CDK2 inhibitors and their preparation methods and uses

Abstract

The present invention provides CDK2 inhibitors, methods for preparing the same, and pharmaceutical compositions, as well as the use of said compounds or pharmaceutical compositions in the preparation of medicaments for preventing or treating CDK2-mediated related diseases, including abnormal cell growth. [Formula 1] TIFF2025539116000135.tif28170

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine, specifically relates to CDK2 inhibitor compounds and their preparation methods, and their use in the treatment of tumor-related diseases mediated by CDK2. [Background technology]

[0002] Since their discovery, tumors have been the leading threat to human health, and from the discovery of the first antitumor drug, nitrogen mustard, in the 1940s to the discovery of the first tumor-targeted drugs in the 1990s, the survival rates of patients with most types of tumors have been constantly increasing.

[0003] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that regulate cell cycle progression and gene transcription through phosphorylation, maintaining orderly progression through each phase of the cell cycle. Currently, cyclin-dependent kinases are divided into two types: cell cycle-related kinases, including CDK1, CDK2, CDK3, CDK4, and CDK6, which primarily regulate each phase of the cell cycle; and transcription-related kinases, including CDK7, CDK8, CDK9, CDK11, CDK12, and CDK13, which primarily regulate gene transcription. CDKs are catalytically active only after binding to regulatory subunits, cyclins, to form heterodimers (CDKs-cyclins). CDKs are also positively and negatively regulated by cyclins and cyclin-dependent kinase inhibitors (CKIs).

[0004] Loss of cell cycle regulatory mechanisms is a hallmark of tumorigenesis, and CDK dysfunction is common in malignant tumors. Therefore, inhibiting CDKs to treat malignant tumors has become a hot topic in anti-tumor therapy. Over the past decade, significant progress has been made in the development of CDK inhibitors, and selective CDK4 / 6 dual inhibitors have already demonstrated potent clinical activity and manageable toxicity. Currently, several CDK4 / 6 inhibitors have been successfully developed and marketed, and are approved for the treatment of breast cancer. They also show excellent clinical efficacy and manageable safety in lung cancer, prostate cancer, and ovarian cancer. CDK2 and CDK4 / 6 belong to the same cell cycle-related kinase family and are crucial core cell cycle regulators, active throughout the late G1 to S phase. These inhibitors are currently a hot topic in CDK development.

[0005] Clinical studies have demonstrated that three CDK4 / 6 inhibitors, Palboclib, Ribociclib, and Abemaciclib, can significantly extend progression-free survival in patients. CDK4 / 6 inhibitors have been established as the standard treatment for endocrine drug resistance in breast cancer. However, treatment after CDK4 / 6 inhibitor resistance remains a major challenge in clinical breast cancer treatment. Phase III clinical studies of Palboclib demonstrated that 70% to 80% of patients developed drug resistance 12 to 36 months after CDK4 / 6 inhibitor treatment. Investigations into the factors underlying drug resistance suggest that CDK2 activity is upregulated through CCNE1 amplification or p27Kip1 downregulation, which then increases Rb phosphorylation, enabling G1 / S phase transition and promoting cell proliferation. 10% to 20% of breast cancer patients exhibited CDK4 / 6 inhibitor insensitivity at the start of treatment, and studies of these patients found that CCNE1 expression was significantly elevated in these patients. Therefore, inhibiting CDK2 is expected to reverse drug resistance following treatment with CDK4 / 6 inhibitors.

[0006] The CCNE1 gene encodes cyclin E1, a gene that can be amplified in various tumors, with amplification rates ranging from 0.4% to 40.4% (including 34.53% of breast cancer patients, 7.09% of breast cancer patients, 15.51% of gastric cancer patients, and 17.33% of lung cancer patients). The cyclin encoded by this gene forms a complex with CDK2 and functions as its regulatory subunit, the activity of which is essential for the G1 / S transition of the cell cycle. This protein accumulates at the G1-S phase boundary and is degraded as cells enter S phase. Studies have shown that CCNE1 amplification is more common in primary platinum-resistant epithelial ovarian cancer, and that this gene amplification is associated with poor prognosis in ovarian cancer, gastric cancer, endometrial cancer, and triple-negative breast cancer. CDK2 inhibitors may have a beneficial effect on tumor growth inhibition in patients with CCNE1 amplification. In addition, preclinical studies have suggested that CDK2 inhibitors have the advantage of being equally effective and safer than CDK2 / 4 / 6 inhibitors. A single CDK2 inhibitor can be used in combination with other CDK inhibitors, offering the advantages of more flexible, safer, and more controllable dosing.

[0007] CDK1 binds to cyclin A and cyclin B and controls the progression of the cell cycle from the S phase to the G2 and M phases. Its function cannot be replaced by other members of the CDK family, and inhibition of the kinase activity of CDK1 causes relatively significant toxicity.

[0008] For these reasons, there is a strong need for the development of highly active and highly specific CDK2 inhibitors for the treatment of various tumors, and there is a huge market demand for such inhibitors. Summary of the Invention

[0009] In one aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof: [ka] Among them, X1 is selected from NH or O; X2 is selected from CH2 or O; R1 is [ka] Selected from R 2a and R 2b are each independently H or C 1-6 alkyl groups, 1-6 The alkyl group is optionally C 1-6 Alkoxy group, R 2c -S(O)2- or R 2c -S(O)(NH)-, and R 2c is H, C 1-6 Alkyl group, C 3-6 selected from a cycloalkyl group or an amino group, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f are each independently H, CH3-S(O)2-CH2-, (CH3)2-P(O)- or [ka] Selected from R4 and R5 are independently H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Fluoroalkyl group, C 2-6 Fluoroalkenyl group, C 2-6 Fluoroalkynyl group, C 3-10 cycloalkyl groups, among which each of the above C 1-6 The terminal C atom of the alkyl group is optionally substituted with a cyano group, of which each of the above C 3-10 the cycloalkyl group is optionally substituted with a difluoromethylene group; Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups.

[0010] In some embodiments of the compounds of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R 2a and R 2b are each independently H or C 1-6 alkyl groups, 1-6 The alkyl group is optionally C 1-6 Alkoxy group, R 2c -S(O)2- or R 2c -S(O)(NH)-, and R 2c is H, C 1-6 Alkyl group, C 3-6 selected from a cycloalkyl group or an amino group, R4 and R5 are independently H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Fluoroalkyl group, C 2-6 Fluoroalkenyl group, C 2-6 Fluoroalkynyl group, C 3-10 cycloalkyl groups, among which each of the above C 1-6 The terminal C atom of the alkyl group is optionally substituted with a cyano group, of which each of the above C 3-10 the cycloalkyl group is optionally substituted with a difluoromethylene group; Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups.

[0011] In some embodiments of the compounds of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R 2a and R 2b are each independently selected from H or a methyl group, wherein the methyl group is optionally substituted with a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, CH3-S(O)2-, CH3CH2-S(O)2-, cyclopropyl-S(O)2-, NH2-S(O)2- or CH3-S(O)(NH)-; R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, n-butan-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, and adamantyl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Form.

[0012] In some embodiments of the compounds of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3fare each independently H, CH3-S(O)2-CH2-, (CH3)2-P(O)- or [ka] Selected from R4 and R5 are independently H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Fluoroalkyl group, C 2-6 Fluoroalkenyl group, C 2-6 Fluoroalkynyl group, C 3-10 cycloalkyl groups, among which each of the above C 1-6 The terminal C atom of the alkyl group is optionally substituted with a cyano group, of which each of the above C 3-10 the cycloalkyl group is optionally substituted with a difluoromethylene group; Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups.

[0013] In some embodiments of the compound of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R 3a , R 3c are each independently selected from H, and R 3b are independently selected from CH3-S(O)2-CH2-; R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, n-butan-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, and adamantyl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Form.

[0014] In some embodiments of the compound of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R 3d , R 3f are each independently selected from H, then R 3e are independently selected from CH3-S(O)2-CH2-, (CH3)2-P(O)-, or R 3d , R 3e are each independently selected from H, then R 3f are independently [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, n-butan-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, and adamantyl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Form.

[0015] In some embodiments of the compounds of Formula (I), X1 is selected from NH, R1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, n-butan-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, and adamantyl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Form.

[0016] In another aspect, the present invention provides a compound of formula (II), a pharmaceutically acceptable salt, stereoisomer or deuterated salt thereof: [ka] Among them, X1 is selected from NH or O; X2 is selected from CH2 or O; L1 is selected from a 6- to 10-membered aryl group, a 6- to 10-membered heteroaryl group, or a 6- to 10-membered heterocyclyl group, and the 6- to 10-membered aryl group, the 6- to 10-membered heteroaryl group, or the 6- to 10-membered heterocyclyl group is optionally substituted with 1, 2, or 3 R6; R4 and R5 are independently H, C 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Fluoroalkenyl group, C 2-6 alkynyl groups, Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups; Each R6 is independently H, halogen, C 1-6 an alkyl group, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7 or a 6- to 10-membered heterocyclyl group; 1-6 The alkyl group is optionally C 1-6 The 6- to 10-membered heterocyclyl group is optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, C 1-6 Alkyl group or C 1-6 substituted with a haloalkyl group; R7 is independently selected from a 6- to 10-membered heterocyclyl group, which optionally contains 1, 2, 3, 4, 5 halogen atoms, C 1-6 Alkyl group or C 1-6 substituted with a haloalkyl group; "N atom marked with *" indicates the N atom in general formula (II) that is connected to R4 and R5.

[0017] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is selected from a phenyl group, a pyridyl group, a pyrazolo[1,5-a]pyrazinyl group, a 2,3-dihydropyrrolo[3,4-c]pyridin-1-one group, and a piperidinyl group, and the phenyl group, the pyridyl group, the pyrazolo[1,5-a]pyrazinyl group, the 2,3-dihydropyrrolo[3,4-c]pyridin-1-one group, and the piperidinyl group are optionally substituted by 1, 2, or 3 R6; R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Forming each R6 is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7, piperidinyl, or piperazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, or isopropoxy groups, and the piperidinyl or piperazinyl groups are optionally substituted with 1, 2, 3, 4, or 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl groups; R7 is independently selected from a piperidinyl group or a piperazinyl group, and the piperidinyl group or the piperazinyl group is optionally substituted with 1, 2, 3, 4, or 5 of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl groups.

[0018] In some embodiments of the compound of Formula (II), X1 is selected from NH or O; X2 is selected from CH2 or O; L1 is selected from a 6- to 10-membered aryl group, a 6- to 10-membered heteroaryl group, or a 6- to 10-membered heterocyclyl group, and the 6- to 10-membered aryl group, the 6- to 10-membered heteroaryl group, or the 6- to 10-membered heterocyclyl group is optionally substituted with 1, 2, or 3 R6; R4 and R5 are independently H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 2-6 fluoroalkenyl groups, Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups; Each R6 is independently H, C 1-6 alkyl group, (CH3)2-P(O)-, CH3-S(O)2- or 6- to 10-membered heterocyclyl group, 1-6 The alkyl group is optionally C 1-6 an alkoxy group, or optionally C 1-6 It is substituted with a 6- to 10-membered heterocyclyl group substituted with an alkyl group.

[0019] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is selected from a phenyl group, a pyridyl group, a pyrazolo[1,5-a]pyrazinyl group, a 2,3-dihydropyrrolo[3,4-c]pyridin-1-one group, and a piperidinyl group, and the phenyl group, the pyridyl group, the pyrazolo[1,5-a]pyrazinyl group, the 2,3-dihydropyrrolo[3,4-c]pyridin-1-one group, and the piperidinyl group are optionally substituted by 1, 2, or 3 R6; R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Forming Each R6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH3)2-P(O)-, CH3-S(O)2-, piperidinyl, and piperazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy, piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, piperazinyl, N-methylpiperazinyl, or N-ethylpiperazinyl.

[0020] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Forming R 6a , R 6b , R 6c , R 6d , R 6eare each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH)-P(O)-, CH-S(O)-, -CHR, -NHR, piperidinyl, and piperazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted by methoxy, ethoxy, n-propoxy, or isopropoxy, and the piperidinyl or piperazinyl group is optionally substituted by 1, 2, 3, 4, or 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl groups; R7 is independently selected from a piperidinyl group or a piperazinyl group, and the piperidinyl group or the piperazinyl group is optionally substituted with 1, 2, 3, 4, or 5 of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl groups.

[0021] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Forming Each R6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH3)2-P(O)-, CH3-S(O)2-, piperidinyl, and piperazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy, piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, piperazinyl, N-methylpiperazinyl, or N-ethylpiperazinyl.

[0022] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; R 6a , R 6b , R 6c , R 6d , R 6eare each independently H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7, [ka] wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, and isopropoxy groups; The above R7 is independently [ka] Selected from Above R 7a , R 7b , R 7c , R 7d , R 7e are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0023] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; R 6a , R 6b are each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, or isopropoxy; R 6c are independently (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7, [ka] Selected from The above R7 is independently [ka] Selected from Above R 7a , R 7b , R 7c , R 7d , R 7e are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0024] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; each R6 independently represents (CH3)2-P(O)-; [ka] Selected from.

[0025] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; R 6a , R 6b , R 6c , R 6dare each independently H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7, [ka] wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, and isopropoxy groups; The above R7 is independently [ka] Selected from Above R 7a , R 7b , R 7c , R 7d , R 7e are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0026] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; R 6c are independently [ka] Selected from.

[0027] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably being selected from H and R5 preferably being selected from 3,3-difluoro-2-propenyl or n-butan-1-yn-3-yl; R 6a is selected from a methoxymethyl group, R 6b is selected from methyl groups.

[0028] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from 3,3-difluoro-2-propenyl or 2-propynyl, R 6a and R 6b are each independently selected from methyl groups.

[0029] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; R 6a are independently selected from CH3-S(O)2-.

[0030] In some embodiments of the compound of Formula (II), X1 is selected from NH, L1 is [ka] Selected from R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; each R6 independently represents (CH3)2-P(O)-; [ka] Selected from.

[0031] In another aspect, the present invention provides a compound of formula (IIA), a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof: [ka] Among them, X2 is selected from CH2 or O; X3 is selected from a bond, CH2, NH or O; R4 and R5 are independently H, C 1-6 C substituted with alkyl or cyano groups 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Fluoroalkenyl group, C 2-6 alkynyl groups, Alternatively, R4 and R5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or [ka] wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups; R 6a , R 6b , R 6d, R 6e are independently H, halogen, or C 1-6 alkyl group, (CH3)2-P(O)-, CH3-S(O)2-, 1-6 The alkyl group is optionally C 1-6 substituted with an alkoxy group, R7 is independently selected from a 6- to 10-membered heterocyclyl group, which optionally contains 1, 2, 3, 4, 5 halogen atoms, C 1-6 Alkyl group or C 1-6 substituted with a haloalkyl group; "N atom marked with *" indicates the N atom in general formula (II) that is connected to R4 and R5.

[0032] In some embodiments of the compound of Formula (IIA), R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Alternatively, R4 and R5 together with the N atom to which they are attached form an azetidinyl group, a 2,2-dimethylazetidinyl group, or [ka] Forming In some embodiments of the compound of Formula (IIA), R 6a , R 6b , R 6d , R 6eare each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH)-P(O)-, and CH-S(O)-, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, or isopropoxy.

[0033] In some embodiments of the compound of Formula (IIA), R7 is independently selected from a piperidinyl group or a piperazinyl group, and the piperidinyl group or the piperazinyl group is optionally substituted with 1, 2, 3, 4, or 5 of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl groups.

[0034] In some embodiments of the compound of Formula (IIA), X2 is selected from CH2 or O; X3 is selected from a bond, CH2, NH or O; R4 and R5 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl, with R4 preferably selected from H and R5 preferably selected from isopropyl; R 6a , R 6b , R 6d , R 6eare each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, (CH)-P(O)-, and CH-S(O)-, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, or isopropoxy; The above R7 is independently [ka] Selected from Above R 7a , R 7b , R 7c , R 7d , R 7e are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0035] In some embodiments of the compound of Formula (IIA), X2 is selected from CH2, X3 is selected from CH2, R4 is selected from H and R5 is C 1-6 alkyl group, preferably an isopropyl group; R 6a , R 6b , R 6d , R 6e are each independently selected from H and halogen; R7 is independently [ka] Selected from R 7a , R 7b , R 7c , R 7d , R 7eare independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0036] In another aspect, the present invention provides the following compounds, pharmaceutically acceptable salts, stereoisomers or deuterated forms thereof, which are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Selected from.

[0037] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described above, or a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof, and a pharmaceutically acceptable carrier, which may contain auxiliary ingredients conventional in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, or wetting agents.

[0038] The pharmaceutical composition can be prepared in various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral solutions, suspensions, granules, powders, microgranules, pills, minitablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally, transmucosally, rectally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally). The dosage can be adjusted appropriately depending on the patient's age, sex, and type of disease.

[0039] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg, of the active ingredient. The appropriate daily dose for humans or other mammals may vary widely depending on the patient's condition and other factors, but may be determined by routine methods.

[0040] The present invention further provides methods / uses of the above compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof as drugs, and methods and uses of the above compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof in preventing, treating, or ameliorating the pathology and / or symptoms of diseases in animals and humans.

[0041] In certain aspects and embodiments of the compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof, methods and uses according to the present invention, the compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof have higher selectivity for CDK2 over other CDKs, particularly CDK1.

[0042] In one aspect, the present invention provides a use / method of using any one of the above-described compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof for the prevention / treatment of a CDK2-mediated related disease. The CDK2-mediated related disease involves abnormal cell growth in a subject, and the abnormal cell growth is cancer. In one embodiment, the cancer is selected from breast cancer, triple-negative breast cancer (TNBC), ovarian cancer, bladder cancer, uterine cancer, cervical cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer, thyroid cancer, skin cancer, esophageal cancer, lymphoma, sarcoma, multiple myeloma, and solid tumors.

[0043] [Definitions and Explanations] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood in its general sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0044] The term "pharmaceutically acceptable," as used herein, refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0045] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, and further include salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into either a base addition salt or an acid addition salt.

[0046] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds that contain an acid or base group by conventional chemical methods. Generally, salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0047] Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

[0048] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. All such compounds are contemplated within the scope of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures. Substituents such as alkyl groups may contain other asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0049] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. Single enantiomers of certain compounds of the present invention can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, whereby the resulting diastereomeric mixture is separated and the groups are assisted in resolving to provide the pure desired enantiomers. Alternatively, if the molecule contains basic (e.g., amino) or acidic (e.g., carboxyl) functional groups, diastereomeric salts can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved and subsequently recovered to provide the pure enantiomers by conventional methods known in the art. Separation of enantiomers and diastereomers is also typically achieved by chromatography, using chiral stationary phases and optionally combined with chemical derivatization (e.g., forming carbamates from amides).

[0050] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of an active agent of the present invention, not interfering with the biological activity of the active agent, and not causing toxicity or adverse side effects to the host or patient, including, but not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersing agents, solubilizing agents, suspending agents, and the like.

[0051] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient dose of the drug or agent to achieve the desired effect. In the oral dosage forms of the present invention, an "effective amount" of one active agent in the composition means the dose necessary to achieve the desired effect when used in combination with other active agents in the composition. Determination of an effective amount varies from person to person and depends on the specific active agent as well as the age and general condition of the recipient, and the appropriate effective amount in each individual case can be determined by one of ordinary skill in the art based on routine testing.

[0052] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, by substituting the appropriate isotopically labeled reagent for an additionally used non-labeled reagent.

[0053] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with deuterium atoms. The term "optionally" or "optionally" indicates that the subsequently described event or circumstance may, but need not, occur, and includes both the occurrence of the described event or circumstance and the absence of the event or circumstance. For example, "optionally substituted with one or more deuterium atoms" refers to the case where the group is not substituted with deuterium atoms, or the case where the group is substituted with one or more deuterium atoms, i.e., the group may be non-deuterated, partially deuterated, and / or fully deuterated.

[0054] The terms "optionally," "optionally," or "optionally substituted with..." indicate that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the described event or circumstance occurs or does not occur. For example, "optionally substituted with..." refers to the presence or absence of a substituent and the inclusion of one, two, three, etc. of the substituent.

[0055] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, and may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =0), this means that two hydrogen atoms have been replaced. Ketone substitution does not occur on aryl groups.

[0056] Unless otherwise specified, the term "alkyl group" is used to refer to a straight or branched chain saturated hydrocarbon group, which may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group), for example, C1 to C 10 indicates 1 to 10 carbons, C 1-10 are C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isoamyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, and the like. As can be understood, the term "alkylene group" refers to a residue obtained by further losing one hydrogen atom based on an "alkyl group," and examples of C1-C6 alkylene groups include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(CH3)-CH2, etc. It should be noted that an alkylene group (e.g., a methylene group) appearing at the end of a straight or branched chain or at the end of a substituent group includes the case of "CH2=," in which the hydrogen atom may be substituted with one or two halogen atoms (e.g., fluorine atoms).

[0057] Unless otherwise specified, the term "alkenyl group" is used to refer to a straight or branched chain hydrocarbon group composed of carbon and hydrogen atoms, having at least one carbon-carbon double bond, which may be in the (E)- or (Z)-configuration, having 2 to 6 carbon atoms, and connected to the remainder of the molecule through a single bond. For example, C 2-6 indicates 2 to 6 carbons, C 2-6 is selected from C2, C3, C4, C5 and C6. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl), 1-methyl-vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl and 2-methyl-2-propenyl groups.

[0058] Unless otherwise specified, the term "alkynyl group" is used to refer to a straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms, having at least one carbon-carbon triple bond, having 2 to 6 carbon atoms, and connected to the rest of the molecule through a single bond. For example, C 2-6 indicates 2 to 6 carbons, C 2-6 is selected from C2, C3, C4, C5 and C6. In one embodiment of an alkynyl group, the number of triple bonds is 1. Examples of alkynyl groups include, but are not limited to, ethynyl groups, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, and n-but-2-yn-1-yl.

[0059] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0060] Unless otherwise specified, the term "fluoroalkyl group" is intended to include straight or branched chain monofluoroalkyl groups and polyfluoroalkyl groups. For example, "C 1-6The term "fluoroalkyl group" is intended to include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 2,2'-difluoroisopropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl groups.

[0061] Unless otherwise specified, the term "fluoroalkenyl group" is intended to include straight-chain or branched mono- and polyfluorinated fluoroalkenyl groups. For example, "C 2-6 Examples of the "fluoroalkenyl group" include a 2-fluorovinyl group, a 2,2-difluorovinyl group, a 3-fluoro-1-propenyl group, a 3,3-difluoro-1-propenyl group, a 3-fluoro-2-propenyl group, and a 3,3-difluoro-2-propenyl group.

[0062] Unless otherwise specified, the term "cycloalkyl group" is intended to include any stable cyclic or polycyclic hydrocarbon group, which may be saturated at any carbon atom, mono- or polysubstituted, and mono-, di-, or polyvalent. For example, C 3-10 indicates 3 to 10 carbon atoms, C 3-10 are C3, C4, C5, C6, C7, C8, C9, C 10 Examples of these cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, tricyclo[3.3.1.1]bicyclooctane, and tricyclo[3.3.1.1]bicyclooctane. 3,7 ]decane group (adamantyl group), and the like.

[0063] Unless otherwise specified, the term "alkoxy group" refers to alkyl-O-, where the alkyl group is as defined above. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxypropyl, n-propoxy, isopropoxy, n-butoxy, OCH(CH3)-C2H5, OCH2-CH(CH3)2, OC(CH3)3, and the like.

[0064] Unless otherwise specified, a "heterocyclyl group" refers to a fully saturated or unsaturated cyclic group, such as a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has one or more oxygen, sulfur, or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, in the ring. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Monocyclic heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, and piperazinyl groups.

[0065] Unless otherwise specified, an "aryl group" refers to a monovalent aromatic carbocyclic group of 6 to 10 carbon atoms, which may have a single ring or multiple condensed rings. Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0066] Unless otherwise specified, a "heteroaryl group" refers to a monovalent aromatic group having 5 to 10 ring atoms, which contains oxygen, nitrogen, and sulfur heteroatoms in one or more rings, preferably 1 to 4 heteroatoms or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heteroaryl group may have a single ring (e.g., a pyridyl or furanyl group) or multiple condensed rings, provided that the point of attachment is through a heteroaryl group ring atom. Monocyclic heteroaryl groups generally contain a 5- or 6-membered aromatic ring, and examples of monocyclic heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, furanyl, thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, and pyrazolyl. Examples of fused-ring heteroaryl groups include benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, pyrazolo[1,5-a]pyrazinyl, quinolyl, benzopyranyl, and indolizinyl.

[0067] Compounds are named manually or in ChemDraw® software; commercially available compounds adopt the supplier's catalogue name. DETAILED DESCRIPTION OF THE INVENTION

[0068] The present invention will be further explained below in combination with specific examples and test examples, but the scope of the present invention is not limited in any way.

[0069] Example 1 Preparation of Fragment 1: [ka] Synthetic Route: [ka]

[0070] Step 1: Synthesis of fragment 1-1: 1500 mL of methanol and SM1 (150 g, 1.00 eq) were added sequentially to a 3000 mL three-neck flask and cooled to 0 °C. Sodium borohydride (41.4 g, 1.04 eq) was added in 40 batches to the reaction solution, and the reaction was carried out at 0 °C for half an hour under nitrogen gas protection. 40 mL of acetic acid was added dropwise to the reaction solution, and the methanol was concentrated to dryness to obtain a crude product. The crude product was extracted twice with ethyl acetate, each time adding 1200 mL of ethyl acetate. The organic phases were combined, washed with 1200 mL of saturated brine, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain Fragment 1-1 (white liquid, 147 g, yield: 52.0%, crude product).

[0071] Step 2: Synthesis of fragment 1-2: 1750 mL of anhydrous tetrahydrofuran and fragment 1-1 (140 g, 1.00 eq) were added sequentially to a 5000 mL three-neck flask. tert-Butyldimethylchlorosilane (292 g, 2.00 eq) and imidazole (132 g, 2.00 eq) were added at room temperature, and the mixture was stirred at room temperature for 12 hours. 700 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate, each time adding 1000 mL of ethyl acetate. The organic phases were combined, washed with 1000 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain fragment 1-2 (white liquid, 190 g, yield: 55.8%, crude product). MS m / z (ESI): 259 [M+H] + ;1H NMR(400MHz CDCl3),δ=4.22(quin,J=5.4Hz,1H),3.67(s,3H),2.73(t,J=8.3Hz,1H),2.16-2.02 (m,2H),1.96-1.76(m,3H),1.73-1.54(m,2H),0.88-0.85(m,9H),0.08-0.02(m,6H).

[0072] Step 3: Synthesis of fragments 1-3: 645 mL of anhydrous tetrahydrofuran and n-butyllithium (2.50 M, 495 mL, 2.00 eq) were added sequentially to a 3000 mL three-neck flask. The temperature was lowered to -65°C, and acetonitrile (50.8 g, 65.2 mL, 2.00 eq) was slowly added dropwise to the reaction liquid. The entire reaction was carried out at -65°C for 1 hour under nitrogen gas protection. Fragment 1-2 (160 g, 1.00 eq) was dissolved in 160 mL of anhydrous tetrahydrofuran, and the compound 1-2 solution was added dropwise to the reaction liquid at -65°C. The reaction was carried out at -65°C for 2 hours under nitrogen gas protection. The reaction mixture was cooled to 0°C, 120 mL of water was added dropwise, and the pH of the mixture was adjusted to 7 with 1 M HCl solution (1338 mL). The mixture was extracted three times with ethyl acetate, each time adding 1000 mL of ethyl acetate. The organic phases were combined, washed with 1200 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain fragment 1-3 (pale yellow liquid, 121 g, yield: 57.7%, purity: 80.0%). MS m / z (ESI): 268 [M+H] + ;1H NMR(400MHz CDCl3),δ=4.39-4.26(m,1H),3.60-3.49(m,2H),3.02(tt,J=6.5,8.9Hz,1H),2.19- 2.03(m,2H),1.96-1.83(m,2H),1.81-1.64(m,2H),0.89-0.81(m,8H),0.05(s,6H).

[0073] Step 4: Synthesis of fragments 1-4: 1073 mL of absolute ethanol and sodium hydroxide (21.7 g, 1.20 eq) were added to a 3000 mL three-neck flask, and tert-butylhydrazine hydrochloride (67.6 g, 1.20 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Fragment 1-3 (121 g, 1.00 eq) was dissolved in 207 mL of absolute ethanol, and the compound 1-3 solution was added dropwise to the room temperature tert-butylhydrazine hydrochloride solution. The entire mixture was heated to 85 °C and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain fragment 1-4 (orange liquid, 147 g, yield: 84.7%, purity: 87.6%). MS m / z (ESI): 338 [M+H] + .

[0074] Step 5: Synthesis of fragments 1-5: 1590 mL of acetonitrile and fragment 1-4 (160 g, 1.00 eq) were added sequentially to a 3000 mL three-neck flask. The mixture was heated to 50 °C and then heated to room temperature. Benzyl chloroformate (161 g, 2.00 eq) was added and the mixture was allowed to react for 16 hours at room temperature. The crude product was obtained by rotary evaporation. 1000 mL of water was added, and the mixture was extracted three times with ethyl acetate, each time adding 1000 mL of water. The organic phases were combined, washed with 1000 mL of saturated brine, dried, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain fragment 1-5 (orange liquid, 183 g, yield: 71.5%). MS m / z (ESI): 472 [M+H] + ;1H NMR(400MHz CDCl3),δ=7.38(br s,5H),6.30-5.91(m,2H),5.20(s,2H),4.42-4.25(m,1H),3.00(br t,J=8.9Hz,1H),2.34-2.11(m,1H),2.01-1.64(m,6H),1.58(s,9H),0.89(s,10H),0.07-0.02(m,6H).

[0075] Step 6: Synthesis of fragments 1-6: 1630 mL of anhydrous methanol and fragment 1-5 (163 g, 1.00 eq) were added to a 3000 mL three-neck flask, and 1 M hydrochloric acid (1.64 L, 4.72 eq) was added at room temperature. The mixture was allowed to react for 1 hour. 1000 mL of water was added to the reaction mixture, and the mixture was extracted three times with 1000 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was first purified by column chromatography to obtain the racemic fragment 1-6 (orange liquid, 77.1 g), which was then separated by SFC to obtain the absolute configuration fragment 1-6 (white solid, 35.7 g, yield: 49.1%, purity: 51.3%). SFC division conditions:Column:Chiralpak AD 50mm*4.6mm*3μm,Mobile phase:A:CO2B:Methanol(0.05% DEA),Gradient:from 5% to 40% of B in 2.5min and hold 40% for 0.5min,then 5% of B for 1min,Flow rate:4mL / min,Column temp.:35℃, ABPR:1500psi. MS m / z(ESI):358[M+H] + ;1H NMR(400MHz CDCl3),δ=7.37(br s,4H),6.49(br s,1H),6.06(br s,1H),5.19(s,2H),4.34(br s, 1H), 3.27-3.17 (m, 1H), 2.13-1.76 (m, 6H), 1.55 (s, 9H).

[0076] Step 7: Synthesis of fragments 1-7: 125 mL of anhydrous tetrahydrofuran and the absolute configuration fragment 1-6 (10.0 g, 1.00 eq) were added to a 100 mL single-neck flask, and tert-butyldimethylchlorosilane (8.43 g, 2.00 eq) and imidazole (3.81 g, 2.00 eq) were added to the reaction solution, in that order, and the reaction was allowed to proceed at room temperature for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 120 mL of ethyl acetate. The organic phases were combined, washed with 150 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain fragment 1-7 (pink solid, 20.4 g, crude product). MS m / z (ESI): 472 [M+H] + . 1H NMR (400MHz CDCl3), δ=7.38(br s,4H),6.26-6.05(m,2H),5.20(s,2H),4.30(dd,J=5.1,6.0Hz,1H),3.00(br t,J=9.0Hz,1H),2.37-2.25(m,1H),2.03-1.89(m,1H),1.89-1.78(m,2H),1.71-1.64(m,2H),0.96-0.85(m,11H),0.14-0.00(m,7H).

[0077] Step 8: Synthesis of fragments 1-8: 392 mL of methanol, fragment 1-7 (20.4 g, 1.00 eq), and wet Pd / C (7.84 g) were added to a 1000 mL hydrogenation flask in that order, and the mixture was reacted under hydrogen gas conditions of 50 °C, 40 Psi, and hydrogen gas for 12 hours. After filtration, fragment 1-8 (pink liquid, 14.0 g, yield: 87.5%, purity: 91.3%) was obtained. MS m / z (ESI): 338 [M+H] + . 1H NMR(400MHz CDCl3),δ=5.47(s,1H),4.28(dd,J=4.7,6.2Hz,1H),3.49(br s,2H),3.00-2.87(m,1H),2.34-2.22(m,1H),1.99-1.63(m,5H),1.61(s,9H),0.93-0.85(m,9H),0.12-0.03(m,6H).

[0078] Step 9: Synthesis of fragments 1-9: 5 mL of N,N-dimethylformamide, 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (459 mg, 1.00 eq), N,N-diisopropylethylamine (697 mg, 2.00 eq), and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.23 g, 1.20 eq) were added sequentially to a 50 mL single-neck flask at room temperature and stirred at room temperature for 1 hour. Fragment 1-8 (1.00 g, 1.10 eq) was added to the reaction mixture and stirred at room temperature for 16 hours (2 batches). 100 mL of water was added to the reaction mixture, and the mixture was extracted four times with 50 mL of ethyl acetate. The organic phases were combined, washed with 240 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give fragment 1-9 (brown liquid, 1.40 g, yield: 34.4%, purity: 65.0%). MS m / z (ESI): 490 [M+H] + . 1H NMR(400MHz CDCl3),δ=8.01(s,1H),7.56(br s,1H),6.64(br s,1H),6.27(s,1H),4.48(s,2H),4.30(dd,J=4.9,6.2Hz,1H),4.19(s,3H),3.49(s,10H),3.03(s,1H),2.96(s,2H),2.88(s ,2H),2.80(s,4H),2.30(dd,J=5.9,13.2Hz,1H),2.09-1.76(m,5H),1.66-1.60(m,9H),0.89(s,9H),0.05(d,J=1.9Hz,6H).

[0079] Step 10: Synthesis of fragments 1-10: 26.7 mL of methanol, fragment 1-9 (2.67 g, 1.00 eq), and 1 M hydrochloric acid (26.7 mL, 4.90 eq) were added sequentially to a 100 mL single-neck flask at room temperature and stirred for 1 hour. 20 mL of water was added to the reaction mixture, and the mixture was extracted ten times with 30 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to dryness to obtain fragment 1-10 (brown liquid, 2.00 g, yield: 67.2%, purity: 68.8%). MS m / z (ESI): 376 [M+H] +. 1H NMR(400MHz CDCl3),δ=7.94(br s,1H),6.72(br s,1H),6.20(s,1H),4.47(s,2H),4.39-4.33(m,1H),4.18(s,3H),3.46-3.37( m,3H),3.33-3.23(m,1H),2.03-1.74(m,5H),1.61(s,8H),0.94-0.85(m,3H).

[0080] Step 11: Synthesis of Fragment 1: 2.4 mL of anhydrous tetrahydrofuran, fragment 1-10 (200 mg, 1.00 eq), and p-nitrophenyl chloroformate (214 mg, 2.00 eq) were added to a 50 mL three-neck flask at room temperature, followed by pyridine (126 mg, 3.00 eq) and 4-dimethylaminopyridine (6.51 mg, 0.10 eq), and the mixture was stirred at 50°C for 28 hours to obtain fragment 1, which was used directly in the next step.

[0081] Example 2 [ka] Synthetic Route: [ka]

[0082] Step 1: Synthesis of compound 1-1: 2.3 mL of anhydrous tetrahydrofuran, N,N-diisopropylethylamine (205 mg, 10.00 eq), and 2-aminopropionitrile hydrochloride (169 mg, 10.0 eq) were added sequentially to a 50 mL three-neck flask at room temperature and stirred for 1 hour. The reaction mixture containing 2-aminopropionitrile hydrochloride was added to the reaction mixture containing fragment 1 at 50 °C and stirred for 12 hours at 50 °C and then for 14 hours at 70 °C. The reaction mixture was adjusted to pH 5 with 1 M hydrochloric acid and extracted three times with 6 mL of dichloromethane. The organic phase was collected, adjusted to pH 8 with aqueous Na2CO3, and washed three times with 10 mL of saturated aqueous sodium chloride. The organic phase was then dried and concentrated to dryness to obtain the crude product. The crude product was purified using a preparative plate to obtain compound 1-1 (brown solid, 68.0 mg, yield: 70.6%, purity: 78.0%). MS m / z(ESI):472[M+H] + . 1H NMR (400MHz CDCl3), δ=7.76-7.62(m,1H),6.69(br s,1H),6.23(br d,J=4.4Hz,1H),5.61(br d,J=8.9Hz,1H),4.65(br d,J=5.4Hz,1H),4.19(d,J=1.1Hz,3H),3.44(s,3H),3.28-3.18(m,1H),2.39-2. 24(m,1H),2.02-1.77(m,5H),1.63(d,J=1.0Hz,9H),1.53(dd,J=4.4,7.3Hz,3H).

[0083] Step 2: Synthesis of Compound 1: 1.95 mL of formic acid and compound 1-1 (39.1 mg, 1.00 eq) were added sequentially to a 10 mL single-neck flask at room temperature and stirred at 80 °C for 16 hours. The reaction mixture was directly rotary evaporated to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 1 (white solid, 21.8 mg, yield: 61.3%, purity: 96.9%). MS m / z (ESI): 416 [M+H] +. 1H NMR (400MHz CDCl3), δ=7.76-7.62(m,1H),6.69(br s,1H),6.23(br d,J=4.4Hz,1H),5.61(br d,J=8.9Hz,1H),4.65(br d,J=5.4Hz,1H),4.19(d,J=1.1Hz,3H),3.44(s,3H),3.28-3.18(m,1H),2.39-2. 24(m,1H),2.02-1.77(m,5H),1.63(d,J=1.0Hz,9H),1.53(dd,J=4.4,7.3Hz,3H).

[0084] Each compound in the table below was synthesized with reference to the synthesis methods in Steps 1 and 2 in Example 2 (Compound 1).

[0085] [Table 1]

[0086] Example 3 Preparation of Fragment 2: [ka] Synthetic Route: [ka]

[0087] Step 1: Synthesis of fragment 2-1: 120 mL of dichloromethane, fragment 1-6 (10.0 g, 1.00 eq), p-nitrophenyl chloroformate (8.46 g, 1.50 eq), pyridine (6.64 g, 3.00 eq), and DMAP (341 mg, 0.10 eq) were added in this order to a 250 mL three-neck flask, and the mixture was reacted at 25 °C for 12 hours under nitrogen gas protection to obtain fragment 2-1, which was used directly in the next step.

[0088] Step 2: Synthesis of fragment 2-2: To the reaction mixture of fragment 2-1, compound isopropylamine (4.96 g, 3.00 eq) and DIEA (10.85 g, 3.00 eq) were added and stirred at 30°C for 4 hours. 200 mL of 1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with 200 mL of dichloromethane. The organic phase was adjusted to pH 8-9, separated, washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain fragment 2-2 (yellow oil, 9.2 g, yield: 33.05%, purity: 80%). MS m / z (ESI): 443 [M+H] + . 1H NMR (400MHz CDCl3), δ=7.38(br s,4H),6.34-6.04(m,2H),5.15(br s,1H),4.65-4.43(m,1H),3.88-3.73(m,1H),3.50(d,J=4.0Hz,1H),3.08(quin,J=8.4Hz,1H ),2.53-2.38(m,1H),2.09-1.98(m,1H),1.96-1.76(m,4H),1.58(s,9H),1.17-1.11(m,6H).

[0089] Step 3: Synthesis of fragment 2: 140 mL of methanol, fragment 2-2 (7.12 g, 1.00 eq), and Pd / C (3.5 g, 10% purity) were added sequentially to a 500 mL hydrogenation flask and reacted at 50 °C, 40 psi, and H for 12 hours. After filtration and rotary evaporation, fragment 2 (pink oil, 5.06 g, crude product) was obtained. MS m / z (ESI): 309 [M+H] + . 1H NMR(400MHz CDCl3),δ=5.12(br s,1H),4.45(br s,1H),3.81(br d,J=4.8Hz,1H),3.49(br d,J=4.4Hz,3H),3.07-2.93(m,1H),2.55-2.40(m,1H),2.07-1.95(m,1H), 1.95-1.86(m,1H),1.84-1.73(m,2H),1.61(s,9H),1.15(d,J=6.5Hz,6H).

[0090] Example 4 [ka] Synthetic Route: [ka]

[0091] Step 1: Synthesis of 4-1: 180 mL of dichloromethane, compound SM4 (18.0 g, 1.00 eq), potassium iodide (668 mg, 0.50 eq), and triethylamine (16.0 g, 1.50 eq) were added sequentially to a 500 mL three-neck flask, followed by methanesulfonyl chloride (13.7 g, 1.14 eq). The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was added to 100 mL of water and stirred for 10 minutes. The organic layer was separated and washed with 100 mL of water, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography to obtain compound 4-1 (yellow liquid, 10.5 g, crude product).

[0092] Step 2: Synthesis of 4-2: 120 mL of N,N-dimethylformamide, compound 4-1 (2.00 g, 1.00 eq), potassium iodide (668 mg, 0.50 eq), and sodium methyl mercaptanate (1.69 g, 3.00 eq) were added sequentially to a 250 mL three-neck flask and reacted for 16 hours at room temperature under a N2 atmosphere. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid, extracted four times with 150 mL of ethyl acetate, washed with brine, dried, and concentrated to dryness to obtain the crude product. 5 mL of the crude product was added dropwise to 40 mL of water, and the solid precipitated from the mixture was filtered to obtain compound 4-2 (brown solid, 1.15 g, yield: 67.9%, purity: 89.0%). MS m / z (ESI): 187 [M+H] + . 1H NMR (400MHz DMSO-d6), δ = 6.70 (s, 1H), 4.01 (s, 3H), 3.61 (s, 2H), 2.01 (s, 3H).

[0093] Step 3: Synthesis of 4-3: 11.4 mL of dichloromethane, 11.4 mL of acetonitrile, compound 4-2 (1.14 g, 1.00 eq), and metachloroperbenzoic acid (3.73 g, 3.00 eq) were added sequentially to a 100 mL three-neck flask and reacted for 12 hours at room temperature under a N2 atmosphere. 20 mL of dichloromethane was added to the reaction mixture, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was added to 100 mL of water and extracted 15 times with 40 mL of ethyl acetate. The organic phase was dried and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 4-3 (pink solid, 182 mg, yield: 19.4%, purity: 93.5%) (white solid, 482 mg, yield: 32.8%, purity: 91.0%). MS m / z (ESI): 187 [M+H] + . 1H NMR (400MHz DMSO-d6), δ = 6.85 (s, 1H), 4.47 (s, 2H), 4.07 (s, 3H), 2.96 (s, 3H).

[0094] Step 4: Synthesis of compound 7-1: 5.3 mL of N,N-dimethylformamide, fragment 2 (530 mg, 1.00 eq), and compound 4-3 (375 mg, 1.00 eq) were added sequentially to a 50 mL three-neck flask. O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (526 mg, 1.20 eq) was added and stirred at room temperature for 2.5 hours. Finally, N,N-diisopropylethylamine (666 mg, 3.00 eq) was added and stirred at 70 °C for 2 hours. 34 mL of water was added to the reaction mixture, which was then extracted four times with 15 mL of ethyl acetate. The organic phase was washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 7-1 (pink solid, 182 mg, yield: 19.4%, purity: 93.5%). MS m / z(ESI):509[M+H] +. 1H NMR (400MHz CDCl3), δ=7.98(br d,J=19.9Hz,1H),6.92(br s,1H),6.19(s,1H),5.12(br d,J=4.1Hz,1H),4.59(br d,J=2.9Hz,1H),4.31(s,2H),4.21(s,3H),3.78(br d,J=5.1Hz,1H),3.18-3.04(m,1H),2.92-2.86(m,3H),2.50-2.35(m,1H),1.99-1.74(m,5H),1.63(s,9H),1.14(dd,J=1.9,6.4Hz,6H).

[0095] Step 5: Synthesis of compound 7: Compound 7-1 (152 mg, 1.00 eq) was dissolved in 7.6 mL of formic acid and incubated at 80°C for 16 hours. The mixture was concentrated to dryness to obtain a crude product, which was then purified by preparative separation to obtain compound 7 (white solid, 75.0 mg, yield: 53.9%, purity: 97.3%). MS m / z (ESI): 453 [M+H] + . 1H NMR (400MHz CD3OD), δ=12.24(s,1H),10.87(s,1H),7.22(s,1H),6.95(br d,J=7.3Hz,1H),6.43(br s,1H),5.01(br s,1H),4.47(s,2H),4.08(s,3H),3.66-3.49(m,1H),3.08(br s,1H),3.00(s,3H),2.47(br s,1H),2.03(br d,J=7.3Hz,1H),1.90(br d,J=3.0Hz,1H),1.80-1.68(m,2H),1.61(br s,1H),1.03(d,J=6.5Hz,6H).

[0096] Each compound in the table below was synthesized with reference to the synthesis method of steps 1 to 5 in Example 4 (Compound 7).

[0097] [Table 2]

[0098] Example 5 [ka] Synthetic Route: [ka]

[0099] Step 1: Synthesis of compound 8-1: 20 mL of dichloroethane, compound 1-(methylsulfonyl)piperidinyl-4-one (344 mg, 1.00 eq), fragment 2 (600 mg, 1.00 eq), and zinc chloride (318 mg, 1.20 eq) were added sequentially to a 100 mL three-neck flask and incubated at 85 °C for 12 hours. After detecting the formation of an intermediate, sodium triacetoxyborohydride (659 mg, 1.60 eq) was added at room temperature and the reaction was incubated at 60 °C for 14 hours. 20 mL of water was added, followed by two extractions with 20 mL of dichloromethane. The organic phase was washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 8-1 (yellow solid, 475 mg, yield: 44.19%, purity: 85%). MS m / z (ESI): 470 [M+H] + .

[0100] Step 2: Synthesis of compound 8: Compound 8-1 (475 mg, 1.00 eq) was dissolved in 23 mL of 12 M concentrated hydrochloric acid and reacted at room temperature for 12 hours. The mixture was concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation and then separated by SFC to obtain compound 8 (white solid, 91 mg, yield: 21.54%, purity: 99%). MS m / z (ESI): 414 [M+H] + . 1H NMR(400MHz CD3OD),δ=5.46(br s,1H),5.06(br s,1H),4.59(s,5H),3.74-3.60(m,3H),3.40-3.33(m,1H),3.12-2.99(m,1H),2.97-2.86(m,2H),2.84(s ,3H),2.55-2.43(m,1H),2.14-2.00(m,3H),1.98-1.66(m,2H),1.57-1.44(m,2H),1.12(d,J=6.6Hz,6H).

[0101] Example 6 [ka] Synthetic Route: [ka]

[0102] Step 1: Synthesis of compound 9-1: 10 mL of toluene, 1-(4-iodophenyl)-4-methylpiperazine (1.02 g, 1.00 eq), fragment 2 (1.00 g, 1.00 eq), sodium tert-butoxide (477 mg, 1.50 eq), tri-tert-butylphosphine (401 mg, 10% purity, 0.06 eq), and tris(dibenzylideneacetone)dipalladium (90 mg, 0.03 eq) were added sequentially to a 25 mL microwave tube and reacted in a microwave at 100 °C for 1 h. The mixture was filtered, extracted twice with 20 mL of dichloromethane, washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to give compound 9-1 (yellow solid, 927 mg, yield: 49.90%, purity: 86%). MS m / z (ESI): 483 [M+H] + . 1 H NMR(400MHz CD3OD), δ=6.85(d,J=8.9Hz,2H),6.69(d,J=8.9Hz,2H),5.87(s,1H),5.31(s,1H),5.13(br s,1H),4.87(s,1H),4.55-4.32(m,1H),3.79(br d,J=3.9Hz,1H),3.25(br t,J=4.8Hz,4H),3.10-3.01(m,1H),2.94(br s, 4H), 2.60 (s, 3H), 2.55-2.46 (m, 1H), 1.96-1.71 (m, 4H), 1.61 (s, 9H), 1.17-1.08 (m, 6H).

[0103] Step 2: Synthesis of compound 9: Compound 9-1 (726 mg, 1.00 eq) was dissolved in 366 mL of formic acid and incubated at 80°C for 12 hours. The mixture was concentrated to dryness to obtain a crude product, which was then purified by preparative separation to obtain compound 9 (white solid, 90 mg, yield: 13.98%, purity: 99.63%). MS m / z (ESI): 427 [M+H] + . 1 H NMR (400MHz CD3OD), δ=7.04(br d,J=8.4Hz,2H),6.87(br d,J=8.8Hz,2H),5.68(s,1H),5.04(br s,1H),4.56(br s,3H),3.71-3.57(m,1H),3.29-3.24(m,4H),3.06(br d,J=4.4Hz,5H),2.68-2.56(m,4H),2.53-2.41(m,1H),2.33(s,3H),2.05(br d,J=7.5Hz,1H),1.95-1.65(m,4H),1.33-1.21(m,1H),1.12-1.00(m,6H).

[0104] Example 7 [ka] Synthetic Route: [ka]

[0105] Step 1: Synthesis of 5-1: 80 mL of tetrahydrofuran, CHO (584 mg, 1.10 eq), and SM5 (4.00 g, 1.00 eq) were added sequentially to a 250 mL three-neck flask and stirred at 25 °C for 30 minutes. NaBH(OAc) (50.0 mg, 3.00 eq) was added and stirred at 25 °C for 12 hours. The reaction mixture was concentrated to dryness, 80 mL of water was added, and the mixture was extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate (1 M, 800 mL), dried, and concentrated to dryness to give compound 5-1 (yellow oil, 3.00 g crude product).

[0106] Step 2: Synthesis of 5-2: Compound 5-1 (3.00 g, 1.00 eq) was added to a 250 mL single-neck flask with 100 mL of dichloromethane. Trifluoroacetic acid (30.4 g, 21.4 eq) was added to the reaction mixture at 0 °C and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated to dryness to give compound 5-2 (yellow oil, 8.90 g, TFA salt, crude). H NMR (400 MHz DMSO-d6), δ = 3.80-3.62 (m, 9H), 3.34-3.21 (m, 2H), 2.92-2.78 (m, 2H), 2.68-2.56 (m, 3H), 2.13-2.03 (m, 2H), 1.89-1.82 (m, 4H), 1.80-1.66 (m, 2H).

[0107] Step 3: Synthesis of compound 10-1: 50 mL of tetrahydrofuran, fragment 2-1 (2.70 g, 1.00 eq), compound 5-2 (4.19 g, 1.10 eq), and DIEA (2.07 mg, 3.10 eq) were added sequentially to a 10 mL single-neck flask and stirred at 0°C for 30 minutes. The reaction mixture was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography and preparative chromatography to obtain compound 10-1 (yellow solid, 900 mg, yield: 33.2%). MS m / z (ESI): 524 [M+H] + . 1 H NMR(400MHz CDCl3),δ=7.38(br s,5H),6.48(s,1H),6.13(br s,1H),5.14(br s,1H),3.77-3.72(m,4H),3.57-3.45(m,2H),3.23-3.05(m,7H),2.75(br s,2H),2.65(br d,J=1.8Hz,1H),2.54-2.21(m,3H),1.91-1.79(m,4H),1.60(s,9H).

[0108] Step 4: Synthesis of compound 10-2: 10 mL of tetrahydrofuran, compound 10-1 (900 mg, 1.00 eq), and dry Pd / C (100 mg, 0.10 eq) were added to a 75 mL hydrogenation flask and stirred under a hydrogen gas atmosphere at 45 Psi and 50°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give the crude product, compound 10-2 (yellow oil, 500 mg, yield: 67.9%). MS m / z (ESI): 390 [M+H] + . 1 H NMR(400MHz CDCl3),δ=5.43-5.37(m,1H),5.16-5.04(m,1H),3.79-3.70(m,6H),3.60-3.50(m,1H),3.12(br s,1H),3.04-2.93(m,1H),2.78(s,3H),2.45(td,J=7.3,14.2Hz,1H),2.13-1.98(m,4H),1.96-1.82(m,4H),1.81-1.68(m,3H),1.62(s,9H).

[0109] Step 5: Synthesis of compound 10-3: 9 mL of toluene, triethylamine (321.9 mg, 2.00 eq), compound 10-2 (600 mg, 1.90 e-1 eq), and 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carbonyl chloride (900.0 mg, 1.00 eq) were added to a 100 mL single-neck flask and stirred at 120 °C for 12 hours. The reaction mixture was concentrated to dryness and purified using a preparative plate to give a mixture of compound 10-3 (yellow solid, 320 mg crude product) and compound 10 (pale yellow solid, 60 mg crude product).

[0110] Step 6: Synthesis of compound 10: 15 mL of HCOOH and compound 10-3 (320 mg, 1.00 eq) were added sequentially to a 50 mL single-neck flask and stirred at 80 °C for 12 hours. The reaction mixture was concentrated to dryness to obtain the crude product. 10 mL of saturated aqueous sodium carbonate solution was added to the crude product, followed by extraction with 20 mL of dichloromethane three times. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified once by preparative plate chromatography and twice by preparative chromatography to obtain compound 10 (white solid, 10.0 mg, purity: 45.37%). MS m / z (ESI): 486 [M+H] + . 1 H NMR(400MHz CDCl3),δ=6.33(s,1H),5.23-5.03(m,1H),3.68(s,3H),3.24-3.00(m,1H),2.50 -2.39(m,2H),2.35-2.23(m,3H),2.14-2.01(m,2H),1.93-1.75(m,8H),1.58(br d,J=6.3Hz,1H),1.52-1.42(m,1H),1.26(s,3H),1.13-1.00(m,2H),0.93-0.78(m,7H).

[0111] Example 8 [ka] Synthetic Route: [ka]

[0112] Step 1: Synthesis of 6-1: To a mixture of SM6 (20.0 g, 158 mmol, 1.00 eq) in DCM (400 mL) at 0 °C, m-CPBA (80.4 g, 396 mmol, 85.0% purity, 2.50 eq) was added. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.30, 0.17) showed complete consumption. The reaction mixture was quenched with NaHCO3 (500 mL) and the pH was adjusted to 7–8. The separated organic layer was washed with Na2S2O3 (200 mL × 2) and brine (300 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (column height 250 mm, diameter 100 mm, 100–200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) gave 6-1 (15.0 g, 104 mmol, yield 66.2%, purity 99.5%) as a yellow oil.

[0113] Step 2: Synthesis of 6-2: Triethylamine trihydrofluoride (25.5 g, 158 mmol, 25.8 mL, 1.50 eq) was added to 6-1 (15.0 g, 105 mmol, 1.00 eq) under N2 at 20 °C. The mixture was stirred at 120 °C for 12 h. TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.30) showed complete reaction. The mixture was cooled to 5 °C and quenched by adding saturated NaHCO3 (500 mL). The mixture was stirred for 1 h and diluted with DCM (200 mL). The layers were separated, and the aqueous layer was extracted with additional DCM (200 mL × 4). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated. The mixture was purified by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1). Compound 6-2 (13.0 g, 79.8 mmol, yield 75.6%, purity 99.6%) was obtained as a colorless oil. 1H NMR:(400MHz,CDCl3)δ=4.97-4.75(m,1H),4.45-4.32(m,1H),3.81-3.64(m,3H),3.17-3.0 4(m,1H),2.54-2.35(m,1H),2.33-2.10(m,2H),1.98(ddd,J=2.4,8.4,14.0Hz,1H),1.90(br s,1H); 19 F NMR: (376MHz, CDCl3)δ=-177.97(s,1F).

[0114] Step 3: Synthesis of 6-3: TBSCl (24.1 g, 160 mmol, 19.6 mL, 2.00 eq) and imidazole (21.8 g, 320 mmol, 4.00 eq) were added to a mixture of 6-2 (13.0 g, 80.1 mmol, 1.00 eq) in DMF (50.0 mL) at 20 °C under N2. The mixture was stirred at 30 °C for 12 h. TLC (petroleum ether:ethyl acetate = 10:1, Rf = 0.49) showed complete consumption. The reaction mixture was quenched with water (100 mL) at 10 °C and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1). Compound 6-3 (13.0 g, 45.7 mmol, yield 57.0%, purity 97.3%) was obtained as a colorless oil. 1 H NMR:(400MHz,CDCl3)δ 4.89-4.62(m,1H),4.35-4.22(m,1H),3.77-3.65(m,3H),3.17-3.01(m,1H),2.52-2.28(m,1H),2.21-2.06(m,2H),1.92(br dd,J=8.1,13.4Hz,1H),0.87(s,9H),0.10-0.05(m,6H); 19 F NMR:(377MHz, CDCl3)δ=-175.84(s,1F).

[0115] Step 4: Synthesis of 6-4: At 5 °C, t-BuOK (4.26 g, 37.9 mmol, 1.00 eq), MeCN (1.56 g, 37.9 mmol, 2.00 mL, 1.00 eq), and IPA (456 mg, 7.60 mmol, 581 μL, 0.20 eq) were added to a mixture of 6-3 (10.5 g, 37.9 mmol, 1.00 eq) in THF (100 mL). The mixture was stirred at 20 °C for 1 h. To the mixture at 5 °C, t-BuOK (4.26 g, 37.9 mmol, 1.00 eq) and MeCN (1.56 g, 37.9 mmol, 2.00 mL, 1.00 eq) were added. The mixture was stirred at 20 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.30) showed complete consumption of the reaction. The reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted with DCM (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) gave 6-4 (7.50 g, 26.2 mmol, 69.1% yield) as a yellow oil.

[0116] Step 5: Synthesis of 6-5: To a mixture of compound 6-4 (7.50 g, 26.2 mmol, 1.00 eq) in ethanol (100 mL), TEA (3.19 g, 31.5 mmol, 4.39 mL, 1.20 eq) and tert-butylhydrazine hydrochloride (3.93 g, 31.5 mmol, 1.20 eq) were added at 20 °C. The mixture was stirred at 70 °C for 12 h. HPLC showed complete consumption of the reactants. The reaction mixture was filtered, and the filtrate was concentrated. Purification by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) afforded both compound 6-5A and compound 6-5B (6.50 g, 18.2 mmol, 69.5% yield) as yellow oils. MS m / z (ESI): 356 [M+H] + .

[0117] Step 6: Synthesis of 6-6: TBAF (1.00 M, 25.3 mL, 1.50 eq) was added to a mixture of compound 6-5A and compound 6-5B (6.00 g, 16.8 mmol, 1.00 eq) in THF (50.0 mL) at 20 °C. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.30, 0.11) showed complete reaction. The mixture was poured into aqueous NH4Cl (50.0 mL) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (30.0 mL × 3), and the combined organic phase was washed with brine (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1). Compound 6-6A and Compound 6-6B (4.07 g, crude) were both yellow oils. MS m / z (ESI): 242 [M+H] + .

[0118] Step 7: Combining 6-7: To a mixture of compound 6-6A and compound 6-6B (4.07 g, 16.8 mmol, 1.00 eq) in MECN (20.0 mL) was added CbzCl (8.63 g, 50.6 mmol, 7.19 mL, 3.00 eq) and NaHCO3 (5.67 g, 67.4 mmol, 2.62 mL, 4.00 eq). The mixture was stirred at 80 °C for 12 h. TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.30, 0.46) showed that the remaining amounts of compound 6-6A and compound 6-6B were 20%, respectively. The reaction mixture was filtered, and the filtrate was concentrated. Preparative high-performance liquid chromatography (column: Agela DuraShell C18 250 × 70 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35% to 55%, 20 min) afforded compound 6-7A (1.00 g, crude) as a yellow solid and compound 6-7B (1.20 g, crude) as a yellow solid. MS m / z (ESI): 376 [M+H] + .

[0119] Step 8: Combining 6-8: To a solution of compound 6-7B (1.20 g, 3.20 mmol, 1.00 eq) in THF (20.0 mL) was added PNBA (1.07 g, 6.39 mmol, 2.00 eq) and PPh3 (1.68 g, 6.39 mmol, 2.00 eq) at 20 °C. DEAD (1.11 g, 6.39 mmol, 1.16 mL, 2.00 eq) was added dropwise at 5 °C. The suspension was degassed under vacuum and purged with nitrogen gas several times. The mixture was stirred under nitrogen gas at 60 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.41) showed complete reaction. The reaction mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1). Compound 6-8 (1.90 g, 2.17 mmol, 68.0% yield, 60.7% purity) was obtained as a yellow oil. MS m / z (ESI): 525 [M+H] + .

[0120] Step 9: Synthesis of 6-9: To a mixture of compound 6-8 (1.90 g, 3.62 mmol, 1.00 eq) in MeOH (20.0 mL) was added NaHCO3 (608 mg, 7.24 mmol, 281 μL, 2.00 eq) at 20 °C. The mixture was stirred at 20 °C for 4 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.20) showed complete consumption. The reaction mixture was filtered, and the filtrate was concentrated. Purification was carried out by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1). Compound 6-9 (600 mg, 1.60 mmol, 44.1% yield, n / a purity) was obtained as an off-white solid. MS m / z (ESI): 376 [M+H] + .

[0121] Step 10: Synthesis of 6-10: Compound 6-9 (600 mg, 1.60 mmol, 1.00 eq) in DCM (2.00 mL) was added with pyridine (379 mg, 4.79 mmol, 386 μL, 3.00 eq) and (4-nitrobenzene)carbonyl chloride (644 mg, 3.20 mmol, 2.00 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.59) showed complete consumption. The reaction mixture was concentrated under reduced pressure and then cooled to 40 °C. Purification by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) afforded compound 6-10 (800 mg, crude product) as a yellow solid. MS m / z (ESI): 541 [M+H] + .

[0122] Step 11: Synthesis of 6-11: DIEA (765 mg, 5.92 mmol, 1.03 mL, 4.00 eq) was added to a mixture of compound 6-10 (800 mg, 1.48 mmol, 1.00 eq) and propan-2-amine (104 mg, 1.78 mmol, 152 μL, 1.20 eq) in THF (10.0 mL). The mixture was stirred at 20 °C for 4 h. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.20) showed complete reaction. The reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography (column height 250 mm, diameter 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) gave compound 6-11 (600 mg, crude) as a yellow oil. MS m / z (ESI): 461 [M+H] + .

[0123] Step 12: Synthesis of 6-12: Pd / C (300 mg, 651 μmol, 20.0% purity, 0.50 eq) was added to a solution of compound 6-11 (600 mg, 1.30 mmol, 1.00 eq) in ethyl acetate (20 mL) and tetrahydrofuran (10 mL) under N₂ conditions. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred at 20 °C under H₂ (20 psi) for 12 h. LCMS showed complete reaction. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by high-performance liquid chromatography (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (NH₄HCO₃)-ACN], B%: 25% to -55%, 8 min) to give compound 6-12 (200 mg, 549 μmol, 42.1% yield, 89.6% purity) as a brown solid. MS m / z(ESI):327[M+H] + .

[0124] Step 13: Synthesis of 6-13: TCFH (85.9 mg, 306 μmol, 2.00 eq) and NMI (37.7 mg, 459 μmol, 36.6 μL, 3.00 eq) were added to a mixture of 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (52.1 mg, 306 μmol, 2.00 eq) in MeCN (2.00 mL) at 20 °C. The mixture was stirred at 20 °C for 30 min. Compound 6-12 (50.0 mg, 153 μmol, 1.00 eq) was added to the mixture at 20 °C. The mixture was stirred at 60 °C for 12 h. LC-MS revealed approximately 14.20% residue of compound 6-12 and approximately 15.4% of the target compound 6-13. The reaction mixture was quenched with 20.0 mL of water at 10 °C, diluted with 5 mL of DCM, extracted with DCM (10 mL × 3), and the combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting compound 6-13 (73.0 mg) was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 0:1, Rf = 0.63) as a brown oil, which was used in the next step. MS m / z (ESI): 479 [M+H] + .

[0125] Step 14: Synthesis of Compound 11: At 20°C, HCOOH (2.00 mL) was added to compound 6-13 (73.0 mg, 152 μmol, 1.00 eq). The mixture was stirred at 100°C for 2 h. LC-MS (ET57793-76-P1A, RT = 1.298) showed complete reaction. The reaction mixture was concentrated under reduced pressure to remove HCOOH (2 mL). HPLC (column: Phenomenex C1875 × 30 mm × 3 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 10% to 40%, B%: 8 min) afforded compound 11 (23.0 mg, 54.3 μmol, yield 35.6%, purity 99.8%) as a white solid. MS m / z (ESI): 423.2 [M+H] + ; 1 H NMR(400MHz DMSO-d6),δ=12.28(br s,1H),10.73(br s,1H),7.25(br d,J=7.5Hz,1H),7.11(br s,1H),6.43(br s,1H),5.17-4.96(m,1H),4.94-4.78(m,1H),4.34(s,2H),4.05(s,3H),3.70-3.50(m,1H),3.29- 3.11(m,4H),2.63-2.51(m,1H),2.45-2.36(m,1H),2.00-1.74(m,2H),1.05(d,J=6.5Hz,6H);19F NMR: (377MHz, DMSO-d6), δ=-188.59 (br s, 1F).

[0126] Example 9 [ka] Synthetic Route: [ka]

[0127] Step 1: Synthesis of compound 23-1 Compound 2-(3-(dimethylphosphoryl)phenyl)acetic acid (314 mg, 1.00 eq) and fragment 1-8 (500 mg, 1.00 eq) were dissolved in 8 mL of anhydrous N,N-dimethylformamide and added to a three-neck flask. N-methylimidazole (364 mg, 354 μL, 3.00 eq) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (498 mg, 1.78 mmol, 1.20 eq) were then added. The reaction mixture was heated to 100 °C and reacted for 6 hours. The reaction mixture was then cooled to room temperature, and 80 mL of water was slowly added to the mixture at room temperature. The mixture was then extracted three times with 30 mL of ethyl acetate. The combined organic phases were then extracted with 30 mL of saturated aqueous sodium chloride. The organic phase was dried and concentrated to dryness to obtain the crude product residue. The crude product was purified by preparative separation under acidic conditions to give compound 23-1 (184 mg, yield: 32.9%, purity: 93.8%, yellow oil). MS (ESI) m / z = 418.1 [M+H] + .

[0128] Step 2: Synthesis of compound 23-2 Compound 23-1 (142 mg, 1.00 eq), p-nitrophenyl chloroformate (171 mg, 2.50 eq), 4-dimethylaminopyridine (4.16 mg, 0.10 eq), and pyridine (80.0 mg, 82.4 μL, 3.00 eq) were added in order to 2.5 mL of anhydrous tetrahydrofuran. The reaction mixture was heated to 75 °C and reacted for 22 hours. The system was then cooled to 30 °C, and the reaction mixture was used directly in the next reaction. MS (ESI) m / z = 583.3 [M+H] + .

[0129] Step 3: Synthesis of compound 23-3 Compound 2,2-dimethylazetidine hydrochloride (82.6 mg, 2.00 eq) and N,N-diisopropylethylamine (131 mg, 177 μL, 3.00 eq) were dissolved in 3 mL of anhydrous tetrahydrofuran. The reaction mixture was stirred at 25 °C for 15 minutes, then slowly added dropwise to the reaction mixture from the previous step. The reaction mixture was heated to 50 °C and reacted for 4 hours. The system was then cooled to room temperature, and 5 mL of water was slowly added to the reaction mixture at room temperature. The mixture was extracted three times with 10 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 23-3 (160 mg, yield: 87.3%, purity: 98.0%, pale yellow oil). MS (ESI) m / z = 529.5 [M+H] + .

[0130] Step 4: Synthesis of compound 23 Compound 23-3 (150 mg, 1.00 eq) was dissolved in 2 mL of trifluoroacetic acid and incubated at 70 °C for 12 hours. The mixture was concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation to obtain compound 23 (white solid, 20.0 mg, yield: 16.8%, purity: 98.0%). MS (ESI) m / z = 473.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 12.46-11.40(m,1H),10.41-10.20(m,1H),8.01-7.89(m,1H),7.56(br,1H),7.48 -7.31(m,2H),6.44(m,1H),5.89(s,1H),5.23-5.00(m,1H),4.80-4.66(m,1H),3.6 6(s,2H),3.38-3.08(m,3H),2.50-2.28(m,1H),2.17(t,J=6.7Hz,1H),2.12-2.00 (m,1H),1.92-1.76(m,4H),1.70(br,13.0Hz,6H),1.67-1.61(m,2H),1.21(s,4H).

[0131] Example 10 [ka] Compound 24 was synthesized by following the synthesis method of Steps 1 to 4 in Example 9 (Compound 23). MS m / z (ESI): 480.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 10.79-10.35(m,1H),8.19(br s,1H),7.49(d,J=8.5Hz,2H),7.20-7.16(m,2H),6.41(br s,1H),5.07-4.99(m,1H),3.74(t,J=7.0Hz,2H),3.56(s,2H),3.33(t,J=6.1Hz,2H),3.11(quin,J=8.1Hz,1H),2. 53(t,J=8.1Hz,2H),2.41-2.32(m,1H),2.12-1.92(m,4H),1.82-1.74(m,3H),1.57(t,J=6.1Hz,2H),1.25(s,6H).

[0132] Example 11 [ka] Synthetic Route: [ka]

[0133] Step 1: Synthesis of compound 25-1 52 mL of tetrahydrofuran, fragment 1-6 (5.20 g, 1.00 eq), 4-iodo-3-hydroxypyridine (3.53 g, 2.00 eq), and triphenylphosphine (5.71 g, 1.50 eq) were added to a three-neck flask in that order. After cooling to 0 °C, diisopropyl azodicarboxylate (4.40 g, 1.50 eq) was added and the mixture was stirred at 20 °C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 25-1 (off-white solid, 8.13 g, purity: 93%). MS (ESI) m / z = 561 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.08(s,1H),7.85(d,J=5.0Hz,1H),7.75(d,J=5.0Hz,1H),7.37(br s,4H),6.21(br s,1H),5.20(s,2H),4.98(br d,J=4.8Hz,1H),3.23-3.13(m,1H),2.69-2.59(m,1H),2.18-1.98(m,6H),1.58(s,9H).

[0134] Step 2: Synthesis of compound 25-2 24 mL of ethylene glycol dimethyl ether, 6 mL of water, compound 25-1 (3.00 g, 1.00 eq), isopropenylboronic acid pinacol ester (1.35 g, 2.00 eq), potassium carbonate (1.48 g, 2.00 eq), and tetrakis(triphenylphosphino)palladium (309 mg, 0.05 eq) were added sequentially to a 250 mL three-neck flask and stirred at 100 °C for 12 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 25-2 (yellow oil, 1.0 g, purity: 99.2%). MS (ESI) m / z = 475.3 [M+H] + .

[0135] Step 3: Synthesis of compound 25-3 Compound 25-2 (1.19 g, 2.50 mmol, 1.00 eq) was dissolved in 12.0 mL of acetonitrile. The reaction mixture was transferred to an ice-water bath and cooled to 0 °C. Trimethyliodosilane (1.50 g, 7.51 mmol, 1.02 mL, 3.00 eq) was then slowly added to the reaction mixture. The ice-water bath was removed and the mixture was stirred at room temperature for 16 hours at 20 °C. 40.0 mL of water was added to the reaction mixture, and the mixture was washed with petroleum ether (30.0 mL x 3). The aqueous phase was collected and combined, and extracted with 30.0 mL of ethyl acetate. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was separated by preparative separation to give compound 25-3 (yellow oil, 850 mg, yield: 20.6%, purity: 67.3%). MS (ESI) m / z = 341.2 [M+H]+ .

[0136] Step 4: Synthesis of compound 25-4 N,N-Dimethylformamide (3.00 mL), compound 25-3 (300 mg, 1.00 eq), N-methylimidazole (217 mg, 3.00 eq), and N,N,N,N-tetramethylformamidinium hexafluorophosphate (370 mg, 1.50 eq) were added sequentially to a 10.00 mL reaction flask and incubated at 70 °C under nitrogen gas protection for 4 hours. 20.0 mL of water was added, followed by extraction with two 20.0 mL portions of ethyl acetate. The organic phase was washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 25-4 (white solid, 25.0 mg, yield: 5.20%, purity: 98%). MS (ESI) m / z = 535.3 [M + H] + . Step 5: Synthesis of Compound 25 Compound 25-4 (20.0 mg, 1.00 eq) was dissolved in trifluoroacetic acid (1.00 mL) and reacted at 70 °C for 4 hours. The mixture was concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation to obtain compound 25 (white solid, 6.00 mg, yield: 32.2%, purity: 96.0%). MS (ESI) m / z = 479.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 12.28-11.44(m,1H),9.98(br s,1H),8.19(s,1H),8.15(d,J=4.8Hz,1H),7.99(br d,J=12.1Hz,1H),7.61(br d,J=7.0Hz,1H),7.49-7.37(m,2H),7.08(d,J=4.8Hz,1H),6.45(br s,1H),5.20(br d,J=12.4Hz,2H),4.92(br d,J=3.1Hz,1H),3.66(s,2H),3.29-3.19(m,1H),2.69-2.59(m,1H),2.2 0-2.11(m,1H),2.06(s,3H),2.02-1.88(m,4H),1.72(d,J=13.0Hz,6H).

[0137] Example 12 [ka]

[0138] Compound 26 was synthesized by following the synthesis method of Steps 1-5 in Example 11 (Compound 25). MS m / z (ESI) = 486.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.23(s,1H),8.19(d,J=4.8Hz,1H),8.02(br s,1H),7.60(br d,J=8.1Hz,2H),7.29(br d,J=8.3Hz,2H),7.11(d,J=4.8Hz,1H),6.45(br s,1H),5.33(s,1H),5.21(s,1H),4.98(br s,1H),3.85(t,J=7.0Hz,2H),3.67(s,2H),3.30(quin,J=7.8Hz,1H),2.62(t,J=8.1Hz,2H),2 .53(ddd,J=5.9,9.3,14.6Hz,1H),2.18(quin,J=7.5Hz,4H),2.09(s,3H),2.07-1.80(m,4H).

[0139] Example 13 [ka] Synthetic Route: [ka]

[0140] Step 1: Synthesis of compound 27-2 p-Toluenesulfonic acid (653.3 mg, 3.79 mmol) and trimethyl orthoformate (90.0 g, 848.55 mmol) were added to a methanol solution (200 mL) of ethyl 4-oxytetrahydrofuran-2-carboxylate (20 g, 126.46 mmol) at 30 °C, and the reaction mixture was stirred at 30 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and concentrated under reduced pressure to remove methanol. The mixture was then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 15 / 1) to give compound 27-2 (23 g, 120.93 mmol, 95.63% yield). 1 H NMR(CDCl3,400MHz)δ 4.62-4.58(m,1H),4.00-3.92(m,1H),3.91-3.84(m,1H),3.77(s,3H),3.25(s,3H),3.23(s,3H),2.43-2.40(m,1H),2.32-2.27(m,1H).

[0141] Step 2: Synthesis of compound 27-3 27-2 (19 g, 99.90 mmol) and acetonitrile (12.30 g, 299.70 mmol) were dissolved in tetrahydrofuran (100 mL). Bis-trimethylsilylaminolithium (1 M, 199.80 mL) was slowly added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (300 mL × 3). The organic phase was washed with brine (300 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 6 / 1 to 2 / 1) to give compound 27-3 (20 g, 100.40 mmol, 83.02% yield). 1H NMR(CDCl3,400MHz)δ 4.51(dd,J1=3.6Hz,J2=9.6Hz,1H),4.01-3.98(m,1H),3.88-3.72(m,3H),3.28(s,3H),3.19(s,3H),2.49-2.42(m,1H),2.36-2.27(m,1H).

[0142] Step 3: Synthesis of compound 27-4 To a solution of tert-butylhydrazine hydrochloride (20 g, 96.38 mmol) in ethanol (150 mL), NaOH (3.86 g, 96.38 mmol) was added and stirred at 25 °C for 1 hour. Compound 27-3 (16 g, 80.32 mmol) was then added at 25 °C. The mixture was stirred at 50 °C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 27-4 (23 g, 85.39 mmol, 85.05% yield). MS m / z (ESI) = 238.1 [M-OMe] + . 1 H NMR(CDCl3,400MHz)δ 4.96(dd,J1=6.8Hz,J2=9.2Hz,1H),3.98(d,J=9.2Hz,1H),3.80(d,J=9.2Hz,1H),3.67-3.37(m,2H),3.28 (d,J=2.0Hz,6H),2.43(dd,J1=6.8Hz,J2=12.8Hz,1H),2.25(dd,J1=9.2Hz,J2=12.8Hz,1H),1.62(s,9H).

[0143] Step 4: Synthesis of compound 27-5 Compound 27-4 (23 g, 55.69 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL) and water (20 mL), sodium bicarbonate (14.04 g, 167.08 mmol), and benzyl chloroformate (14.25 g, 83.54 mmol, 1.5 eq) were added at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was added to 100 mL of water and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 27-5 (30 g, 74.35 mmol, 87.07% yield). MS m / z (ESI) = 404.3 [M+H]. + . 1 H NMR(CDCl3,400MHz)δ 7.39~ 7.32(m,5H),6.35~ 6.27(m,1H),6.27(br s,1H),5.19(s,2H),5.01(dd,J1=6.4Hz,J2=9.4Hz,1H),3.97(d,J=9.2Hz,1H),3.81(d, J=9.2Hz,1H),3.27(d,J=2.0Hz,6H),2.47-2.39(m,1H),2.35-2.26(m,1H),1.57(s,9H).

[0144] Step 5: Synthesis of compound 27-6 A solution of compound 27-5 (30 g, 74.35 mmol) in tetrahydrofuran (150 mL) was added to aqueous hydrochloric acid (12 M, 20 mL) and stirred at 25 °C for 1 hour. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 27-6 (26 g, 72.75 mmol, 97.84% yield). MS m / z (ESI) = 358.0 [M+H] + . 1H NMR(CDCl3,400MHz)δ 7.40~ 7.35(m,5H),6.35~ 6.31(m,2H),5.34(t,J=7.2Hz,1H),5.21(s,2H),4.09(d,J=8.8Hz,1H),3 .94(d,J=8.8Hz,1H),2.97-2.86(m,1H),2.83-2.72(m,1H),1.59(s,9H).

[0145] Step 6: Synthesis of compound 27-7 Compound 27-6 (15 g, 41.97 mmol) was dissolved in ethanol (150 mL) and NaBH (7.94 g, 209.85 mmol) was slowly added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (300 mL × 3). The organic phase was washed with brine (300 mL × 3) and dried over anhydrous NaSO. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance liquid chromatography (0.1% FA / MeCN) and then separated by SFC to give compound 27-7 (2.5 g, 6.89 mmol, 16.41% yield). MS m / z (ESI) = 360.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.39~ 7.34(m,5H),6.26~ 6.22(m,2H),5.20(s,2H),5.14(dd,J1=6.4Hz,J2=9.2Hz,1H),4.63~ 4.61(m,1H),4.12(dd,J1=4.4Hz,J2=9.6Hz,1H),3.80(d,J=10.0Hz,1H),2.38-2.30(m,1H),2.29-2.19(m,1H),1.59(s,9H).

[0146] Step 7: Synthesis of compound 27-8 Compound 27-7 (6 g, 16.69 mmol, 1 eq) and imidazole (5.68 g, 83.47 mmol, 5 eq) were dissolved in dichloromethane (50 mL) and tert-butyldimethylchlorosilane (5.03 g, 33.39 mmol, 2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with brine (50 mL × 3) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 27-8 (7 g, 14.78 mmol, 88.52% yield). MS m / z (ESI) = 474.3 [M+H]. + . 1 H NMR(400MHz,CDCl3)δ 7.39~ 7.34(m,5H),6.35(br s,1H),6.23~ 6.19(m,1H),5.20(s,2H),4.85(t,J=7.6Hz,1H),4.56-4.52(m,1H),3.89-3.86(m,1H),3.84 -3.80(m,1H),2.55-2.43(m,1H),2.11-2.08(m,1H),1.58(s,9H),0.89(s,9H),0.07(s,6H).

[0147] Step 8: Synthesis of compound 27-9 To a solution of compound 27-8 (7 g, 14.78 mmol, 1 eq) in methanol (20 mL) was added palladium / carbon (1 g, 10% purity). The mixture was stirred at 25 °C under hydrogen gas (20 psi) for 12 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 27-9 (4.5 g, 89.6% yield). MS m / z (ESI) = 340.3 [M+H] + . 1 H NMR(CDCl3,400MHz)δ 5.72(s,1H),4.78(t,J=8.0Hz,1H),4.55-4.50(m,1H),3.86-3.79(m,2H),3.69-3.17 (m,2H),2.52-2.45(m,1H),2.06-2.00(m,1H),1.62(s,9H),0.90(s,9H),0.08(s,6H).

[0148] Step 9: Synthesis of compound 27-10 To a solution of fragment 4-3 (385.6 mg, 1.77 mmol, 1 eq) in dichloromethane (6 mL) were added 4-dimethylaminopyridine (323.8 mg, 2.65 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (338.7 mg, 1.77 mmol, 1 eq), and compound 27-9 (0.6 g, 1.77 mmol, 1 eq). The mixture was stirred at 25 °C for 12 h. The mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give compound 27-10 (0.6 g, 1.11 mmol, 62.91% yield). MS m / z(ESI)=540.3[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.63(br s,1H),6.82(br s,1H),6.44(s,1H),4.89(t,J=7.6Hz,1H),4.57-4.54(m,1H),4.32(s,2H),4.20(s,3H),3.89-3.86(m,1H),3 .82-3.78(m,1H),2.92(s,3H),2.57-2.49(m,1H),2.15-2.11(m,1H),1.64(s,9H),0.89(s,9H),0.08(s,6H).

[0149] Step 10: Synthesis of compound 27-11 To a solution of compound 27-10 (0.6 g, 1.11 mmol, 1 eq) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1 M, 2.22 mL, 2 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 27-11 (0.4 g, 940.07 μmol, 84.57% yield). MS m / z (ESI) = 426.2 [M+H]+ . 1 H NMR(400MHz,CDCl3)δ 8.00(br s,1H),6.90(br s,1H),6.31(s,1H),5.11(d,J=8.4Hz,1H),4.50~ 4.47(m,1H),4.31(s,2H),4.20(s,3H),3.99(s,2H),2.92(s,3H),2.52-2.40(m,1H),2.37-2.28(m,1H),1.62(s,9H).

[0150] Step 11: Synthesis of compound 27-12 To a solution of compound 27-11 (0.4 g, 940.07 μmol, 1 eq) in dichloromethane (5 mL) was added sodium carbonate (498.2 mg, 4.70 mmol, 5 eq) and 4-nitrobenzoyl chloride ester (568.5 mg, 2.82 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 27-12 (0.35 g, 592.61 μmol, 63.04% yield). MS m / z (ESI) = 591.3 [M+H]. + . 1 H NMR(400MHz,CDCl3)δ 8.28(dd,J1=2.0Hz,J2=7.2Hz,2H),7.52(br s,1H),7.40(dd,J1=2.0Hz,J2=7.2Hz,2H),6.83(br s,1H),6.50(s,1H),5.43-5.38(m,1H),4.97(t,J=7.6Hz,1H),4.33(s,2H),4.26(d,J=11.2Hz,1H),4.21(s ,3H),3.98(dd,J1=4.8Hz,J2=11.2Hz,1H),2.92(s,3H),2.82-2.75(m,1H),2.52-2.43(m,1H),1.66(s,9H).

[0151] Step 12: Synthesis of compound 27-13 Compound 27-12 (0.35 g, 592.61 μmol, 1 eq) was dissolved in formic acid (4 mL) and stirred at 75 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 27-13 (0.3 g, 98% yield). MS m / z (ESI) = 535.2 [M+H]. + .

[0152] Step 13: Synthesis of Compound 27 N,N-Diisopropylethylamine (217.6 mg, 1.68 mmol, 3 eq) and compound 27-13 (0.3 g, 561.27 μmol, 1 eq) were added to a solution of 2,2-dimethylazetidine hydrochloride (68.3 mg, 561.27 μmol, 1 eq, HCl) in tetrahydrofuran (5 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 15 / 1 to 10 / 1) to give compound 27 (0.1 g, 208.10 μmol, 51% yield). MS m / z (ESI) = 481.2 [M+H]. + . 1 H NMR(,400MHz,DMSO-d6)δ 12.50(br s,1H),10.93(br s,1H),7.22(s,1H),6.58(s,1H),5.21-5.12(m,1H),4.99~ 4.95(m,1H),4.47(s,2H),4.08(s,3H),3.91-3.81(m,2H),3.75-3.62(m,2H),3.00(s,3H),2 .69-2.55(m,1H),2.10-2.05(m,1H),1.95-1.84(m,2H),1.38(d,J=4.8Hz,3H),1.26(s,3H).

[0153] Each compound in the table below was synthesized with reference to the synthesis method of Steps 1 to 13 in Example 13 (Compound 27).

[0154] [Table 3]

[0155] Example 14 [ka] Synthetic Route: [ka]

[0156] Step 1: Synthesis of compound 36-2 To a solution of compound 36-1 (5 g, 17.91 mmol) in dioxane (90 mL) and water (9 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (4.84 g, 23.28 mmol) and potassium carbonate (7.43 g, 53.73 mmol) at 25 °C. The mixture was degassed and purged with nitrogen three times. 1,1-Bis(diphenylphosphino)ferrocenedichloropalladium (1.31 g, 1.79 mmol) was added to the reaction mixture, which was then purged with nitrogen three times. The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was poured into 100 mL of water and extracted four times with 50 mL of ethyl acetate. The combined organic phase was washed three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give compound 36-2 (5 g, yield: 83.64%) as a brown solid. 1 H NMR (400MHz, CDCl3) δ 7.54-7.51 (m, 1H), 6.56-6.54 (m, 1H), 3.17 (s, 2H), 2.61-2.56 (m, 2H), 1.55 (s, 9H).

[0157] Step 2: Synthesis of compound 36-3 Sodium borohydride (860 mg, 22.73 mmol) was added to a solution of compound 36-2 (5 g, 17.84 mmol, 1 eq) in methanol (150 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by pouring into 200 mL of water and then extracted four times with 200 mL of ethyl acetate. The combined organic layers were washed three times with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 0 / 1) to give compound 36-3 (3.5 g, 59% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.32(s,1H),7.17-7.04(m,1H),6.34(q,J=2.0Hz,1H),5.07-4.99(m,1H),3.07-2 .93(m,1H),2.81-2.69(m,1H),2.53-2.41(m,1H),1.93-1.83(m,1H),1.53(s,9H).

[0158] Step 3: Synthesis of compound 36-4 Under an argon atmosphere, wet palladium on carbon (1.50 g, 1.41 mmol, 10% purity) was added to a 30 mL solution of compound 36-3 (3.5 g, 12.40 mmol) in methanol. The reaction mixture was degassed and purged with argon and hydrogen gas three times. The reaction mixture was stirred at 25 °C under a 50 Psi hydrogen atmosphere for 5 hours. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give compound 36-4 (3.33 g, yield: 90.69%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.20-7.17(m,1H),4.54-4.38(m,1H),3.76-3.63(m,1H),3.57-3.44(m,1H),2.40-2.08(m,3H),2.03-1.81(m,3H),1.52(s,9H).

[0159] Step 4: Synthesis of compound 36-5 To a solution of compound 36-4 (3.33 g, 11.71 mmol) in N,N-dimethylformamide (100 mL) was added cuprous chloride (1.16 g, 11.71 mmol, 280.02 μL) and 2-isocyanate propane (1.10 g, 12.88 mmol, 1.26 mL) at 18 °C. The reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was diluted with 200 mL of water and extracted four times with 100 mL of ethyl acetate. The combined organic layers were washed three times with 50 mL of saturated brine. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give compound 36-5 (4.25 g, 9.66 mmol, 82.51% yield) as a dark brown oil. 1 H NMR(400MHz,CDCl3)δ 8.06-7.99(m,2H),7.16-7.06(m,1H),5.29-5.13(m,1H),4.63-4.39(m,1H),4.12-3.94(m,1H),3.50-3.31(m,1H),2.96 (s,6H),2.91-2.87(m,6H),2.68-2.49(m,1H),2.24-2.15(m,1H),2.11-1.88(m,4H),1.51(s,9H),1.15(d,J=6.4Hz,6H).

[0160] Step 5: Synthesis of compound 36-6 Compound 36-5 (2.1 g, 5.68 mmol) was added to hexafluoroisopropanol (955.08 mg, 5.68 mmol, 160 mL) at 18 °C. The mixture was stirred at 60 °C for 60 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The solid residue was diluted with 100 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to obtain yellow liquid compound 36-6 (4.8 g, 77.2% yield). 1H NMR(400MHz,CDCl3)δ 6.91(s,1H),5.27-5.13(m,1H),4.55-4.40(m,1H),3.91-3.70(m,2H),3.59-3.47(m,1H),3.39-3.29( m,1H),2.63-2.52(m,1H),2.29-2.13(m,2H),1.98-1.90(m,J=5.1Hz,3H),1.16(dd,J=4.4,6.4Hz,6H).

[0161] Step 6: Synthesis of Compound 36 To a solution of 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (562.24 mg, 3.30 mmol) in dichloromethane (35 mL) was added 4-dimethylaminopyridine (605.48 mg, 4.96 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (950.09 mg, 4.96 mmol) at 20 °C. The reaction mixture was cooled to 0 °C and stirred for 0.25 h. Compound 36-6 (890 mg, 3.30 mmol) was then added at 0 °C and stirred at 25 °C for 5 h. The reaction mixture was quenched by pouring into 100 mL of water and extracted six times with 100 mL of ethyl acetate. The combined organic layers were washed six times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by SFC to give a pale yellow solid compound 36 (550 mg, 39.10% yield). MS m / z (ESI) = 422.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.33-8.28(m,1H),7.48-7.44(m,1H),6.72(s,1H),5.32-5.24(m,1H),4.51-4.43(m,3H),4.23-4.20(m,3H),3 .88-3.75(m,1H),3.69-3.57(m,1H),3.43(s,3H),2.37-2.10(m,4H),1.98-1.80(m,2H),1.17(d,J=6.8Hz,6H).

[0162] Example 15 [ka] Synthetic Route: [ka]

[0163] Step 1: Synthesis of compound 41-2 Sodium hydrogen carbonate (21.24 g, 530.99 mmol, 60% purity) was added to a solution of compound 41-1 (40 g, 252.85 mmol) in tetrahydrofuran (200 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 hours, followed by the slow dropwise addition of benzyl bromide (51.90 g, 303.42 mmol, 36.04 mL). After the addition was complete, the mixture was warmed to 25 °C and stirred for 12 hours. After completion of the reaction, the mixture was quenched with saturated aqueous NH4Cl (300 mL), diluted with water (100 mL), and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with saturated brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether=0-20%) to give compound 41-2 (55 g, 221.49 mmol, yield 93%). 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.20(m,5H),4.47(s,2H),3.88-3.80(m,4H),3.54-3.42(m,1H),1.83-1.73(m,2H),1.73-1.59(m,4H),1.52-1.42(m,2H).

[0164] Step 2: Synthesis of compound 41-3 p-Toluenesulfonic acid monohydrate (114.90 g, 604.07 mmol) was added to a solution of compound 41-2 (30 g, 120.81 mmol) in methanol (300 mL) and water (30 mL) at 20 °C, and the reaction mixture was stirred at 0 °C for 12 h. After concentration under reduced pressure, the residue was slowly poured into water (500 mL) and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 41-3 (23 g, 112.60 mmol, yield: 93.2%). 1 H NMR(400MHz,CDCl3)δ 7.41-7.32(m,4H),7.31-7.25(m,1H),4.56(s,2H),3.83-3.76(m,1H),2.47-2.35(m,2H),2.28-2.16(m,2H),2.00-1.95(m,4H).

[0165] Step 3: Synthesis of compound 41-4 To a toluene solution (200 mL) of compound 41-3 (23 g, 112.60 mmol), sodium chloride (60.83 g, 337.80 mmol, 30% purity) was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and then ethyl formate (50.5 g, 675.60 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 h. After completion of the addition, the mixture was quenched with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with saturated brine (500 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 41-4 (23.7 g, 90.6% yield). 1H NMR(400MHz,CDCl3)δ 14.44(br.s,1H),8.55(s,1H),7.38-7.33(m,4H),7.32-7.28(m,1H),4.65-4.53(m,2H),3.8 5-3.76(m,1H),2.69-2.55(m,2H),2.53-2.46(m,1H),2.45-2.33(m,1H),1.96-1.88(m,2H).

[0166] Step 4: Synthesis of compound 41-5 Compound 41-4 (23.7 g, 102.03 mmol) and hydroxyamine hydrochloride (7.80 g, 112.24 mmol) were added to acetic acid (150 mL), and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was added to 200 mL of water, adjusted to pH 7 with saturated NaHCO3 solution, and then extracted with ethyl acetate (500 mL × 3). The organic phase was washed with brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 10% to 30%) to obtain compound 41-5 (6.7 g, yield: 26.6%). 1 HNMR(400MHz, CDCl3)δ 8.15-8.01(m,1H),7.39-7.25(m,5H),4.68-4.52(m,2H),3.99-3.82(m,1H),3.08-2.54(m,4H),2.19-1.94(m,2H).

[0167] Step 5: Synthesis of compound 41-6 To a toluene solution (70 mL) of compound 41-5 (6.7 g, 27.09 mmol), sodium chloride (6.34 g, 35.22 mmol, 30% purity) was added at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, the mixture was quenched with water (300 mL) and extracted with ethyl acetate (150 mL × 3). The organic phase was washed with saturated brine (1000 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 10-30%) to give compound 41-6 (4.8 g, yield: 77.3%). 1H NMR(400MHz,DMSO-d6)δ 10.37(br.s,1H),7.37-7.25(m,5H),4.51(s,2H),3.75-3.61(m,1H),2.47-2.37(m,1H),2.30-2.13(m,3H),1.88-1.70(m,2H).

[0168] Step 6: Synthesis of compound 41-7 N,N-Diisopropylethylamine (4.17 g, 32.28 mmol) was added dropwise to a solution of tert-butylhydrazine hydrochloride in ethanol (40 mL) at 25 °C and stirred for 1 h. Compound 41-6 (4.8 g, 20.94 mmol) was then added to the reaction mixture and stirred at 90 °C for 3 h. After completion of the reaction, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with brine (200 mL × 2) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 10% to 100%) to give compound 41-7 (4 g, 13.36 mmol, yield: 82.8%). 1 H NMR(400MHz,DMSO-d6)δ 7.40-7.31(m,4H),7.31-7.23(m,1H),4.55(s,2H),4.46(s,2H),3.76-3.64(m,1H),2.73-2.62(m,1H),2. 49-2.46(m,1H),2.42-2.32(m,1H),2.27-2.18(m,1H),1.98-1.89(m,1H),1.80-1.67(m,1H),1.48(s,9H).

[0169] Step 7: Synthesis of compound 41-8 Compound 41-7 (2 g, 6.68 mmol) and 5-(methoxymethyl)-2-methylpyrazole-3-carboxylic acid (1.48 g, 8.68 mmol) were dissolved in dichloromethane (40 mL), and N,N-diisopropylethylamine (3.45 g, 26.72 mmol) and a 50% solution of tri-n-propylcyclophosphoric anhydride in ethyl acetate (12.65 g, 19.88 mmol) were slowly added at 0 °C. The mixture was stirred at 25 °C for 36 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 2) and dried over anhydrous Na2SO4. The filtrate was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether=10%-100%) to give compound 41-8 (1.6 g, yield: 53.0%). 1 H NMR(400MHz,DMSO-d6)δ 9.84(br.s,1H),7.38-7.29(m,4H),7.29-7.23(m,1H),7.03(s,1H),4.58-4.49(m,2H),4.37(s,2H),4.05-4.02 (m,3H),3.84-3.73(m,1H),3.29(s,3H),2.72-2.53(m,3H),2.35-2.26(m,1H),1.98-1.82(m,2H),1.50(s,9H).

[0170] Step 7: Synthesis of compound 41-9 Palladium / carbon (0.16 g, 10% purity) was added to a methanol solution (20 mL) of compound 41-8 (1.6 g, 3.54 mmol). The reaction mixture was stirred under a hydrogen gas atmosphere (30 psi) for 1 hour. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 41-9 (1.2 g, yield: 93.7%). 1H NMR(400MHz,DMSO-d6)δ 9.82(br.s,1H),7.02(s,1H),4.37(s,2H),4.03(s,3H),3.88-3.79(m,2H),3.29(s,3H),2.68-2.5 4(m,2H),2.48-2.42(m,1H),2.15-2.03(m,1H),1.94-1.81(m,1H),1.71-1.59(m,1H),1.49(s,9H).

[0171] Step 8: Synthesis of compound 41-10 To a solution of compound 41-9 (1.2 g, 3.32 mmol) in N,N-dimethylformamide (5 mL) was added cuprous chloride (273.90 mg, 2.77 mmol) and isopropyl isocyanate (323.8 mg, 2.65 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was added to water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 10% to 100%) to give compound 41-10 (1.1 g, 89.0% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.85(br.s,1H),7.10-6.92(m,2H),4.98-4.83(m,1H),4.37(s,2H),4.03(s,3H),3.66-3.50(m,1H),3 .29(s,3H),2.69-2.55(m,3H),2.35-2.24(m,1H),1.98-1.82(m,2H),1.50(s,9H),1.08-0.97(m,6H).

[0172] Step 9: Synthesis of Compound 41 A solution of compound 41-10 (1.1 g, 2.46 mmol) in formic acid (10 mL) was heated to 90°C and stirred for 24 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain the crude product (0.9 g, yield: 85.9%). Separation and purification by SFC yielded compound 41 (394 mg, 1.01 mmol, yield: 43.78%, purity: 100%). MS m / z (ESI) = 391.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.19(br.s,1H),10.23(br.s,1H),7.04(s,1H),7.01-6.92(m,1H),5.04-4.84(m,1H),4.34(s,2H),4.03(s,3H) ),3.66-3.48(m,1H),3.27(s,3H),2.76-2.60(m,3H),2.46-2.31(m,1H),2.02-1.79(m,2H),1.13-0.89(m,6H).

[0173] Example 16 [ka] Synthetic Route: [ka]

[0174] Step 1: Synthesis of compound 42-2 A solution of compound 42-1 (9 g, 70.24 mmol), benzyl bromide (13.22 g, 77.27 mmol), potassium carbonate (29.12 g, 210.73 mmol), and potassium iodide (233.21 mg, 1.40 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25 °C for 3 h. After completion of the reaction, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 5% to 30%) to give compound 42-2 (15 g, yield: 97.8%). 1 H NMR(400MHz,DMSO-d6)δ 7.47-7.24(m,5H),5.13(s,2H),3.28-3.18(m,1H),2.44-2.29(m,2H),2.29-2.11(m,3H),2.05-1.98(m,1H).

[0175] Step 2: Synthesis of compound 42-3 To a solution of compound 42-2 (15 g, 68.73 mmol) in methanol (150 mL) was added sodium borohydride (4.14 g, 109.44 mmol) in several portions at 0 °C, followed by stirring for 0.3 h at 0 °C. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL), the pH was adjusted to 7 with 1 M hydrochloric acid solution, and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 10% to 50%) to give compound 42-3 (12.3 g, yield: 81.3%). 1 H NMR(400MHz,DMSO-d6)δ 7.52-7.27(m,5H),5.19-5.04(m,2H),4.63-4.51(m,1H),4.25-4.04(m,1H),3.05-2.7 3(m,1H),2.12-2.02(m,1H),1.96-1.85(m,1H),1.83-1.59(m,3H),1.57-1.46(m,1H).

[0176] Step 3: Synthesis of compound 42-4 To a solution of compound 42-3 (4 g, 18.16 mmol) in N,N-dimethylformamide (40 mL) was added cuprous chloride (1.80 g, 18.16 mmol) and isopropyl isocyanate (1.85 g, 21.79 mmol). The reaction mixture was stirred at 25 °C for 3 h. After completion of the reaction, the reaction mixture was filtered, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 5% to 30%) to give compound 42-4 (5 g, 90.2% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.52-7.22(m,5H),7.00-6.76(m,1H),5.10(s,2H),5.04-4.83(m,1H),3.66-3.46(m,1H),3. 09-2.78(m,1H),2.35-2.16(m,1H),1.97-1.73(m,4H),1.71-1.54(m,1H),1.09-0.89(m,6H).

[0177] Step 4: Synthesis of compound 42-5 Palladium on carbon (500 mg, 10% purity) was added to a solution of compound 42-4 (5 g, 16.37 mmol) in methanol (20 mL). The mixture was stirred at 25 °C under a hydrogen gas atmosphere (30 psi) for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 42-5 (3.4 g, yield: 96.5%). 1 H NMR(400MHz,DMSO-d6)δ 11.96(br.s,1H),6.90(br.s,1H),5.09-4.80(m,1H),3.70-3.47(m,1H),2.87-2.63 (m,1H),2.34-2.11(m,1H),2.00-1.70(m,4H),1.69-1.52(m,1H),1.09-0.96(m,6H).

[0178] Step 5: Synthesis of compound 42-6 To a mixture of compound 42-5 (30 g, 74.35 mmol) and thiosemicarbazide (1.44 g, 15.80 mmol), phosphorus oxychloride (10 mL) was added and the atmosphere was purged with nitrogen gas three times. The reaction mixture was stirred at 40 °C for 3 h. After completion of the reaction, the reaction mixture was quenched by adding water (200 mL). The pH was adjusted to 9 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 10% to 20%) to give compound 42-6 (3.7 g, 13.69 mmol, yield: 86.6%). 1 H NMR(400MHz,DMSO-d6)δ 7.06-7.00(m,2H),6.98-6.85(m,1H),5.12-4.89(m,1H),3.64-3.50(m,1H), 2.39-2.24(m,1H),2.16-1.99(m,2H),1.92-1.59(m,4H),1.07-0.96(m,6H).

[0179] Step 6: Synthesis of Compound 42 Compound 42-6 (1 g, 3.70 mmol) and 5-(methoxymethyl)-2-methylpyrazole-3-carboxylic acid (629.43 mg, 3.70 mmol) were dissolved in dichloromethane (20 mL). N,N-Diisopropylethylamine (1.43 g, 11.10 mmol) and a 50% solution of tri-n-butylcyclophosphoric anhydride in ethyl acetate (5.33 g, 7.40 mmol) were slowly added at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL × 2) and dried over anhydrous Na2SO4. The filtrate was filtered and concentrated under reduced pressure to give the crude product (1 g, yield: 61.8%). Compound 42 (540 mg, 1.25 mmol, yield: 52.9%, purity: 98.1%) was obtained by separation and purification using SFC. MS m / z (ESI) = 423.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 12.99(br.s,1H),7.21-7.04(m,1H),7.02-6.90(m,1H),5.21-5.01(m,1H),4.35(s,2H),4.10(s,3H),3.72-3.49(m, 2H),3.27(s,3H),2.29-2.19(m,1H),2.17-2.06(m,3H),1.88-1.77(m,1H),1.75-1.64(m,1H),1.05(d,J=6.4Hz,6H).

[0180] Example 17 [ka]

[0181] Step 1: Synthesis of compound 49-2 20 mL of toluene, 2-bromo-5-iodopyridine (1.00 g, 1.00 eq), N-methylpiperazine (352 mg, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (122 mg, 0.06 eq), sodium tert-butoxide (507 mg, 1.50 eq), and tris(dibenzylideneacetone)dipalladium (64.5 mg, 0.02 eq) were added sequentially to a 100 mL three-neck flask and incubated at 100 °C for 12 hours under nitrogen gas protection. The reaction mixture was filtered, 200 mL of water was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phase was washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 49-2 (red oil, 880 mg, yield: 93.63%, purity: 96%). MS (ESI) m / z: [M + H] + =256. 1 H NMR(400MHz, CHLORO FORM-d)δ=8.01(d,J=3.1Hz,1H),7.29(d,J=8.8Hz,1H),7.07(dd,J=3.3,8.8Hz,1H),3.24-3.19(m,4H),2.60-2.55(m,4H),2.36(s,3H).

[0182] Step 2: Synthesis of compound 49-3 25 mL of dioxane, compound 49-2 (415 mg, 1.00 eq), compound fragment 2 (500 mg, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.9 mg, 0.05 eq), cesium carbonate (1.06 g, 2.00 eq), and tris(dibenzylideneacetone)dipalladium (74.2 mg, 0.05 eq) were added sequentially to a 100 mL three-neck flask and incubated at 100 °C for 12 hours under nitrogen gas protection. The reaction mixture was filtered, 200 mL of water was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic phase was washed with brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to obtain compound 49-3 (pink oil, 26.0 mg, yield: 3.625%, purity: 98%). MS(ESI)m / z:[M+H] + =484.

[0183] Step 3: Synthesis of compound 49 Compound 49-3 (26 mg, 1.00 eq) was dissolved in 1 mL of formic acid and reacted at 80 °C for 12 hours. The mixture was concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation to obtain compound 49 (white solid, 7 mg, yield: 30.30%, purity: 98.5%). MS (ESI) m / z = 428 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ=7.88(d,J=2.6Hz,1H),7.25(dd,J=2.9,9.1Hz,1H),7.02(br d,J=8.4Hz,2H),5.86(br s,1H),5.19(br s,1H),4.66(br s,1H),3.80(br s,1H),3.22-3.06(m,5H),2.70-2.59(m,4H),2.55-2.44(m,1H),2.40(s,3H),2.15-2.05(m,1H),1.99-1.80(m,4H),1.19-1.07(m,6H).

[0184] Example 18 [ka]

[0185] Step 1: Synthesis of compound 50-1 Compound fragment 2 (1.8 g, 5.84 mmol), 1-[(4-bromophenyl)methyl]-4-methylpiperazine (2.04 g, 7.59 mmol), and cesium carbonate (3.8 g, 11.67 mmol) were added to tert-amyl alcohol (50 mL), and then (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (490.33 mg, 0.58 mmol) was added, and the atmosphere was replaced with nitrogen gas. The reaction mixture was stirred under a nitrogen gas atmosphere at 100° C. for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by reverse-phase separation (0.1% formic acid, 0-45% acetonitrile) to give compound 50-1 (2.2 g, brown solid, 75.89% yield). MS (ESI) m / z = 497.4 [M+H] + .

[0186] Step 2: Synthesis of Compound 50 Compound 50-1 (2.2 g, 4.43 mmol) was added to methanesulfonic acid (20 mL) and the reaction mixture was stirred at 30°C for 3 hours. After completion of the reaction, the reaction mixture was cooled in an ice bath and quenched by slowly adding the mixture dropwise to ice water. The crude product was purified by reverse-phase separation (0.1% formic acid and 0-40% acetonitrile) and further purified (0.1% aqueous ammonia and 15-45% acetonitrile) to give compound 50 (1.2 g, white solid, 61.49% yield). MS (ESI) m / z = 441.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.19(s,1H),7.28-7.17(m,2H),7.05(d,J=8.4Hz,2H),6.97(d,J=7.2Hz,1H),5.60(s,1H),4.99 (m,1H),3.65-3.50(m,1H),3.29(s,2H),3.10-2.96(m,1H),2.46-2.19(m,8H),2.12(s,3H),2.02-1.52(m,6H),1.03(d,J=6.4Hz,6H).

[0187] Example 19 [ka]

[0188] Step 1: Synthesis of compound 51-1 Compound fragment 2 (101 mg, 1.00 eq), 6-bromo-1'-methyl-1',2',3',6'-tetrahydro-3,4'-bipyridine (100 mg, 1.20 eq), cesium carbonate (161 mg, 1.50 eq), and PdG4 (30.3 mg, 0.10 eq) were added to 1 mL of a mixed solvent of tert-butanol and 1 mL of dioxane and reacted at 100 °C for 2 hours under microwave conditions. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, dried, concentrated, and rotary evaporated to give the crude product. The crude product was purified by preparative separation and separation using a preparative plate to give compound 51-1 (white solid, 245 mg). MS (ESI) m / z = 481.3 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ 8.09(d,J=2.8Hz,1H),7.25(d,J=8.6Hz,1H),6.98-6.94(m,1H),6.45(t,J=3.4Hz,1H),5.93(s,1H),5.14(br s,1H),5.05(s,1H),4.52-4.35(m,1H),3.86-3.68(m,1H),3.18(br s,2H),3.13-3.01(m,1H),2.69(br s,3H),2.56-2.46(m,1H),2.43(s,3H),2.07-1.99(m,1H),1.93-1.74(m,5H),1.61(s,9H),1.11(br d,J=6.5Hz,6H).

[0189] Step 2: Synthesis of compound 51-2 Compound 51-1 (245 mg, 1.00 eq) was dissolved in 2.5 mL of methanol, and wet Pd / C (49.0 mg, 10.0% purity, 0.09 eq) was added under an argon atmosphere. The mixture was stirred at 30 °C and 30 psi for 12 hours under a H atmosphere. After the reaction was complete, the reaction mixture was filtered, concentrated, and rotary dried to give the crude product, compound 51-2 (yellow gel, 188 mg, yield: 76.4%). MS (ESI) m / z = 483.3 [M+H] + .

[0190] Step 3: Synthesis of compound 51 Compound 51-2 (173 mg, 1.00 eq) was dissolved in 7 mL of formic acid and stirred at 80°C for 7 hours, followed by stirring at 85°C for 14 hours. After the reaction was completed, the reaction mixture was concentrated and rotary evaporated. The pH was adjusted to 7-8 with saturated aqueous sodium carbonate, extracted with dichloromethane, and the organic phase was dried, concentrated, and rotary evaporated to obtain the crude product. The crude product was purified by preparative separation and chiral separation to obtain compound 51 (white solid, 36.0 mg, yield: 23.1%, purity: 98.0%). 1H NMR(400MHz,CHLOROFORM-d)δ 10.47-9.29(m,1H),8.35(d,J=2.8Hz,1H),7.61-7.53(m,1H),7.07(d,J=8.5Hz,1H),6.19(br s,1H),5.79(s,1H),5.19(br s,1H),4.77-4.62(m,1H),3.90-3.70(m,1H),3.21-3.11(m,1H),3.00(br d,J=11.5Hz,2H),2.69-2.59(m,1H),2.55-2.44(m,1H),2.34(s,3H),2.10(br t,J=10.9Hz,3H),1.99-1.90(m,4H),1.88-1.78(m,4H),1.18-1.07(m,6H).

[0191] Example 20 [ka]

[0192] Step 1: Synthesis of compound 127-1 Compound fragment 2 (405 mg, 1.00 eq), 1-(2,2-difluoroethyl)-4-(4-iodophenyl)piperazine (555 mg, 1.20 eq), CsCO (642 mg, 1.50 eq), and BrettPhos PdG (119 mg, 0.10 eq) were added sequentially to a solution of tert-butanol (4 mL) / dioxane (4 mL) under nitrogen gas protection. The reaction mixture was placed in a 100 °C oil bath and stirred for 5 h. The solvent was removed by concentration, 10 mL of water was added, and the solution was adjusted to pH 5 with 1 M HCl. The mixture was extracted twice with 10 mL of dichloromethane. The combined organic phases were concentrated to give the crude product. The crude product was separated by preparative separation to give compound 127-1 (yellow solid, 293 mg, yield: 40.8%, purity: 97.2%). MS(ESI) m / z=533.3[M+H] + . 1HNMR(400MHz,CHLOROFORM-d)δ 6.94-6.78(m,2H),6.70(br d,J=8.6Hz,2H),6.13-6.03(m,1H),5.98-5.77(m,1H),5.14(br s,1H),4.93-4.77(m,1H),4.50-4.34(m,1H),3.89-3.72(m,1H),3.25-3.01(m,5H),2.95-2.69(m,6H),2. 51(td,J=7.4,14.3Hz,1H),2.10-1.98(m,1H),1.96-1.82(m,2H),1.82-1.72(m,2H),1.62(s,9H),1.12(br d,J=6.5Hz,6H).

[0193] Step 2: Synthesis of Compound 127 Compound 127-1 (233 mg, 1.00 eq) and TFA (18.4 g, 12 mL, 369 eq) were added to a 25 mL reaction flask and placed in a 100 °C oil bath with stirring for 24 hours. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was separated by fractionation to give compound 127 (gray solid, 42.9 mg, yield: 19.9%, purity: 96.6%). MS (ESI) m / z = 477 [M+H] + . 1 HNMR(400MHz,CHLOROFORM-d)δ7.09(br d,J=8.5Hz,2H),6.89(br d,J=8.6Hz,2H),6.09-5.78(m,2H),5.75(s,1H),5.20(br s,1H),4.59(br d,J=2.6Hz,1H),3.86-3.76(m,1H),3.20-3.10(m,5H),2.86-2.80(m,2H),2.78-2.75(m,4H),2.54-2.43(m,1H),2.16-1.79(m,6H),1.15(br d,J=6.3Hz,6H).

[0194] Example 21 [ka]

[0195] Step 1: Synthesis of compound 128-2 10 mL of N,N-dimethylformamide, 2,2-difluoroethyl p-toluenesulfonate (3.22 g, 2.00 eq), compound 128-1 (2.00 g, 1.00 eq), and triethylamine (1.93 mL, 2.00 eq) were added to a 100 mL single-neck flask and reacted at 100 °C for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted three times with 50 mL of ethyl acetate. The mixture was then dried and rotary evaporated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 128-2 (white solid, 1.10 g, yield: 41.1%, purity: 96%). MS (ESI) m / z: [M+H] + =371. 1 H NMR (400MHz, CHLOROFORM-d)δ=7.55-7.50(m,2H),6.69(d,J=8.9Hz,2H),3.21-3.17(m,4H),3.04(q,J=9.5Hz,2H),2.86-2.81(m,4H).

[0196] Step 2: Synthesis of compound 128-3 3 mL of tert-butanol, 3 mL of dioxane, compound fragment 2 (300 mg, 972.71 μmol, 100 eq), compound 128-2 (432.06 mg, 1.17 mmol, 1.20 eq), Brettphos Pd G3 (88.18 mg, 97.27 μmol, 0.1 eq), and cesium carbonate (475.39 mg, 1.46 mmol, 1.50 eq) were added in this order to a sealed tube, and the atmosphere was replaced with nitrogen gas. The external temperature was then raised to 100° C. and the mixture was stirred while maintaining the temperature for 3 hours. The reaction mixture was concentrated to dryness, 10 mL of water was added, and the pH was adjusted to 5 with 1N hydrochloric acid. The mixture was then extracted twice with 10 mL of dichloromethane. The organic phase was concentrated to dryness to obtain the crude product, which was then purified by preparative chromatography to obtain compound 128-3 (white solid, 250 mg, yield: 45%, purity: 96%). MS (ESI) m / z: [M+H] + =551.4.

[0197] Step 3: Synthesis of Compound 128 Compound 128-3 (250 mg, 1.00 eq) was dissolved in 15 mL of formic acid and incubated at 80 °C for 12 hours. The mixture was concentrated to dryness to obtain a crude product, which was then purified by preparative chromatography to obtain compound 128 (white solid, 42 mg, yield: 17%, purity: 98.63%). MS m / z (ESI): 495.3 [M+H] + . 1 HNMR(400MHz,CHLOROFORM-d)δ 7.08(br d,J=8.4Hz,2H),6.88(br d,J=8.6Hz,2H),5.96-5.82(m,1H),5.75(s,1H),5.24-5.16(m,1H),4.64(br s,1H),3.80(br d,J=5.6Hz,1H),3.18-3.09(m,5H),2.87-2.82(m,4H),2.54-2.42(m,1H),2.16-2.06(m,1H),1.97-1.79(m,5H),1.16-1.12(m,6H).

[0198] Example 22 [ka] Step 1: Synthesis of compound 129-1 Compound fragment 2 (550 mg, 1.78 mmol, 1 eq) and p-bromonitrobenzene (648.42 mg, 3.21 mmol, 1.8 eq) were dissolved in anhydrous 1,4-dioxane (8 mL). Cesium carbonate (1.16 g, 3.57 mmol, 2 eq) was added to the reaction mixture, which was then purged with nitrogen three times. BrettPhos(Pd, G4) (164.16 mg, 178.33 μmol, 0.1 eq) was then added, and the mixture was purged with nitrogen three times. The mixture was then heated at 100 °C for 5 h. After completion of the reaction was confirmed by LCMS, the reaction mixture was poured into 40 mL of water and extracted four times with 20 mL of ethyl acetate. The combined organic phase was washed three times with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by normal phase column chromatography (SiO2 column, petroleum ether:ethyl acetate = 1 / 0 to 1 / 10) and concentrated to give compound 129-1 (720 mg, yellow solid, 94% yield). MS (ESI) m / z = 430.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.12(d,J=8.4Hz,2H),6.69(d,J=8.8Hz,2H),6.00(s,1H),5.66(s,1H),5.15(br s,1H),4.41(s,1H),3.80(s,1H),3.16-3.01(m,1H),2.59-2.47(m,1H) ,2.13-1.92(m,2H),1.90-1.74(m,3H),1.59(s,9H),1.18-1.08(m,6H).

[0199] Step 2: Synthesis of compound 129-2 Compound 129-1 (700 mg, 1.63 mmol, 1 eq) was added to formic acid (10 mL) and stirred at 80 °C for 24 hours. After completion of the reaction was confirmed by LCMS, the mixture was concentrated to give compound 129-2 (800 mg, yellow oil, 98.59% yield). MS (ESI) m / z = 374.2 [M+H] + .

[0200] Step 3: Synthesis of compound 129-3 Compound 129-2 (800 mg, 1.54 mmol, 1 eq, 76% purity) was dissolved in anhydrous tetrahydrofuran (4 mL). Pd / C (80 mg, 10% purity) was added to the reaction mixture under a nitrogen gas purge. The mixture was then purged with hydrogen gas three times and stirred at 20°C for 3 hours. After completion of the reaction was confirmed by LCMS, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (0.1% formic acid, acetonitrile:water = 0-60%) and lyophilized to give compound 129-3 (223 mg, gray solid, 40.41% yield). MS (ESI) m / z = 344.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.19(s,1H),6.97(d,J=8.4Hz,2H),6.67(d,J=8.8Hz,2H),5.69(s,1H),5.62-5.44(m,1H),5.25(br s,1H),3.88-3.78(m,3H),3.31-3.18(m,1H),2.49-2.28(m,1H),2.21-2 .07(m,1H),2.05-1.95(m,1H),1.94-1.81(m,3H),1.16(d,J=6.4Hz,6H).

[0201] Step 4: Synthesis of Compound 129 Compound 129-3 (0.1 g, 262.07 μmol, 1 eq) and N-methylpiperidone (59.31 mg, 524.14 μmol, 60.96 μL, 2 eq) were dissolved in absolute ethanol (1 mL), followed by the addition of sodium cyanoborohydride (82.34 mg, 1.31 mmol, 5 eq) and acetic acid (62.95 mg, 1.05 mmol, 60.01 μL, 4 eq). The mixture was stirred at 80 °C for 4 h. After completion of the reaction was confirmed by LCMS, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (0.1% aqueous ammonia, acetonitrile:water = 0-75%). After freeze-drying, the product was purified by reverse-phase column chromatography (0.1% formic acid, acetonitrile:water = 0-55%) and freeze-dried to give 129 (37.51 mg, yellow gel, 29.41% yield). MS(ESI) m / z = 441.3 [M+H] + .1 H NMR(400MHz,METHANOL-d4)δ 8.48(s,1H),7.00(s,2H),6.79-6.49(m,2H),5.64(br s,1H),5.07(br s,1H),4.83-4.67(m,1H),3.80-3.59(m,1H),3.56-3.36(m,2H),3.17-2.92(m,3H),2.80 (s,3H),2.58-2.43(m,1H),2.32-2.01(m,3H),1.99-1.57(m,6H),1.10(d,J=6.4Hz,6H).

[0202] Example 23 [ka]

[0203] Step 1: Synthesis of Compound 130 Compound 3-fluoro-1-methyl-4-piperidone (69 mg, 526.12 μmol, 3.01 eq) and compound 129-3 (60 mg, 174.71 μmol, 1 eq) were added to anhydrous methanol (2 mL), followed by the addition of acetic acid (11 mg, 183.17 μmol, 1.05 eq) and sodium cyanoborohydride (44 mg, 700.17 μmol, 4.0 eq). The reaction mixture was stirred at 30°C for 48 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by prep-HPLC (column: C18 150 × 30 mm, mobile phase: [water(FA)-ACN], gradient: 8% to 38% B over 7 min) and lyophilized to give compound 130 (23.79 mg, yellow solid, 26.98% yield). MS(ESI) m / z=459.3[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.01(d,J=8.8Hz,2H ),6.62(d,J=8.4Hz,2H ),5.69(s,1H),5.43-5.10(m,2H),4.82(d,J=49.2Hz,1H ),4.60-4.25(m,2H),4.21-3.95(m,2H),3.82-3.77(m,1H),3.40-3.20(m,2H),3.00(d,J=11.6Hz,1H ),2.47-2.34(m,4H),2.33-2.05(m,3H),1.97(s,2H),1.96-1.94(m,1H),1.90-1.80(m,3H),1.17(s,3H),1.15(s,3H).

[0204] Example 24 [ka]

[0205] Step 1: Synthesis of compound 134-1 Compound 1-(4-bromo-2-fluorobenzyl)-4-methylpiperazine (120 mg, 389.08 μmol) was dissolved in dioxane (3 mL) and compound fragment 2 (138.53 mg, 466.90 μmol), cesium carbonate (380.31 mg, 1.17 mmol), and BrettPhos(Pd, G4) (35.82 mg, 38.91 μmol) were added in that order. The reaction mixture was purged with nitrogen gas three times and then stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was rotary evaporated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (0.1% trifluoroacetic acid in water, 0-75% acetonitrile) and lyophilized to obtain 134-1 (150 mg, white solid, 74.90% yield). MS m / z (ESI): 515.3 [M+H] + .

[0206] Step 2: Synthesis of compound 134 Compound 134-1 (120 mg, 194.30 μmol) was dissolved in methanesulfonic acid (2 mL) and stirred at 30°C for 12 hours. The reaction mixture was slowly added dropwise to ice water (3 mL) at 0°C, purified by reverse-phase column chromatography (C18 column, 0.1% formic acid solution), and lyophilized to obtain the crude product. The crude product was again purified by reverse-phase column chromatography (0.1% aqueous ammonia, 0-75% acetonitrile) and lyophilized to obtain compound 134 (31.44 mg, white solid, 29.41% yield). MS m / z (ESI): 459.3 [M+H] + . 1 H NMR(DMSO-d6,400MHz)δ 11.75(s,1H),8.52(s,1H),7.27(d,J=12.4Hz,1H),7.09(t,J=12.4Hz,1H ),7.00-6.85(m,2H),5.61(s,1H),5.03-4.93(m,1H),3.65-3.49(m,1H), 3.35(s,2H),3.09-2.98(m,1.1H),2.38-2.24(m,8H),2.13(s,3H),2.05- 1.83(m,3H),1.76-1.66(m,2H),1.64.1.53(m,1H),1.03(d,J=6.4Hz,6H). Each compound in the table below was synthesized with reference to the synthesis method in steps 1 and 2 in Example 24 (compound 134).

[0207] [Table 4]

[0208] Test Example 1: CDK2 kinase antagonist activity test 1.1 Test materials [Table 5]

[0209] 2.2 Experimental equipment [Table 6]

[0210] 2.3 Test Method Compounds were prepared in DMSO and serially diluted 3-fold to 11 concentrations. 100 nL of compound was added to a 384-well plate. 5 μL of 2× CDK2 / Cyclin E1 or CDK1 / Cyclin B enzyme mixture was added. For full inhibition control wells, 5 μL of buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1 mM EDTA, 0.01% Brij-35, 2 mM DTT, added immediately) was added. After centrifugation at 1,000 rpm for 30 s and incubation at 23 °C for 15 min, 5 μL of 2× MLight-MBP peptide (containing 10 μM ATP) was added to all wells of each assay plate. The plate was then centrifuged at 1,000 rpm for 30 s and incubated at 23 °C for 90 min.

[0211] After incubation, the reaction was stopped with detection buffer containing 15 mM EDTA and 2 nM Eu-anti-P-MBP antibody, centrifuged at 1,000 rpm for approximately 1 min, and incubated at 23°C for 60 min. The plate was then read on a PerkinElmer Envision. The TR-FRET ratio (665 nm value / 615 nm value) was automatically calculated using Envision and normalized to calculate the % inhibition, as follows: Inhibition = (100% inhibition control - sample data) / (100% inhibition control - 0% inhibition control) × 100. The 0% inhibition control was a mixture of enzyme, peptide, and ATP without any compound, and the 100% inhibition control was a mixture of assay buffer, ATP-containing peptide, and no enzyme solution.

[0212] Compound IC by GraphPad nonlinear fitting equation 50 was calculated, and the results are shown in Table 1.

[0213] [Table 7]

[0214] As a result, most of the compounds of the present invention have good CDK2 kinase inhibitory activity, but relatively weak inhibitory activity against CDK1 kinase.

[0215] Test Example 2: HCT116 cell proliferation antagonism test 2.1 Experimental materials [Table 8]

[0216] 2.2 Test equipment [Table 9]

[0217] 2.3 Test Method Cryopreserved HCT116 cells were removed from liquid nitrogen and rapidly transferred to a 37°C water bath, where they were thawed by rapid shaking. The cell suspension was transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes. The supernatant was discarded, and the cells were pelleted and resuspended in RPMI-1640 complete medium (containing 10% fetal bovine serum and 1% penicillin / streptomycin). The cells were then transferred to a cell culture dish containing 10 mL of medium and cultured in a 37°C, 5% CO2 incubator. After the cells adhered to the wall, they were passaged.

[0218] Logarithmic growth phase HCT116 cells in good condition were harvested, digested with pancreatic cell digestion solution, and resuspended in a fixed volume of RPMI-1640 complete medium to form a single-cell suspension. They were counted using a cell counting plate and seeded at a density of 800 cells / well into 96-well white plates. After 5 minutes of incubation, the cells were cultured overnight in a 37°C, 5% CO2 incubator. The following day, different concentrations of compounds were added to the cells. Control groups were treated with the corresponding concentrations of DMSO. Compounds were diluted 1:1000 in RPMI-1640 complete medium to final concentrations of 10.00 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.04 μM, and 0.01 μM. Three parallel wells were prepared for each group, and 100 μL of the administration solution was added to each well. The cells were then placed in an incubator at 37°C and 5% CO 2 for 72 hours.

[0219] After 72 hours of drug action, CellTitle-Glo detection was performed. 100 μL of CellTitle-Glo solution was added to each well of the control and treatment groups, and the wells were mixed on a shaker for 2 minutes to induce cell lysis. The 96-well plate was incubated at room temperature for 10 minutes to stabilize the fluorescent signal. Luminescence signals were detected using a microplate reader. The DMSO-treated cell group was used as the control group, and the 50% inhibitory concentration (IC) was calculated according to the median efficacy equation. 50 ) was calculated.

[0220] Inhibition rate (%) = (control group L value - drug-treated group L value) / control group A value × 100% Compound IC by GraphPad nonlinear fitting equation 50 was calculated, and the results are shown in Table 2.

[0221] [Table 10]

[0222] As a result, most of the compounds of the present invention have good inhibitory activity against HCT116 cell proliferation.

[0223] Test Example 3. Evaluation of in vitro liver microsome stability Equipment: water purifier, Millipore, electronic balance, Mettler Toledo, high-speed tabletop centrifuge, Thermo, water bath constant temperature shaker, Shanghai Yikheng Technology Co., Ltd., vortex shaker, Thermo, LC-MS / MS, AB SCIEX.

[0224] Methods: Liver microsomes from humans, dogs, and SD rats were used to evaluate the metabolic stability of test compounds. Test compounds were incubated with liver microsomes from different species and NADPH in a 37°C water bath. The final concentration of the test or control compound in the incubation system was 1 μM, the final concentration of liver microsomes was 0.5 mg / mL, the final concentration of NADPH was 1 mM, and the final concentration of MgCl2 was 3 mM. At predetermined time points (5, 10, 20, 30, and 60 min), the reaction was stopped by adding a cold acetonitrile solution containing tolbutamide (200 ng / mL) as an internal standard. At 0 min, the stop solution was added to the sample, followed by the NADPH working solution. Testosterone and dextromethorphan were used as positive controls under the same conditions to verify the stability and reliability of the system. After sample pretreatment, semi-quantitative analysis was performed using LC-MS / MS. The retention times of the analytes and internal standards, chromatogram collection, and chromatogram integration were processed using the software Analyst (AB Sciex, Framingham, Massachusetts, USA). The remaining percentage of the test article after 60 min of incubation was calculated, and the test results are shown in Table 3.

[0225] [Table 11]

[0226] As a result, compounds 1, 3, 4, 7, 10, 11, and 27 all showed low clearance in rat, dog, and human liver microsomes, and compounds 9, 13, 27, 33, and 50 all showed low clearance in human liver microsomes, and all had good stability and potential for drug discovery.

[0227] Test Example 4. Evaluation of permeability and transporter substrates Cell: Caco-2 cell Equipment: Water purification system, ELGA LabWate; Biological safety cabinet, Nuaire; Constant temperature CO2 incubator, Thermo; Microplate reader, PerkinElmer; LC-MS / MS, AB SCIEX.

[0228] Methods: The purpose of this study was to measure the bidirectional permeability of compounds using a Caco-2 monolayer cell model and evaluate whether they were efflux-transported via P-glycoprotein (P-gp). Caco-2 cells were seeded in 96-well cell plates and cultured for 24 days before use in the transport experiments. Compounds were administered bidirectionally at a concentration of 2.00 μM with or without verapamil. After 120 minutes of incubation, apical (A) and basolateral (B) samples were collected, and the content of the test article in each sample was detected by liquid chromatography-tandem mass spectrometry (LC / MS / MS). The apparent permeability coefficient and efflux rate were calculated. This section was tested sequentially using two experimental systems, and the data, along with a control compound (PF-07104091), are summarized in Tables 4 and 5.

[0229] [Table 12]

[0230] As a result, compounds 6, 9 and 24 have intermediate permeability, superior to the control compound PF-07104091, while the other compounds have low permeability.

[0231] [Table 13] As a result, compounds 50 and 134 have better permeability than the control compound PF-07104091.

Claims

1. A compound of formula (IIA), a pharmaceutically acceptable salt, stereoisomer or deuterated derivative thereof, 【Chemistry 1】 Among them, X ２ is CH ２ or O, X ３ is CH ２ , NH, O or a bond; R ４ and R ５ are independently H, C １－６ C substituted with alkyl group or cyano group １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Fluoroalkenyl group, C ２－６ alkynyl groups, Or, R ４ and R ５ together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or 【Chemistry 2】 wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups; R ６ａ , R ６ｂ , R ６ｄ , R ６ｅ are each independently H, halogen, or C １－６ Alkyl group, (CH ３ ) ２ -P(O)-, CH ３ -S(O) ２ -, and said C １－６ The alkyl group is optionally C １－６ substituted with an alkoxy group, R ７ are independently selected from 6- to 10-membered heterocyclyl groups, said 6- to 10-membered heterocyclyl groups optionally containing 1, 2, 3, 4, 5 halogens, C １－６ Alkyl group or C １－６ substituted with haloalkyl groups; The compound, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

2. R ４ and R ５ are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, propionitrile-2-yl, 2-methylpropionitrile-2-yl, vinyl, 1-propenyl, 2-propenyl, 3,3-difluoro-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, n-butan-1-yn-3-yl, and n-butan-1-yn-4-yl; Or, R ４ and R ５ together with the N atom to which they are attached, represent an azetidinyl group, a 2,2-dimethylazetidinyl group, or 【Transformation 3】 Forming R ６ａ , R ６ｂ , R ６ｄ , R ６ｅ each independently represents H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, (CH ３ ) ２ -P(O)-, CH ３ -S(O) ２ wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, and isopropoxy groups; R ７ are independently selected from a piperidinyl group or a piperazinyl group, and the piperidinyl group or the piperazinyl group is optionally substituted with 1, 2, 3, 4 or 5 of F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, or 2,2,2-trifluoroethyl group; 2. The compound of claim 1, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

3. R ７ are independently 【Chemistry 4】 Selected from R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ are independently selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof.

4. X ２ is CH ２ Selected from X ３ is CH ２ Selected from R ４ is selected from H, and R ５ is C １－６ alkyl group, preferably an isopropyl group; R ６ａ , R ６ｂ , R ６ｄ , R ６ｅ are each independently selected from H and halogen; 4. The compound of claim 3, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

5. A compound of formula (II), a pharmaceutically acceptable salt, stereoisomer or deuterated derivative thereof, 【Transformation 5】 X １ is selected from NH or O, X ２ is CH ２ or O, L １ is selected from a 6- to 10-membered aryl group, a 6- to 10-membered heteroaryl group, or a 6- to 10-membered heterocyclyl group, and the 6- to 10-membered aryl group, the 6- to 10-membered heteroaryl group, and the 6- to 10-membered heterocyclyl group may optionally be selected from one, two, or three R ６ is replaced by R ４ and R ５ are independently H, C １－６ C substituted with alkyl group or cyano group １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Fluoroalkenyl group, C ２－６ alkynyl groups, Or, R ４ and R ５ together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or 【Transformation 6】 wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups; Each R ６ are independently H, halogen, C １－６ Alkyl group, (CH ３ ) ２ -P(O)-, CH ３ -S(O) ２ -, -CH ２ R ７ , -NHR ７ or a 6- to 10-membered heterocyclyl group, １－６ The alkyl group is optionally C １－６ and the 6- to 10-membered heterocyclyl group is optionally substituted with 1, 2, 3, 4, 5 halogen, C １－６ Alkyl group or C １－６ substituted with a haloalkyl group; R ７ are independently selected from 6- to 10-membered heterocyclyl groups, said 6- to 10-membered heterocyclyl groups optionally containing 1, 2, 3, 4, 5 halogens, C １－６ Alkyl group or C １－６ substituted with haloalkyl groups; The compound, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

6. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or deuterated derivative thereof, 【Transformation 7】 Among them, X １ is selected from NH or O, X ２ is CH ２ or O, R １ teeth, 【Transformation 8】 Selected from R ２ａ is selected from H, R ２ｂ is C １－６ alkyl group, １－６ The alkyl group is R ２ｃ -S(O) ２ - or R ２ｃ -S(O)(NH)-substituted, and ２ｃ is H, C １－６ Alkyl group, C ３－６ selected from a cycloalkyl group or an amino group, R ３ａ , R ３ｂ , R ３ｃ are each independently H, CH ３ -S(O) ２ -CH ２ -, (CH ３ ) ２ -P(O)- or 【Chemistry 9】 Selected from R ３ｄ , R ３ｆ are each independently selected from H, R ３ｅ are independently CH ３ -S(O) ２ -CH ２ -, (CH ３ ) ２ -P(O)-, or R ３ｄ , R ３ｅ are each independently selected from H, R ３ｆ are independently 【Chemistry 10】 Selected from R ４ and R ５ are independently H, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Fluoroalkyl group, C ２－６ Fluoroalkenyl group, C ２－６ Fluoroalkynyl group, C ３－１０ cycloalkyl groups, among which each of the C １－６ The terminal C atoms of the alkyl groups are optionally substituted with cyano groups, of which each of said C ３－１０ the cycloalkyl group is optionally substituted with a difluoromethylene group; Or, R ４ and R ５ together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl group or 【Chemistry 11】 wherein the 4- to 6-membered heterocyclyl group is optionally substituted with 1 to 2 methyl groups. The compound, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

7. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer or deuterated derivative thereof, 【Chemistry 12】 X １ was selected from NH, X ２ is CH ２ or O, R １ teeth 【Chemistry 13】 Selected from R ２ａ and R ２ｂ are each independently selected from H or a methyl group, and the methyl group is optionally selected from methoxy, ethoxy, n-propoxy, isopropoxy, CH ３ -S(O) ２ -, CH ３ CH ２ -S(O) ２ -, cyclopropyl-S(O) ２ -, NH ２ -S(O) ２ - or CH ３ substituted with —S(O)(NH)—, R ４ is selected from H or a methyl group, R ５ is selected from propionitrile-2-yl, 2-methylpropionitrile-2-yl, 3,3-difluoro-2-propenyl, n-butan-1-yn-3-yl, difluoromethylenecyclohexyl, and adamantyl; Or, R ４ and R ５ together with the N atom to which they are attached, represent an azetidinyl group, a 2,2-dimethylazetidinyl group, or 【Chemistry 14】 The compound, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof.

8. The following compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: 【Chemistry 15(1)】 【Chemistry 15(2)】 【Chemistry 15(3)】 【Chemistry 15(4)】 【Chemistry 15(5)】 【Chemistry 15(6)】 【Chemistry 15(7)】 【Chemistry 15(8)】 【Chemistry 15(9)】 Selected from A compound, a pharmaceutically acceptable salt, or a stereoisomer thereof.

9. A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, and a pharmaceutically acceptable carrier. Drug composition.

10. A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated product thereof, or a pharmaceutical composition according to claim 7 in the preparation of a drug. use.

11. The drug is used to prevent or treat related diseases mediated by CDK2.

9. The use according to claim 8.

12. The medicament is used to prevent or treat abnormal cell growth in a subject.

9. The use according to claim 8.

13. the abnormal cell growth is cancer, and the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, cervical cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, skin cancer, lymphoma, sarcoma, multiple myeloma, and solid tumors; 12. The use according to claim 11.

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