CDK2 inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a CDK2 inhibitor as well as a preparation method and a pharmaceutical composition thereof. The invention also relates to application of the compound or the pharmaceutical composition in preparation of drugs for preventing or treating CDK2-mediated related diseases, wherein the diseases comprise abnormal cell growth. # imgabs0 #

Description

CDK2 inhibitors and their preparation method and application Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a class of CDK2 inhibitor compounds and a preparation method thereof, as well as the application of CDK2 inhibitors in medicines for tumor-related diseases. Background Art

[0002] Since their discovery, tumors have been the main factor endangering human health. From the discovery of the first anti-tumor drug, nitrogen mustard, in the 1940s to the discovery of the first tumor-targeted drug in the 1990s, the survival rate of patients with most types of tumors has continued to rise.

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

[0004] The loss of cell cycle regulatory mechanisms is one of the characteristics of tumor formation. Dysfunction of CDKs is often seen in malignant tumors. Therefore, treating malignant tumors by inhibiting CDKs has always been a hot topic in anti-tumor therapy. In the past decade, great progress has been made in the drug development of CDK inhibitors. Selective dual CDK4 / 6 inhibitors have shown strong clinical activity and controllable toxicity. Currently, a number of CDK4 / 6 inhibitors have been successfully developed and marketed and approved for the treatment of breast cancer. They have also shown good clinical efficacy and controllable safety in lung cancer, prostate cancer, and ovarian cancer. CDK2 and CDK4 / 6 are both cell cycle-related kinases. They are a very critical core cell cycle regulator that is active from late G1 to the entire S phase. It is also one of the current hot spots in CDKs research and development.

[0005] Clinical studies have demonstrated that three CDK4 / 6 inhibitors—palboclib, ribociclib, and abemaciclib—can significantly prolong progression-free survival. CDK4 / 6 inhibitors have become standard treatment for endocrine-resistant breast cancer. However, the management of post-resistance resistance has become a major clinical challenge. Phase III clinical studies of palboclib revealed that 70% to 80% of patients develop resistance to CDK4 / 6 inhibitors 12 to 36 months after treatment. Investigations into resistance factors have revealed that CCNE1 amplification or downregulation of p27Kip1 upregulates CDK2 activity. CDK2 subsequently increases Rb phosphorylation, allowing the G1 / S transition and promoting cell proliferation. Ten to 20% of breast cancer patients initially exhibit insensitivity to CDK4 / 6 inhibitors. Studies of these patients have shown significant increases in CCNE1 expression. Therefore, CDK2 inhibition holds promise for reversing resistance to CDK4 / 6 inhibitors.

[0006] The CCNE1 gene, encoding cyclin E1, has been detected in various tumors, with amplification ranging from 0.4% to 40.4% (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, among others). The cyclin encoded by this gene forms a complex with CDK2 and functions as its regulatory subunit, and its activity is required 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 found that CCNE1 amplification is more common in primary platinum-resistant epithelial ovarian cancer and is associated with poor prognosis in ovarian cancer, gastric cancer, endometrial cancer, and triple-negative breast cancer. For patients with CCNE1 amplification, CDK2 inhibitors may be effective in inhibiting tumor proliferation. At the same time, preclinical studies suggest that CDK2 inhibitors have the advantages of comparable effectiveness and higher safety compared to CDK2 / 4 / 6 inhibitors. A single CDK2 inhibitor can be used in combination with other CDK inhibitors, showing the advantages of more flexible, safe and controllable medication.

[0007] CDK1 binds to Cyclin A and Cyclin B to control the progression of the cell cycle from S phase to G2 and M phases. Its function cannot be replaced by other CDK family members, and inhibiting the kinase activity of CDK1 will lead to greater toxicity.

[0008] Based on the above factors, there is an urgent need to develop CDK2 inhibitors with high activity and specificity for the treatment of various tumors, and there is a huge market demand.

[0009] Summary of the Invention

[0010] In one aspect, the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0011] in,

[0012] X1 is selected from NH, or O;

[0013] X2 is selected from CH2, or O;

[0014] R1 is selected from

[0015] R 2a and R 2b Each independently selected from H, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy, R 2c -S(O)2-, or R 2c -S(O)(NH)-substituted, the R 2c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, or amino;

[0016] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f Each independently selected from H, CH3-S(O)2-CH2-, (CH3)2-P(O)-, or

[0017] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Fluorinated alkyl, C 2-6 Fluoroalkenyl, C 2-6 Fluoroalkynyl, C 3-10 Cycloalkyl, wherein each of said C 1-6 The terminal C atoms of the alkyl group are optionally substituted with a cyano group, wherein each of the C 3-10 Cycloalkyl is optionally substituted with difluoromethylene;

[0018] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups.

[0019] In some embodiments of the compound of Formula (I):

[0020] X1 is selected from NH;

[0021] R1 is selected from

[0022] R 2a and R 2b Each independently selected from H, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy, R 2c -S(O)2-, or R 2c -S(O)(NH)-substituted, the R 2c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, or amino;

[0023] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Fluorinated alkyl, C 2-6 Fluoroalkenyl, C 2-6 Fluoroalkynyl, C 3-10 Cycloalkyl, wherein each of said C 1-6 The terminal C atoms of the alkyl group are optionally substituted with a cyano group, wherein each of the C 3-10 Cycloalkyl is optionally substituted with difluoromethylene;

[0024] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups.

[0025] In some embodiments of the compound of Formula (I):

[0026] X1 is selected from NH;

[0027] R1 is selected from

[0028] R 2a and R 2b Each is independently selected from H, or methyl, the methyl being optionally substituted by methoxy, ethoxy, n-propoxy, isopropoxy, CH3-S(O)2-, CH3CH2-S(O)2-, cyclopropyl-S(O)2-, NH2-S(O)2-, or CH3-S(O)(NH)-;

[0029] 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-but-1-yn-3-yl, n-but-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, adamantyl,

[0030] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0031] In some embodiments of the compound of Formula (I):

[0032] X1 is selected from NH;

[0033] R1 is selected from

[0034] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f Each independently selected from H, CH3-S(O)2-CH2-, (CH3)2-P(O)-, or

[0035] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Fluorinated alkyl, C 2-6 Fluoroalkenyl, C 2-6 Fluoroalkynyl, C 3-10 Cycloalkyl, wherein each of said C 1-6 The terminal C atoms of the alkyl group are optionally substituted with a cyano group, wherein each of the C 3-10 Cycloalkyl is optionally substituted with difluoromethylene;

[0036] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups.

[0037] In some embodiments of the compound of Formula (I):

[0038] X1 is selected from NH;

[0039] R1 is selected from

[0040] R 3a、R 3c are each independently selected from H, R 3b independently selected from CH3-S(O)2-CH2-;

[0041] 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-but-1-yn-3-yl, n-but-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, adamantyl,

[0042] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0043] In some embodiments of the compound of Formula (I):

[0044] X1 is selected from NH;

[0045] R1 is selected from

[0046] When R 3d 、R 3f Each independently selected from H, R 3e are independently selected from CH3-S(O)2-CH2-, (CH3)2-P(O)-, or when R 3d 、R 3e Each independently selected from H, R 3f Independently selected from

[0047] 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-but-1-yn-3-yl, n-but-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, adamantyl,

[0048] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0049] In some embodiments of the compound of Formula (I):

[0050] X1 is selected from NH;

[0051] R1 is selected from

[0052] 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-but-1-yn-3-yl, n-but-1-yn-4-yl, cyclohexyl, difluoromethylenecyclohexyl, adamantyl,

[0053] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0054] In another aspect, the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0055] in,

[0056] X1 is selected from NH, or O;

[0057] X2 is selected from CH2, or O;

[0058] L1 is selected from 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl, wherein the 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 R6;

[0059] R4 and R5 are independently selected from H, C 1-6 Alkyl, C substituted by cyano 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl;

[0060] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups;

[0061] Each R6 is independently selected from H, halogen, C 1-6 Alkyl, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7 or 6-10 membered heterocyclic group, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy substituted, the 6-10 membered heterocyclic group is optionally substituted by 1, 2, 3, 4, 5 halogen, C 1-6 Alkyl, or C 1-6 haloalkyl substitution;

[0062] R7 is independently selected from 6-10 membered heterocyclic groups, which are optionally substituted by 1, 2, 3, 4, 5 halogens, C 1-6 Alkyl, or C 1- 6 haloalkyl substitution;

[0063] The “N atom marked with *” represents the N atom connected to R4 and R5 in the general formula (II).

[0064] In some embodiments of the compound of formula (II):

[0065] X1 is selected from NH;

[0066] L1 is selected from phenyl, pyridyl, pyrazolo[1,5-a]pyrazinyl, 2,3-dihydropyrrolo[3,4-c]pyridin-1-one, or piperidinyl, wherein the phenyl, pyridyl, pyrazolo[1,5-a]pyrazinyl, 2,3-dihydropyrrolo[3,4-c]pyridin-1-one, piperidinyl is optionally substituted with 1, 2, or 3 R6;

[0067] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0068] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0069] Each R is 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, or piperazinyl, said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl being optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy; said piperidinyl or piperazinyl being optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl;

[0070] R7 is independently selected from piperidinyl, or piperazinyl, and the piperidinyl, or piperazinyl is optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0071] In some embodiments of the compound of formula (II):

[0072] X1 is selected from NH, or O;

[0073] X2 is selected from CH2, or O;

[0074] L1 is selected from 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl, wherein the 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 R6;

[0075] R4 and R5 are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Fluoroalkenyl;

[0076] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups;

[0077] Each R6 is independently selected from H, C 1-6 Alkyl, (CH3)2-P(O)-, CH3-S(O)2- or 6-10 membered heterocyclic group, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy, or optionally C 1-6 The 6- to 10-membered heterocyclic group is substituted by an alkyl group.

[0078] In some embodiments of the compound of formula (II):

[0079] X1 is selected from NH;

[0080] L1 is selected from phenyl, pyridyl, pyrazolo[1,5-a]pyrazinyl, 2,3-dihydropyrrolo[3,4-c]pyridin-1-one, or piperidinyl, wherein the phenyl, pyridyl, pyrazolo[1,5-a]pyrazinyl, 2,3-dihydropyrrolo[3,4-c]pyridin-1-one, or piperidinyl is optionally substituted with 1, 2, or 3 R6;

[0081] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0082] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0083] 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, or piperazinyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl is optionally substituted by methoxy, ethoxy, n-propoxy, isopropoxy, piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, piperazinyl, N-methylpiperazinyl, or N-ethylpiperazinyl.

[0084] In some embodiments of the compound of formula (II):

[0085] X1 is selected from NH;

[0086] L1 is selected from

[0087] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0088] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0089] R 6a 、R 6b 、R 6c 、R 6d 、R 6e Each 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, tert-butyl is optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy; the piperidinyl or piperazinyl is optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl;

[0090] R7 is independently selected from piperidinyl, or piperazinyl, and the piperidinyl, or piperazinyl is optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0091] In some embodiments of the compound of formula (II):

[0092] X1 is selected from NH;

[0093] L1 is selected from

[0094] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0095] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0096] 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, or piperazinyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl is optionally substituted by methoxy, ethoxy, n-propoxy, isopropoxy, piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, piperazinyl, N-methylpiperazinyl, or N-ethylpiperazinyl.

[0097] In some embodiments of the compound of formula (II):

[0098] X1 is selected from NH;

[0099] L1 is selected from

[0100] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0101] R 6a 、R 6b 、R6c 、R 6d 、R 6e Each 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, The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, and isopropoxy groups;

[0102] The R7 is independently selected from

[0103] The R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0104] In some embodiments of the compound of formula (II):

[0105] X1 is selected from NH;

[0106] L1 is selected from

[0107] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0108] R 6a 、R 6b Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl is optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy;

[0109] R 6c Independently selected from (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7,

[0110] The R7 is independently selected from

[0111] The R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0112] In some embodiments of the compound of formula (II):

[0113] X1 is selected from NH;

[0114] L1 is selected from

[0115] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0116] Each R6 is independently selected from (CH3)2-P(O)-,

[0117] In some embodiments of the compound of formula (II):

[0118] X1 is selected from NH;

[0119] L1 is selected from

[0120] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0121] R 6a 、R 6b 、R 6c 、R 6d Each 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, The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are optionally substituted with methoxy, ethoxy, n-propoxy, and isopropoxy groups;

[0122] The R7 is independently selected from

[0123] The R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0124] In some embodiments of the compound of formula (II):

[0125] X1 is selected from NH;

[0126] L1 is selected from

[0127] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0128] R 6c Independently selected from

[0129] In some embodiments of the compound of formula (II):

[0130] X1 is selected from NH;

[0131] L1 is selected from

[0132] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, R5 is preferably selected from 3,3-difluoro-2-propenyl, or n-but-1-yn-3-yl;

[0133] R 6a selected from methoxymethyl;

[0134] R 6b Selected from methyl.

[0135] In some embodiments of the compound of formula (II):

[0136] X1 is selected from NH;

[0137] L1 is selected from

[0138] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, R5 is preferably selected from 3,3-difluoro-2-propenyl, or 2-propynyl;

[0139] R 6a and R 6b are each independently selected from methyl.

[0140] In some embodiments of the compound of formula (II):

[0141] X1 is selected from NH;

[0142] L1 is selected from

[0143] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0144] R 6a Independently selected from CH3-S(O)2-.

[0145] In some embodiments of the compound of formula (II):

[0146] X1 is selected from NH;

[0147] L1 is selected from

[0148] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0149] Each R6 is independently selected from (CH3)2-P(O)-,

[0150] In another aspect, the present invention provides a compound represented by formula (IIA), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0151] in,

[0152] X2 is selected from CH2, or O;

[0153] X3 is selected from a bond, CH2, NH or O;

[0154] R4 and R5 are independently selected from H, C 1-6 Alkyl, C substituted by cyano 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl;

[0155] or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups;

[0156] R 6a 、R 6b 、R 6d 、R 6e are each independently selected from H, halogen, C 1-6 Alkyl, (CH3)2-P(O)-, CH3-S(O)2-, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy substitution;

[0157] R7 is independently selected from 6-10 membered heterocyclic groups, which are optionally substituted by 1, 2, 3, 4, 5 halogens, C 1-6 Alkyl, or C 1- 6 haloalkyl substitution;

[0158] The “N atom marked with *” represents the N atom connected to R4 and R5 in the general formula (II).

[0159] In some embodiments of the compound of Formula (IIA):

[0160] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl;

[0161] Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or

[0162] In some embodiments of the compound of Formula (IIA):

[0163] R 6a 、R 6b 、R 6d 、R 6e Each 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-, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl group is optionally substituted by methoxy, ethoxy, n-propoxy, isopropoxy.

[0164] In some embodiments of the compound of Formula (IIA):

[0165] R7 is independently selected from piperidinyl, or piperazinyl, and the piperidinyl, or piperazinyl is optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0166] In some embodiments of the compound of Formula (IIA):

[0167] X2 is selected from CH2, or O;

[0168] X3 is selected from a bond, CH2, NH or O;

[0169] 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; R4 is preferably selected from H, and R5 is preferably selected from isopropyl;

[0170] R6a 、R 6b 、R 6d 、R 6e Each 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-, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl group is optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy;

[0171] The R7 is independently selected from

[0172] The R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0173] In some embodiments of the compound of Formula (IIA):

[0174] X2 is selected from CH2; X3 is selected from CH2;

[0175] R4 is selected from H; R5 is selected from C 1-6 Alkyl, preferably isopropyl;

[0176] R 6a 、R 6b 、R 6d 、R 6e Each independently selected from H, halogen;

[0177] R7 is independently selected from

[0178] R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0179] In another aspect, the present invention provides the following compounds, pharmaceutically acceptable salts, stereoisomers or deuterated derivatives thereof, selected from:

[0180] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the aforementioned compounds, pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives thereof, and a pharmaceutically acceptable carrier. The carrier includes conventional excipients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, or wetting agents.

[0181] The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral solutions, suspensions, granules, powders, microgranules, pills, mini tablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally, transmucosally, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type.

[0182] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in dosage unit form containing a specific amount of active ingredient. For example, the pharmaceutical composition can be provided as a tablet or capsule containing an amount of active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The suitable daily dose for humans or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0183] The present invention further provides methods and uses of the compounds, pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof as medicaments. The compounds, pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof can be used to prevent, treat, or ameliorate the pathology and / or symptoms of diseases in animals or humans.

[0184] In certain aspects and embodiments of the compounds, pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions, methods, and uses described herein, the compounds, pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof are selective for CDK2 over other CDKs, particularly CDK1.

[0185] In one aspect, the present invention provides any of the above-mentioned compounds, pharmaceutically acceptable salts thereof, stereoisomers thereof, or pharmaceutical compositions thereof for use in preventing / treating CDK2-mediated related diseases / methods. The CDK2-mediated related diseases include abnormal cell growth of the subject, and the abnormal cell growth is cancer. In certain embodiments, 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, solid tumors.

[0186] Definition and Description

[0187] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0188] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0189] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by reacting a compound having specific substituents discovered by the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, and salts of amino acids (such as arginine, etc.), as well as salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0190] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0191] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0192] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0193] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0194] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0195] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0196] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not 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 processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0197] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with a deuterium atom. The term "optional" or "optionally" means that the event or situation described subsequently may but need not occur, and that the description includes instances where the event or situation occurs as well as instances where the event or situation does not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group may be unsubstituted or substituted with one or more deuterium atoms, i.e., includes instances where the group is unsubstituted, partially substituted, and / or fully substituted.

[0198] The terms "optionally," "optionally," or "optionally substituted with" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with" means that a substituent may or may not be present, and that the substituent includes one, two, or three, etc.

[0199] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which 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 keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0200] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 10 Indicates 1 to 10 carbons, C 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10Examples 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, isopentyl, 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, etc. It will be understood that the term "alkylene" refers to a residue which has lost a 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 the alkylene group (e.g., methylene) appearing at the end of a straight chain or branched chain or at the end of a substituent includes the case of "CH2=", in which the hydrogen atom may be replaced by one or two halogen atoms (e.g., fluorine atoms).

[0201] Unless otherwise specified, the term "alkenyl" is used to denote a straight or branched chain hydrocarbon radical composed of carbon and hydrogen atoms, having at least one carbon-carbon double bond, in either the (E)- or (Z)-configuration, having 2 to 6 carbon atoms, and attached to the rest of the molecule by a single bond. For example, C 2-6 Indicates 2 to 6 carbons, C 2-6 Selected from C2, C3, C4, C5, and C6. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl.

[0202] Unless otherwise specified, the term "alkynyl" is used to refer to a straight or branched chain hydrocarbon radical composed of carbon and hydrogen atoms, having at least one carbon-carbon triple bond, having 2 to 6 carbon atoms, and attached to the rest of the molecule by a single bond. 2-6 Indicates 2 to 6 carbons, C 2-6 is selected from C2, C3, C4, C5, and C6. In one embodiment of the alkynyl group, the number of triple bonds is 1. Examples of alkynyl groups include, but are not limited to, ethynyl, 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.

[0203]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0204] Unless otherwise specified, the term "fluoroalkyl" is intended to include monofluoroalkyl and polyfluoro linear or branched fluoroalkyl. For example, the term "C 1-6 Fluoroalkyl is meant to include, but is not limited to, fluoromethyl, difluoromethyl, trichloromethyl, 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.

[0205] Unless otherwise specified, the term "fluoroalkenyl" is intended to include linear or branched mono- and poly-fluoroalkenyl groups. For example, "C 2-6 Examples of the fluoroalkenyl group include 2-fluorovinyl, 2,2-difluorovinyl, 3-fluoro-1-propenyl, 3,3-difluoro-1-propenyl, 3-fluoro-2-propenyl, 3,3-difluoro-2-propenyl.

[0206] Unless otherwise specified, the term "cycloalkyl" is intended to include any stable cyclic or polycyclic hydrocarbon radical, any carbon atom of which is saturated, which may be monosubstituted or polysubstituted, and which may be monovalent, divalent, or polyvalent. 3-10 represents 3 to 10 carbon atoms, C 3-10 Selected from C3, C4, C5, C6, C7, C8, C9, C 10 Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctyl, [4.4.0]bicyclodecyl, tricyclo[3.3.1.1 3,7 ]Decanyl (adamantyl), etc.

[0207] Unless otherwise specified, the term "alkoxy" refers to an alkyl-O- group, wherein alkyl 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.

[0208] Unless otherwise specified, "heterocyclyl" refers to a fully saturated or unsaturated cyclic group, such as a 3 to 7-membered monocyclic, a 7 to 11-membered bicyclic, or a 10 to 15-membered tricyclic ring system having one or more oxygen, sulfur or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms, on the ring. Nitrogen and sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized. Monocyclic heterocyclic groups include, but are not limited to, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl.

[0209] Unless otherwise specified, "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 10 carbon atoms, which has a single ring or multiple condensed rings. Examples of aryl include, but are not limited to, phenyl and naphthyl.

[0210] Unless otherwise specified, "heteroaryl" refers to a monovalent aromatic group of 5 to 10 ring atoms having one or more oxygen, nitrogen and sulfur heteroatoms, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms in the ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The heteroaryl group can have a monocyclic ring (e.g., pyridyl or furyl) or multiple fused rings, provided that the point of attachment is via a heteroaryl ring atom. Monocyclic heteroaryl groups generally include 5- or 6-membered aromatic rings. Examples of monocyclic heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, furyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl. Examples of fused ring heteroaryl groups include benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, pyrazolo[1,5-a]pyrazinyl, quinolinyl, benzopyranyl, indolizinyl, and the like.

[0211] Compounds are manually or The software named the commercially available compounds using the supplier's catalog name. DETAILED DESCRIPTION

[0212] The present invention is further described below with reference to specific embodiments and test examples, but they are not intended to limit the scope of the present invention in any form.

[0213] Example 1

[0214] Preparation of Fragment 1:

[0215] Synthesis route:

[0216] Step 1: Synthesis of fragment 1-1:

[0217] 1500 mL of methanol and SM 1 (150 g, 1.00 eq) were added sequentially to a 3000 mL three-necked flask. The temperature was lowered to 0°C, and sodium borohydride (41.4 g, 1.04 eq) was added to the reaction solution in 40 batches. Under nitrogen protection, the reaction was allowed to proceed at 0°C for half an hour. 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, adding 1200 mL each time. 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 1-1 (white liquid, 147 g, yield: 52.0%, crude product).

[0218] Step 2: Synthesis of fragment 1-2:

[0219] 1750 mL of anhydrous tetrahydrofuran and fragment 1-1 (140 g, 1.00 eq) were added sequentially to a 5000 mL three-necked flask. Tert-butyldimethylsilyl chloride (292 g, 2.00 eq) and imidazole (132 g, 2.00 eq) were added at room temperature and stirred at room temperature for 12 hours. 700 mL of water was added to the reaction solution and extracted three times with ethyl acetate, adding 1000 mL each time. The organic phases were combined, washed with 1000 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 1-2 (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).

[0220] Step 3: Synthesis of fragments 1-3:

[0221] 645 mL of anhydrous tetrahydrofuran and n-butyllithium (2.50 M, 495 mL, 2.00 eq) were added sequentially to a 3000 mL three-necked flask. The reaction mixture was cooled to -65°C, and acetonitrile (50.8 g, 65.2 mL, 2.00 eq) was slowly added dropwise to the reaction mixture. The reaction was allowed to proceed at -65°C for one hour under a nitrogen atmosphere. 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 -65°C reaction mixture. The reaction was allowed to proceed at -65°C for two hours under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, and 120 mL of water was added dropwise. The pH of the reaction mixture was adjusted to 7 with 1 M HCl solution (1338 mL). The mixture was extracted with ethyl acetate three times, adding 1000 mL each time. 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 (light 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).

[0222] Step 4: Synthesis of fragments 1-4:

[0223] 1073 mL of anhydrous ethanol and sodium hydroxide (21.7 g, 1.20 eq) were added to a 3000 mL three-necked flask. Tert-butylhydrazine hydrochloride (67.6 g, 1.20 eq) was added at room temperature, and 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 anhydrous ethanol, and the compound 1-3 solution was added dropwise to the room temperature tert-butylhydrazine hydrochloride solution. The 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] + .

[0224] Step 5: Synthesis of fragments 1-5:

[0225] 1590 mL of acetonitrile and fragment 1-4 (160 g, 1.00 eq) were added sequentially to a 3000 mL three-necked flask. Benzyl chloroformate (161 g, 2.00 eq) was added at 50°C and room temperature, and the mixture was allowed to react for 16 hours at room temperature. The crude product was dried and extracted with 1000 mL of water and ethyl acetate three times, adding 1000 mL each time. The organic phases were combined and washed with 1000 mL of saturated brine. The organic phases were dried, filtered, and concentrated 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).

[0226] Step 6: Synthesis of fragments 1-6:

[0227] 1630 mL of anhydrous methanol and fragment 1-5 (163 g, 1.00 eq) were added to a 3000 mL three-necked flask. 1 M hydrochloric acid (1.64 L, 4.72 eq) was added at room temperature and allowed to react for 1 hour. 1000 mL of water was added to the reaction solution, and the mixture was extracted three times with 1000 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to yield the crude product. The crude product was first purified by column chromatography to afford the racemic fragment 1-6 (orange liquid, 77.1 g), which was then resolved by SFC to afford the absolute configuration of fragment 1-6 (white solid, 35.7 g, yield: 49.1%, purity: 51.3%). SFC splitting conditions: Column: Chiralpak AD 50mm*4.6mm*3um, Mobile phase: A: CO2B: Methanol (0.05% DEA), Gradient: from5% 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).

[0228] Step 7: Synthesis of fragments 1-7:

[0229] 125 mL of anhydrous tetrahydrofuran and the absolutely configured fragment 1-6 (10.0 g, 1.00 eq) were added to a 100 mL single-necked bottle. Tert-butyldimethylsilyl chloride (8.43 g, 2.00 eq) and imidazole (3.81 g, 2.00 eq) were added to the reaction solution in sequence and reacted at room temperature for 12 hours. 100 mL of water was added to the reaction solution and extracted three times with ethyl acetate, each time with 120 mL. The organic phases were combined. Washed with 150 mL of saturated brine and dried, and concentrated to dryness to obtain a 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).

[0230] Step 8: Synthesis of fragments 1-8:

[0231] 392 mL of methanol, fragment 1-7 (20.4 g, 1.00 eq), and wet Pd / C (7.84 g) were added sequentially to a 1000 mL hydrogenation flask and reacted at 50°C, 40 psi, and hydrogen for 12 hours. Filtration afforded fragment 1-8 (pink liquid, 14.0 g, yield: 87.5%, purity: 91.3%). 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).

[0232] Step 9: Synthesis of fragments 1-9:

[0233] 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 hexafluorophosphonate (1.23 g, 1.20 eq) were added sequentially to a 50 mL single-necked flask at room temperature and stirred for 1 hour. Fragment 1-8 (1.00 g, 1.10 eq) was added to the reaction solution and stirred for 16 hours (two batches). 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate four times (50 mL each). 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 obtain 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).

[0234] Step 10: Synthesis of fragments 1-10:

[0235] 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-necked flask at room temperature and stirred at room temperature for 1 hour. 20 mL of water was added to the reaction solution, and the mixture was extracted ten times with 30 mL of ethyl acetate each time. 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).

[0236] Step 11: Synthesis of Fragment 1:

[0237] 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 sequentially to a 50 mL three-necked flask at room temperature, followed by the addition of pyridine (126 mg, 3.00 eq) and 4-dimethylaminopyridine (6.51 mg, 0.10 eq). The mixture was stirred at 50 ° C for 28 hours to obtain fragment 1, which was used directly in the next step.

[0238] Example 2

[0239] Synthesis route:

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

[0241] 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-necked flask at room temperature and stirred for 1 hour. The 2-aminopropionitrile hydrochloride reaction mixture was added to the fragment 1 reaction mixture at 50°C and stirred at 50°C for 12 hours and then at 70°C for 14 hours. 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 saturated sodium chloride solution (10 mL each). The organic phase was then dried and concentrated to dryness to obtain the crude product. The crude product was purified on a preparative plate to yield 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).

[0242] Step 2: Synthesis of compound 1:

[0243] 1.95 mL of formic acid and compound 1-1 (39.1 mg, 1.00 eq) were added sequentially to a 10 mL single-necked vial at room temperature and stirred at 80°C for 16 hours. The reaction mixture was directly spin-dried 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).

[0244] Referring to the synthetic method of step 1 and step 2 in Example 2 (Compound 1), the compounds in the following table were synthesized:

[0245] Example 3

[0246] Preparation of Fragment 2:

[0247] Synthesis route:

[0248] Step 1: Synthesis of fragment 2-1:

[0249] 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 sequentially to a 250 mL three-necked flask and reacted at 25 ° C for 12 hours under nitrogen protection to obtain fragment 2-1, which was used directly in the next step.

[0250] Step 2: Synthesis of fragment 2-2:

[0251] Isopropylamine (4.96 g, 3.00 eq) and DIEA (10.85 g, 3.00 eq) were added to the reaction mixture of fragment 2-1, and the mixture was 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 each time. The organic phase was separated, and the pH of the solution was adjusted to 8-9. The organic phase was 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 (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).

[0252] Step 3: Synthesis of fragment 2:

[0253] 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 H2 for 12 hours. Filter and spin dry to obtain fragment 2 (pink oil, 5.06 g, crude product). 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).

[0254] Example 4

[0255] Synthesis route:

[0256] Step 1: Synthesis of 4-1:

[0257] 180 mL of dichloromethane, compound SM 4 (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-necked flask, followed by the addition of methanesulfonyl chloride (13.7 g, 1.14 eq) and the reaction was allowed to proceed at room temperature for 16 hours. The reaction liquid 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 a crude product. The crude product was purified by column chromatography to obtain compound 4-1 (yellow liquid, 10.5 g, crude product).

[0258] Step 2: Synthesis of 4-2:

[0259] 120 mL of N,N-dimethylformamide, compound 4-1 (2.00 g, 1.00 eq), potassium iodide (668 mg, 0.50 eq), and sodium thiomethoxide (1.69 g, 3.00 eq) were added sequentially to a 250 mL three-necked flask and reacted at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate four times, each time using 150 mL. The organic phase was washed with brine, dried, and concentrated to dryness to obtain a crude product. 5 mL of the crude product was added dropwise to 40 mL of water. A solid precipitated from the mixed solution and 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).

[0260] Step 3: Synthesis of 4-3:

[0261] 11.4 mL of dichloromethane, 11.4 mL of acetonitrile, compound 4-2 (1.14 g, 1.00 eq), and m-chloroperbenzoic acid (3.73 g, 3.00 eq) were added sequentially to a 100 mL three-necked flask and reacted at room temperature under a nitrogen atmosphere for 12 hours. 20 mL of dichloromethane was added to the reaction mixture, filtered, and the filtrate concentrated to obtain a crude product. The crude product was added to 100 mL of water and extracted with ethyl acetate fifteen times, each time using 40 mL. The organic phase was dried and concentrated to dryness to obtain a crude product. Column chromatography of the crude product afforded 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).

[0262] Step 4: Synthesis of compound 7-1:

[0263] 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-necked flask. O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (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. The reaction mixture was added with 34 mL of water and extracted with ethyl acetate four times (15 mL each time). 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 afford 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).

[0264] Step 5: Synthesis of compound 7:

[0265] 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 yield 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).

[0266] Referring to the synthesis method of steps 1-5 in Example 4 (Compound 7), the compounds in the following table were synthesized:

[0267] Example 5

[0268] Synthesis route:

[0269] Step 1: Synthesis of compound 8-1:

[0270] 20 mL of dichloroethane, compound 1-(methylsulfonyl)piperidin-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-necked flask and incubated at 85°C for 12 hours. After the formation of an intermediate was detected, sodium triacetoxyborohydride (659 mg, 1.60 eq) was added at room temperature and incubated at 60°C for 14 hours. 20 mL of water was added, and the mixture was extracted twice with 20 mL of dichloromethane each time. 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 yield compound 8-1 (yellow solid, 475 mg, yield: 44.19%, purity: 85%). MS m / z (ESI): 470 [M+H] + .

[0271] Step 2: Synthesis of compound 8:

[0272] Compound 8-1 (475 mg, 1.00 eq) was dissolved in 23 mL of 12 M concentrated hydrochloric acid and allowed to react at room temperature for 12 hours. The mixture was concentrated to dryness to obtain a crude product, which was then purified by preparative separation and then separated by SFC to yield 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).

[0273] Example 6

[0274] Synthesis route:

[0275] Step 1: Synthesis of compound 9-1:

[0276] 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 microwaved at 100°C for 1 hour. The mixture was filtered and extracted twice 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 yield compound 9-1 (yellow solid, 927 mg, yield: 49.90%, purity: 86%). MS m / z (ESI): 483 [M+H] + . 1H 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).

[0277] Step 2: Synthesis of compound 9:

[0278] Compound 9-1 (726 mg, 1.00 eq) was dissolved in 366 mL of formic acid and allowed to react at 80°C for 12 hours. The residue was concentrated to dryness to obtain a crude product, which was then purified by preparative separation to yield 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).

[0279] Example 7

[0280] Synthesis route:

[0281] Step 1: Synthesis of 5-1:

[0282] 80 mL of tetrahydrofuran, CHO (584 mg, 1.10 eq), and SM 5 (4.00 g, 1.00 eq) were added sequentially to a 250 mL three-necked flask and stirred at 25°C for 30 minutes. NaBH(OAc) (50.0 mg, 3.00 eq) was added, and the mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated to dryness, 80 mL of water was added, and the mixture was extracted with dichloromethane three times, 200 mL each time. The organic phases were combined and washed with saturated sodium bicarbonate solution (1 M, 800 mL), dried, and concentrated to dryness to obtain compound 5-1 (yellow oil, 3.00 g crude product).

[0283] Step 2: Synthesis of 5-2:

[0284] 100 mL of dichloromethane and compound 5-1 (3.00 g, 1.00 eq) were added to a 250 mL single-necked flask. 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 obtain compound 5-2 (crude, yellow oil, 8.90 g, TFA salt). 1H 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).

[0285] Step 3: Synthesis of compound 10-1:

[0286] 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-necked flask and stirred at 0°C for 30 minutes. The reaction mixture was concentrated to dryness to obtain a 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] + . 1H 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).

[0287] Step 4: Synthesis of compound 10-2:

[0288] 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 bottle and stirred at 50°C under a hydrogen atmosphere at 45 psi for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness to obtain crude 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).

[0289] Step 5: Synthesis of compound 10-3:

[0290] 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-necked flask and stirred at 120°C for 12 hours. The reaction mixture was concentrated to dryness and purified on a preparative plate to yield a mixture of compound 10-3 (yellow solid, 320 mg crude) and compound 10 (pale yellow solid, 60 mg crude).

[0291] Step 6: Synthesis of compound 10:

[0292] 15 mL of HCOOH and compound 10-3 (320 mg, 1.00 eq) were added sequentially to a 50 mL single-necked flask and stirred at 80°C for 12 hours. The reaction solution was concentrated to dryness to obtain a crude product. 10 mL of saturated aqueous sodium carbonate solution was added to the crude product, followed by extraction with dichloromethane three times, 20 mL each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. Compound 10 was purified once on a preparative plate and twice via 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).

[0293] Example 8

[0294] Synthesis route:

[0295] Step 1: Synthesis of 6-1:

[0296] To a mixture of SM 6 (20.0 g, 158 mmol, 1.00 eq) in DCM (400 mL) at 0°C was added m-CPBA (80.4 g, 396 mmol, 85.0% purity, 2.50 eq). The mixture was stirred at 20°C for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.30, 0.17) indicated complete consumption of the reaction. 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.

[0297] Step 2: Synthesis of 6-2:

[0298] 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) at 20°C under N2. The mixture was stirred at 120°C for 12 hours. TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.30) indicated complete consumption of the reaction. The mixture was cooled to 5°C and quenched with saturated NaHCO3 (500 mL). The mixture was stirred for 1 hour and diluted with DCM (200 mL). The layers were separated, and the aqueous layer was extracted with additional DCM (200 mL x 4). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated. Purification was performed 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. 1 H 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).

[0299] Step 3: Synthesis of 6-3:

[0300] 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 hours. TLC (petroleum ether:ethyl acetate = 10:1, Rf = 0.49) indicated complete consumption of the reaction. The reaction mixture was quenched with water (100 mL) at 10°C and then 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 obtain 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) δ4.89-4.62(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).

[0301] Step 4: Synthesis of 6-4:

[0302] 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 hour. To the mixture at 5°C were added 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). The mixture was stirred at 20°C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.30) indicated complete consumption of the product. The reaction mixture was quenched with NH4Cl aq (100 mL) and then 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 obtain 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) afforded 6-4 (7.50 g, 26.2 mmol, 69.1% yield) as a yellow oil.

[0303] Step 5: Synthesis of 6-5:

[0304] To a mixture of compound 6-4 (7.50 g, 26.2 mmol, 1.00 eq) in ethanol (100 mL) were added TEA (3.19 g, 31.5 mmol, 4.39 mL, 1.20 eq), tert-butylhydrazine, and hydrochloric acid (3.93 g, 31.5 mmol, 1.20 eq) at 20°C. The mixture was stirred at 70°C for 12 hours. HPLC indicated 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 compounds 6-5A and 6-5B (6.50 g, 18.2 mmol, yield 69.5%), both as yellow oils. MS m / z (ESI): 356 [M+H] + .

[0305] Step 6: Synthesis of 6-6:

[0306] 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 hours. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.30, 0.11) indicated complete consumption of the reaction. The mixture was poured into aq. NH4Cl (50.0 mL) and stirred for 20 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL*3). The combined organic phases were washed with brine (20 mL*1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification was performed 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] + .

[0307] Step 7: Synthesis of 6-7:

[0308] In MECN (20.0 mL), 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) were added to a mixture of compound 6-6A and compound 6-6B (4.07 g, 16.8 mmol, 1.00 eq). The mixture was stirred at 80°C for 12 hours. TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.30, 0.46) indicated that the residual amounts of compound 6-6A and compound 6-6B were 20%, respectively. The reaction mixture was filtered, and the filtrate was concentrated. Pre-HPLC (column: Agela DuraShell C18 250*70mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-55%, 20 minutes) yielded 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] + .

[0309] Step 8: Synthesis of 6-8:

[0310] To a solution of compound 6-7B (1.20 g, 3.20 mmol, 1.00 eq) in THF (20.0 mL) at 20°C were added PNBA (1.07 g, 6.39 mmol, 2.00 eq) and PPh3 (1.68 g, 6.39 mmol, 2.00 eq). 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 several times. The mixture was stirred at 60°C under nitrogen for 12 hours. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.41) indicated complete consumption of the reaction product. The reaction mixture was concentrated under reduced pressure and 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, yield 68.0%, purity 60.7%) was obtained as a yellow oil. MS m / z (ESI): 525 [M+H] + .

[0311] Step 9: Synthesis of 6-9:

[0312] 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 hours. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.20) indicated complete consumption of the product. The reaction mixture was filtered, and the filtrate was concentrated. Purification was performed 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, yield 44.1%, purity n / a) was obtained as an off-white solid. MS m / z (ESI): 376 [M+H] + .

[0313] Step 10: Synthesis of 6-10:

[0314] To compound 6-9 (600 mg, 1.60 mmol, 1.00 eq) in DCM (2.00 mL) at 20°C were added pyridine (379 mg, 4.79 mmol, 386 μL, 3.00 eq) and (4-nitrobenzene)carbonyl chloride (644 mg, 3.20 mmol, 2.00 eq). The mixture was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 3:1, Rf = 0.59) indicated complete consumption of the reaction. The reaction mixture was concentrated under reduced pressure and deconcentrated at 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) as a yellow solid. MS m / z (ESI): 541 [M+H] + .

[0315] Step 11: Synthesis of 6-11:

[0316] 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 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.20) showed complete consumption of the 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]+ .

[0317] Step 12: Synthesis of 6-12:

[0318] 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 replaced with H₂ several times. The mixture was stirred under H₂ (20 psi) at 20°C for 12 hours. LCMS showed complete consumption of the reaction. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by HPLC (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH₄HCO₃)-ACN]; B%: 25% to 55% over 8 minutes) to obtain compound 6-12 (200 mg, 549 μmol, 42.1% yield, 89.6% purity) as a brown solid. MS m / z(ESI):327[M+H] + .

[0319] Step 13: Synthesis of 6-13:

[0320] 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 minutes. 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 hours. LC-MS analysis revealed approximately 14.20% 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, then diluted with 5 mL of DCM and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. 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 and used in the next step. MS m / z (ESI): 479 [M+H] + .

[0321] Step 14: Synthesis of compound 11:

[0322] 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 hours. LC-MS (ET57793-76-P1A, RT = 1.298) showed complete consumption of the product. The reaction mixture was concentrated under reduced pressure to remove HCOOH (2 ml). HPLC analysis (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 8 minutes) yielded 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).

[0323] Example 9

[0324] Synthesis route:

[0325] Step 1: Synthesis of compound 23-1

[0326] 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-necked flask. N-methylimidazole (364 mg, 354 μL, 3.00 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (498 mg, 1.78 mmol, 1.20 eq) were then added sequentially. The reaction mixture was heated to 100°C for 6 hours. The reaction system was cooled to room temperature, and 80 mL of water was slowly added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate three times, each time using 30 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated sodium chloride solution, dried, and concentrated to dryness to obtain a crude residue. The crude product was separated and purified under acidic conditions to obtain compound 23-1 (184 mg, yield: 32.9%, purity: 93.8%, yellow oil). MS (ESI) m / z = 418.1 [M+H] + .

[0327] Step 2: Synthesis of compound 23-2

[0328] 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 sequentially 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 used directly in the next reaction. MS (ESI) m / z = 583.3 [M+H] + .

[0329] Step 3: Synthesis of compound 23-3

[0330] 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 solution was stirred at 25°C for 15 minutes and then slowly added dropwise to the reaction solution from the previous step. The reaction solution was heated to 50°C and reacted for 4 hours. The system was cooled to room temperature and 5 mL of water was slowly added to the reaction solution at room temperature. The solution was extracted with ethyl acetate three times, each time using 10 mL. 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%, light yellow oil). MS (ESI) m / z = 529.5 [M+H] + .

[0331] Step 4: Synthesis of compound 23

[0332] Compound 23-3 (150 mg, 1.00 eq) was dissolved in 2 mL of trifluoroacetic acid and allowed to react at 70°C for 12 hours. The product was concentrated to dryness to obtain a crude product, which was then purified by preparative separation to yield 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) δ12.46-11.40(m,1H),10.41-10.20(m,1H),8.01-7.89(m,1H),7.5 6(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),3.66(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).

[0333] Example 10

[0334] Compound 24 was synthesized by referring to the synthetic method of steps 1-4 in Example 9 (Compound 23). MS m / z (ESI): 480.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.79-10.35(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).

[0335] Example 11

[0336] Synthesis route:

[0337] Step 1: Synthesis of compound 25-1

[0338] 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 sequentially to a three-necked flask. The temperature was cooled to 0°C, followed by the addition of diisopropyl azodicarboxylate (4.40 g, 1.50 eq). The mixture was stirred at 20°C for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was then purified by preparative separation to yield compound 25-1 (off-white solid, 8.13 g, purity: 93%). MS (ESI) m / z = 561 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.08(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).

[0339] Step 2: Synthesis of compound 25-2

[0340] 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(triphenylphosphine)palladium (309 mg, 0.05 eq) were added sequentially to a 250 mL three-necked flask and stirred at 100°C for 12 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was then purified by preparative separation to yield compound 25-2 (yellow oil, 1.0 g, purity: 99.2%). MS (ESI) m / z = 475.3 [M+H] + .

[0341] Step 3: Synthesis of compound 25-3

[0342] Compound 25-2 (1.19 g, 2.50 mmol, 1.00 eq) was dissolved in 12.0 mL of acetonitrile. The reaction solution was transferred to an ice-water bath and cooled to 0°C. Iodotrimethylsilane (1.50 g, 7.51 mmol, 1.02 mL, 3.00 eq) was then slowly added to the reaction solution. The ice-water bath was removed and the reaction was stirred at 20°C for 16 hours. 40.0 mL of water was added to the reaction solution and washed with petroleum ether (30.0 mL x 3). The combined aqueous phases were collected and extracted with 30.0 mL of ethyl acetate. The resulting organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford the crude product. Preparative separation of the crude product afforded compound 25-3 (850 mg, 20.6% yield, 67.3% purity) as a yellow oil. MS (ESI) m / z = 341.2 [M+H] + .

[0343] Step 4: Synthesis of compound 25-4

[0344] 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-tetramethylchloroformamidine hexafluorophosphate (370 mg, 1.50 eq) were added sequentially to a 10.00 mL reaction flask and allowed to react at 70°C under nitrogen for 4 hours. 20.0 mL of water was added, and the mixture was extracted twice with 20.0 mL of ethyl acetate each time. 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 yield compound 25-4 (white solid, 25.0 mg, yield: 5.20%, purity: 98%). MS (ESI) m / z = 535.3 [M+H] + .

[0345] Step 5: Synthesis of compound 25

[0346] 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, which was then purified by preparative separation to yield compound 25 (white solid, 6.00 mg, yield: 32.2%, purity: 96.0%). MS (ESI) m / z = 479.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ12.28-11.44(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).

[0347] Example 12

[0348] Compound 26 was synthesized by referring to the synthetic method of steps 1-5 in Example 11 (Compound 25). MS m / z (ESI) = 486.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.23(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).

[0349] Example 13

[0350] Synthesis route:

[0351] Step 1: Synthesis of compound 27-2

[0352] p-Toluenesulfonic acid (653.3 mg, 3.79 mmol) and trimethyl orthoformate (90.0 g, 848.55 mmol) were added to a solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (20 g, 126.46 mmol) in methanol (200 mL) at 30°C. The reaction mixture was stirred at 30°C for 12 hours. The mixture was quenched with saturated aqueous NaHCO₃ (50 mL) and concentrated under reduced pressure to remove the methanol. The mixture was then extracted with ethyl acetate (50 mL x 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 afford compound 27-2 (23 g, 120.93 mmol, 95.63% yield). 1 H NMR(CDCl3,400MHz)δ4.62-4.58(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).

[0353] Step 2: Synthesis of compound 27-3

[0354] 27-2 (19 g, 99.90 mmol) and acetonitrile (12.30 g, 299.70 mmol) were dissolved in tetrahydrofuran (100 mL). Lithium bis-trimethylsilylamide (1 M, 199.80 mL) was slowly added dropwise to the reaction mixture at -78°C. The mixture was stirred at -78°C for 2 hours. The mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 6 / 1 to 2 / 1) to afford compound 27-3 (20 g, 100.40 mmol, 83.02% yield). 1 H NMR (CDCl3, 400MHz) δ4.51 (dd, J1=3.6Hz, J2=9.6Hz, 1H), 4.01-3.98 (m, 1H), 3.8 8-3.72(m,3H),3.28(s,3H),3.19(s,3H),2.49-2.42(m,1H),2.36-2.27(m,1H).

[0355] Step 3: Synthesis of compound 27-4

[0356] To a solution of tert-butylhydrazine hydrochloride (20 g, 96.38 mmol) in ethanol (150 mL) was added NaOH (3.86 g, 96.38 mmol). After stirring at 25°C for 1 hour, compound 27-3 (16 g, 80.32 mmol) was 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 obtain a crude product. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 27-4 (23 g, 85.39 mmol, yield 85.05%). MS m / z (ESI) = 238.1 [M-OMe] + . 1 H NMR (CDCl3, 400MHz) δ4.96 (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).

[0357] Step 4: Synthesis of compound 27-5

[0358] Compound 27-4 (23 g, 55.69 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL). 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 hours. The reaction solution was added to 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 27-5 (30 g, 74.35 mmol, 87.07% yield). MS m / z (ESI) = 404.3 [M+H] + . 1H NMR (CDCl3, 400MHz) δ7.39~7.32(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).

[0359] Step 5: Synthesis of compound 27-6

[0360] To a solution of compound 27-5 (30 g, 74.35 mmol) in tetrahydrofuran (150 mL) was added 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*3). The organic phase was washed with brine (100 mL*3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 27-6 (26 g, 72.75 mmol, yield 97.84%). MS m / z (ESI) = 358.0 [M+H] + . 1 H NMR(CDCl3,400MHz)δ7.40~7.35(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).

[0361] Step 6: Synthesis of compound 27-7

[0362] Compound 27-6 (15 g, 41.97 mmol) was dissolved in ethanol (150 mL) and NaBH4 (7.94 g, 209.85 mmol) was slowly added at 0°C. The mixture was stirred at 25°C for 2 hours. 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), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (0.1% FA / MeCN) and separated by SFC to obtain compound 27-7 (2.5 g, 6.89 mmol, yield 16.41%). MS m / z (ESI) = 360.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.39~7.34(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).

[0363] Step 7: Synthesis of compound 27-8

[0364] 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). Tert-butyldimethylsilyl chloride (5.03 g, 33.39 mmol, 2 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction solution 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), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 27-8 (7 g, 14.78 mmol, yield 88.52%). MS m / z (ESI) = 474.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.39~7.34(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).

[0365] Step 8: Synthesis of compound 27-9

[0366] Palladium on carbon (1 g, 10% purity) was added to a methanol solution (20 mL) of compound 27-8 (7 g, 14.78 mmol, 1 eq). The mixture was stirred under hydrogen (20 psi) at 25°C for 12 hours. The reaction mixture was filtered through a pad of celite, 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) δ5.72 (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).

[0367] Step 9: Synthesis of compound 27-10

[0368] 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 hours. 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 to obtain the crude product. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain 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)δ7.63(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).

[0369] Step 10: Synthesis of compound 27-11

[0370] Tetrabutylammonium fluoride (1 M, 2.22 mL, 2 eq) was added to a solution of compound 27-10 (0.6 g, 1.11 mmol, 1 eq) in tetrahydrofuran (10 mL). Stir 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, yield 84.57%). MS m / z (ESI) = 426.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ8.00(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).

[0371] Step 11: Synthesis of compound 27-12

[0372] To a solution of compound 27-11 (0.4 g, 940.07 μmol, 1 eq) in dichloromethane (5 mL) at 0°C were added sodium carbonate (498.2 mg, 4.70 mmol, 5 eq) and 4-nitrobenzenecarbonyl chlorate (568.5 mg, 2.82 mmol, 3 eq). The mixture was stirred at 25°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 27-12 (0.35 g, 592.61 μmol, yield 63.04%). MS m / z (ESI) = 591.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.28 (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).

[0373] Step 12: Synthesis of compound 27-13

[0374] 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 solution was concentrated under reduced pressure to give compound 27-13 (0.3 g, yield 98%). MS m / z (ESI) = 535.2 [M+H] + .

[0375] Step 13: Synthesis of compound 27

[0376] To a solution of 2,2-dimethylazetidine hydrochloride (68.3 mg, 561.27 μmol, 1 eq, HCl) in tetrahydrofuran (5 mL) at 25°C was added N,N-diisopropylethylamine (217.6 mg, 1.68 mmol, 3 eq) and compound 27-13 (0.3 g, 561.27 μmol, 1 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. The crude product was purified by silica 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] + . 1H NMR(,400MHz,DMSO-d6)δ12.50(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),3.7 5-3.62(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).

[0377] Referring to the synthetic method of steps 1-13 in Example 13 (Compound 27), the compounds in the following table were synthesized:

[0378] Example 14

[0379] Synthesis route:

[0380] Step 1: Synthesis of compound 36-2

[0381] To a mixture of compound 36-1 (5 g, 17.91 mmol) in dioxane (90 mL) and water (9 mL) at 25°C, 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) were added. The mixture was degassed and purged with nitrogen three times. 1,1-Bis(diphenylphosphino)ferrocenepalladium dichloride (1.31 g, 1.79 mmol) was added to the reaction mixture. After purging 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 phases were washed three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to obtain brown solid compound 36-2 (5 g, yield: 83.64%). 1 H NMR (400MHz, CDCl3) δ7.54-7.51(m,1H),6.56-6.54(m,1H),3.17(s,2H),2.61-2.56(m,2H),1.55(s,9H).

[0382] Step 2: Synthesis of compound 36-3

[0383] 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 hours. The reaction mixture was poured into 200 mL of water to quench the mixture, 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, and filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 0 / 1) to obtain compound 36-3 (3.5 g, 59% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.32 (s, 1H), 7.17-7.04 (m, 1H), 6.34 (q, J = 2.0Hz, 1H), 5.07-4.99 (m, 1 H),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).

[0384] Step 3: Synthesis of compound 36-4

[0385] Under an argon atmosphere, wet palladium on carbon (1.50 g, 1.41 mmol, 10% purity) was added to a solution of compound 36-3 (3.5 g, 12.40 mmol) in 30 mL of methanol. The reaction mixture was degassed and replaced with argon and hydrogen three times. The reaction mixture was stirred at 25°C under a 50 psi hydrogen atmosphere for 5 hours. The reaction mixture was decompressed, filtered through celite, and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 36-4 (3.33 g, yield: 90.69%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ7.20-7.17(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).

[0386] Step 4: Synthesis of compound 36-5

[0387] To a solution of compound 36-4 (3.33 g, 11.71 mmol) in N,N-dimethylformamide (100 mL) at 18°C ​​were added cuprous chloride (1.16 g, 11.71 mmol, 280.02 μL) and 2-isocyanatopropane (1.10 g, 12.88 mmol, 1.26 mL). The reaction mixture was stirred at 25°C for 5 hours. 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 dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to afford compound 36-5 (4.25 g, 9.66 mmol, 82.51% yield) as a dark brown oil. 1 H NMR (400MHz, CDCl3) δ8.06-7.99(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).

[0388] Step 5: Synthesis of compound 36-6

[0389] Hexafluoroisopropanol (955.08 mg, 5.68 mmol, 160 mL) was added to compound 36-5 (2.1 g, 5.68 mmol) at 18°C. The mixture was stirred at 60°C for 60 hours. 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 then 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, and filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to obtain compound 36-6 (4.8 g, 77.2% yield) as a yellow liquid. 1H NMR(400MHz, CDCl3)δ6.91(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).

[0390] Step 6: Synthesis of compound 36

[0391] To a solution of 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (562.24 mg, 3.30 mmol) in dichloromethane (35 mL) at 20°C was added 4-dimethylaminopyridine (605.48 mg, 4.96 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (950.09 mg, 4.96 mmol). The reaction mixture was then cooled to 0°C and stirred for 0.25 hours. Compound 36-6 (890 mg, 3.30 mmol) was then added at 0°C and stirred at 25°C for 5 hours. 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, and filtered and concentrated under reduced pressure to obtain a residue. The crude product was separated by SFC to afford Compound 36 (550 mg, 39.10% yield) as a pale yellow solid. MS m / z (ESI) = 422.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.33-8.28(m,1H),7.48-7.44(m,1H),6.72(s,1H),5.32-5.24(m,1H),4.51-4.43(m,3H),4.23-4.2 0(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).

[0392] Example 15

[0393] Synthesis route:

[0394] Step 1: Synthesis of compound 41-2

[0395] Sodium hydroxide (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, and then benzyl bromide (51.90 g, 303.42 mmol, 36.04 mL) was slowly added dropwise. After the addition was complete, the mixture was warmed to 25°C and stirred for 12 hours. After completion, the reaction 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 afford compound 41-2 (55 g, 221.49 mmol, 93% yield). 1 H NMR(400MHz,DMSO-d6)δ7.41-7.20(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).

[0396] Step 2: Synthesis of compound 41-3

[0397] 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. The reaction mixture was stirred at 0°C for 12 hours. After the reaction, the residue, after vacuum concentration, was slowly poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 0-30%) to afford compound 41-3 (23 g, 112.60 mmol, yield: 93.2%). 1 H NMR (400MHz, CDCl3) δ7.41-7.32(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).

[0398] Step 3: Synthesis of compound 41-4

[0399] To a toluene solution (200 mL) of compound 41-3 (23 g, 112.60 mmol) was added sodium methoxide (60.83 g, 337.80 mmol, 30% purity) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, followed by the slow addition of ethyl formate (50.5 g, 675.60 mmol). After the addition was complete, the reaction mixture was stirred at 20°C for 12 hours. After completion, the reaction was quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with saturated brine (500 mL x 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 afford compound 41-4 (23.7 g, 90.6% yield). 1 H NMR (400MHz, CDCl3) δ14.44(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),3.85-3.76(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).

[0400] Step 4: Synthesis of compound 41-5

[0401] Compound 41-4 (23.7 g, 102.03 mmol) and hydroxylamine 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 hours. The reaction mixture was added to 200 mL of water, the pH was adjusted to 7 with saturated NaHCO₃ solution, and then extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 10%-30%) to obtain compound 41-5 (6.7 g, yield: 26.6%). 1 HNMR (400MHz, CDCl3) δ8.15-8.01(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).

[0402] Step 5: Synthesis of compound 41-6

[0403] To a toluene solution (70 mL) of compound 41-5 (6.7 g, 27.09 mmol) was added sodium methoxide (6.34 g, 35.22 mmol, 30% purity) at 0°C. The reaction mixture was stirred at 25°C for 12 hours. After completion, the reaction was quenched with water (300 mL) and then extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (1000 mL x 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 afford compound 41-6 (4.8 g, yield: 77.3%). 1 H NMR(400MHz,DMSO-d6)δ10.37(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).

[0404] Step 6: Synthesis of compound 41-7

[0405] 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 hour. Compound 41-6 (4.8 g, 20.94 mmol) was then added to the reaction mixture and stirred at 90°C for 3 hours. After completion of the reaction, water (200 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (ethyl acetate:petroleum ether = 10%-100%) to obtain compound 41-7 (4 g, 13.36 mmol, yield: 82.8%). 1 H NMR(400MHz,DMSO-d6)δ7.40-7.31(m,4H),7.31-7.23(m,1H),4.55(s,2H),4.46(s,2H),3.76-3.64(m,1H),2.73-2.6 2(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).

[0406] Step 7: Synthesis of compound 41-8

[0407] 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). N,N-diisopropylethylamine (3.45 g, 26.72 mmol) and a 50% ethyl acetate solution of tri-n-propyl cyclophosphoric anhydride (12.65 g, 19.88 mmol) were slowly added at 0°C. The mixture was stirred at 25°C for 36 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 10%-100%) to obtain compound 41-8 (1.6 g, yield: 53.0%). 1 H NMR(400MHz,DMSO-d6)δ9.84(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).

[0408] Step 7: Synthesis of compound 41-9

[0409] Palladium on 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 atmosphere (30 psi) for 1 hour. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain compound 41-9 (1.2 g, yield: 93.7%). 1 H NMR(400MHz,DMSO-d6)δ9.82(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 ),2.68-2.54(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).

[0410] Step 8: Synthesis of compound 41-10

[0411] To a solution of compound 41-9 (1.2 g, 3.32 mmol) in N,N-dimethylformamide (5 mL) were 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 hours. 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 obtain the crude product. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 10%-100%) to obtain compound 41-10 (1.1 g, yield 89.0%). 1 H NMR(400MHz,DMSO-d6)δ9.85(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).

[0412] Step 9: Synthesis of compound 41

[0413] 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 solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain a crude product (0.9 g, yield: 85.9%). Compound 41 (394 mg, 1.01 mmol, yield: 43.78%, purity: 100%) was obtained by SFC separation and purification. MS m / z (ESI) = 391.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.19(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).

[0414] Example 16

[0415] Synthesis route:

[0416] Step 1: Synthesis of compound 42-2

[0417] 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 hours. After completion of the reaction, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with brine (200 mL x 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%-30%) to afford compound 42-2 (15 g, yield: 97.8%). 1 H NMR (400MHz, DMSO-d6) δ7.47-7.24(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).

[0418] Step 2: Synthesis of compound 42-3

[0419] To a solution of compound 42-2 (15 g, 68.73 mmol) in methanol (150 mL) at 0°C, sodium borohydride (4.14 g, 109.44 mmol) was slowly added portionwise, followed by stirring at 0°C for 0.3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL), the pH adjusted to 7 with 1 M hydrochloric acid solution, and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 10%-50%) to afford compound 42-3 (12.3 g, yield: 81.3%). 1 H NMR(400MHz,DMSO-d6)δ7.52-7.27(m,5H),5.19-5.04(m,2H),4.63-4.51(m,1H),4.25-4.04(m,1H ),3.05-2.73(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).

[0420] Step 3: Synthesis of compound 42-4

[0421] To a solution of compound 42-3 (4 g, 18.16 mmol) in N,N-dimethylformamide (40 mL) were added cuprous chloride (1.80 g, 18.16 mmol) and isopropyl isocyanate (1.85 g, 21.79 mmol). The reaction was stirred at 25°C for 3 hours. After completion of the reaction, the reaction solution was filtered, diluted with 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 sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate:petroleum ether = 5%-30%) to afford compound 42-4 (5 g, 90.2% yield). 1 H NMR(400MHz,DMSO-d6)δ7.52-7.22(m,5H),7.00-6.76(m,1H),5.10(s,2H),5.04-4.83(m,1H),3.66-3.4 6(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).

[0422] Step 4: Synthesis of compound 42-5

[0423] To a solution of compound 42-4 (5 g, 16.37 mmol) in methanol (20 mL) was added palladium on carbon (500 mg, 10% purity). The mixture was stirred at 25°C under a hydrogen atmosphere (30 psi) for 3 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford compound 42-5 (3.4 g, yield: 96.5%). 1 H NMR(400MHz,DMSO-d6)δ11.96(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).

[0424] Step 5: Synthesis of compound 42-6

[0425] Phosphorus oxychloride (10 mL) was added to a mixture of compound 42-5 (30 g, 74.35 mmol) and thiosemicarbazide (1.44 g, 15.80 mmol), and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 40°C for 3 hours. After completion, 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 x 3). The organic phase was washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica chromatography (methanol:dichloromethane = 10%-20%) to afford compound 42-6 (3.7 g, 13.69 mmol, yield: 86.6%). 1 H NMR(400MHz,DMSO-d6)δ7.06-7.00(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).

[0426] Step 6: Synthesis of compound 42

[0427] 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% ethyl acetate solution of tri-n-butyl cyclophosphoric anhydride (5.33 g, 7.40 mmol) were slowly added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product (1 g, yield: 61.8%). Compound 42 (540 mg, 1.25 mmol, yield: 52.9%, purity: 98.1%) was obtained by SFC separation and purification. MS m / z (ESI) = 423.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.99(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).

[0428] Example 17

[0429] Step 1: Synthesis of compound 49-2

[0430] 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-necked flask. The mixture was incubated at 100°C under nitrogen for 12 hours. The reaction mixture was filtered, 200 mL of water was added, and the mixture was extracted twice with ethyl acetate (200 mL each). 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 49-2 (a 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).

[0431] Step 2: Synthesis of compound 49-3

[0432] 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-necked flask and incubated at 100°C under nitrogen for 12 hours. The reaction mixture was filtered, 200 mL of water was added, and the mixture was extracted twice with ethyl acetate (200 mL each). 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.

[0433] Step 3: Synthesis of compound 49

[0434] 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 crude product was concentrated to dryness, and then purified by preparative separation to yield 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).

[0435] Example 18

[0436] Step 1: Synthesis of compound 50-1

[0437] 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 to replace the nitrogen atmosphere. The reaction solution was stirred at 100 ° C for 5 hours under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. 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, yield 75.89%). MS (ESI) m / z = 497.4 [M+H] + .

[0438] Step 2: Synthesis of compound 50

[0439] 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 the reaction, the reaction mixture was cooled in an ice bath and slowly added dropwise to ice water to quench the reaction. The crude product was purified by reverse phase separation (0.1% formic acid and 0-40% acetonitrile) and further purified (0.1% ammonia water and 15-45% acetonitrile) to obtain compound 50 (1.2 g, white solid, yield 61.49%). MS (ESI) m / z = 441.3 [M+H] + . 1 H 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).

[0440] Example 19

[0441] Step 1: Synthesis of compound 51-1

[0442] 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 Pd G4 (30.3 mg, 0.10 eq) were added to a mixed solvent of 1 mL of tert-butanol and 1 mL of dioxane and reacted at 100° C. under microwave conditions for two hours. After completion of the reaction, water was added, extracted with ethyl acetate, dried, concentrated, and spin-dried to obtain a crude product. Preparative separation and purification and preparative plate separation and purification gave compound 51-1 (white solid, 245 mg). MS (ESI) m / z = 481.3 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ8.09(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).

[0443] Step 2: Synthesis of compound 51-2

[0444] Compound 51-1 (245 mg, 1.00 eq) was dissolved in 2.5 mL of methanol. Wet Pd / C (49.0 mg, 10.0% purity, 0.09 eq) was added under an argon atmosphere. The mixture was stirred for 12 hours at 30°C and 30 psi under a H2 atmosphere. After completion of the reaction, the reaction solution was filtered, concentrated, and dried to give crude compound 51-2 (yellow gum, 188 mg, yield: 76.4%). MS (ESI) m / z = 483.3 [M+H] + .

[0445] Step 3: Synthesis of compound 51

[0446] Compound 51-2 (173 mg, 1.00 eq) was dissolved in 7 mL of formic acid and stirred at 80°C for 7 hours, then at 85°C for 14 hours. After completion of the reaction, the reaction solution was concentrated and dried, adjusted to pH 7-8 with saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic phase was dried, concentrated, and dried to afford the crude product. The crude product was purified by preparative separation and chiral separation to afford compound 51 (white solid, 36.0 mg, yield: 23.1%, purity: 98.0%). 1 H NMR (400MHz, CHLOROFORM-d) δ10.47-9.29(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).

[0447] Example 20

[0448] Step 1: Synthesis of compound 127-1

[0449] Compound fragment 2 (405 mg, 1.00 eq), 1-(2,2-difluoroethyl)-4-(4-iodophenyl)piperazine (555 mg, 1.20 eq), Cs2CO3 (642 mg, 1.50 eq) and BrettPhos PdG3 (119 mg, 0.10 eq) were added to a solution of tert-butyl alcohol (4 mL) / dioxane (4 mL) in sequence under nitrogen protection. The reaction solution was placed in 100 ℃ The mixture was stirred in an oil bath for 5 hours. The solvent was concentrated and removed, 10 mL of water was added, and the pH of the solution was adjusted to approximately 5 with 1 M HCl. The mixture was extracted twice with 10 mL of dichloromethane each time. The combined organic phases were concentrated to obtain the crude product. The crude product was subjected to preparative separation to obtain 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)δ6.94-6.78(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).

[0450] Step 2: Synthesis of compound 127

[0451] 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 solution was concentrated in vacuo to obtain the crude product. Preparative separation of the crude product afforded 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).

[0452] Example 21

[0453] Step 1: Synthesis of compound 128-2

[0454] 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-necked flask and reacted at 100°C for 12 hours. 100 mL of water was added to the reaction solution, and extraction was performed with ethyl acetate three times, 50 mL each time, followed by drying and spin drying to obtain a 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).

[0455] Step 2: Synthesis of compound 128-3

[0456] 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 sequentially to a sealed tube. After nitrogen replacement, the temperature was raised to 100°C and stirred for 3 hours. The reaction solution was concentrated to dryness, 10 mL of water was added, and the pH was adjusted to 5 with 1N hydrochloric acid. The solution was then extracted twice with dichloromethane (10 mL each). The organic phase was concentrated to dryness to obtain the crude product, which was then purified by preparative separation to obtain compound 128-3 (white solid, 250 mg, yield: 45%, purity: 96%). MS (ESI) m / z: [M+H] + =551.4.

[0457] Step 3: Synthesis of compound 128

[0458] 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 separation to yield compound 128 (white solid, 42 mg, yield: 17%, purity: 98.63%). MS m / z (ESI): 495.3 [M+H] + . 1HNMR(400MHz,CHLOROFORM-d)δ7.08(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).

[0459] Example 22

[0460] Step 1: Synthesis of compound 129-1

[0461] 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 solution, and the atmosphere was purged with nitrogen three times. BrettPhos(Pd, G4) (164.16 mg, 178.33 μmol, 0.1 eq) was added, and the atmosphere was purged with nitrogen three times again. The reaction was then incubated at 100°C for 5 hours. After completion of the reaction as determined 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 phases were washed three times with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (SiO2 column, petroleum ether:ethyl acetate = 1 / 0 to 1 / 10) and concentrated to give compound 129-1 (720 mg, yellow solid, yield 94%). MS (ESI) m / z = 430.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.12(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).

[0462] Step 2: Synthesis of compound 129-2

[0463] 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 the reaction was complete as determined by LCMS, the mixture was concentrated to afford compound 129-2 (800 mg, yellow oil, 98.59% yield). MS (ESI) m / z = 374.2 [M+H] + .

[0464] Step 3: Synthesis of compound 129-3

[0465] 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 solution under nitrogen purge. The atmosphere was then replaced with hydrogen three times and stirred at 20°C for 3 hours. After completion of the reaction, the reaction solution 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 obtain compound 129-3 (223 mg, gray solid, 40.41% yield). MS (ESI) m / z = 344.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.19(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).

[0466] Step 4: Synthesis of compound 129

[0467] 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 anhydrous ethanol (1 mL). Sodium cyanoborohydride (82.34 mg, 1.31 mmol, 5 eq) and acetic acid (62.95 mg, 1.05 mmol, 60.01 μL, 4 eq) were then added and stirred at 80°C for 4 hours. After completion of the reaction, 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% ammonia water, acetonitrile:water = 0-75%). After lyophilization, the product was further purified by reverse-phase column chromatography (0.1% formic acid, acetonitrile:water = 0-55%) to afford 129 (37.51 mg, yellow gum, 29.41% yield). MS (ESI) m / z = 441.3 [M+H] + . 1 H NMR(400MHz,METHANOL-d4)δ8.48(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).

[0468] Example 23

[0469] Step 1: Synthesis of compound 130

[0470] 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). Acetic acid (11 mg, 183.17 μmol, 1.05 eq) and sodium cyanoborohydride (44 mg, 700.17 μmol, 4.0 eq) were added sequentially. The reaction mixture was stirred at 30°C for 48 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by prep-HPLC (column: C18 150×30 mm; mobile phase: [water(FA)-ACN]; gradient: 8%-38% B over 7 min.) and lyophilized to obtain compound 130 (23.79 mg, yellow solid, 26.98% yield). MS (ESI) m / z = 459.3 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ7.01(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).

[0471] Example 24

[0472] Step 1: Synthesis of compound 134-1

[0473] 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 sequentially. The reaction mixture was purged with nitrogen three times and then stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was dried 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, 74.90% yield, as a white solid). MS m / z (ESI): 515.3 [M+H] + .

[0474] Step 2: Synthesis of compound 134

[0475] 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 solution was slowly added dropwise to ice water (3 mL) at 0°C, then purified by reverse-phase column chromatography (C18 column, 0.1% formic acid solution) and lyophilized to obtain the crude product. The product was further 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] + . 1H NMR(DMSO-d6,400MHz)δ11.75(s,1H),8.52(s,1H),7.27(d,J=12.4Hz,1H),7.0 9(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).

[0476] Referring to the synthetic method of steps 1-2 in Example 24 (Compound 134), the compounds in the following table were synthesized:

[0477] Test Example 1. CDK2 kinase antagonist activity test

[0478] 1.1 Test materials

[0479] 2.2 Experimental instruments

[0480] 2.3 Test methods

[0481] Compounds were prepared in DMSO and serially diluted three-fold to 11 concentrations. 100 nL of compound was added to a 384-well plate, along with 5 μL of 2× CDK2 / Cyclin E1 or CDK1 / Cyclin B enzyme mix. Complete inhibition control wells were replaced with 5 μL of buffer (50 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EDTA, 0.01% Brij-35, and 2 mM DTT (added immediately upon use). After centrifugation at 1000 rpm for 30 seconds, the plates were incubated at 23°C for 15 minutes. 5 μL of 2×ΜLight-MBP peptide (containing 10 μM ATP) was added to all wells of each assay plate, followed by centrifugation at 1000 rpm for 30 seconds and incubation at 23°C for 90 minutes.

[0482] After incubation, the reaction was terminated with detection buffer containing 15 mM EDTA and 2 nM Eu-anti-P-MBP antibody, centrifuged at 1000 rpm for approximately 1 minute, and incubated at 23°C for 60 minutes. The plate was read on a Perkin Elmer Envision reader. TR-FRET ratios (665 nm value / 615 nm value) were automatically calculated using the Envision reader. The TR-FRET ratios were normalized to calculate percent inhibition: inhibition = (100% inhibition control - sample data) / (100% inhibition control - 0% inhibition control) * 100, where the 0% inhibition control consisted of a mixture of enzyme, peptide, and ATP without compound; the 100% inhibition control consisted of a mixture of assay buffer and peptide containing ATP without enzyme solution.

[0483] Calculate compound IC using GraphPad nonlinear fitting formula 50 The results are shown in Table 1.

[0484] Table 1 Kinase activity assay

[0485] Results: Most of the compounds of the present invention have good CDK2 kinase inhibitory activity, and weak inhibitory activity against CDK1 kinase.

[0486] Experimental Example 2. HCT116 Cell Proliferation Antagonism Test

[0487] 2.1 Experimental Materials

[0488] 2.2 Test instruments

[0489] 2.3 Test methods

[0490] Remove frozen HCT116 cells from liquid nitrogen and quickly transfer them to a 37°C water bath. Thaw with rapid shaking. Transfer the cell suspension to a 15mL centrifuge tube and centrifuge at 1500rpm for 5 minutes. Discard the supernatant and resuspend the cell pellet in RPMI-1640 complete medium (containing 10% fetal bovine serum and 1% penicillin / streptomycin). Transfer the pellet to a cell culture dish containing 10mL of culture medium and culture in a 37°C, 5% CO2 incubator. Subculture after cells have adhered.

[0491] HCT116 cells in logarithmic growth phase and in good condition were digested with trypsin and resuspended in a defined amount of RPMI-1640 complete medium to a single-cell suspension. Cells were counted using a cell counter and seeded into 96-well plates at a density of 800 cells / well. After 5 minutes of rest, cells were incubated overnight at 37°C in a 5% CO2 incubator. The next day, cells were treated with various concentrations of the compound, while a control group was treated with the corresponding concentration of DMSO. Compounds dissolved in DMSO 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 replicate wells were set up for each group, and 100 μL of the dosing solution was added to each well. The cells were incubated at 37°C in a 5% CO2 incubator for 72 hours.

[0492] 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 group and the drug-treated group, and mixed on an oscillator for 2 minutes to induce cell lysis. The 96-well plate was incubated at room temperature for 10 minutes to stabilize the fluorescence signal value. The luminescence signal was detected using a microplate reader. The DMSO-treated cell group was used as the control group, and the half-maximal inhibition rate (50% Inhibitory Concentration, IC 50 ): Inhibition rate (%) = (control group L value - drug treatment group L value) / control group A value × 100%

[0493] Calculate compound IC using GraphPad nonlinear fitting formula 50 The results are shown in Table 2.

[0494] Table 2 Inhibitory effect of the compounds of the present invention on HCT116 cell proliferation

[0495] Results: Most of the compounds of the present invention have good inhibitory effects on the proliferation of HCT116 cells.

[0496] Test Example 3. In vitro liver microsome stability evaluation

[0497] Instruments: water purifier, Millipore; electronic balance, Mettler Toledo; high-speed desktop centrifuge, Thermo; water bath constant temperature oscillator, Shanghai Yiheng Technology Co., Ltd.; vortex oscillator, Thermo; LC-MS / MS, AB SCIEX.

[0498] Methods: The metabolic stability of the analytes was evaluated using human, canine, and SD rat liver microsomes. The analytes were incubated with liver microsomes from different species and NADPH in a 37°C water bath. The final concentration of the test or control 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. The reaction was terminated at designated time points (5, 10, 20, 30, and 60 min) by the addition of cold acetonitrile containing tolbutamide (200 ng / mL) as an internal standard. The 0 min sample was first added with the stop solution 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 pretreatment, the samples were semi-quantitatively analyzed by LC-MS / MS. Retention times of the analytes and internal standards, chromatogram acquisition, and chromatogram integration were performed using Analyst software (AB Sciex, Framingham, Massachusetts, USA). The remaining percentage of the test sample after 60 min of incubation was calculated. The results are shown in Table 3.

[0499] Table 3 Experimental data of the compounds of the present invention in human, dog and rat liver microsomes

[0500] Results: Compounds 1, 3, 4, 7, 10, 11 and 27 were all lowly cleared in rat, dog and human liver microsomes, and compounds 9, 13, 27, 33 and 50 were lowly cleared in human liver microsomes. All compounds had good stability and druggability.

[0501] Experimental Example 4. Permeability and Transporter Substrate Evaluation

[0502] Cells: Caco-2 cells

[0503] Instruments: water purifier, ELGA LabWate; biological safety cabinet, Nuaire; constant temperature CO2 incubator, Thermo; microplate reader, PerkinElmer; LC-MS / MS, AB SCIEX.

[0504] Methods: The purpose of this study was to determine the bidirectional permeability of the compounds using a Caco-2 monolayer cell model and to evaluate whether they are transported by P-glycoprotein (P-gp). In the experiment, Caco-2 cells were seeded into 96-well cell plates and cultured continuously for 24 days before transport experiments. The compounds were administered bidirectionally with or without verapamil at a concentration of 2.00 μM. After incubation for 120 minutes, samples from the apical A and basal B 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 part was tested in two experimental systems, accompanied by a control compound (PF-07104091). The data are summarized in Tables 4 and 5.

[0505] Table 4 Permeability test results

[0506] Results: The permeability of compounds 6, 9 and 24 was better than that of the control compound PF-07104091, which were medium permeability, while the other compounds were low permeability.

[0507] Table 5 Permeability test results

[0508] Results: Compounds 50 and 134 had better permeability than the control compound PF-07104091.

Claims

1. A compound represented by formula (IIA), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof: in, X2 is selected from CH2, or O; X3 is selected from CH2, NH, O or a bond; R4 and R5 are independently selected from H, C 1-6 Alkyl, C substituted by cyano 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups; R 6a 、R 6b 、R 6d 、R 6e are each independently selected from H, halogen, C 1-6 Alkyl, (CH3)2-P(O)-, CH3-S(O)2-, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy substitution; R7 is independently selected from 6-10 membered heterocyclic groups, which are optionally substituted by 1, 2, 3, 4, 5 halogens, C 1- 6 alkyl, or C 1-6 Haloalkyl substitution.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, 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-but-1-yn-3-yl, or n-but-1-yn-4-yl; Or R4 and R5 together with the nitrogen atom to which they are attached form azetidinyl, 2,2,-dimethylazetidinyl, or R 6a 、R 6b 、R 6d 、R 6e Each 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-, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl group is optionally substituted with methoxy, ethoxy, n-propoxy, isopropoxy; R7 is independently selected from piperidinyl, or piperazinyl, and the piperidinyl, or piperazinyl is optionally substituted with 1, 2, 3, 4, 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, R7 is independently selected from R 7a 、R 7b 、R 7c 、R 7d 、R 7e Independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

4. The compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, X2 is selected from CH2; X3 is selected from CH2; R4 is selected from H; R5 is selected from C 1-6 Alkyl, preferably isopropyl; R 6a 、R 6b 、R 6d 、R 6e Each is independently selected from H, halogen.

5. The compound represented by formula (II), its pharmaceutically acceptable salt, stereoisomer or deuterated substance: X1 is selected from NH, or O; X2 is selected from CH2, or O; L1 is selected from 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl, wherein the 6-10 membered aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl is optionally substituted with 1, 2, or 3 R6; R4 and R5 are independently selected from H, C 1-6 Alkyl, C substituted by cyano 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups; Each R6 is independently selected from H, halogen, C 1-6 Alkyl, (CH3)2-P(O)-, CH3-S(O)2-, -CH2R7, -NHR7 or 6-10 membered heterocyclic group, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy substituted, the 6-10 membered heterocyclic group is optionally 1, 2, 3, 4, 5 halogen, C 1-6 Alkyl, or C 1-6 haloalkyl substitution; R7 is independently selected from 6-10 membered heterocyclic groups, which are optionally substituted by 1, 2, 3, 4, 5 halogens, C 1- 6 alkyl, or C 1-6 Haloalkyl substitution.

6. The compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer or deuterated substance: in, X1 is selected from NH, or O; X2 is selected from CH2, or O; R1 is selected from R 2a and R 2b Each independently selected from H, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by a C 1-6 Alkoxy, R 2c -S(O)2-, or R 2c -S(O)(NH)-substituted, the R 2c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, or amino; R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f Each independently selected from H, CH3-S(O)2-CH2-, (CH3)2-P(O)-, or R4 and R5 are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Fluorinated alkyl, C 2-6 Fluoroalkenyl, C 2-6 Fluoroalkynyl, C 3-10 Cycloalkyl, wherein each of said C 1-6 The terminal C atoms of the alkyl group are optionally substituted with a cyano group, wherein each of the C 3-10 Cycloalkyl is optionally substituted with difluoromethylene; or R4 and R5 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, or The 4-6 membered heterocyclic group is optionally substituted by 1-2 methyl groups.

7. A compound, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, stereoisomer, deuterated substance, or the pharmaceutical composition according to claim 7 in the preparation of a medicament.

10. The use according to claim 8, wherein the drug is used to prevent or treat CDK2-mediated related diseases.

11. The use according to claim 8, wherein the medicament is for preventing or treating abnormal cell growth in a subject.

12. The method of claim 11, wherein the abnormal cell growth is cancer, and the cancer is selected from the group consisting of 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, stomach cancer, thyroid cancer, skin cancer, esophageal cancer, lymphoma, sarcoma, multiple myeloma, and solid tumors.

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