, J = 1.8 Hz, 2H), 7.06 (dd, J = 2.1, 8.6 Hz, 1H), 6.39 (d, J = 3.0 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.08 (s, 3H), 3.77 (q, J = 6.3 Hz, 2H), 3.42 (br s, 4H), 3.03 - 2.85 (m, 6H), 2.35 - 2.13 (m, 4H), 1.61 (br s, 4H), 0.37 (s, 4H). ESI-MS m / z: 602 [M+H] + .

[0186] Example 5: Synthesis of compound 513

[0187]

change

[0188] ステップ1:Synthesis of compound int_513-2

[0189]

change

[0190] int_513-1(25.0g, 84.2mmol), K 2 CO 3(34.9 g, 252 mmol), MeI (119 g, 842 mmol, 52.4 mL) were dissolved in acetone (250 mL) and the reaction was heated to 60 °C and reacted under nitrogen atmosphere for 18 h. TLC monitoring showed the reaction was complete. Water (200 mL) was added to the reaction to quench the reaction. The aqueous phase was extracted with dichloromethane (200 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 purified by column chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent: 0-7% ethyl acetate / petroleum ether gradient, at 80 mL / min) to obtain a solid (23 g, yield: 87.8%). 1 H NMR (400 MHz, DMSO-d6) δ= 8.49 (m, 2H) 3.91 (s, 3H).

[0191] Step 2: Synthesis of compound int_513-3

[0192] [ka]

[0193] int_513-2(12.0g, 38.5mmol), NH 2 Boc (4.52 g, 38.5 mmol), Cs 2 CO 3 (25.1 g, 77.1 mmol), XantPhos Pd G3 (1.83 g, 1.93 mmol) were dissolved in methylbenzene (120 mL). The reaction was heated to 100 °C and reacted under nitrogen atmosphere for 3 h. LC-MS monitoring showed the reaction was complete. Water (500 mL) was added to the reaction. The aqueous phase was extracted with dichloromethane (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 purified by column chromatography (ISCO®; 200 g SepaFlash® silica flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient, at 80 mL / min) to obtain a solid (9 g, yield: 67.1%). 1 H NMR (400 MHz, DMSO-d6)δ= 9.16 (s, 1 H) 8.77 (d,J= 2.81 Hz, 1 H) 8.12 (d,J= 2.81 Hz, 1 H) 3.84 (s, 3 H) 1.51 (s, 9 H).

[0194] Step 3: Synthesis of compound int_513-5

[0195] [ka]

[0196] int_513-3(4g, 11.52mmol), int_513-4(2.79g, 23.0mmol), Pd 2 (dba) 3 (1.06 g, 1.15 mmol, 0.10 equiv.), Xantphos (1.33 g, 2.30 mmol, 0.20 equiv.), and Cs 2 CO 3 (7.51 g, 23.0 mmol, 2.00 equiv) was dissolved in methylbenzene (100 mL) and the reaction was heated to 100 °C and stirred under nitrogen atmosphere for 3 h. LC-MS monitoring showed the reaction was complete. 50 mL of water was added to the reaction. The aqueous phase was extracted with dichloromethane (50 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 purified by column chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient, at 50 mL / min) to obtain a solid (1.78 g, 39.8% yield). 1 H NMR (400 MHz, DMSO-d6)δ= 8.71 (s, 1 H) 8.46 (d, J = 2.50 Hz, 1 H) 7.51 (d, J = 2.75 Hz, 1 H) 3.87 (m, 3 H) 3.19 (br t, J = 5.19 Hz, 4 H) 2.16 (m, 4 H) 1.49 (s, 9 H).

[0197] Step 4: Synthesis of compound int_513-6

[0198] [ka]

[0199] int_513-5 (1.78 g, 4.60 mmol) was dissolved in ethyl acetate (10 mL) and HCl / ethyl acetate solution (2.50 M, 2.00 mL) was slowly added dropwise to the reaction under nitrogen atmosphere. The reaction was heated to 40° C. and stirred for 3 h. LC-MS monitoring showed the reaction was complete. The reaction was distilled under reduced pressure to give the crude product (1.65 g, yield: 99.8%). The crude product was used as is in the next step. ESI-MS m / z: 288 [M+H] +

[0200] Step 5: Synthesis of compound int_513-7

[0201] [ka]

[0202] Int_513-6 (798 mg, 2.78 mmol) was dissolved in DCM (10 mL) and incubated at 0 °C under a nitrogen atmosphere with BBr 3 (2.79 g, 11.1 mmol, 1.07 mL) was added to the reaction. The reaction was slowly heated to room temperature and allowed to react for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient, at 50 mL / min) to obtain the desired product (0.52 g, yield: 68.4%). 1H NMR (400 MHz, DMSO-d6)δ= 7.35 (d,J= 2.69 Hz, 1 H) 7.25 (d,J= 2.69 Hz, 1 H) 4.09 (br s, 1 H) 3.17 (s, 2 H) 2.94 (br t,J= 5.20 Hz, 4 H) 2.18 (m, 4H).

[0203] Step 6: Synthesis of compound int_513-8

[0204] [ka]

[0205] int_513-7 (0.52 g, 1.90 mmol) was dissolved in trimethyl orthoformate (50.3 g, 474 mmol, 52.0 mL) and the reaction was heated to 105° C. and stirred under nitrogen for 18 h. LC-MS monitoring showed the reaction was complete. The reaction was distilled under reduced pressure to give the crude product (0.5 g). The crude product was used directly in the next step. ESI-MS m / z: 284 [M+H] + .

[0206] Step 7: Synthesis of compound int_513-9

[0207] [ka]

[0208] int_513-8 (0.50 g, 1.77 mmol) and Pd / C (0.05 g, 1.77 mmol, 10% purity) were dissolved in methanol (5 mL). The reaction was allowed to react under hydrogen atmosphere at 25° C. for 18 h, and LC-MS monitoring showed the reaction was complete. The reaction was filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 30% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain a solid (0.3 g, yield: 68.2%). 1 H NMR (400 MHz, DMSO-d6)δ=7.35 (d, J = 2.69 Hz, 1 H) 7.25 (d, J = 2.69 Hz, 1 H) 4.09 (br s, 1 H) 3.17 (s, 2 H) 2.94 (br t, J = 5.20 Hz, 4 H) 2.18 (m, 4 H).

[0209] Step 8: Synthesis of compound int_513-10

[0210] [ka]

[0211] int_1-5 (124 mg, 0.3 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 mmol) was added. The reaction was stirred at room temperature for 2 h, then concentrated under reduced pressure to remove the solvent and obtain an acyl chloride solid. int_513-9 (76 mg, 0.3 mmol) was dissolved in THF (5 mL) and sodium hydride (72 mg, 1.8 mmol, 60% purity) was added at 0° C. under nitrogen atmosphere. The reaction was heated to room temperature and reacted for 1 h, after which the reaction was cooled to 0° C. The acyl chloride prepared above was slowly added to the reaction, and the reaction was heated to 40° C. and stirred for 12 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (100 mg, yield: 56.2%). ESI-MS m / z: 593 [M+H] + .

[0212] Step 9: Synthesis of compound 513

[0213] [ka]

[0214] int_1-8 (63 mg, 0.51 mmol), dimethylcyclohexane-1,2-diamine (12 mg, 0.085 mmol), cuprous iodide (16 mg, 0.085 mmol), and potassium phosphate (108 mg, 0.51 mmol) were dissolved in DMF (5 mL). The solution was purged with argon three times and int_513-10 (100 mg, 0.17 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (33 mg, yield: 33%). 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.09 (s, 1H), 8.67 (s, 1H), 7.87 (d,J= 1.7 Hz, 1H), 7.82 (d,J= 8.5 Hz, 1H), 7.21 (d,J= 1.8 Hz, 1H), 7.15 (d,J= 2.1 Hz, 1H), 7. 01 (dd,J= 8.5, 2.1 Hz, 1H), 3.74 (t,J= 6.6 Hz, 2H), 3.50 (t,J= 5.8 Hz, 4H), 2.96 (t,J= 5.3 Hz, 4H), 2.15 (tt,J= 13.4, 5.6 Hz, 4H), 1.53 (s, 4H), 0.32 (s, 4H). ESI-MS m / z: 590 [M+H] + .

[0215] Example 6: Synthesis of Compound 522

[0216] [ka]

[0217] Step 1: Synthesis of compound int_522-2

[0218] [ka]

[0219] Int_522-1 (620 mg, 1.87 mmol) and int_522-2 (226 mg, 1.87 mmol) were dissolved in 1,4-dioxane (15 mL) and cesium carbonate (913 mg, 2.8 mmol), Pd 2 (dba) 3 (171 mg, 0.187 mmol), and XantPhOS (108 mg, 0.187 mmol) were added to the reaction. The reaction was heated to 100° C. and stirred under nitrogen for 18 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO 2 , EtOAc:Hexanes=1:25) to give the desired product (486 mg, yield: 70%). ESI-MS m / z: 372 [M+H] + .

[0220] Step 2: Synthesis of compound int_522-4

[0221] [ka]

[0222] int_522-3(486mg, 1.309mmol), NH 2 Boc (460 mg, 3.8 mmol), Pd 2 (dba) 3(24 mg, 0.026 mmol), X-PhOS (18 mg, 0.039 mmol), and cesium carbonate (633 mg, 1.95 mmol) were dissolved in 1,4-dioxane (5 mL) and the reaction was heated to 100 °C and stirred under nitrogen atmosphere for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was diluted with water (30 mL) and the aqueous phase was extracted with ethyl acetate (30 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 purified by column chromatography (SiO 2 , EtOAc:Hexanes=1:10) to give the desired product (406 mg, yield: 68.3%). ESI-MS m / z: 453 [M+H] + .

[0223] Step 3: Synthesis of compound int_522-5

[0224] [ka]

[0225] int_522-4 (400 mg, 0.878 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (4 mL) was added at 0° C. The mixture was heated to 25° C. and reacted for 2 h, and LC-MS monitoring showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction at 0° C. to adjust the pH to 7. The aqueous phase was extracted with dichloromethane (30 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 purified by column chromatography to obtain a solid (220 mg, yield: 100%). ESI-MS m / z: 253 [M+H] + .

[0226] Step 4: Synthesis of compound int_522-6

[0227] [ka]

[0228] int_1-5 (140 mg, 0.396 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_522-5 (100 mg, 0.396 mmol) was dissolved in DCM (10 mL) and DIPEA (255 mg, 1.98 mmol) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to room temperature and stirred for 1 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (106 mg, yield: 45.2%). ESI-MS m / z: 592 [M+H] + .

[0229] Step 5: Synthesis of compound 522

[0230] [ka]

[0231] int_1-8 (45 mg, 0.358 mmol), dimethylcyclohexane-1,2-diamine (13 mg, 0.0895 mmol), cuprous iodide (17 mg, 0.0895 mmol), and potassium phosphate (114 mg, 0.537 mmol) were dissolved in DMF (10 mL). The solution was purged with argon three times and int_522-6 (106 mg, 0.179 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (10 mg, yield: 9.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 11.33 (s, 1H), 8.12 - 7.99 (m, 2H), 7.44 (t, J = 2.8 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 3.73 (t, J = 6.5 Hz, 2H), 3.52 (t, J = 5.7 Hz, 4H), 2.96 (s, 4H), 2.30 - 2.11 (m, 4H), 1.67 (s, 4H), 0.37 (s, 4H). ESI-MS m / z: 589 [M+H] + .

[0232] Example 7: Synthesis of Compound 530

[0233] [ka]

[0234] Step 1: Synthesis of compound int_530-2

[0235] [ka]

[0236] int_530-1 (7.40 g, 42.5 mmol) was dissolved in concentrated sulfuric acid (50 mL) and NBS (8.32 g, 46.74 mmol) was added to the reaction. The reaction was heated to 50° C. and stirred under nitrogen atmosphere for 5 h. LC-MS monitoring showed the reaction was complete. The reaction was slowly added to ice water (200 mL). The aqueous phase was extracted with ethyl acetate (200 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 purified by column chromatography to obtain the desired product (9 g, yield: 83.7%). 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.26 (dd, J = 1.6, 4.1 Hz, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.46 - 8.40 (m, 1H), 7.69 (dd, J = 4.3, 8.3 Hz, 1H).

[0237] Step 2: Synthesis of compound int_530-4

[0238] [ka]

[0239] int_522-2(9.00g, 35.6mmol), int_522-3(6.46g, 53.6mmol), Cs 2 CO 3 (23.1 g, 71.1 mmol), RuPhos Pd G3 (2.97 g, 3.56 mmol) were dissolved in methylbenzene (100 mL) and the reaction was heated to 80 °C and stirred under nitrogen atmosphere for 16 h. LC-MS monitoring 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 to obtain the desired product (4 g, yield: 38.4%). ESI-MS m / z: 294 [M+H] + .

[0240] Step 3: Synthesis of compound int_530-5

[0241] [ka]

[0242] int_530-4 (2.00 g, 6.82 mmol) was dissolved in methanol (30 mL) and Pd / C (1.00 g, 10% purity) was added. The reaction was reacted under hydrogen atmosphere at 25° C. for 16 h, and LC-MS monitoring showed the reaction was complete. The reaction was filtered and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (2.2 g, yield: 61.3%). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.57 (br d, J = 2.5 Hz, 1H), 7.79 (br d, J = 8.1 Hz, 1H), 7.23 - 7.13 (m, 2H), 6.60 - 6.46 (m, 2H), 4.05 - 3.63 (m, 2H), 3.39 (br t, J = 4.8 Hz, 4H), 2.35 - 2.14 (m, 4H).

[0243] Step 4: Synthesis of compound int_530-6

[0244] [ka]

[0245] int_1-5 (124 mg, 0.3 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_530-5 (80 mg, 0.3 mmol) was dissolved in DCM (10 mL) and NaH (72 mg, 1.8 mmol, 60% purity) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to 40° C. and stirred for 12 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (58 mg, yield: 32.2%). ESI-MS m / z: 603 [M+H] + .

[0246] Step 5: Synthesis of compound 530

[0247] [ka]

[0248] int_1-8 (19 mg, 0.15 mmol), dimethylcyclohexane-1,2-diamine (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 solution was purged with argon three times and int_530-6 (58 mg, 0.1 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (14 mg, yield: 98.1%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 12.84 (s, 1H), 8.85 - 8.75 (m, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.45 - 7.29 (m, 2H), 7.04 (d, J = 32.6 Hz, 2H), 4.15 (s, 2H), 3.55 (d, J = 6.4 Hz, 4H), 3.34 (s, 2H), 3.12 (s, 4H), 2.32 (d, J = 14.4 Hz, 4H), 1.71 (s, 4H), 0.45 (s, 4H). ESI-MS m / z: 600 [M+H] + .

[0249] Example 10: Synthesis of Compound 537

[0250] [ka]

[0251] Step 1: Synthesis of compound int_537-2

[0252] [ka]

[0253] int_1-5 (100 mg, 0.28 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_537-1 (71.7 mg, 0.28 mmol) was dissolved in DCM (10 mL) and NAH (112 mg, 2.8 mmol, 60% purity) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to 45° C. and stirred for 3 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (127 mg, yield: 76.1%). ESI-MS m / z: 596 [M+H] + .

[0254] Step 2: Synthesis of compound 537

[0255] [ka]

[0256] int_1-8 (25 mg, 0.2 mmol), dimethylcyclohexane-1,2-diamine (18 mg, 0.125 mmol), cuprous iodide (26 mg, 0.125 mmol), and potassium phosphate (164 mg, 0.747 mmol) were dissolved in DMF (5 mL). The solution was purged with argon three times and int_537-2 (120 mg, 0.2 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (76 mg, yield: 64.1%). ESI-MS m / z: 593 [M+H] + .

[0257] Example 9: Synthesis of Compound 539

[0258] [ka]

[0259] Step 1: Synthesis of compound int_539-2

[0260] [ka]

[0261] Int_539-1 (500 mg, 2.34 mmol) was dissolved in concentrated sulfuric acid (6 mL) and KNO 3 (356 mg, 3.51 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred under nitrogen atmosphere for 2 h. LC-MS monitoring showed the reaction was complete. The reaction was slowly added to ice water (50 mL). The aqueous phase was extracted with dichloromethane (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 purified by column chromatography to obtain the desired product (395 mg, yield: 65.2%). ESI-MS m / z: 258 [M+H] + .

[0262] Step 2: Synthesis of compound int_539-4

[0263] [ka]

[0264] int_539-2(300mg, 1.16mmol), int_539-3(155mg, 1.27mmol), Cs 2 CO 3 (756 mg, 2.32 mmol), RuPhos Pd G3 (97 mg, 0.116 mmol) were dissolved in 1,4-dioxane (20 mL) and the reaction was heated to 100 °C and stirred under nitrogen atmosphere for 12 h. LC-MS monitoring 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 purified by column chromatography to obtain the desired product (200 mg, yield: 44.4%). ESI-MS m / z: 299 [M+H] + .

[0265] Step 3: Synthesis of compound int_539-5

[0266] [ka]

[0267] int_530-4 (200 mg, 0.67 mmol) was dissolved in methanol (15 mL) and Pd / C (200 mg, 10% purity) was added. The reaction was allowed to react under hydrogen atmosphere at 25° C. for 16 h, and LC-MS monitoring showed the reaction was complete. The reaction was filtered and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (140 mg, yield: 78.2%). ESI-MS m / z: 269 [M+H] + .

[0268] Step 4: Synthesis of compound int_539-6

[0269] [ka]

[0270] int_1-5 (200 mg, 0.559 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_539-5 (120 mg, 0.447 mmol) was dissolved in DCM (10 mL) and DIPEA (173 mg, 1.34 mmol) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to 40° C. and stirred at room temperature for 1 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (235 mg, yield: 74.3%). ESI-MS m / z: 608 [M+H] + .

[0271] Step 5: Synthesis of compound 539

[0272] [ka]

[0273] int_1-8 (97 mg, 0.773 mmol), dimethylcyclohexane-1,2-diamine (27 mg, 0.193 mmol), cuprous iodide (37 mg, 0.193 mmol), and potassium phosphate (246 mg, 1.158 mmol) were dissolved in DMF (15 mL). The solution was purged with argon three times and int_539-6 (235 mg, 0.386 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (160 mg, yield: 68.6%). 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.5, 2.1 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.73 (t, J = 6.6 Hz, 2H), 3.31 (s, 2H), 3.05 (t, J = 5.5 Hz, 4H), 2.93 (t, J = 5.3 Hz, 4H), 2.72 (t, J = 6.5 Hz, 2H), 2.06 (q, J = 6.0 Hz, 4H), 1.90 (p, J = 6.1 Hz, 2H), 1.53 (t, J = 5.3 Hz, 4H), 0.33 (s, 4H). ESI-MS m / z: 605 [M+H] + .

[0274] Example 10: Synthesis of Compound 583

[0275] [ka]

[0276] Step 1: Synthesis of compound int_583-2

[0277] [ka]

[0278] int_1-5 (100 mg, 0.28 mmol) was dissolved in DCM (10 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_530-5 (74 mg, 0.28 mmol) was dissolved in DCM (10 mL) and NaH (112 mg, 2.8 mmol, 60% purity) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to 45° C. and stirred for 3 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (150 mg, yield: 88.8%). ESI-MS m / z: 604 [M+H] + .

[0279] Step 2: Synthesis of compound 583

[0280] [ka]

[0281] int_1-8 (34 mg, 0.249 mmol), dimethylcyclohexane-1,2-diamine (18 mg, 0.125 mmol), cuprous iodide (26 mg, 0.125 mmol), and potassium phosphate (164 mg, 0.747 mmol) were dissolved in DMF (5 mL). The solution was purged with argon three times and int_583-2 (150 mg, 0.249 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (57 mg, yield: 38%). 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.70 (dd, J = 4.2, 1.8 Hz, 1H), 8.22 (dd, J = 8.5, 1.8 Hz, 1H), 8.09 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.4, 4.1 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 4.17 (t, J = 5.3 Hz, 4H), 3.73 (t, J = 6.5 Hz, 2H), 2.99 (d, J = 6.7 Hz, 4H), 2.15 (dq, J = 14.0, 7.2, 5.8 Hz, 4H), 1.73 (s, 4H), 0.39 (s, 4H). ESI-MS m / z: 601 [M+H] + .

[0282] Example 11: Synthesis of Compound 584

[0283]

change

[0284] ステップ1:Synthesis of compound int_584-3

[0285]

change

[0286] int_584-1 (100 mg, 0.341 mmol) was dissolved in DCM (5 mL) and oxalyl chloride (253.8 mg, 2 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 an acyl chloride solid. int_584-2 (90 mg, 0.321 mmol) was dissolved in THF (5 mL) and NAH (112 mg, 2.8 mmol, 60% purity) was added under nitrogen atmosphere. The reaction was then cooled to 0° C. and the acyl chloride prepared above was slowly added to the reaction. The reaction was heated to 45° C. and stirred for 12 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a solid (150 mg, yield: 83.8%). ESI-MS m / z: 556 [M+H] + .

[0287] Step 2: Synthesis of compound 584

[0288] [ka]

[0289] int_1-8 (84 mg, 0.674 mmol), dimethylcyclohexane-1,2-diamine (32 mg, 0.225 mmol), cuprous iodide (43 mg, 0.225 mmol), and potassium phosphate (286 mg, 1.348 mmol) were dissolved in DMF (10 mL). The solution was purged with argon three times and int_584-3 (150 mg, 0.270 mmol) was added. The reaction was heated to 100 °C under argon atmosphere and reacted for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature, concentrated to dryness on a rotary evaporator, and purified by column chromatography to give a solid (50 mg, yield: 30.9%). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.97 (dt, J = 4.1, 2.1 Hz, 1H), 8.47 (dd, J = 8.3, 1.9 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.72 - 7.58 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.6, 2.3 Hz, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 5.5 Hz, 4H), 3.22 (t, J = 6.7 Hz, 2H), 2.86 (t, J = 5.2 Hz, 4H), 2.24 (q, J = 12.2 Hz, 4H), 1.51 (s, 4H), 0.32 (d, J = 2.3 Hz, 4H).

[0290] Example 12: Synthesis of Compound 595

[0291] [ka]

[0292] Step 1: Synthesis of compound int_595-2

[0293] [ka]

[0294] 1 (0.50 g, 846 μmol) was dissolved in tetrahydrofuran (10 mL), and int_595-1 (919 mg, 4.23 mmol), BOPCl (538 mg, 2.12 mmol), 3-nitro-4H-1,2,4-triazole (241 mg, 2.12 mmol) and DIPEA (547 mg, 4.23 mmol) were added. The mixture was reacted at room temperature for 4 h, and LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO 2, PE / EtOAc=10 / 0→1 / 1) to obtain the desired product (0.6 g, yield: 89.7%). ESI-MS m / z: 790 [M+H] + .

[0295] Step 2: Synthesis of compound 595

[0296] [ka]

[0297] int_595-2 (0.60 g, 759 μmol) was dissolved in HCl / dioxane solution (4M, 6 mL). The solution was reacted at room temperature for 2 h, and LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was then diluted with saturated NaHCO 3 The solution (6 mL) was added to the crude product and the pH was adjusted to 7-8. The aqueous phase was extracted with dichloromethane (6 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the desired product (490 mg, yield: 90.3%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 12.13 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 7.26 (d, J = 1.9 Hz, 1H), 7.06 (s, 1H), 6.98 (dd, J = 1.9, 8.5 Hz, 1H), 4.60 - 4.46 (m, 4H), 3.43 - 3.35 (m, 2H), 3.27 - 3.20 (m, 5H), 3.17 (t, J = 8.8 Hz, 2H), 3.00 (br t, J = 5.1 Hz, 4H), 2.15 - 1.92 (m, 5H), 1.58 (br s, 4H), 0.90 (dd, J = 6.9, 11.5 Hz, 6H), 0.35 (s, 4H). ESI-MS m / z: 690 [M+H] + .

[0298] Example 13: Synthesis of Compound 611

[0299] [ka]

[0300] Step 1: Synthesis of compound int_611-1

[0301] [ka]

[0302] 385 (0.58 g, 985 μmol) was dissolved in tetrahydrofuran (10 mL), and int_595-1 (1.07 g, 4.93 mmol), BOPCl (627 mg, 2.46 mmol), 3-nitro-4H-1,2,4-triazole (281 mg, 2.46 mmol) and DIPEA (637 mg, 4.93 mmol) were added. The mixture was reacted at room temperature for 4 hours, and LC-MS monitoring showed the reaction was complete. The reaction solution was filtered to obtain the filtrate, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO 2 , PE / EtOAc=5 / 1→3 / 1) to give the desired product (0.17 g, yield: 38.5%). ESI-MS m / z: 788 [M+H] + .

[0303] Step 2: Synthesis of compound 611

[0304] [ka]

[0305] int_611-1 (0.93 g, 1.18 mmol) was dissolved in HCl / dioxane solution (4 M, 2.95 mL). The solution was reacted at room temperature for 0.5 h, and LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was then washed with saturated NaHCO 3Solution (10 mL) was added to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the desired product (130 mg, yield: 28.5%). 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.20 - 8.18 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 4.51 (t, J = 5.8 Hz, 2H), 3.45 (m, 4H), 3.39 (m, 2H), 3.25 - 3.16 (m, 1H), 3.12 (br s, 4H), 2.39 - 2.22 (m, 4H), 2.01 - 1.83 (m, 1H), 1.81 - 1.64 (m, 4H), 0.97 - 0.87 (m, 6H), 0.48 (s, 4H). ESI-MS m / z: 688 [M+H] + .

[0306] Example 14: Synthesis of Compound 643

[0307] [ka]

[0308] Step 1: Synthesis of compound int_643-1

[0309] [ka]

[0310] 385 (0.50 g, 831 μmol) was dissolved in tetrahydrofuran (10 mL), and int_595-1 (902 mg, 4.15 mmol), BOPCl (528 mg, 2.08 mmol), 3-nitro-4H-1,2,4-triazole (237 mg, 2.08 mmol) and DIPEA (537 mg, 4.15 mmol) were added. The mixture was reacted at room temperature for 4 h, and LC-MS monitoring 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 purified by column chromatography (SiO 2 , PE / EtOAc=10 / 0→1 / 1) to obtain the desired product (0.5 g, yield: 75.1%). ESI-MS m / z: 801 [M+H] + .

[0311] Step 2: Synthesis of compound 643

[0312] [ka]

[0313] int_643-1 (0.50 g, 624.3 μmol) was dissolved in HCl / dioxane solution (4 M, 5 mL). The solution was allowed to react at room temperature for 2 h, and LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product, which was then washed with saturated NaHCO 3 Solution (5 mL) was added to adjust the pH to 7-8. The aqueous phase was extracted with dichloromethane (5 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the desired product (130 mg, yield: 28.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ 12.27 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.11 (br d, J = 7.0 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.51 - 6.47 (m, 1H), 4.73 - 4.50 (m, 2H), 4.18 - 4.09 (m, 3H), 3.57 - 3.47 (m, 2H), 3.35 (br d, J = 10.4 Hz, 2H), 3.11 (br t, J = 5.2 Hz, 7H), 2.13 (br s, 5H), 1.65 (br s, 4H), 1.06 - 0.96 (m, 6H), 0.46 - 0.37 (m, 4H). ESI-MS m / z: 701 [M+H] + .

[0314] By using different starting materials and employing the above synthesis methods, the target compounds 2-64, 66-128, 130-384, 386-512, 514-521, 523-529, 531-536, 538, 540-582, 585-594, 596-610, 612-642, and 644-814 in Table 1 were obtained.

[0315] [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

[0316] Biological Example 1: In vitro inhibition assay of KIF18A enzymatic activity by compounds of the present invention 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 MgCl 2, 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 minutes, followed by the addition of ATP (Km, 75 μM). The resulting reaction mixture was incubated at room temperature for another 15 minutes. 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 minutes. 10 μL of ADP-Glo ​​detection reagent was added, and the mixture was incubated at room temperature for 40 minutes. Luminescence was measured using a microplate reader, and compared with the DMSO group, and the inhibition rate and IC of the compounds were calculated. 50 The values ​​were calculated, and the results are shown in Table 2 below.

[0317] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0318] As can be seen from the data in Table 2, the compounds of the present invention have good inhibitory activity against the enzyme activity of KIF18A.

[0319] 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 at a 1:5 ratio starting from 5 μM were added. 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 3 below.

[0320] [Table 3]

[0321] The reference compound AMG650 is compound 4 in WO2020132648A1.

[0322] [ka]

[0323] As can be seen from the data in Table 3, some of the compounds of the present invention have stronger antiproliferative activity against HT-29 cells than AMG650.

[0324] 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 at a 1:5 ratio starting from 5 μM were added. Viability was evaluated 72 hours after administration by measuring the intracellular ATP content. The inhibition rate of viable cells by the compounds was calculated compared to the DMSO group and was expressed as IC 50 The values ​​were also calculated and the results are shown in Table 4 below.

[0325] [Table 4]

[0326] As can be seen from the data in Table 4, none of the compounds of the present invention have antiproliferative activity against HCT116 cells.

[0327] 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. Compounds of general formula (1), their isomers, crystals thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates 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, Ring A is 7- to 10-membered cycloalkylene, 7- to 10-membered heterocycloalkylene, 7- to 10-membered heteroarylene, or 10-membered arylene, where the 7- to 10-membered cycloalkylene, the 7- to 10-membered heterocycloalkylene, the 7- to 10-membered heteroarylene, or the 10-membered arylene is optionally substituted with 0, 1, 2, or 3 groups selected from H, halogen, -C １～４ hydrocarbyl, -C １～４ halohydrocarbyl, or -O-C １～４ hydrocarbyl and may be optionally substituted with any 0, 1, 2, or 3 groups selected therefrom, L is -(C=O)-NR ３ - ＊＊＊＊ or -NR ３ - (C = O) - ＊＊＊＊ And, ＊＊＊＊ teeth, 【Chemistry 2】 This represents a bond to the terminal, R １ is -CN or -Z-R １０ Here, Z is a chemical bond, -C ０～４ Hydrocarbylene-,-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 Hydrocarbylene-O- ＊＊ , -(C=O)-, -(C=O)NR １１ -, -C(=N-OH)-, or -NR １１ (C=O)- ＊＊ It is either or base-Z-R １０ is -N=S(=O)-(R １０ ) ２ And here, the two R １０ These may combine with the sulfur atoms bonded to them to form saturated or partially saturated three-, four-, five-, or six-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. ＊＊ R １０ Represents bonding to the terminal, R ２ is a halogen or group -Y-R １２ Here, Y is a chemical bond, -C ０～４ Hydrocarbylene-,-N(C) ０～１ Hydrocarbyl)-C ０～４ Hydrocarbylene - ＊＊＊ , -C(=O)NR ａ (C １～４ Hydrocarbil) - ＊＊＊ , -O-C ０～４ Hydrocarbylene - ＊＊＊ , -S-, -S(=O)-, -SO ２ -, -SO ２ NR １２ - ＊＊＊ , or -S(=O)(=NH)- ＊＊＊ And, ＊＊＊ R １２ Represents bonding to the terminal, R ３ is H, or C １～６ It is hydrocarbil, R ５ H, halogen, C １～８ Alkyl, or C １～４ It is a haloalkyl, R ６ H, halogen, C １～８ Alkyl, C １～４ Haloalkyl, -OH, -O-R ６ａ , or -OR ６ｂ And, R ７ H, halogen, C １～８ Hydrocarbil, or C １～４ It is halohydrocarbil, R ８ teeth, 【Transformation 3】 Selected from the group consisting of, R １３ａ 、R １３ｂ 、R １３ｃ 、R １３ｄ 、R １３ｅ 、R １３ｆ 、R １３ｇ 、R １３ｈ 、R １３ｉ 、R １３ｊ 、R １３ｋ 、and R １３ｌ are each independently H, halogen, R １３ｍ 、or R １３ｎ 、or, 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 which may independently form, together with the carbon atom to which they are each attached, a saturated or partially saturated monocyclic 3-membered, 4-membered, 5-membered or 6-membered ring spiro-fused to the R ８ ring, where the 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further, the 3-membered, 4-membered, 5-membered or 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups 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 １０ H, R １０ａ , R １０ｂ , or R １０ｃ And, R １１ H, R １１ａ , or R １１ｂ And, R １２ R １２a or R １２b And, R ６ａ , R １０ａ , R １１ａ , R １２ａ , or R １３ｍ In each case, the monocyclic ring is independently selected from saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 4-, 5-, 6-, 7-membered bicyclic rings, each containing independently 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, where the monocyclic ring and the bicyclic ring are independently selected from F, Cl, Br, and C. １～６ Hydrocarbil, C １～４ Halohydrocarbil, -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 Hydrocarbil NR ａ R ａ , -OC ２～６ Hydrocarbil 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 Hydrocarbil NR ａ R ａ , -NR ａ C ２～６ Hydrocarbil OR ａ , -C １～６ Hydrocarbil NR ａ R ａ , -C １～６ Hydrocarbil OR ａ , -C １～６ Hydrocarbyl N(R) ａ )C(=O)R ｂ , -C １～６ Hydrocarbyl OC(=O)R ｂ , -C １～６ Hydrocarbyl C(=O)NR ａ R ａ , -C １～６ Hydrocarbyl C(=O)OR ａ , R ４ , and may be optionally substituted with 0, 1, 2, or 3 groups selected from oxo, R ６ｂ , R １０ｂ , R １１ｂ , R １２ｂ , or R １３ｎ In each case, C １～６ Selected independently from hydrocarbyl, where hydrocarbyl is F, Cl, Br, -R ａ , -OR ａ , -OC １～４ It may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from halohydrocarbyl and CN. R １０ｃ In each case, C １～６ Selected independently from hydrocarbyl, where hydrocarbyl is F, Cl, Br, -R ａ , -R ｃ , -OR ａ , -OC １～４ They may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from halohydrocarbyl and CN. R ４ In each case, independently, the group is selected from a saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-membered bicyclic ring, each containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, where the monocyclic ring and the bicyclic ring are independently F, Cl, Br, and C １～６ Hydrocarbil, C １～４ Halohydrocarbil, -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 Hydrocarbil NR ａ R ａ , -OC ２～６ Hydrocarbil 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 Hydrocarbil NR ａ R ａ , -NR ａ C ２～６ Hydrocarbil OR ａ , -C １～６ Hydrocarbil NR ａ R ａ , -C １～６ Hydrocarbil OR ａ , -C １～６ Hydrocarbyl N(R) ａ )C(=O)R ｂ , -C １～６ Hydrocarbyl OC(=O)R ｂ , -C １～６ Hydrocarbyl C(=O)NR ａ R ａ , -C １～６ Hydrocarbyl C(=O)OR ａ , and may be optionally substituted with 0, 1, 2, or 3 groups selected from oxo, R ａ In each case, independently, H or R ｂ And, R ｂ In each case, independently, C １～６ Hydrocarbyl, phenyl, or benzyl, where the hydrocarbyl is a halogen, -OH, -OC １～４ Hydrocarbyl, -NH ２ , - NHC １～４ Hydrocarbyl, -OC(=O)C １～４ Hydrocarbyl, or -N(C) １～４ Hydrocarbyl C １～４ They may be optionally substituted with 0, 1, 2, or 3 groups selected from hydrocarbyl, and the phenyl and benzyl may each be independently substituted with halogens, C １～４ Hydrocarbil, C １～３ Halohydrocarbyl, -OH, -OC １～４ Hydrocarbyl, -NH ２ , - NHC １～４ Hydrocarbyl, -OC(=O)C １～４ Hydrocarbyl, or -N(C) １～４ Hydrocarbyl C １～４ It may be optionally substituted with 0, 1, 2, or 3 groups selected from hydrocarbyl: R ｃ In each case, independently, -OC(=O)C １～５ It is a hydrocarbyl, where the hydrocarbyl is -OH or -NH ２ (One, two, or three of these may be arbitrarily substituted.)

2. The above general formula (1) has the following structure: 【Chemistry 4】 A compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having the above.

3. In the general formula (1) above, ring A is a 9-10 membered cycloalkylene, a 9-10 membered heterocycloalkylene, a 9-10 membered heteroarylene, or a 10 membered arylene, where the 9-10 membered cycloalkylene, the 9-10 membered heterocycloalkylene, the 9-10 membered heteroarylene, or the 10 membered arylene is H, F, Cl, Br, -C １～４ Hydrocarbyl, -C １～４ Halohydrocarbil, or -O-C １～４ It may be optionally substituted with 0, 1, 2, or 3 groups selected from hydrocarbyl, Preferably, ring A is 【Chemistry 5-1】 【Chemistry 5-2】 Here, * represents a bond to the L-terminus, and the above group may be optionally substituted with 0, 1, 2, or 3 groups selected from H, F, Cl, Br, -CH3, -CH2CH3, -CF3, -CH2CF3, -OCH3, or -OCH2CH3. More preferably, ring A is 【Transformation 6】 The compound according to claim 1, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, wherein * represents a bond to the L terminus, and the above group may be optionally substituted with 0, 1, 2, or 3 groups selected from H, F, Cl, Br, -CH3, -CH2CH3, -CF3, -CH2CF3, -OCH3, or -OCH2CH3, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

4. In the above general formula (1), R ３ The compound according to claim 1, or its isomer, its crystalline form, its pharmaceutically acceptable salt, its hydrate or solvate, wherein the compound is H, methyl, or ethyl, preferably H.

5. In the above general formula (1), R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ , R １３ｉ , R １３ｊ , R １３ｋ , and R １３ｌ However, each is independent of H, halogen, and C. １～６ Hydrocarbil, or C １～４ It is halohydrocarbil, R １３ａ / R １３ｂ R in the pair １３ａ and R １３ｂ However, when combined with the carbon atoms bonded to each of them, R ８ A saturated three-, four-, or five-membered monocyclic ring may be formed by spirobonding to the ring, wherein the monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, preferably R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ , R １３ｉ , R １３ｊ , R １３ｋ , and R １３ｌ However, each is independently H, methyl, or ethyl, and R １３ａ / R １３ｂ R in the pair １３ａ and R １３ｂ However, when combined with the carbon atoms bonded to each of them, R ８ The compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may form a cyclopropyl, cyclobutyl, or cyclopentyl ring spirobonded to the ring.

6. In the above general formula (1), the structural unit is: 【Transformation 7】 but, 【Transformation 8】 Preferably, 【Chemistry 9】 The compound described in claim 1, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

7. In the general formula (1) above, Z is a chemical bond, -NH-, -NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ The compound according to claim 1, which is -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, or an isomer thereof, a crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

8. In the above general formula (1), R １０ However, (a) H; or (b) C １～６ A hydrocarbyl, wherein the hydrocarbyl is F, Cl, Br, -OH, or -OCH ３ C may be optionally substituted with 0, 1, 2, or 3 of the groups. １～６ Hydrocarbyl; or (c) group, wherein the group-Z-R １０ However, -N=S(=O)-(R １０ ) ２ In that case, two of the R １０ However, when combined with the sulfur atoms bonded to them, they can form saturated, partially saturated, or unsaturated 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, where the monocyclic ring is composed of F, Cl, Br, C １～６ Hydrocarbil, C １～４ Halohydrocarbil, -C １～６ Hydrocarbylene OH, -OH, -OCH ３ , -NH ２ , or a group substituted with 0, 1, 2 or 3 groups selected from oxo; or (d) C １～６ A hydrocarbyl, where C １～６ Hydrocarbyl is -OC(=O)C １～５ It may be optionally substituted with one, two, or three groups selected from hydrocarbyl, where C １～５ Hydrocarbyl is -OH or -NH ２ The C may be arbitrarily substituted with one or two of the groups, １～６ Hydrocarbyl is F, Cl, Br, -OH or -OCH ３ C may be optionally substituted with 0, 1, 2, or 3 of the groups. １～６ A compound selected from hydrocarbyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

9. In the above general formula (1), R １ However, -CN or base-Z-R １０ Here, 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)-, R １０ but, (a) H; (b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranil, oxetanil, tetrahydrofuranil, azetidinil, imidazolyl, morpholinil, pyrrolidinil, piperazinil, 【Chemistry 10】 (Here, each ring is independently OH, F, methyl, -CH ２ OH, -C(=O)OCH ３ , -C(=O)OC(CH ３ ) ３ NH ２ Preferably, oxetanyl or cyclopropyl (which may be optionally substituted with 0, 1, 2, or 3 groups from among CN and oxo; (c) 0, 1, 2 or 3 OH, F, -C(=O)OCH ３ , -NH ２ ,-NH(CH ３ ) or -N(CH ３ ) ２ C replaced by １～６ Hydrocarbyl, preferably substituted with 0, 1, 2, or 3 OH groups, C １～６ Hydrocarbyl, more preferably substituted with one OH group, C １～６ Hydrocarbil; or (d) C １～６ Hydrocarbyl, and the C １～６ Hydrocarbil, 【Chemistry 11】 The C may be optionally replaced with one, two, or three of the selected groups. １～６ Hydrocarbyl is F, Cl, Br, -OH or -OCH ３ C may be optionally substituted with 0, 1, 2, or 3 of the groups. １～６ A compound selected from hydrocarbyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

10. In the above general formula (1), the base-Z-R １０ However, -N=S(=O)-(R １０ ) ２ And here, the two R １０ However, these may be combined with the sulfur atoms bonded to them to form saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, preferably the group-Z-R １０ but, 【Chemistry 12】 Selected from, or, In the general formula (1) above, R1 is the group -Z-R10, where Z is -NHSO2- or -SO2NH-; R10 is oxetanyl or cyclopropyl, or R10 is C1-6 hydrocarbyl substituted with 0, 1, 2 or 3 OH groups, or R10 is C1-6 hydrocarbyl, where the C1-6 hydrocarbyl is 【Chemistry 13】 It may be optionally replaced by one, two, or three elements selected from, or In the general formula (1) above, R 10 is selected from C 1 to 6 hydrocarbil, where the hydrocarbil is 【Chemistry 14】 Preferably, 【Chemistry 15】 It may be optionally substituted with 0, 1, 2, or 3 groups selected from; Z is -NHSO₂- or -SO₂NH-, and Z is preferably -NHSO₂- or In the general formula (1) above, R 10 is selected from C 1 to 6 hydrocarbil, where the hydrocarbil is 【Chemistry 16】 The compound according to claim 1, or an isomer thereof, the same, a pharmaceutically acceptable salt thereof, the same, or the same solvate thereof, wherein Z is optionally substituted with one, two, or three of the groups, and Z is -NHSO₂- or -SO₂NH-.

11. In general formula (1), R ２ However, halogen or base-Y-R １２ Here, Y is a chemical bond, -NH-, -NH- (CH ２ ) ０～４ -, or -O-(CH ２ ) ０～４ - and R １２ However, the monocyclic ring is saturated, partially saturated, or unsaturated, comprising 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and is a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic ring, or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring, where the monocyclic ring and the bicyclic ring are independently composed of F, Cl, Br, and C. １～６ Hydrocarbil, C １～４ Halohydrocarbyl, -OH, -OC １～４ Halohydrocarbyl, CN, R １４ , and may be optionally substituted with 0, 1, 2, or 3 groups selected from oxo, or R １２ However, C １～６ It is a hydrocarbyl, where the hydrocarbyl is F, Cl, Br, -OH, -OC １～４ The compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from halohydrocarbyl or CN.

12. In the above general formula (1), R ２ However, it is a saturated five-membered or six-membered monocyclic ring, and each of the rings contains 0, 1 or 2 N atoms and 0 or 1 O atom, and each of the rings contains F, Cl, Br, C １～６ Hydrocarbil, C １～４ Halohydrocarbyl, -OH, -OC １～４ Halohydrocarbyl, CN, R １４ , and are substituted with 0, 1, 2, or 3 groups selected from oxo, or In the general formula (1) above, R2 is (a) halogen; (b) group-Y-R12 (wherein Y is a chemical bond, and R12 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, 【Chemistry 17】 (c) a group -Y-R12 (wherein Y is -NH-, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2), and R12 is, [Chemistry 18] Either R 12 is C 1-6 hydrocarbyl, where the hydrocarbyl may be optionally substituted with 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, methyl, CF3, -OH, or CN), or In the general formula (1) above, R2 is morpholinyl or piperidinyl, where the morpholinyl and piperidinyl may be optionally substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2, and CN, or In the general formula (1) above, R2 is piperidinyl substituted with 1, 2, or 3 fluorine groups, or In the above general formula (1), R 2 is 【Chemistry 19】 and, or, In the general formula (1) above, R2 is morpholinyl substituted with 1, 2, or 3 methyl groups, or In the above general formula (1), R 2 is 【Chemistry 20】 The compound described in claim 1, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

13. In the above general formula (1), R １０ The compound according to claim 1, or an isomer thereof, the crystal thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, wherein R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiadinyl, and R 5 is H or F, R 6 is H or F, and R 7 is H.

14. The compound has the following structure: 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 【Chemistry 21-7】 【Chemistry 21-8】 【Chemistry 21-9】 【Chemistry 21-10】 【Chemistry 21-11】 【Chemistry 21-12】 [Chemistry 21-13] [Chemistry 21-14] 【Chemistry 21-15】 【Chemistry 21-16】 【Chemistry 21-17】 [Chemistry 21-18] 【Chemistry 21-19】 A compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the above.

15. The compound has the following structure: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 【Chemistry 22-4】 【Chemistry 22-5】 【Chemistry 22-6】 【Chemistry 22-7】 A compound according to claim 1, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the above.

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