Phthalazinon compounds, methods for preparing them, and their pharmaceutical uses.

Abstract

The present invention provides compounds for the prevention and / or treatment of cancer or Kennedy disease, as well as their medicinal uses. [Solution] The compound represented by formula (I) and a pharmacodynamically acceptable salt, as well as the use of the compound as an androgen receptor (AR) for decomposition, are disclosed. TIFF2026053536000269.tif43170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to Chinese patent applications CN202010536221.6 filed on 12 June 2020, CN202011147078.8 filed on 23 October 2020, CN202011261665.X filed on 12 November 2020, CN202110485680.0 filed on 30 April 2021, and CN202110614030.1 filed on 2 June 2021. The aforementioned Chinese patent applications are incorporated herein by reference in their entirety.

[0002] The present invention relates to a compound represented by formula (I) and a pharmacodynamically acceptable salt thereof, as well as its use as an androgen receptor (AR) for the degradation of the compound. [Background technology]

[0003] Background technology Prostate cancer (PCa) is one of the most common cancers worldwide and the second most common and deadly cancer among adult men globally. Prostate cancer often presents with no significant symptoms, grows relatively slowly in its early stages, and later presents with symptoms such as frequent urination, dysuria, hematuria, and dysuria (odynuria), and may metastasize to other parts of the body. Therefore, patients are generally found to have advanced cancer. In the United States, prostate cancer is the leading risk to men's health, with an incidence exceeding that of lung cancer. In 2016, there were 120,000 new cases of prostate cancer in China, which is estimated to reach 237,000 by 2030, with a compound annual growth rate of 5% for new cases. This also means that in the next decade, the incidence of prostate cancer in China will enter a peak period, and such cancer will become the leading deadly cancer among men. Due to low rates of early diagnosis, the mortality rate for prostate cancer patients in China is much higher than in developed countries. In the United States, the five-year survival rate for patients with this disease is over 98%, while in China, the survival rate for the same patients is only 50%.

[0004] Prostate cancer is an androgen-dependent tumor, where androgens stimulate the proliferation of prostate cancer cells, leading to disease progression. Endocrine therapy is one of the conventional treatment options. For example, the standard treatment for advanced PCa is androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or chemical castration (e.g., Zoladex injection). While ADT therapy is highly effective in the early stages of treatment, as the disease progresses, the androgen receptor (AR) undergoes mutations. These mutated ARs become more sensitive to low levels of androgens, leading to progression to castration-resistant prostate cancer (CRPC). Almost all patients with advanced prostate cancer eventually progress to CRPC after receiving endocrine therapy. Furthermore, up to 30% of prostate cancer patients will develop metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment. Currently, clinically, patients diagnosed with early-stage localized prostate cancer are usually curable, but patients diagnosed with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) have no clinically curative options.

[0005] Oral drugs currently approved for the treatment of metastatic castration-resistant prostate cancer primarily include abiraterone and enzalutamide. Among these, abiraterone is a novel androgen biosynthesis inhibitor that can block androgen synthesis in the testicular, adrenal, or tumor cell environment. Enzalutamide, however, is an androgen receptor inhibitor that can competitively inhibit the binding of androgens to their receptors. After binding to AR, enzalutamide can further inhibit the nuclear transport of AR, thereby blocking the interaction between AR and DNA.

[0006] Despite castration resistance, CRPCs still rely on the AR signaling axis for continued growth. Mutations in ARs reduce the small molecule antagonistic activity of target ARs and even convert them into AR agonists, which manifest clinically as drug resistance. Therefore, selective androgen receptor degraders (SARDs) can not only inhibit androgen receptors and block the process of androgen receptor signaling, but also degrade the receptors themselves, thus providing greater benefits.

[0007] This invention primarily relies on proteolytically targeted chimeric (PROTAC) technology to obtain certain selective AR degradation agents (SARDs). PROTAC technology primarily relies on the intracellular ubiquitin-proteasome system. This system is the intracellular "vacuum cleaner," and the main role of the ubiquitination system is to ubiquitinate denatured, mutated, or harmful proteins within the cell. Ubiquitinated proteins are then degraded by the intracellular proteasome system. The design concept of the reconstructed PROTAC is that one end of the molecule is an AR interaction fragment, and the other end is a ubiquitin-proteasome interaction fragment, with the two ends linked by an intermediate bond to form a chimeric molecule. PROTAC interacts simultaneously with the target protein (AR) and the proteasome system, resulting in the proteasome and AR protein being spatially close to each other, and therefore the AR is degraded by ubiquitination.

[0008] Small molecule PROTAC technology was reported in 2008. Currently, only the small molecule drug ARV-110 (whose structure is currently unknown), based on the AR degradation of Albinus, is in Phase I clinical development. PROTAC technology belongs to a frontier field. In recent years, as shown in numerous literature reports, PROTACs act by simultaneously binding degradation targets and ubiquitination systems. Their mechanism of action is far more complex than that of conventional small molecule drugs: the mechanism of action of such molecules involves triplicate kinetics and is influenced by the catalytic properties of the PROTAC itself (and the potential problem of the Hook effect). Therefore, the molecular design philosophy of PROTACs is entirely different from that of small molecule design, and there is no obvious regularity whatsoever. General drug-chemical strategies such as equivalent substitution of effective fragments are not necessarily applicable to the design of such molecules.

[0009] Currently, there is still a need to develop PROTAC molecules with novel structures that can be used for AR degradation. [Overview of the project]

[0010] Summary of the Invention In one aspect of the present invention, the present invention relates to formula (I) [ka] (In the formula, R1 is H, F, Cl, Br, I and C) 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Ring B is selected from phenyl and 5-6 membered heteroaryls, and the phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 R atoms. Ring C is C 4~6 Selected from cycloalkyl groups, R2 is H and C 1~6 Selected from alkyl groups, C 1~6Alkyl is optionally substituted with 1, 2 or 3 R, Ring A is selected from 6- to 12-membered aryl and 5- to 12-membered heteroaryl, R A is selected from H, NO2, halogen, NH2, CN, C 1~6 alkyl and C 1~6 alkoxy, C 1~6 alkyl or C 1~6 alkoxy is optionally substituted with 1, 2 or 3 R, R D is selected from H, CN, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl and 3- to 6-membered heterocycloalkyl, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1~6 alkyl respectively, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R', Each of L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 alkyl, -C 1~6 alkyl-O-, C 2~3 alkenyl, C 2~3 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 9-membered heteroaryl respectively, C 1~6 alkyl, -C 1~6 alkyl-O-, C 2~3 alkenyl, C 2~3 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or 5- to 9-membered heteroaryl is optionally substituted with 1, 2 or 3 R L and, R L is independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 Each is selected from alkylaminos, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independent of H, halogen, and C. 1~6 Alkyl, OH, NH2, [ka] Selected from CH3, CH2F, CHF2, and CF3 respectively. n is 0, 1, 2, 3, or 4. m is 0, 1, 2, 3, or 4. q is 1, 2, 3, or 4. A 3-10 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, a 5-12 membered heteroaryl, a 5-6 membered heteroaryl, or a 5-9 membered heteroaryl contains one, two, or three heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. We propose the compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0011] In another aspect of the present invention, the present invention relates to formula (IX-1) or formula (IX-2) [ka] TIFF2026053536000005.tif40170 (in the formula, ring A, ring B, ring C, R1, R2, RA , R D (G, L1, L2, L3, m, n, and q are as described in the present invention.) We further propose the compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0012] In another aspect of the present invention, the present invention relates to formula (II) [ka] (In the formula, R1 is H, F, Cl, Br, I and C) 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Ring B is selected from phenyl and 5-6 membered heteroaryls, and the phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 R atoms. Ring C is C 4~6 Selected from cycloalkyl groups, R2 is H and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Each of R3 and R4 independently contains H, NO2, halogen, NH2, CN, and C. 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. Each R D1 , R D2 and R D3 These are independently H, CN, halogen, and C 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R is independently selected from H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, respectively, and C 1~6 alkyl is optionally substituted with 1, 2, or 3 R's, [[ID=,6]]each of L1, L2, and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 alkyl, -C 1~6 alkyl-O-, C 2~3 alkenyl, C 2~3 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl, respectively, and C 1~6 alkyl, -C 1~6 alkyl-O-, C 2~3 alkenyl, C 2~3 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl is optionally substituted with 1, 2, or 3 R L and R L is independently H, halogen, OH, NH2, CN,

Chemical formula

Chemical formula

[0013] In another aspect of the present invention, the present invention provides a compound represented by formula (II-A-1) or formula (II-A-2)

Chemical formula

[0014] In another aspect of the present invention, the present invention provides a compound represented by formula (III)

Chemical formula

[0015] In yet another aspect of the present invention, the present invention relates to formula (III-A-1) or formula (III-A-2) [ka] TIFF2026053536000015.tif46170 (in the formula, R1, R3, R4, R D1 , R D2 , R D3 (G, L1, L2, L3, X1, X2, X3 and X4 are as described in the present invention.) We further propose the compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0016] In yet another aspect of the present invention, the present invention relates to formula (IA) [ka] (In the formula, R1 is H, F, Cl, Br, I and C)1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Ring B is selected from phenyl and 5-6 membered heteroaryls, and the phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 R atoms. Ring C is C 4~6 Selected from cycloalkyl groups, R2 is H and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Each of R3 and R4 independently contains H, NO2, halogen, NH2, CN, and C. 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. Each R D1 , R D2 and R D3 These are independently H, CN, halogen, and C 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R D4 These are independently H, CN, halogen, and C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl and 3-6 member heterocycloalkyl groups, C 1~6 Alkyl, C 3~6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms. R is independently H, F, Cl, Br, I, OH, NH2 and C 1~6 Each is selected from alkyl groups, C 1~6The alkyl group is optionally substituted with 1, 2, or 3 R' atoms. Each of L1, L2, and L3 independently consists of a single bond, O, S, NH, C(=O), S(=O), S(=O)2, and C 1~6 Alkyl, -C 1~6 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~10 Selected from cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-9 member heteroaryl, C 1~6 Alkyl, -C 1~6 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~10 Cycloalkyl, 3-10 member heterocycloalkyl, phenyl, or 5-9 member heteroaryl has 1, 2, or 3 R L It is arbitrarily replaced with, R L These are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 Each is selected from alkylaminos, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independent of H, halogen, and C. 1~6 Alkyl, OH, NH2, [ka] Selected from CH3, CH2F, CHF2, and CF3 respectively, m is 0, 1, 2, 3, or 4. A 3-10 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, a 5-6 membered heteroaryl, or a 5-9 membered heteroaryl contains one, two, or three heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. We further propose the compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0017] In yet another aspect of the present invention, the present invention relates to formula (II-A-1) or formula (II-A-2) [ka] TIFF2026053536000020.tif50170 (in the formula, ring B, ring C, R1, R2, R3, R4, R D1 , R D2 , R D3 , R D4 (G, L1, L2, L3 and m are as described in the present invention.) Further, the present invention provides a compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0018] In yet another aspect of the present invention, the present invention relates to formula (IB) [ka] (In the formula, R1 is H, F, Cl, Br, I and C) 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C 1~6 Selected from alkyl groups, C 1~6 Alkyl can be optionally substituted with 1, 2, or 3 R atoms. Each of R3 and R4 independently contains H, NO2, halogen, NH2, CN, and C. 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. Each of X1, X2, X3, and X4 is independently selected from C(R) and N, respectively. Each R D1 , R D2 and R D3 These are independently H, CN, halogen, and C 1~6 Alkyl and C 1~6 Each is selected from the alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R D4 These are independently H, CN, halogen, and C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl and 3-6 member heterocycloalkyl groups, C 1~6 Alkyl, C 3~6 Cycloalkyl or 3-6 membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms. R is independently H, F, Cl, Br, I, OH, NH2 and C 1~6 Each is selected from alkyl groups, C 1~6 The alkyl group is optionally substituted with 1, 2, or 3 R' atoms. Each of L1, L2, and L3 independently consists of a single bond, O, S, NH, C(=O), S(=O), S(=O)2, and C 1~6 Alkyl, -C 1~6 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~10 Selected from cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-9 member heteroaryl, C 1~6 Alkyl, -C 1~6 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~10 Cycloalkyl, 3-10 member heterocycloalkyl, phenyl, or 5-9 member heteroaryl has 1, 2, or 3 R L It is arbitrarily replaced with, R L These are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 Each is selected from alkylaminos, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independent of H, halogen, and C. 1~6 Alkyl, OH, NH2, [ka] Selected from CH3, CH2F, CHF2, and CF3 respectively, A 3-10 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-9 membered heteroaryl contains one, two, or three heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. We further propose the compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0019] In yet another aspect of the present invention, the present invention relates to formula (IB-1) or formula (IB-2) [ka] TIFF2026053536000025.tif45170 (in the formula, R1, R3, R4, R D1 , R D2 , R D3 , R D4 (L1, L2, L3, X1, X2, X3, X4 and G are as described in the present invention.) Further, the present invention provides a compound represented by [formula], its optical isomers, and pharmacodynamically acceptable salts thereof.

[0020] In some schemes of the present invention, the aforementioned ring A is selected from phenyl, and the other variables are as described in the present invention.

[0021] In some schemes of the present invention, each of the above R3 and R4 is independently selected from H, NO2, F, Cl, Br, I, NH2, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy, respectively, and the other variables are as described in the present invention.

[0022] In some schemes of the present invention, R2 is selected from H, methyl, and ethyl, and the other variables are as described in the present invention.

[0023] In some schemes of the present invention, the aforementioned ring C is selected from cyclobutyl and cyclohexanyl, and the other variables are as described in the present invention.

[0024] In some schemes of the present invention, the above-mentioned building block [ka] teeth, [ka] Selected from the above, the other variables are as described in the present invention.

[0025] In some schemes of the present invention, the above ring B is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl is optionally substituted with 1, 2, or 3 Rs, and the other variables are as described in the present invention.

[0026] In some schemes of the present invention, the above-mentioned components [ka] teeth, [ka] Selected from the above, the other variables are as described in the present invention.

[0027] In some schemes of the present invention, each of L1, L2, and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, and C, respectively. 1~3 Alkyl, -C 1~3 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~6 These are cycloalkyl, 4-8 member heterocycloalkyl, phenyl, and 5-6 member heteroaryl, C 1~3 Alkyl, -C 1~3 Alkyl-O-,C 2~3 Alkenil, C 2~3 Alkinyl, C 3~6 One, two, or three R groups consisting of a cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl group. L This can be arbitrarily substituted, and the other variables are as described in the present invention.

[0028] In some schemes of the present invention, the above R L These are independently H, halogen, OH, NH2, CN, [ka] , C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkyl-C(=O)-, C 1~3 Alkoxy, C 1~3 Alkylthio and C 1~3 Each is selected from alkylaminos, and the C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkyl-C(=O)-, C 1~3 Alkoxy, C 1~3 Alkylthio or C1~3 The alkylamino is optionally substituted with one, two or three R', and the other variables are as described in the present invention.

[0029] In some schemes of the present invention, the above L1, L2 and L3 are independently a single bond, O, S, NH, C(=O), S(=O)2, CH2,

Chemical formula

[0030] In some schemes of the present invention, the above components

Chemical formula

Chemical formula

[0031] In some schemes of the present invention, the above R D4 is independently selected from H, CN, F, Cl, Br, I, CF3, CH3, CH2CH3 and cyclopropyl respectively, and the other variables are as described in the present invention.

[0032] In yet another aspect of the present invention, the present invention further proposes a compound of the following formula, its optical isomers and its pharmaceutically acceptable salts, which are

Chemical formula

[0033] In yet another aspect of the present invention, the present invention further proposes a compound of the following formula, its optical isomers and its pharmaceutically acceptable salts, which are

Chemical formula

[0034] In yet another aspect of the present invention, the present invention further proposes the use of the above-mentioned compounds, their optical isomers and pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating cancer or Kennedy disease.

[0035] In some schemes of the present invention, the above-mentioned cancer is an AR-related cancer such as prostate cancer, breast cancer, etc.

[0036] In yet another aspect of the present invention, the present invention further proposes a method for treating cancer (such as prostate cancer, breast cancer, etc.) or Kennedy disease. This method includes administering the aforementioned compounds, their optical isomers and pharmaceutically acceptable salts thereof to a patient.

Embodiments for Carrying out the Invention

[0037] Definitions and Explanations Unless otherwise specified, the following terms and phrases used in this specification are intended to have the following meanings. A particular term or phrase should not be considered uncertain or ambiguous without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this specification, it is intended to refer to the corresponding commercially available product or its active ingredient.

[0038] When used in this invention, the phrase "at least one" is intended to mean at least one element selected from any one or more elements in a list of elements, but it should be understood that this does not necessarily include at least one of each element specifically enumerated in the list of elements, nor does it exclude any combination of elements in the list of elements. This definition further allows for the presence of elements other than those specifically determined in the list of elements to which the phrase "at least one" refers, regardless of whether they are related to those specifically determined elements or not.

[0039] As used herein, the term “pharmacodynamically acceptable” refers to compounds, materials, compositions and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0040] The term "pharmacodynamically acceptable salt" refers to a salt of the compound of the present invention prepared from a compound having a specific substituent discovered by the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmacodynamically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacodynamically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, monohydrogen phosphate radical, dihydrogen phosphate radical, sulfuric acid, hydrogen sulfate radical, hydroiodic acid, and phosphorous acid; organic acid salts and organic acids include, for example, acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; these examples also include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either a base addition salt or an acid addition salt.

[0041] The pharmacodynamically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the method for preparing such salts is as follows: these compounds in the form of free acids or free bases are reacted with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0042] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. All such compounds contemplated in the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically concentrated mixtures, all of which fall within the scope of the present invention. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are incorporated into the scope claimed in the present invention.

[0043] Unless otherwise specified, wedge-shaped solid line connections ( [ka] ) and wedge-shaped dotted line connection ( [ka] ) is used to represent the absolute arrangement of the center of a solid.

[0044] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the terms “tautomer” or “tautomer form” mean that isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted at room temperature. If tautomerism is possible (in solution, for example), then chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called protic tautomers) include interconversion by proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversion by recombination of some bonding electrons. Here, a specific example of keto-enol tautomerization is the interconversion between two tautomers, pentan-2,4-dione and 4-hydroxypenta-3-en-2-one, or, for example, [ka] and [ka] are tautomers.

[0045] The 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 particular compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary group to obtain the pure desired enantiomer. Alternatively, if the molecule contains an alkaline functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed using an appropriate optically active acid or base, followed by separation of the diastereoisomers by conventional methods known in the art, and then recovering the pure enantiomer. Further, enantiomers and diastereomers are usually separated by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (for example, carbamates are formed from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compounds. For example, the compounds can be labeled with radioactive isotopes such as tritium ([ 3 H), iodine-125 ([ 125 I) or C-14 ([ 14 C). As another example, deuterated drugs can be formed by substituting hydrogen with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduction of toxicity and side effects, increase of drug stability, improvement of therapeutic effect, and extension of the biological half-life of drugs. The conversion of all isotope compositions of the compounds of the present invention is included within the scope of the present invention regardless of radioactivity. "Optional" or "optionally" means that the subsequently described event or situation may or may not occur, including the case where the event or situation occurs or does not occur.

[0046] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 They can be labeled with radioactive isotopes such as C). As another example, deuterated drugs can be formed by substituting hydrogen with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, improved therapeutic effect, and extended biological half-life of the drug. All isotopic compositions of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. "Optional" or "optionally" means that the events or circumstances described below may or may not occur, including when the events or circumstances occur or when they do not.

[0047] The valence bond of the base is represented by a dotted line. [ka] If it has, for example [ka] In this diagram, the dotted lines represent the bond points of the group to the rest of the molecule. Single bonds are [ka] If it has, for example, [ka] In this, the dotted line represents a single connection or non-existence. [ka] is a single bond [ka] or double bond [ka] It also means that it represents something.

[0048] The terms "substituted" or "substituted with..." mean that any one or more hydrogen atoms on the specified atom are substituted with substituents that may include deuterium and hydrogen variants, provided that the valence of the specified atom is normal and the substituted compound is stable. The terms "optionally substituted" or "optionally substituted with..." mean that it may or may not be substituted; unless otherwise specified, the type and number of substituents may be of any choice to a chemically achievable standard.

[0049] If any variable (e.g., R) appears two or more times in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted with one, two, or three R's, that group may be arbitrarily substituted with one, two, or three R's, and in each case, there are independent substitutes for R'. Furthermore, combinations of substituents and / or their variants are only permissible if such combinations produce a stable compound.

[0050] If one of the variables is selected from a single bond, it indicates that the two groups bonded to it are directly bonded, for example, [ka] If L1 represents a single bond, then the structure is actually [ka] It means that.

[0051] If it is not indicated which atoms a listed substituent is bonded to, such substituents may be bonded to any of their atoms; for example, pyridyl as a substituent may be bonded to the substituent via any one of the carbon atoms on the pyridine ring.

[0052] If the listed linking units do not indicate their linking direction, the linking direction is arbitrary, for example, [ka] In this, the linker group L is -CH2O, and -CH2O- is bonded to phenyl and cyclopentyl in the same direction as the left-to-right reading sequence. [ka] It can form a sequence that is read from left to right and is bound to phenyl and cyclopentyl in the opposite direction to the left-to-right reading sequence. [ka] It is also possible to form such combinations. Combinations of linking groups, substituents, and / or their variants are only permissible if such combinations produce stable compounds.

[0053] Unless otherwise specified, the number of atoms on a ring is generally defined as the ring member number. For example, a "3- to 6-membered ring" refers to a "ring" that has 3 to 6 atoms arranged around it.

[0054] Unless otherwise specified, "C 1~6 The term "alkyl" is used to describe a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1~6 Alkyl includes C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 This includes C6 and C5 alkyl groups, which are monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g., hypo- [ka] ) could be C 1~6 Examples of alkyl groups, though not limited to them, include CH3. [ka] These are some examples.

[0055] Unless otherwise specified, "C 1~4 The term "alkyl" is used to describe a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1~4 Alkyl includes C 1~2 , C 1~3 , C 3~4 and C 2~3 Alkyl compounds are included, and they are monovalent (e.g., CH3), divalent (e.g., -CH2-), or polyvalent (e.g., sec-) [ka] ) could be C 1~4 Examples of alkyl groups, though not limited to them, include CH3. [ka] Examples include TIFF2026053536000060.tif15170.

[0056] Unless otherwise specified, "C 2~3 The term "alkenyl" is used to represent a straight-chain or branched-chain hydrocarbon group consisting of 2-3 carbon atoms and containing at least one carbon-carbon double bond, where the carbon-carbon double bond can be located at any position on the group. 2~3 Alkenyls include C3 and C2 alkenyls, 2~3 Alkenyls can be monovalent, divalent, or polyvalent. 2~3 Examples of alkenils are not limited to these, [ka] These are some examples.

[0057] Unless otherwise specified, "C 2~3The term "alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2-3 carbon atoms and containing at least one carbon-carbon triple bond, where the carbon-carbon triple bond can be located at any position on the group. It can be monovalent, divalent, or polyvalent. 2~3 Alkynnyl includes C3 and C2 alkynyls. 2~3 Examples of alkinyl are not limited to this, but [ka] Examples include TIFF2026053536000063.tif23170.

[0058] Unless otherwise specified, "C 1~6 The term "alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms, bonded to the rest of the molecule via one oxygen atom. 1~6 Alkoxy contains C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 This includes C6, C5, C4, and C3 alkoxys, etc. 1~6 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), and hexyloxy.

[0059] Unless otherwise specified, "C 1~3 The term "alkoxy" refers to an alkyl group that contains 1 to 3 carbon atoms and is bonded to the rest of the molecule via one oxygen atom. 1~3 Alkoxy contains C 1~3 , C 1~2 , C 2~3 This includes C1, C2, and C3 alkoxys, etc. 1~3Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy and isopropoxy).

[0060] Unless otherwise specified, "C 1~6 The term "alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms that is bonded to the rest of the molecule via an amino acid. 1~6 Alkylaminos include C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 This includes C6, C5, C4, C3 and C2 alkylaminos, etc. 1~6 Examples of alkylaminos, though not limited to them, include -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, and -NHCH2CH2CH2CH3.

[0061] Unless otherwise specified, "C 1~3 The term "alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms that is bonded to the rest of the molecule via an amino acid. 1~3 Alkoxy contains C 1~3 , C 1~2 , C 2~3 C includes C1, C2, and C3 alkylaminos, etc. 1~3 Examples of alkylaminos, though not limited to them, include -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0062] Unless otherwise specified, "C 1~6 The term "alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms, which are bonded to the rest of the molecule via a sulfur atom. 1~6 Alkylthio contains C 1~4 , C 1~3 , C 1~2 , C 2~6, C 2~4 This includes C6, C5, C4, C3 and C2 alkylthios, etc. 1~6 Examples of alkylthio groups, though not limited to them, include -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH2(CH3)2.

[0063] Unless otherwise specified, "C 1~3 The term "alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms, bonded to the rest of the molecule via a sulfur atom. 1~3 Alkylthio contains C 1~3 , C 1~2 , C 2~3 This includes C1, C2, and C3 alkylthios. 1~3 Examples of alkylthio groups include -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH2(CH3)2.

[0064] Unless otherwise specified, "C 3~9 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 9 carbon atoms, which can be monocyclic or bicyclic. 3~9 Cycloalkyls include C 3~8 , C 3~7 , C 3~6 , C 3~5 and C 5~6 It contains cycloalkyl compounds, which may be monovalent, divalent, or polyvalent. 3~9 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0065] Unless otherwise specified, "C 3~6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3~6 Cycloalkyls include C 3~5 , C 4~5 and C 5~6 It contains cycloalkyl compounds, which may be monovalent, divalent, or polyvalent. 3~6Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0066] Unless otherwise specified, "C 4~6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4~6 Cycloalkyls include C 4~5 , C 4~6 and C 5~6 It contains cycloalkyl compounds, which may be monovalent, divalent, or polyvalent. 4~6 Examples of cycloalkyl compounds include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.

[0067] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" alone or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). This includes monocyclic, bicyclic, and tricyclic systems, with bicyclic and tricyclic systems including spiro rings, fused rings, and bridging rings. Furthermore, with respect to "3-10 membered heterocycloalkyls," heteroatoms may occupy bonding positions in the heterocycloalkyl and the rest of the molecule. 3-10 membered heterocycloalkyls include 3-9 membered, 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. Examples of 3- to 10-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidyl (including 1-piperidyl, 2-piperidyl and 3-piperidyl, etc.), piperazinyl (including 1-piperidyl and 2-piperidyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, hexahydropyridazinyl, homopiperidyl, homopiperidyl, dioxepanil, or [ka] These are some examples.

[0068] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" alone or in combination with other terms refers to a saturated cyclic group consisting of 4-8 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2)). It includes monocyclic and bicyclic systems, and the bicyclic system includes spiro rings, fused rings, and bridging rings. Furthermore, with respect to "4- to 8-membered heterocycloalkyls," the heteroatoms may occupy bonding positions in the heterocycloalkyl and the rest of the molecule. Examples of 4- to 8-membered heterocycloalkyls include 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, 6-membered, 7-membered, and 8-membered heterocycloalkyls. Examples of 4- to 8-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidyl (including 1-piperidyl, 2-piperidyl and 3-piperidyl, etc.), piperazinyl (including 1-piperidyl and 2-piperidyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, hexahydropyridazinyl, homopiperidyl, homopiperidyl or [ka] These are some examples.

[0069] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" alone or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, the remainder being carbon atoms, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2)). It includes monocyclic and bicyclic systems, and the bicyclic system includes spiro rings, fused rings, and bridging rings. Furthermore, with respect to "3-6 membered heterocycloalkyls," the heteroatoms may occupy bonding positions in the heterocycloalkyl and the rest of the molecule. Examples of 3-6 membered heterocycloalkyls include 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls. Examples of 3- to 6-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidyl (including 1-piperidyl, 2-piperidyl and 3-piperidyl, etc.), piperazinyl (including 1-piperidyl and 2-piperidyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, hexahydropyridazinyl, homopiperadinyl, or homopiperidyl.

[0070] Unless otherwise specified, "C 6~10 "Aryl ring" and "C 6~10 The term "aryl" can be used interchangeably in this invention, and "C 6~10 "Aryl ring" or "C 6~10 The term "aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms and having a conjugated π-electron system, which may be monocyclic, fused bicyclic, or fused tricyclic, with each ring being aromatic. It can be monovalent, divalent, or polyvalent, C 6~10 In Ariel, C 6~9 , C9, C 10 and C6 aryls are included. 6~10 Examples of aryl compounds include, but are not limited to, phenyl and naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0071] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" can be used interchangeably in this invention; "5-12 membered heteroaryl" represents a cyclic group consisting of 5-12 ring atoms and having a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. This can be a monocyclic, fused bicyclic, or fused tricyclic system, with each ring being aromatic. In this system, the nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). 5- to 12-membered heteroaryls can be bonded to the rest of the molecule via heteroatoms or carbon atoms. 5- to 12-membered heteroaryls include 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5-membered, and 6-membered heteroaryls, etc. Examples of 5- to 12-membered heteroaryls include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), and thiazolyl (2-thiazolyl, 4-thiazo Examples include lyl and 5-thiazolyl, furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl (including 2-pyridinyl and 4-pyridinyl), benzothiazolyl (including 5-benzothiazolyl), prinyl, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indolyl (including 5-indolyl), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl), or quinolinyl (including 3-quinolinyl and 6-quinolinyl).

[0072] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" can be used interchangeably in this invention; "5-6 membered heteroaryl" represents a monocyclic group consisting of 5-6 ring atoms and having a conjugated π-electron system, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. In this group, the nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2)). 5- to 6-membered heteroaryls can be bonded to the rest of the molecule via heteroatoms or carbon atoms. 5- to 6-membered heteroaryls include 5-membered and 6-membered heteroaryls. Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) Examples include tetrazolyl (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyridinyl and 4-pyridinyl, etc.).

[0073] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" can be used interchangeably in this invention; "5-10 membered heteroaryl" represents a monocyclic group consisting of 5-10 ring atoms and having a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. In this group, the nitrogen atom may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2)). 5- to 10-membered heteroaryls can be bonded to the rest of the molecule via heteroatoms or carbon atoms. 5- to 10-membered heteroaryls include 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heteroaryls. Examples of 5- to 10-membered heteroaryls include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) Examples include triazolyl (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyridinyl and 4-pyridinyl, etc.).

[0074] Unless otherwise specified, C n~n+m or C n ~C n+m This includes any specific example of n ~ n + m carbon atoms, for example, 1~12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11and C 12 This includes n to n+m, and also any range n to n+m, for example, C 1~12 C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 and C 9~12 This includes, for example, n~n+m member rings, where n~n+m members represent the number of atoms on the ring, for example, 3~12 member rings include 3-member rings, 4-member rings, 5-member rings, 6-member rings, 7-member rings, 8-member rings, 9-member rings, 10-member rings, 11-member rings and 12-member rings, and also any range of n~n+m, for example, 3~12 member rings include 3~6 member rings, 3~9 member rings, 5~6 member rings, 5~7 member rings, 5~10 member rings, 6~7 member rings, 6~8 member rings and 6~10 member rings.

[0075] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). Examples of typical leaving groups include: triflates; chloro, bromo, and iodine; sulfonic acid groups, such as mesylates, tosylates, p-bromobenzenesulfonate, and p-toluenesulfonate; and acyloxy groups, such as acetoxy and trifluoroacetoxy.

[0076] The term "protecting group" includes, but is not limited to, "amino protecting groups," "hydroxy protecting groups," or "thiol protecting groups." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyls, e.g., alkanoyls (acetyl, trichloroacetyl, or trifluoroacetyl, etc.); alkoxycarbonyls, e.g., tert-butoxycarbonyl (Boc); arylmethoxycarbonyls, e.g., benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyls, e.g., benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; methylsilyls, e.g., trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Typical hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (acetyl, etc.); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (DPM); and methylsilyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

[0077] The compounds of the present invention can be prepared by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthesis methods, and equivalent substitutes well known to those skilled in the art; preferred embodiments include, but are not limited to, embodiments of the present invention.

[0078] The solvent used in this invention is commercially available.

[0079] The compounds were named according to conventional nomenclature in the art or by using ChemDraw® software, and commercially available compounds were named according to the supplier's catalog.

[0080] Detailed description of the embodiment This application is described in detail below with reference to embodiments, but this does not mean that there are any undesirable limitations. This application is described in detail herein, and specific embodiments thereof are also disclosed. It will be apparent to those skilled in the art that various modifications and improvements can be made to specific embodiments of this application without departing from the spirit and scope of this application.

[0081] Preparation of intermediates Reference Example 1: Preparation of Intermediate I-1 [ka]

[0082] 2-Bromo-4-fluorobenzoic acid (7.00 g, 31.9 mmol) was dissolved in thionyl chloride (30.0 mL), and N,N-dimethylformamide (0.25 mL) was added. The reaction solution was stirred at 80°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, thionyl chloride was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). Diethylamine (11.7 g, 159.8 mmol) was added, and the reaction solution was stirred overnight at room temperature. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (30.0 mL), water (30.0 mL), and saturated physiological saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-1, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 274.0. 1 H NMR(400 MHz,Chloroform-d)δ 7.30(dd,J=8.3,2.5 Hz,1H),7.22(dd,J=8.5,5.8 Hz,1H),7.05(td,J=8.3,2.5 Hz,1H),3.78(dt,J=14.5,7.1 Hz,1H),3.42-3.21(m,1H),3.12(ddt,J=17.6,10.5,7.2 Hz,2H),1.24(t,J=7.1 Hz,3H),1.04(t,J=7.1 Hz,3H).

[0083] Reference Example 2: Preparation of Intermediate I-2 [ka]

[0084] Intermediate I-1 (8.50 g), potassium vinylfluoroborate (4.98 g, 37.2 mmol), and potassium carbonate (10.7 g, 77.5 mmol) were dissolved in a mixed solution of dioxane (80.0 mL) and water (20.0 mL), and bistriphenylphosphine palladium dichloride (1.09 g, 1.55 mmol) was added. The reaction solution was stirred overnight at 90°C under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was dissolved in ethyl acetate (100.0 mL), washed sequentially with water (30.0 mL) and saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-2, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 222.2. 1 H NMR(400 MHz,Chloroform-d)δ 7.24(d,J=2.6 Hz,1H),7.17(dd,J=8.4,5.7 Hz,1H),6.97(td,J=8.3,2.5 Hz,1H),6.67(ddd,J=17.4,11.0,1.7 Hz,1H),5.75(d,J=17.4 Hz,1H),5.36(d,J=11.0 Hz,1H),3.55(brs,2H),3.10-3.01(m,2H),1.25(t,J=7.1 Hz,3H),1.00(t,J=7.1 Hz,3H).

[0085] Reference Example 3: Preparation of Intermediate I-3 [ka]

[0086] Intermediate I-2 (7.00 g) was dissolved in a mixed solvent of dioxane (70.0 mL) and water (30.0 mL), and then potassium osminate dihydrate (466.0 mg, 1.27 mmol) and sodium periodate (13.5 g, 63.2 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The residue was dissolved in ethyl acetate (100.0 mL), washed sequentially with water (30.0 mL) and saturated physiological saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the residue, which was separated and purified by silica gel chromatography to obtain intermediate I-3. 1 H NMR(400 MHz,Chloroform-d)δ 9.99(d,J=2.3 Hz,1H),7.63-7.57(m,1H),7.38-7.28(m,2H),3.59(q,J=7.1 Hz,2H),3.11(q,J=7.1 Hz,2H),1.27(t,J=7.1 Hz,3H),1.02(t,J=7.1 Hz,3H).

[0087] Reference Example 4: Preparation of Intermediate I-4 [ka]

[0088] Intermediate I-3 (3.00 g, 13.4 mmol) was dissolved in acetic acid (10.0 mL), and hydrazine hydrate (1.03 g, 17.4 mmol, mass fraction 85.0%) was added. The reaction solution was stirred at 145°C for 1 hour under microwave irradiation. The reaction solution was cooled to room temperature, filtered, and the filtration cake was dried to obtain the crude product of intermediate I-4, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 165.0. 1 H NMR(400 MHz,DMSO-d6)δ 12.69(brs,1H),8.34(s,1H),8.28(dd,J=8.8,5.5 Hz,1H),7.79(dd,J=9.0,2.6 Hz,1H),7.70(td,J=8.9,2.6 Hz,1H).

[0089] Reference Example 5: Preparation of Intermediate I-5 [ka]

[0090] Intermediate I-4 (200.0 mg) was dissolved in N,N-dimethylformamide (5.00 mL), and sodium hydride (58.0 mg, 1.46 mmol, 60.0% mass fraction) was added. The reaction solution was stirred at room temperature under nitrogen protection for 30 minutes, and 3-bromopiperidine-2,6-dione (280.0 mg, 1.46 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (100.0 mL), the organic phase was washed with water (30.0 mL) and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of intermediate I-5, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 276.2.

[0091] Reference Example 6: Preparation of Intermediate I-6 [ka]

[0092] Intermediate I-5 (200.0 mg), 1-Boc-piperazine (176.0 mg, 0.94 mmol), and N,N-diisopropylethylamine (200.0 μL) were dissolved in dimethyl sulfoxide (3.00 mL), and the reaction solution was stirred overnight at 130°C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100.0 mL), washed with water (30.0 mL) and saturated physiological saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was separated and purified by chromatography to obtain intermediate I-6. LC-MS(ESI)[M+H] + 442.3.

[0093] Reference Example 7: Preparation of Intermediate I-7 [ka]

[0094] Intermediate I-6 (20.0 mg, 0.045 mmol) was dissolved in dichloromethane (2.00 mL), and trifluoroacetic acid (2.00 mL) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the crude product of intermediate I-7, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 342.2.

[0095] Reference Example 8: Preparation of Intermediate I-8 [ka]

[0096] 3.00 g, 15.3 mmol of tert-butyl 4-fluorobenzoate and 2.10 g, 18.2 mmol of 4-hydroxymethylpiperidine were dissolved in 20.0 mL of N,N-dimethylformamide, and potassium carbonate (2.64 g, 19.1 mmol) was added. The reaction solution was stirred overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100.0 mL), and the organic phase was washed with water (30.0 mL) and saturated saline. The solution was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-8. LC-MS(ESI)[M+H] + 292.2.

[0097] Reference Example 9: Preparation of Intermediate I-9 [ka]

[0098] To a solution of intermediate I-8 (400.0 mg, 1.37 mmol) in dichloromethane (20.0 mL), dess-martin periodinane (864.0 mg, 2.03 mmol) was added, and the reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-9. LC-MS(ESI)[M+H] + 290.2.

[0099] Reference Example 10: Preparation of Intermediate I-10 [ka]

[0100] Intermediate I-7 (15.0 mg) and I-9 (19.0 mg, 0.066 mmol) were dissolved in 1,2-dichloroethane (3.00 mL), followed by the addition of potassium acetate (3.60 mg, 0.044 mmol) and sodium triacetoxyborohydride (18.0 mg, 0.085 mmol). The reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-10. LC-MS(ESI)[M+H-56] + 559.3.

[0101] Reference Example 11: Preparation of Intermediate I-11 [ka]

[0102] Intermediate I-10 (21.0 mg, 0.034 mmol) was dissolved in dichloromethane (3.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the crude product of intermediate I-11, which was used directly in the next reaction without purification.

[0103] Reference Example 12: Preparation of Intermediate I-12 [ka]

[0104] 2-chloropyrimidine-5-carboxylate ethyl (500 mg, 2.68 mmol), 4-hydroxymethylpiperidine (309 mg, 2.68 mmol), and potassium carbonate (370 mg, 2.68 mmol) were mixed and dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was stirred and reacted overnight at 50°C. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-12. LC-MS(ESI)[M+H] + 266.1.

[0105] Reference Example 13: Preparation of Intermediate I-13 [ka]

[0106] At room temperature, intermediate I-12 (19.0 g, 71.6 mmol) was dissolved in tetrahydrofuran (200 mL), and then a solution of lithium hydroxide monohydrate (6.01 g, 143 mmol) in water (50 mL) was added dropwise to the solution. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was adjusted to pH=3 with 2N hydrochloric acid aqueous solution to precipitate the white solid. The mixture was filtered to obtain the crude product of intermediate I-13, which was used directly in the next step without purification. LC-MS(ESI)[M+H] + 238.2.

[0107] Reference Example 14: Preparation of Intermediate I-14 [ka]

[0108] At room temperature, intermediate I-13 (2.50 g, 10.5 mmol), reagent 1 (3.31 g), and diisopropylethylamine (5.22 mL, 31.6 mmol) were dissolved in N,N-dimethylformamide (150 mL). Under argon substitution and stirring conditions, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (6.01 g, 15.8 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3); the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-14. LC-MS(ESI)[M+H] + 498.2.

[0109] Reference Example 15: Preparation of Intermediate I-15 [ka]

[0110] At room temperature, intermediate I-14 (400 mg, 0.803 mmol) and Dess-Martin periodinane (681 mg, 1.606 mmol) were dissolved in dichloromethane (10 mL). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. Saturated sodium thiosulfate aqueous solution (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the reaction solution and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate I-15. The intermediate was used directly in the next reaction without purification.

[0111] Reference Example 16: Preparation of Intermediate I-16 [ka]

[0112] At room temperature, reagent 2 (777 mg, 4.11 mmol) was dissolved in N,N-dimethylformamide (15 mL); under nitrogen protection, sodium hydride (296 mg, 60% content, 7.40 mg) was added at 0°C and the mixture was stirred for 30 minutes; 4-fluoro-2-(trifluoromethyl)benzonitrile (1.00 g, 4.11 mmol) was added and the mixture was stirred at 40°C for 3 hours; water (50 mL) was added to the reaction solution and extracted with acetic acid (50 mL x 3); the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated; the crude product was purified by normal-phase column chromatography, then hydrogen chloride dioxane solution (15 mL, 3 M) was added and the mixture was reacted at room temperature for 1 hour; the reaction solution was directly spin-dried and concentrated to obtain intermediate I-16. The intermediate was used directly in the next reaction without purification.

[0113] Reference Example 18: Preparation of Intermediate I-18 [ka]

[0114] Intermediate I-8 (54.0 g, 185 mmol) was dissolved in anhydrous dioxane (500 mL), and a solution of hydrogen chloride in dioxane (1500 mL, 3 M) was added. The reaction system was protected with argon, heated to 75°C, and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by beating with ethyl acetate (500 mL), followed by suction filtration. The filtration cake was purified by beating with anhydrous acetonitrile (500 mL), followed by suction filtration, and the filtration cake was dried to obtain intermediate I-18.

[0115] Reference Example 19: Preparation of Intermediate I-19 [ka]

[0116] Intermediate I-18 (200 mg) was dissolved in N,N-dimethylformamide (30 mL), followed by the sequential addition of 1-hydroxybenzotriazole (230 mg, 1.702 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (327 mg, 1.702 mmol), N,N-diisopropylethylamine (0.42 mL, 2.55 mmol), and intermediate I-16 (385 mg). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted using dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-19.

[0117] Reference Example 20: Preparation of Intermediate I-20 [ka]

[0118] Intermediate I-19 (120 mg, 0.226 mmol) was dissolved in anhydrous dichloromethane (20 mL), the system was cooled to 0°C, and Dess-Martin periodinane (192 mg, 0.452 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (200 mL) and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated physiological saline (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-20.

[0119] Reference Example 21: Preparation of Intermediate I-21 [ka]

[0120] At room temperature, methyl 6-chloronicotinate (500 mg, 2.91 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of 4-piperidine methanol (402 mg, 3.50 mmol) and N,N-diisopropylethylamine (1.13 g, 8.73 mmol). After the additions were complete, the reaction mixture was stirred and reacted at 80°C for 3 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-21.

[0121] Reference Example 22: Preparation of Intermediate I-22 [ka]

[0122] At room temperature, intermediate I-21 (250 mg, 1.00 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of lithium hydroxide monohydrate (420 mg, 10.0 mmol) in water (2 mL) was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was acidified to pH=6 with 1N hydrochloric acid solution, concentrated under reduced pressure, and the residue was separated and purified by reverse-phase silica gel chromatography to obtain intermediate I-22.

[0123] Reference Example 23: Preparation of Intermediate I-23 [ka]

[0124] At room temperature, intermediate I-22 (100 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the sequential addition of reagent 1 (117 mg), 1-hydroxybenzotriazole (113 mg, 0.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol), and N,N-diisopropylethylamine (163 mg, 1.26 mmol). After the additions were complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel chromatography to obtain intermediate I-23.

[0125] Reference Example 24: Preparation of Intermediate I-24 [ka]

[0126] In an ice bath, intermediate I-23 (100 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), and dess-martin periodinane (170 mg, 0.40 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react at room temperature for 2 hours. The mixture was diluted with saturated sodium sulfite solution (10 mL), and layering was performed. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the organic phases were combined. The mixture was then washed sequentially with saturated sodium sulfite solution (10 mL), saturated sodium bicarbonate solution (10 mL), and water (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-24. The intermediate was used directly in the next reaction without further purification.

[0127] Reference Example 25: Preparation of Intermediate I-25 [ka]

[0128] At room temperature, methyl 3,4-difluorobenzoate (200 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 4-piperidine methanol (133 mg, 1.16 mmol) and potassium carbonate (480 g, 3.48 mmol). After the additions were complete, the reaction mixture was stirred and reacted at 100°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-25. LC-MS(ESI)[M+H] + 268.1.

[0129] Reference Example 26: Preparation of Intermediate I-26 [ka]

[0130] At room temperature, intermediate I-25 (160 mg, 0.60 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of lithium hydroxide monohydrate (252 mg, 6.0 mmol) in water (2 mL) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. The reaction solution was adjusted to pH 4-5 with 1N hydrochloric acid aqueous solution, filtered, and the filtration cake was dried to obtain intermediate I-26. LC-MS(ESI)[M+H] + 254.1.

[0131] Reference Example 27: Preparation of Intermediate I-27 [ka]

[0132] At room temperature, intermediate I-26 (120 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the sequential addition of reagent 1 (131 mg), 1-hydroxybenzotriazole (127 mg, 0.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol), and N,N-diisopropylethylamine (182 mg, 1.41 mmol). After the additions were complete, the reaction mixture was stirred and allowed to react at room temperature for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3); the organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-27. LC-MS(ESI)[M+H] + 514.1.

[0133] Reference Example 28: Preparation of Intermediate I-28 [ka]

[0134] At 0°C, intermediate I-27 (122 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), and dess-martin periodinane (204 mg, 0.48 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react at room temperature for 2 hours. The mixture was diluted with saturated sodium sulfite solution (20 mL), and layering was performed. The aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was combined, and the mixture was sequentially washed with saturated sodium sulfite solution (20 mL x 2), saturated sodium bicarbonate solution (20 mL x 3), and water (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-28. The intermediate was used directly in the next reaction without further purification.

[0135] Reference Example 29: Preparation of Intermediate I-29 [ka]

[0136] 2,6-Difluoronicotinic acid (1.0 g, 0.322 mmol) was dissolved in ethanol (20 mL), concentrated sulfuric acid (61.7 mg, 0.629 mmol) was added, the system was protected with nitrogen, and the reaction was carried out with stirring at 100°C for 16 hours. The mixture was added to water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate I-29. The intermediate was used directly in the next reaction without further purification.

[0137] Reference Example 30: Preparation of Intermediate I-30 [ka]

[0138] Intermediate I-29 (350 mg, 2.02 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), followed by the sequential addition of 4-hydroxymethylpiperidine (255 mg, 2.22 mmol) and potassium carbonate (558 mg, 4.04 mmol). The reaction system was heated to 100°C under nitrogen protection and reacted for 16 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography to obtain intermediate I-30. LC-MS(ESI)[M+H] + 269.1.

[0139] Reference Example 31: Preparation of Intermediate I-31 [ka]

[0140] Intermediate I-30 (100 mg, 0.373 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), then lithium hydroxide monohydrate (78.3 mg, 1.87 mmol) was dissolved in water (5.00 mL) and added dropwise to the reactants. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was adjusted to weak acidity with 1 N hydrochloric acid, the solid was precipitated, and the mixture was filtered to obtain the crude product of intermediate I-31. The intermediate was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 255.2.

[0141] Reference Example 32: Preparation of Intermediate I-32 [ka]

[0142] Intermediate I-31 (55 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 1-hydroxybenzotriazole (58.6 mg, 0.434 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (83.3 mg, 0.434 mmol), N,N-diisopropylethylamine (0.107 mL, 0.651 mmol), and Reagent 1 (60.5 mg). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL x 3), and dried to obtain intermediate I-32. LC-MS(ESI)[M+H] + 515.2.

[0143] Reference Example 33: Preparation of Intermediate I-33 [ka]

[0144] Intermediate I-32 (80 mg, 0.155 mmol) was dissolved in anhydrous dichloromethane (10 mL), the system was cooled to 0°C, and Dess-Martin periodinane (98.8 mg, 0.233 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-33.

[0145] Reference Example 34: Preparation of Intermediate I-34 [ka]

[0146] Reagent 2 (500 mg, 2.05 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 4-fluoro-2-methylbenzonitrile (277 mg, 2.05 mmol) was added sequentially. When the temperature dropped to 0°C, 60% sodium hydride (164 mg, 4.1 mmol) was added, and the entire system was carried out under nitrogen. After the addition was complete, the system was heated to 70°C and reacted for 2 hours. Water was added to quench the reaction, and the mixture was extracted using ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-34. LC-MS(ESI)[M-100+H] + 259.2.

[0147] Reference Example 35: Preparation of Intermediate I-35 [ka]

[0148] Intermediate I-34 (120 mg, 0.335 mmol) was dissolved in anhydrous dioxane (10 mL), and a solution of hydrogen chloride in the dioxane (15 mL, 3 M) was added. The reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by beating with ethyl acetate (20 mL), followed by suction filtration. The filtration cake was purified by beating with anhydrous acetonitrile (20 mL), followed by suction filtration, and the filtration cake was dried to obtain intermediate I-35. LC-MS(ESI)[M+H] + 259.1.

[0149] Reference Example 36: Preparation of Intermediate I-36 [ka]

[0150] Intermediate I-18 (100 mg) was dissolved in N,N-dimethylformamide (15 mL), and then 1-hydroxybenzotriazole (114 mg, 0.85 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (163 mg, 0.85 mmol), N,N-diisopropylethylamine (0.21 mL, 1.28 mmol), and intermediate I-35 (125 mg) were added sequentially. The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, the filtration cake was washed with ethyl acetate (5 mL x 3), and dried to obtain intermediate I-36. LC-MS(ESI)[M+H] + 476.2.

[0151] Reference Example 37: Preparation of Intermediate I-37 [ka]

[0152] Intermediate I-36 (63 mg, 0.132 mmol) was dissolved in anhydrous dichloromethane (10 mL), the system was cooled to 0°C, and Dess-Martin periodinane (83.9 mg, 0.198 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-37.

[0153] Reference Example 38: Preparation of Intermediate I-38 [ka]

[0154] At room temperature, methyl 6-chloropyridazine-3-carboxylate (7.00 g, 40.6 mmol) and diisopropylethylamine (10.5 mL, 81.1 mmol) were dissolved in 1,4-dioxane (200 mL). 4-hydroxymethylpiperidine (9.34 g, 81.1 mmol) was added to the mixture. After the addition was complete, the reaction mixture was stirred overnight at 110°C under argon protection. The reaction solution was concentrated under reduced pressure to remove the organic solvent and obtain the crude product of intermediate I-38, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 252.2.

[0155] Reference Example 39: Preparation of Intermediate I-39 [ka]

[0156] At room temperature, intermediate I-38 (10.0 g, 39.8 mmol) was dissolved in tetrahydrofuran (150 mL) and methanol (50 mL), and then a solution of lithium hydroxide monohydrate (3.34 g, 79.6 mmol) in water (30 mL) was added dropwise to the above solution. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was adjusted to pH=3 with aqueous hydrochloric acid (2N). The mixture was separated and purified by chromatography to obtain intermediate I-39. LC-MS(ESI)[M+H] + 238.2. 1 H NMR(400 MHz,DMSO-d6)δ 7.79(d,J=8.0 Hz,1H),7.27(d,J=12.0 Hz,1H),4.52(d,J=12.0 Hz,2H),3.28(d,J=8.0 Hz,2H),2.99(t,J=12.0 Hz,2H),1.70-1.80(m,3H),1.15-1.20(m,2H).

[0157] Reference Example 40: Preparation of Intermediate I-40 [ka]

[0158] At room temperature, intermediate I-39 (200 mg, 0.843 mmol) and reagent 1 (266 mg) were dissolved in N,N-dimethylformamide (10 mL). Under argon purging and stirring conditions, 1-hydroxybenzotriazole (171 mg, 1.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg, 1.26 mmol), and N,N-diisopropylethylamine (0.418 mL, 2.53 mmol) were added to the mixture. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was dried, and filtered. The organic solvent was removed by vacuum concentration, and the residue was purified by silica gel chromatography to obtain intermediate I-40. LC-MS(ESI)[M+H] + 498.2.

[0159] Reference Example 41: Preparation of Intermediate I-41 [ka]

[0160] Intermediate I-40 (120 mg, 0.241 mmol) was dissolved in dichloromethane (10 mL) in an ice bath. Dess-Martin periodinane (204 mg, 0.482 mmol) was added under argon displacement and stirring conditions. After the addition was complete, the reaction mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was quenched with saturated sodium sulfite solution (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate (50 mL), dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-41.

[0161] Reference Example 42: Preparation of Intermediate I-42 [ka]

[0162] A compound of methyl 5-fluoropyridine-2-carboxylate (900 mg, 5.80 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of compounds of 4-piperidinemethanol (670 mg, 5.82 mmol) and diisopropylethylamine (2.87 mL, 17.4 mmol). The reaction mixture was stirred at 100°C for 16 hours. After concentration, the mixture was diluted with water (100 mL) and extracted using ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated physiological saline (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-42. LC-MS(ESI)[M+H] + 251.0.

[0163] Reference Example 43: Preparation of Intermediate I-43 [ka]

[0164] Intermediate I-42 (300 mg, 1.20 mmol) was dissolved in tetrahydrofuran and water (5 mL / 5 mL), and lithium hydroxide monohydrate (403 mg, 9.60 mmol) was added. The reaction mixture was stirred and allowed to react at room temperature for 18 hours. Most of the tetrahydrofuran was removed by concentration, the solution was adjusted to a pH of approximately 5 with 1N hydrochloric acid aqueous solution, and then the solution was separated and purified by chromatography to obtain intermediate I-43. LC-MS(ESI)[M+H] + 237.0.

[0165] Reference Example 44: Preparation of Intermediate I-44 [ka]

[0166] At room temperature, intermediate I-43 (260 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of reagent 1 (300 mg), 1-hydroxybenzotriazole (257 mg, 1.904 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (366 mg, 1.904 mmol), and N,N-diisopropylethylamine (0.47 mL, 2.856 mmol). The reaction mixture was stirred and allowed to react at room temperature for 48 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-44. LC-MS(ESI)[M+H] + 497.1.

[0167] Reference Example 45: Preparation of Intermediate I-45 [ka]

[0168] Intermediate I-44 (70 mg, 0.141 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin periodinane (120 mg, 0.282 mmol) was slowly added. The reaction mixture was stirred and allowed to react at room temperature for 2 hours. The reaction solution was filtered, the filtrate was quenched with aqueous sodium bicarbonate (20 mL), and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated physiological saline (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-45.

[0169] Reference Example 46: Preparation of Intermediate I-46 [ka]

[0170] A compound of 5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of a compound of 4-piperidinem ethanol (365 mg, 3.17 mmol) and N,N-diisopropylethylamine (1.56 mL, 9.45 mmol). The reaction mixture was stirred and reacted at 100°C for 16 hours. After concentration, the mixture was diluted with water (80 mL) and extracted using dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated physiological saline (80 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-46. LC-MS(ESI)[M+H] + 238.3.

[0171] Reference Example 47: Preparation of Intermediate I-47 [ka]

[0172] Intermediate I-46 (200 mg, 0.843 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of reagent 1 (235 mg), 1-hydroxybenzotriazole (227 mg, 1.69 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (323 mg, 1.69 mmol), and N,N-diisopropylethylamine (0.42 mL, 2.53 mmol). The reaction mixture was stirred and allowed to react at room temperature for 48 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-47. LC-MS(ESI)[M+H] + 498.2.

[0173] Reference Example 48: Preparation of Intermediate I-48 [ka]

[0174] Intermediate I-47 (120 mg, 0.241 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin periodinane (204 mg, 0.482 mmol) was slowly added. The reaction mixture was stirred and allowed to react at room temperature for 2 hours. The reaction solution was filtered, the filtrate was quenched with aqueous sodium bicarbonate (20 mL), and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product of intermediate I-48. The crude product was used directly in the next reaction without further purification.

[0175] Reference Example 49: Preparation of Intermediate I-49 [ka]

[0176] At room temperature, isobenzofuran-1(3H)-one (1.00 g, 7.46 mmol) was dissolved in a mixed solvent of chloroform (20 mL) and glacial acetic acid (10 mL). N-bromosuccinimide (1.59 g, 8.95 mmol) was added under stirring and argon protection, and nitrogen purging was performed again. Under nitrogen protection, the mixture was stirred and reacted at 80°C for 16 hours. The mixture was cooled to room temperature, then poured into water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was separated and purified by silica gel chromatography to obtain intermediate I-49. 1 H NMR(400 MHz,CDCl3)δ 8.06(d,J=1.5 Hz,1H),7.81(dd,J=8.1,1.7 Hz,1H),7.40(dd,J=8.1,0.4 Hz,1H),5.29(s,2H).

[0177] Reference Example 50: Preparation of Intermediate I-50 [ka]

[0178] At 25°C, intermediate I-49 (700 mg, 3.29 mmol) was dissolved in carbon tetrachloride (10 mL), followed by the addition of N-bromosuccinimide (702 mg, 3.95 mmol) and benzoyl peroxide (79.7 mg, 0.329 mmol). The reaction was then carried out at 60°C for 3 hours, the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and then purified by silica gel chromatography to obtain intermediate I-50. 1H NMR(400 MHz,CDCl3)δ 8.05(d,J=1.6 Hz,1H),7.90(dd,J=8.2,1.7 Hz,1H),7.53(d,J=8.2 Hz,1H),7.37(s,1H).

[0179] Reference Example 51: Preparation of Intermediate I-51 [ka]

[0180] At 25°C, intermediate I-50 (700 mg, 2.40 mmol) was dissolved in ethanol (10 mL). The temperature was then lowered to 0°C, and 85% hydrazine hydrate (600.7 mg) was added. Under nitrogen protection, the reaction mixture was refluxed with stirring and allowed to react for 2 hours. The reaction system was poured into water (10 mL) and filtered. The filtration cake was washed with water (10 mL x 3) to obtain intermediate I-51. 1 H NMR(400 MHz,DMSO-d6)δ 12.82(s,1H),8.40(s,1H),8.32(d,J=1.9 Hz,1H),8.13(dd,J=8.4,2.0 Hz,1H),7.92(d,J=8.4 Hz,1H).

[0181] Reference Example 52: Preparation of Intermediate I-52 [ka]

[0182] At 25°C, intermediate I-51 (400 mg, 1.77 mmol) was dissolved in 1,4-dioxane (15 mL). N-BOC piperazine (330 mg, 1.77 mmol) and sodium tert-butoxide (510 mg, 5.31 mmol) were added, and the nitrogen was substituted; chloro(2-dicyclohexylphosphin-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (138 mg, 0.177 mmol) was added, and the reaction mixture was stirred overnight at 100°C. The reaction system was filtered, then concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product residue was separated and purified by silica gel chromatography to obtain intermediate I-52. LC-MS(ESI)[M+H] + 331.1.

[0183] Reference Example 53: Preparation of Intermediate I-53 [ka]

[0184] At 25°C, intermediate I-52 (400 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL), 60% sodium hydride (96.8 mg, 2.42 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. 3-bromopiperidine-2,6-dione (464.6 mg, 2.42 mmol) was added dropwise, dissolved in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted using ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was separated and purified by silica gel chromatography to obtain intermediate I-53. LC-MS(ESI)[M+H-56] + 386.1.

[0185] Reference Example 54: Preparation of Intermediate I-54 [ka]

[0186] At 25°C, intermediate I-53 (240 mg, 0.544 mmol) was dissolved in dichloromethane (3 mL). A solution of hydrogen chloride in dioxane (3 mL, 4 M) was added, and the reaction mixture was stirred and allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain intermediate I-54. The crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 342.2.

[0187] Reference Example 55: Preparation of Intermediate I-55 [ka]

[0188] Intermediate I-18 (38.8 g) was dissolved in N,N-dimethylformamide (300 mL), followed by the sequential addition of 1-hydroxybenzotriazole (25.7 g, 190.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.56 g, 190.4 mmol), N,N-diisopropylethylamine (42.25 mL, 285.6 mmol), and reagent 1 (30.0 g). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (20 mL x 3), and dried to obtain intermediate I-55. LC-MS(ESI)[M+H] + 496.2.

[0189] Reference Example 56: Preparation of Intermediate I-56 [ka]

[0190] Intermediate I-55 (32 g, 64.52 mmol) was dissolved in anhydrous dichloromethane (200.0 mL), the system was cooled to 0°C, and Dess-Martin periodinane (41 g, 96.77 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The filtrate was quenched with saturated sodium bicarbonate aqueous solution (200 mL) and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated physiological saline (200 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-56.

[0191] Reference Example 57: Preparation of Intermediate I-57 [ka]

[0192] 2,2,6,6-Tetramethylpiperidine (4.42 g, 31.3 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL); butyllithium (1.6 M) (19.6 mL, 31.3 mmol) was added dropwise at -60°C. After the addition was complete, the mixture was stirred and reacted at -60°C for 1 hour under argon protection. A solution of m-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (50 mL) was added dropwise at -60°C, and the mixture was stirred and reacted at -60°C for 1 hour under argon protection. N,N-dimethylformamide (4.36 g, 59.6 mmol) was added dropwise at -60°C. After the addition was complete, the temperature was slowly raised to room temperature, and the mixture was stirred and reacted at room temperature for 0.5 hours. At 0°C, the product was quenched with water (500 mL), and the product was extracted with ethyl acetate (200 mL x 3); the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-57. 1H NMR(400 MHz,DMSO-d6)δ 8.28(s,1H),7.99(dd,J=7.9,0.7 Hz,1H),7.88-7.81(m,1H),7.60(t,J=7.7 Hz,1H),6.62(s,1H).

[0193] Reference Example 58: Preparation of Intermediate I-58 [ka]

[0194] Intermediate I-57 (700 mg, 3.06 mmol) was dissolved in glacial acetic acid (10.0 mL), the system was protected with argon, and heated to 90°C; 85% hydrazine hydrate (460 mg) was added dropwise, and after the addition was complete, the mixture was stirred and reacted at 90°C for 4 hours; the temperature was maintained at 80°C, and preheated hot water (20.0 mL) at 80°C was slowly added dropwise. After the addition was complete, the mixture was slowly cooled to room temperature to precipitate the solid; suction filtration was performed, the filtration cake was washed with water (10.0 mL), and dried under reduced pressure and in a vacuum to obtain intermediate I-58. LC-MS(ESI)[M+H] + 225.0.

[0195] Reference Example 59: Preparation of Intermediate I-59 [ka]

[0196] Intermediate I-58 (510 mg, 2.27 mmol) was dissolved in anhydrous dioxane (50.0 mL), followed by the addition of tert-butylpiperazine-1-carboxylate (635 mg, 3.41 mmol), sodium tert-butoxide (654 mg, 6.81 mmol), and chloro(2-dicyclohexylphosphin-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (87.8 mg, 0.227 mmol). The reaction system was protected with argon and stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-59. LC-MS(ESI)[M+H] + 331.2.

[0197] Reference Example 60: Preparation of Intermediate I-60 [ka]

[0198] Intermediate I-59 (150 mg, 0.454 mmol) was dissolved in a mixed solvent of dimethyl sulfoxide / tetrahydrofuran (2.00 mL / 2.00 mL), and sodium hydride (60%, 90.8 mg, 2.27 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 0.5 hours. A solution of 3-bromopiperidine-2,6-dione (174 mg, 0.908 mmol) in tetrahydrofuran (0.50 mL) was added dropwise. After the addition was complete, the mixture was stirred and reacted at room temperature for 0.5 hours. The mixture was quenched with citric acid (100 mg). The mixture was poured into water (20.0 mL), and the product was extracted with ethyl acetate (20.0 mL x 3); the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-60. LC-MS(ESI)[M+H] + 442.1.

[0199] Reference Example 61: Preparation of Intermediate I-61 [ka]

[0200] Intermediate I-60 (120 mg, 0.272 mmol) was dissolved in dichloromethane (2.00 mL), and trifluoroacetic acid (0.50 mL) was added. The reaction system was protected with argon, and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated, the organic solvent was removed to obtain the crude product, and the crude product was separated and purified by silica gel chromatography to obtain intermediate I-61. LC-MS(ESI)[M+H] + 342.1.

[0201] Reference Example 62: Preparation of Intermediate I-62 [ka]

[0202] In an ice bath, trans-4-Boc-aminocyclohexanol (5.00 g, 23.2 mmol) was dissolved in N,N-dimethylformamide (100 mL); sodium hydride (1.11 g, 27.9 mmol, 60% mass fraction) was added while stirring under nitrogen protection. The reaction mixture was stirred in an ice bath for 1 hour, after which 2-chloro-4-fluorobenzonitrile (3.65 g, 23.5 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was dried and filtered. The filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel chromatography to obtain the white solid intermediate I-62. LC-MS(ESI)[M-56+H] + 295.1.

[0203] Reference Example 63: Preparation of Intermediate I-63 [ka]

[0204] At room temperature, intermediate I-62 (6.00 g, 17.1 mmol) was dissolved in a dioxane solution of hydrogen chloride (100 mL, 4 M). After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to remove the organic solvent and obtain the crude product of intermediate I-63, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 251.2.

[0205] Reference Example 64: Preparation of Intermediate I-64 [ka]

[0206] Intermediate I-18 (1.40 g, 5.95 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the sequential addition of 1-hydroxybenzotriazole (1.21 g, 8.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g, 8.93 mmol), N,N-diisopropylethylamine (2.31 g, 17.9 mmol), and intermediate I-63 (1.71 g). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (15 mL x 3), and dried to obtain intermediate I-64. LC-MS(ESI)[M+H] + 468.1.

[0207] Reference Example 65: Preparation of Intermediate I-65 [ka]

[0208] Intermediate I-64 (100 mg, 0.214 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), the system was cooled to 0°C, and Dess-Martin periodinane (181 mg, 0.428 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10.0 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product of intermediate I-65. The crude product was used directly in the next reaction without purification.

[0209] Reference Example 66: Preparation of Intermediate I-66 [ka]

[0210] Intermediate I-63 (700 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of intermediate I-13 (578 mg), 1-hydroxybenzotriazole (660 mg, 4.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (940 mg, 4.90 mmol), and N,N-diisopropylethylamine (1.2 mL, 7.32 mmol). The reaction mixture was stirred and allowed to react at room temperature for 4 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-66. LC-MS(ESI)[M+H] + 470.0.

[0211] Reference Example 67: Preparation of Intermediate I-67 [ka]

[0212] Intermediate I-66 (150 mg, 0.319 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then 2-iodoxybenzoic acid (270 mg, 0.964 mmol) was slowly added. The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with aqueous solution (30 mL), and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, washed with saturated physiological saline (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-67.

[0213] Reference Example 68: Preparation of Intermediate I-68 [ka]

[0214] Methyl p-fluorobenzoate (5.00 g, 32.4 mmol) was dissolved in anhydrous N,N-dimethylformamide (20.0 mL), followed by the sequential addition of 3-azetidine methanol hydrochloride (4.81 g, 38.9 mmol) and anhydrous potassium carbonate (11.2 g, 81.1 mmol). The reaction system was protected with argon and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, water (20.0 mL) was added, and the product was extracted with ethyl acetate (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-68. LC-MS(ESI)[M+H] + 222.2.

[0215] Reference Example 69: Preparation of Intermediate I-69 [ka]

[0216] Intermediate I-68 (200 mg, 0.904 mmol) was dissolved in anhydrous tetrahydrofuran (5.00 mL), then lithium hydroxide monohydrate (190 mg, 4.52 mmol) was dissolved in water (5.00 mL) and added dropwise to the reactants. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was adjusted to weak acidity with 1N hydrochloric acid, the solid was precipitated, and the mixture was filtered to obtain the crude product of intermediate I-69. The crude product was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 208.0.

[0217] Reference Example 70: Preparation of Intermediate I-70 [ka]

[0218] Intermediate I-69 (160 mg) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the sequential addition of 1-hydroxybenzotriazole (209 mg, 1.546 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg, 1.546 mmol), N,N-diisopropylethylamine (0.380 mL, 2.17 mmol), and intermediate I-63 (194 mg, 0.773 mmol). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, the filtration cake was washed with ethyl acetate (2 mL x 3), and dried to obtain intermediate I-70. LC-MS(ESI)[M+H] + 440.0.

[0219] Reference Example 71: Preparation of Intermediate I-71 [ka]

[0220] Intermediate I-70 (100 mg, 0.227 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), the system was cooled to 0°C, and Dess-Martin periodinane (193 mg, 0.454 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10.0 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-71.

[0221] Reference Example 72: Preparation of Intermediate I-72 [ka]

[0222] 3-Hydroxymethylpyrrole hydrochloride (1.20 g, 8.72 mmol) was dissolved in anhydrous N,N-dimethylformamide (20.0 mL), followed by the addition of methyl p-fluorobenzoate (1.48 g, 9.59 mmol) and anhydrous potassium carbonate (3.62 g, 26.2 mmol). The reaction system was protected with argon and stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the product was extracted with ethyl acetate (50.0 mL x 3); the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-72. LC-MS(ESI)[M+H] + 236.2.

[0223] Reference Example 73: Preparation of Intermediate I-73 [ka]

[0224] Intermediate I-72 (400 mg, 1.70 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol (2.00 mL / 2.00 mL), and a solution of sodium hydroxide (204 mg, 5.10 mmol) in water (2.00 mL) was added. The reaction system was protected with argon and stirred at 70°C for 4 hours. The pH was adjusted to 6.0 with dilute hydrochloric acid (1 N), and a large amount of solid precipitated. The mixture was filtered by suction, and the filtered cake was dried to obtain intermediate I-73. LC-MS(ESI)[M+H] + 222.2.

[0225] Reference Example 74: Preparation of Intermediate I-74 [ka]

[0226] Intermediate I-73 (350 mg, 1.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (20.0 mL), followed by the addition of reagent 1 (599 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (454 mg, 2.37 mmol), 1-hydroxybenzotriazole (320 mg, 2.37 mmol), and N,N-diisopropylethylamine (613 mg, 4.74 mmol). The reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was poured into water (100 mL), a solid precipitated, and the mixture was filtered by suction. The solid was dried, washed by beating with ethyl acetate (25 mL), filtered by suction, and the filtration cake was dried to obtain intermediate I-74. LC-MS(ESI)[M+H] + 482.3.

[0227] Reference Example 75: Preparation of Intermediate I-75 [ka]

[0228] Intermediate I-74 (150 mg, 0.311 mmol) was dissolved in anhydrous dichloromethane (20.0 mL), and Dess-Martin periodinane (198 mg, 0.467 mmol) was added at 0°C. The reaction system was protected with argon and stirred at 20°C for 16 hours. The mixture was diluted with dichloromethane (50.0 mL) and washed with water (20.0 mL x 2); the organic phase was separated, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-75. LC-MS(ESI)[M+H] + 480.1.

[0229] Reference Example 76: Preparation of Intermediate I-76 [ka]

[0230] Intermediate I-5 (230 mg) was dissolved in anhydrous dimethyl sulfoxide (10.0 mL), followed by the addition of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (198 mg, 1.00 mmol) and N,N-diisopropylethylamine (324 mg, 2.51 mmol). The reaction system was protected with argon and stirred at 140 °C for 24 hours. The reaction solution was cooled to room temperature, diluted with water (50.0 mL), and the product was extracted with ethyl acetate (20.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-76. LC-MS(ESI)[M+H] + 454.1.

[0231] Reference Example 77: Preparation of Intermediate I-77 [ka]

[0232] Intermediate I-76 (234 mg, 0.516 mmol) was dissolved in dichloromethane (3.00 mL), and trifluoroacetic acid (1.00 mL) was added. The reaction system was protected with argon, and the reaction was stirred at room temperature for 16 hours. The mixture was loaded as a sample by a wet process, separated and purified by silica gel chromatography to obtain intermediate I-77. LC-MS(ESI)[M+H] + 354.1.

[0233] Reference Example 78: Preparation of Intermediate I-78 [ka]

[0234] Intermediate I-5 (200 mg), (R)-1-Boc-3-methylpiperazine (729 mg, 3.64 mmol), and N,N-diisopropylethylamine (2 mL) were mixed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred and reacted at 130°C for 3 days. The mixture was cooled to room temperature, then poured into water (100 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-78. LC-MS(ESI)[M+H] + 456.1.

[0235] Reference Example 79: Preparation of Intermediate I-79 [ka]

[0236] Intermediate I-78 (50.0 mg, 0.110 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise at room temperature while stirring. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed from the mixture under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-79. LC-MS(ESI)[M+H] + 356.1.

[0237] Reference Example 80: Preparation of Intermediate I-80 [ka]

[0238] Intermediate I-5 (200 mg), (S)-1-Boc-3-methylpiperazine (729 mg, 3.64 mmol), and N,N-diisopropylethylamine (2 mL) were mixed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred and reacted at 130°C for 3 days. The mixture was cooled to room temperature, then poured into water (100 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-80. LC-MS(ESI)[M+H] + 456.1.

[0239] Reference Example 81: Preparation of Intermediate I-81 [ka]

[0240] Intermediate I-80 (30.0 mg, 0.0659 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise at room temperature while stirring. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed from the mixture under reduced pressure to obtain intermediate I-81, and the crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 356.1.

[0241] Reference Example 82: Preparation of Intermediate I-82 [ka]

[0242] Intermediate I-69 (150 mg) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the sequential addition of 1-hydroxybenzotriazole (147 mg, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (208 mg, 1.09 mmol), N,N-diisopropylethylamine (0.400 mL, 2.17 mmol), and reagent 1 (202 mg). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The reaction solution was filtered, and the filtration cake was washed three times with ethyl acetate (2 mL x 3) and dried to obtain intermediate I-82.

[0243] Reference Example 83: Preparation of Intermediate I-83 [ka]

[0244] Intermediate I-82 (200 mg, 0.43 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), the system was cooled to 0°C, and Dess-Martin periodinane (274 mg, 0.645 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The filtrate was quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10.0 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure to remove the organic solvent, and the crude product of intermediate I-83 was obtained. The crude product was used directly in the next reaction without further purification.

[0245] Reference Example 84: Preparation of Intermediate I-84 [ka]

[0246] At room temperature, (R)-1-BOC-3-hydroxymethylpyrrolidine (1.60 g, 8.00 mmol) was dissolved in dioxane (2.00 mL). Then, a solution of hydrogen chloride in dioxane (20.0 mL, 4 M) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated to obtain the crude product of intermediate I-84. The crude product was used directly in the next reaction without purification.

[0247] Reference Example 85: Preparation of Intermediate I-85 [ka]

[0248] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.68 mmol) was dissolved in dimethyl sulfoxide (8.00 mL), followed by the addition of intermediate I-84 (406 mg) and N,N-diisopropylethylamine (1.33 mL, 8.04 mmol); the reaction solution was stirred at 50°C for 2 hours. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated to obtain the crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-85. LC-MS(ESI)[M+H] + 252.2.

[0249] Reference Example 86: Preparation of Intermediate I-86 [ka]

[0250] At room temperature, intermediate I-85 (520 mg, 2.06 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8.00 mL) and water (2.00 mL); then lithium hydroxide monohydrate (433 mg, 10.3 mmol) was added and the mixture was stirred overnight at room temperature. Water (6.00 mL) was added first, followed by extraction with ethyl acetate (5.00 mL); the aqueous phase was adjusted to pH 1.0 with 2N dilute hydrochloric acid, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain intermediate I-86. LC-MS(ESI)[M+H] + 224.1.

[0251] Reference Example 87: Preparation of Intermediate I-87 [ka]

[0252] At room temperature, intermediate I-86 (200 mg, 0.897 mmol) was dissolved in N,N-dimethylformamide (5.00 mL), followed by the addition of N,N-diisopropylethylamine (347 mg, 2.69 mmol), reagent 1 (283 mg, 0.897 mmol), 1-hydroxybenzotriazole (242 mg, 1.79 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mmol); the mixture was stirred at room temperature for 1 hour. Water (10.0 mL) was added first, and a large amount of solid precipitated; the mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and combined with the filter residue obtained immediately beforehand. The mixture was spin-dried to obtain intermediate I-87. LC-MS(ESI)[M+H] + 484.1.

[0253] Reference Example 88: Preparation of Intermediate I-88 [ka]

[0254] At room temperature, intermediate I-87 (150 mg, 0.310 mmol) was dissolved in dimethyl sulfoxide (5.00 mL); then 2-iodoxybenzoic acid (434 mg, 1.55 mmol) was added, and the mixture was stirred at 80°C for 30 minutes after three argon substitutions. The mixture was cooled to room temperature, diluted with water (10.0 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-88. The crude product was used directly in the next reaction without further purification.

[0255] Reference Example 89: Preparation of Intermediate I-89 [ka]

[0256] (S)-1-BOC-3-hydroxymethylpyrrolidine (1.0 g, 4.97 mmol) was dissolved in anhydrous dioxane (10 mL), and a solution of hydrogen chloride in dioxane (15 mL, 4 M) was added; the reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by beating with ethyl acetate (20 mL), followed by suction filtration. The filtration cake was purified by beating with anhydrous acetonitrile (20 mL), followed by suction filtration, and the filtration cake was dried to obtain intermediate I-89. LC-MS(ESI)[M+H] + 102.4.

[0257] Reference Example 90: Preparation of Intermediate I-90 [ka]

[0258] Intermediate I-89 (500 mg, 3.61 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the sequential addition of ethyl 2-chloropyrimidine-5-carboxylate (670 mg, 3.61 mmol) and N,N-diisopropylethylamine (1.78 mL, 10.8 mmol). After three argon substitutions at room temperature, the reaction mixture was stirred and reacted at 50°C for 3 hours under argon protection. After cooling to room temperature, liquid-liquid extraction was performed, and the organic phase was concentrated to dryness under reduced pressure. Water (10 mL) was added to the residue, and it was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by silica gel chromatography to obtain intermediate I-90. LC-MS(ESI)[M+H] + 252.0.

[0259] Reference Example 91: Preparation of Intermediate I-91 [ka]

[0260] Intermediate I-90 (700 mg, 2.79 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), then lithium hydroxide monohydrate (583 mg, 13.9 mmol) was dissolved in water (10.00 mL) and added dropwise to the reaction solution. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was adjusted to weak acidity with 1 N hydrochloric acid, the solid was precipitated, and the mixture was filtered to obtain the crude product of intermediate I-91. The crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 224.1.

[0261] Reference Example 92: Preparation of Intermediate I-92 [ka]

[0262] Intermediate I-91 (200 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 1-hydroxybenzotriazole (242 mg, 1.794 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.794 mmol), N,N-diisopropylethylamine (0.4 mL, 2.69 mmol), and reagent 1 (245 mg). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL x 3), and dried to obtain intermediate I-92. LC-MS(ESI)[M+H] + 484.0.

[0263] Reference Example 93: Preparation of Intermediate I-93 [ka]

[0264] Intermediate I-92 (150 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (10 mL), the system was cooled to 0°C, and Dess-Martin periodinane (197 mg, 0.465 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The filtrate was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated physiological saline (10 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-93.

[0265] Reference Example 94: Preparation of Intermediate I-94 [ka]

[0266] At 0°C, sodium hydride (60% by mass fraction) (438 mg, 11.0 mmol) was added to tetrahydrofuran (10 mL) and the mixture was purged with argon; after stirring at 0°C for 5 minutes, a solution of triethyl phosphonoacetate (2.66 g, 11.9 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, and the reaction mixture was stirred at 0°C for 30 minutes; then, a solution of N-Cbz-3-pyrrolidone (2.00 g, 9.13 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise; after the addition was complete, the reaction mixture was stirred and allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water (30 mL), concentrated under reduced pressure, and the residual solution was extracted with ethyl acetate (30 mL x 3); the organic phases were combined, washed with water (30 mL x 3), dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-94. LC-MS(ESI)[M+H] + 290.2.

[0267] Reference Example 95: Preparation of Intermediate I-95 [ka]

[0268] At room temperature, intermediate I-94 (1.84 g, 6.37 mmol) was dissolved in methanol (20 mL), and palladium / carbon (10% mass fraction) (1.35 g, 1.27 mmol) was added. After the addition was complete, the mixture was purged with hydrogen, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-95. The crude product was used directly in the next reaction without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 4.09-4.01(m,2H),3.40(d,J=8.4 Hz,3H),2.93-2.65(m,2H),2.38-2.20(m,3H),1.95-1.75(m,1H),1.36-1.20(m,1H),1.18(t,J=7.1 Hz,3H).

[0269] Reference Example 96: Preparation of Intermediate I-96 [ka]

[0270] Intermediate I-95 (900 mg, 5.73 mmol) was dissolved in tetrahydrofuran (20 mL) and pallidated with argon; lithium aluminum hydride (435 mg, 11.5 mmol) was slowly added little by little at 0°C; after the addition was complete, the reaction mixture was stirred and reacted at 0°C for 2 hours. After the reaction was complete, water (0.9 mL) was added and stirred for 5 minutes; then, anhydrous sodium sulfate was added under stirring, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-96. The crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 116.1.

[0271] Reference Example 97: Preparation of Intermediate I-97 [ka]

[0272] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (730 mg, 3.9 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of intermediate I-96 (450 mg) and N,N-diisopropylethylamine (1.5 g, 11.7 mmol). After the addition was complete, the reaction mixture was stirred and reacted at 50°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-97. LC-MS(ESI)[M+H] + 266.0.

[0273] Reference Example 98: Preparation of Intermediate I-98 [ka]

[0274] At room temperature, intermediate I-97 (170 mg, 0.64 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of lithium hydroxide monohydrate (134 mg, 3.2 mmol) in water (1 mL) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was adjusted to pH 5-6 with 1N hydrochloric acid solution, diluted with saturated physiological saline (10 mL), and extracted with ethyl acetate (10 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-98. The crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 238.1.

[0275] Reference Example 99: Preparation of Intermediate I-99 [ka]

[0276] At room temperature, intermediate I-98 (120 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the sequential addition of reagent 1 (142 mg), 1-hydroxybenzotriazole (138 mg, 1.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg, 1.02 mmol), and N,N-diisopropylethylamine (197 mg, 1.53 mmol). After the additions were complete, the reaction mixture was stirred and allowed to react at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-99. LC-MS(ESI)[M+H] + 498.1.

[0277] Reference Example 100: Preparation of Intermediate I-100 [ka]

[0278] At room temperature, intermediate I-99 (80 mg, 0.16 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodoxybenzoic acid (224 mg, 0.80 mmol) was added; after the addition was complete, the reaction mixture was stirred and reacted at 80°C for 30 minutes. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3); the organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-100. The crude product was used directly in the next reaction without further purification.

[0279] Reference Example 101: Preparation of Intermediate I-101 [ka]

[0280] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.07 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of 4-piperidineethanol (165 mg, 1.28 mmol) and N,N-diisopropylethylamine (414 g, 3.21 mmol). The reaction mixture was stirred and reacted at 50°C for 2 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-101. LC-MS(ESI)[M+H] + 280.1.

[0281] Reference Example 102: Preparation of Intermediate I-102 [ka]

[0282] At room temperature, intermediate I-101 (240 mg, 0.86 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of lithium hydroxide monohydrate (181 mg, 4.3 mmol) in water (1 mL) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was adjusted to pH 5-6 with 1N hydrochloric acid solution, filtered, and the filtration cake was dried to obtain intermediate I-102. LC-MS(ESI)[M+H] + 252.1.

[0283] Reference Example 103: Preparation of Intermediate I-103 [ka]

[0284] At room temperature, intermediate I-102 (140 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the sequential addition of reagent 1 (156 mg), 1-hydroxybenzotriazole (157 mg, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg, 1.12 mmol), and N,N-diisopropylethylamine (217 mg, 1.68 mmol). After the additions were complete, the reaction mixture was stirred and allowed to react at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-103. LC-MS(ESI)[M+H] + 512.3.

[0285] Reference Example 104: Preparation of Intermediate I-104 [ka]

[0286] At 0°C, intermediate I-103 (60 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL), dess-martin periodinane (102 mg, 0.24 mmol) was added, and the reaction mixture was stirred and allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with saturated sodium sulfite solution (10 mL), and layering was performed. The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed sequentially with saturated sodium sulfite solution (10 mL x 2), saturated sodium bicarbonate solution (10 mL x 3), and water (10 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-104. The crude product was used directly in the next reaction without further purification.

[0287] Reference Example 105: Preparation of Intermediate I-105 [ka]

[0288] At room temperature, hydroxylamine hydrochloride (8.69 g, 125 mmol) was dissolved in water (130 mL), and anhydrous sodium acetate (13.6 g, 166 mmol) was added; the mixture was stirred at room temperature for 10 minutes, and ethyl p-cyclohexanoneformate (13.0 g, 83.2 mmol) was added dropwise. The reaction system was protected with argon, and the mixture was stirred at 45 °C for 16 hours. The reaction solution was cooled to room temperature, and the product was extracted with ethyl acetate (100 mL x 2); the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-105. LC-MS(ESI)[M+H] + 186.1.

[0289] Reference Example 106: Preparation of Intermediate I-106 [ka]

[0290] At room temperature, intermediate I-105 (11.2 g, 60.5 mmol) was dissolved in anhydrous pyridine (50.0 mL), the reaction system was protected with argon, cooled to -15°C, and 4-toluenesulfonyl chloride (17.3 g, 90.8 mmol) was added. The reaction mixture was stirred and reacted at 15°C for 2 hours. The mixture was poured into ice water and a solid precipitated; after stirring at 5°C for 20 minutes, it was filtered by suction, and the filtered cake was dried to obtain intermediate I-106. LC-MS(ESI)[M+H] + 340.2.

[0291] Reference Example 107: Preparation of Intermediate I-107 [ka]

[0292] At room temperature, intermediate I-106 (12.5 g, 36.8 mmol) was dissolved in glacial acetic acid (30.0 mL), the reaction system was protected with argon, and the reaction was stirred and allowed to proceed at room temperature for 16 hours. The glacial acetic acid was removed by reducing the pressure and concentrated the mixture. Saturated sodium bicarbonate aqueous solution (40.0 mL) was added to the residue and stirred for 15 minutes, after which the product was extracted with ethyl acetate (30.0 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-107. LC-MS(ESI)[M+H] + 186.2.

[0293] Reference Example 108: Preparation of Intermediate I-108 [ka]

[0294] Lithium aluminum hydride (2.56 g, 67.5 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL); at 0°C, a solution of intermediate I-107 (2.50 g, 13.5 mmol) in anhydrous tetrahydrofuran (20.0 mL) was added dropwise. The reaction system was protected with argon and stirred at room temperature for 2 hours. Then, the temperature was raised to 60°C and stirred for 4 hours. The mixture was cooled to room temperature, and at 0°C, sodium sulfate decahydrate (10.0 g) was added, and the reaction was stirred for 0.5 hours. The mixture was filtered by suction, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain intermediate I-108. LC-MS(ESI)[M+H] + 130.1.

[0295] Reference Example 109: Preparation of Intermediate I-109 [ka]

[0296] At room temperature, intermediate I-108 (560 mg, 4.33 mmol) was dissolved in anhydrous dichloromethane (50.0 mL), followed by the addition of ethyl 2-chloropyrimidine-5-carboxylate (970 mg, 5.20 mmol) and N,N-diisopropylethylamine (1.68 g, 13.0 mmol). The reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was separated and purified by silica gel chromatography to obtain intermediate I-109. LC-MS(ESI)[M+H] + 280.2.

[0297] Reference Example 110: Preparation of Intermediate I-110 [ka]

[0298] At room temperature, intermediate I-109 (240 mg, 0.860 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol (3.00 mL / 3.00 mL), and a solution of lithium hydroxide monohydrate (114 mg, 2.72 mmol) in water (3.00 mL) was added. The reaction system was protected with argon and stirred at room temperature for 16 hours. The system pH was adjusted to 6.0 with 1N hydrochloric acid, the solid was precipitated, and the reaction was carried out by suction filtration. The filtration cake was dried to obtain intermediate I-110. LC-MS(ESI)[M+H] + 252.2.

[0299] Reference Example 111: Preparation of Intermediate I-111 [ka]

[0300] At room temperature, intermediate I-110 (180 mg, 0.716 mmol) was dissolved in anhydrous N,N-dimethylformamide (20.0 mL), followed by the addition of reagent 1 (293 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (274 mg, 1.43 mmol), 1-hydroxybenzotriazole (193 mg, 1.43 mmol), and N,N-diisopropylethylamine (370 mg, 2.86 mmol). The reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was separated and purified by column chromatography (C18, acetonitrile / water = 0%~70%) to obtain intermediate I-111. LC-MS(ESI)[M+H] + 512.2.

[0301] Reference Example 112: Preparation of Intermediate I-112 [ka]

[0302] Intermediate I-111 (200 mg, 0.391 mmol) was dissolved in anhydrous dichloromethane (20.0 mL), and Dess-Martin periodinane (249 mg, 0.587 mmol) was added at 0°C. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was separated and purified by silica gel chromatography to obtain intermediate I-112. LC-MS(ESI)[M+H] + 510.1.

[0303] Reference Example 113: Preparation of Intermediate I-113 [ka]

[0304] At room temperature, 1.00 g of 2-chloro-3-fluoro-5-methylpyridine (6.87 mmol) was added to 5.00 mL of water, followed by 2.17 g of potassium permanganate (13.7 mmol) and 5.52 mL of pyridine (68.7 mmol). The mixture was stirred at 100°C for 1 hour, followed by the addition of 4.34 g of potassium permanganate (27.4 mmol), and the mixture was stirred at 100°C overnight. 10.0 mL of water was added, and the mixture was extracted with ethyl acetate (20.0 mL x 2). The aqueous phase was adjusted to approximately 2.0 pH with 2N dilute hydrochloric acid and extracted with ethyl acetate (20.0 mL x 2). The combined organic phase was washed with saturated physiological saline (20 mL), concentrated, and the crude product of intermediate I-113 was obtained. The crude product was used directly in the following reaction without purification. LC-MS(ESI)[2M-H] - 349.0.

[0305] Reference Example 114: Preparation of Intermediate I-114 [ka]

[0306] At room temperature, intermediate I-113 (650 mg) was dissolved in ethanol (10.0 mL) and cooled to 0°C in an ice bath; thionyl chloride (0.676 mL, 9.26 mmol) was gradually added with an injector, the temperature was slowly raised to room temperature, and the mixture was heated under reflux for 4 hours. After concentration, saturated sodium bicarbonate solution (10.0 mL) was added and extracted with ethyl acetate (30.0 mL × 2); the organic phases were combined, washed with saturated physiological saline (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product; the crude product was separated and purified by silica gel chromatography to obtain intermediate I-114. LC-MS(ESI)[M+H] + 204.1.

[0307] Reference Example 115: Preparation of Intermediate I-115 [ka]

[0308] At room temperature, intermediate I-114 (340 mg, 1.67 mmol) was dissolved in dimethyl sulfoxide (10.0 mL), followed by the addition of 4-hydroxymethylpiperidine (192 mg, 1.67 mmol) and N,N-diisopropylethylamine (646 mg, 5.01 mmol), and the mixture was stirred overnight at 50°C. The reaction solution was cooled to room temperature, water (10.0 mL) was added, and then the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated physiological saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-115. LC-MS(ESI)[M+H] + 283.1.

[0309] Reference Example 116: Preparation of Intermediate I-116 [ka]

[0310] At room temperature, intermediate I-115 (340 mg, 1.20 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5.00 mL) and water (1.00 mL), followed by the addition of lithium hydroxide monohydrate (252 mg, 6.00 mmol), and the mixture was stirred overnight at room temperature. Water (5.00 mL) was added first, followed by ethyl acetate (3.00 mL) for washing; the aqueous phase was adjusted to pH 2.0 with 2N dilute hydrochloric acid, and then extracted with ethyl acetate (8 mL × 2); the extracts were combined, washed with saturated physiological saline (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of intermediate I-116. The crude product was used directly in the following reaction without purification. LC-MS(ESI)[M+H] + 255.1.

[0311] Reference Example 117: Preparation of Intermediate I-117 [ka]

[0312] Intermediate I-116 (130 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of 1-hydroxybenzotriazole (138 mg, 1.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg, 1.02 mmol), N,N-diisopropylethylamine (0.3 mL, 1.53 mmol), and reagent 1 (142 mg). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (2 mL x 3), and dried to obtain intermediate I-117. LC-MS(ESI)[M+H] + 515.0.

[0313] Reference Example 118: Preparation of Intermediate I-118 [ka]

[0314] Intermediate I-117 (100 mg, 0.194 mmol) was dissolved in anhydrous dichloromethane (15.0 mL), the system was cooled to 0°C, and Dess-Martin periodinane (123 mg, 0.291 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was quenched with saturated sodium bicarbonate aqueous solution (20.0 mL), and extracted with dichloromethane (15.0 mL x 3). The organic phases were combined, washed with saturated physiological saline (10.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product of intermediate I-118. The crude product was used directly in the next reaction without purification.

[0315] Reference Example 119: Preparation of Intermediate I-119 [ka]

[0316] Methyl 5-bromopyridine-2-carboxylate (10.0 g, 46.3 mmol) was dissolved in anhydrous toluene (200 mL), followed by the sequential addition of 4-piperidine methanol (10.7 g, 92.6 mmol), anhydrous potassium carbonate (19.2 g, 139 mmol), tris(dibenzylideneacetone)dipalladium (848 mg, 0.926 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (864 mg, 1.85 mmol). The mixture was stirred under argon protection and reacted at 100°C for 16 hours. The mixture was cooled and filtered by suction. The filtrate was washed with dichloromethane (100 mL), and the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-119. LC-MS(ESI)[M+H] + 251.2.

[0317] Reference Example 120: Preparation of Intermediate I-120 [ka]

[0318] Intermediate I-119 (300 mg, 1.20 mmol) was dissolved in anhydrous tetrahydrofuran (30.0 mL), N-bromosuccinimide (214 mg, 1.20 mmol) was added, and the mixture was stirred under nitrogen protection and reacted at room temperature for 16 hours. The reaction solution was concentrated, separated and purified by silica gel chromatography to obtain intermediate I-120.

[0319] Reference Example 121: Preparation of Intermediate I-121 [ka]

[0320] Intermediate I-120 (220 mg, 0.668 mmol) was dissolved in anhydrous dimethyl sulfoxide (10.0 mL), and potassium fluoride (116 mg, 2.00 mmol) was added. The reaction system was protected with argon, stirred, and reacted at 150°C for 3 days. The mixture was cooled to room temperature, filtered, and separated and purified by preparative high-performance liquid phase (under formic acid conditions) to obtain intermediate I-121. LC-MS(ESI)[M+H] + 255.2.

[0321] Reference Example 122: Preparation of Intermediate I-122 [ka]

[0322] At room temperature, intermediate I-121 (35 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the sequential addition of reagent 1 (39 mg), 1-hydroxybenzotriazole (38 mg, 0.28 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg, 0.28 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol). The reaction mixture was stirred and allowed to react at room temperature for 16 hours. The mixture was diluted with water (20 mL) and extracted using ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-122. LC-MS(ESI)[M+H] + 515.0.

[0323] Reference Example 123: Preparation of Intermediate I-123 [ka]

[0324] At room temperature, intermediate I-122 (30 mg, 0.058 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodoxybenzoic acid (81 mg, 0.29 mmol) was added; after the addition was complete, the reaction mixture was stirred and reacted at 80°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3); the organic phases were combined, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I-123. The crude product was used directly in the next reaction without further purification.

[0325] Reference Example 124: Preparation of Intermediate I-124 [ka]

[0326] At 25°C, 4-bromophthalic anhydride (20.0 g, 88.1 mmol) was dissolved in glacial acetic acid (200 mL), and the mixture was heated to 120°C and stirred for 1 hour. After cooling to room temperature, hydrazine hydrate (4.85 g, 96.9 mmol) was added dropwise to produce a large amount of white solid, and the mixture was heated to 120°C and reacted for 1 hour. The mixture was cooled to room temperature, filtered, and the filtered cake was rinsed with water (200 mL) and ethyl acetate (200 mL), respectively. The filtered cake was collected and dried to obtain intermediate I-124. LC-MS(ESI)[M+H] + 243.0.

[0327] Reference Example 125: Preparation of Intermediate I-125 [ka]

[0328] At 25°C, I-124 (16.2 g, 67.2 mmol) was dissolved in phosphorus oxychloride (100 mL), and the mixture was heated to 100°C and reacted for 3 hours. After cooling, the mixture was dehydrated to obtain the crude product. The crude product was dissolved in ethyl acetate (200 mL), added to water (200 mL), and a white solid precipitated. A filtration cake was obtained by filtration, rinsed with ethyl acetate (200 mL), and dried. The organic phase was separated from the filtrate, washed with water (100 mL) and saturated physiological saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtration cake and the organic phase were combined, and the resulting residue was concentrated to obtain intermediate I-125. LC-MS(ESI)[M+H] + 277.0.

[0329] Reference Example 126: Preparation of Intermediate I-126 [ka]

[0330] At 25°C, I-125 (8.00 g, 28.8 mmol) was dissolved in N,N-dimethylacetamide (100 mL), followed by the addition of potassium fluoride (8.36 g, 143.9 mmol) and 18-crown-6 (3.04 g, 11.5 mmol). The mixture was heated to 120°C and reacted for 16 hours. After cooling, water (200 mL) was added. The reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain intermediate I-126. LC-MS(ESI)[M+H] + 247.0.

[0331] Reference Example 127: Preparation of Intermediate I-127 [ka]

[0332] I-126 (1.50 g, 6.12 mmol) was dissolved in dimethyl sulfoxide (25 mL) and water (5 mL) at 25°C, and the mixture was heated to 100°C and reacted for 5 hours. After cooling, water (200 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-127. LC-MS(ESI)[M+H] + 245.0.

[0333] Reference Example 128: Preparation of Intermediate I-128 [ka]

[0334] At 25°C, N-tert-butoxycarbonylpiperazine (1.50 g, 8.03 mmol), tris(dibenzylideneacetone)dipalladium (494.49 mg, 0.54 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (666.28 mg, 1.07 mmol), and sodium tert-butoxide (1.29 g, 13.38 mmol) were sequentially added to a solution of I-127 (1.30 g, 5.35 mmol) in N,N-dimethylacetamide (20 mL). The mixture was heated to 85°C and reacted for 2 hours. After cooling, water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-128. LC-MS(ESI)[M+H] + 349.2.

[0335] Reference Example 129: Preparation of Intermediate I-129 [ka]

[0336] At 25°C, I-128 (330 mg, 0.95 mmol) was dissolved in tetrahydrofuran (10 mL); 3-bromo-2,6-piperidinedione (364 mg, 1.89 mmol), sodium hydride (75.8 mg, 1.89 mmol, 60%), and potassium iodide (314 mg, 1.89 mmol) were added sequentially, and the mixture was heated to 60°C and reacted for 3 hours. After cooling, saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-129. LC-MS(ESI)[M+H] + 460.2.

[0337] Reference Example 130: Preparation of Intermediate I-130 [ka]

[0338] At 25°C, a solution of I-129 (220 mg, 0.48 mmol) in dichloromethane (10 mL) was mixed with trifluoroacetic acid (5 mL), followed by stirring for 1 hour. The reaction solution was concentrated under reduced pressure to obtain intermediate I-130. LC-MS(ESI)[M+H] + 360.2.

[0339] Reference Example 131: Preparation of Intermediate I-131 [ka]

[0340] Intermediate I-4 (22.0 g, 134 mmol) was dissolved in anhydrous DMSO (500 mL), and then 1-tert-butoxycarbonylpiperazine (37.4 g, 201 mmol) and diisopropylethylamine (52.0 g, 402 mmol) were added sequentially. The reaction system was heated to 140 °C under argon protection and stirred for 24 hours. The mixture was cooled to room temperature and then poured into water (1000 mL), where a large amount of solid precipitated. The mixture was then filtered by suction, the filtered cake was collected, and purified by beating with ethyl acetate (300 mL) for 16 hours. The filtered cake was then dried by suction filtration to obtain intermediate compound I-131. LC-MS(ESI)[M+H] + 331.1.

[0341] Reference Example 132: Preparation of Intermediate I-132 [ka]

[0342] I-131 (5.00 g, 15.15 mmol) and potassium carbonate (4.18 g, 30.30 mmol) were dissolved in N,N-dimethylformamide (300 mL), and benzyltrimethylammonium tribromide (11.78 g, 30.30 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 48 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted using ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated physiological saline (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was separated and purified by silica gel chromatography to obtain intermediate I-132. LCMS(ESI)[M+H] + 409.2.

[0343] Reference Example 133: Preparation of Intermediate I-133 [ka]

[0344] At 0°C, I-132 (600 mg, 1.47 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (294 mg, 7.35 mmol, 60%) was added, and the mixture was stirred at 0°C for 30 minutes. Then, 3-bromo-2,6-piperidinedione (422 mg, 2.20 mmol) and potassium iodide (200 mg) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated physiological saline (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was separated and purified by silica gel chromatography to obtain intermediate I-133. LCMS(ESI)[M+H] + 520.2.

[0345] Reference Example 134: Preparation of Intermediate I-134 [ka]

[0346] I-134 (134 mg, 0.26 mmol), potassium cyclopropylfluoroborate (114 mg, 0.78 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (19.0 mg, 0.026 mmol), and potassium carbonate (106.6 mg, 0.78 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL), and the reaction solution was microwaved at 100°C for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated physiological saline (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was separated and purified by silica gel chromatography to obtain intermediate I-134. LCMS(ESI)[M+H] + 482.2.

[0347] Reference Example 135: Preparation of Intermediate I-135 [ka]

[0348] At room temperature, I-134 (80.00 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The organic solvent was removed by vacuum concentration to obtain intermediate compound I-135, which was used directly in the next reaction without purification. LCMS(ESI)[M+H] + 382.2.

[0349] Reference Example 136: Preparation of Intermediate I-136 [ka]

[0350] At room temperature, I-132 (1.00 g, 2.44 mmol) was dissolved in N,N-dimethylacetamide (15 mL), cuprous cyanide (656 mg, 7.33 mmol) was added, and the reaction was carried out in a microwave at 140 °C for 16 hours. The reaction solution was filtered, the filtration cake was rinsed with ethyl acetate (100 mL), and the filtrate was collected. The filtrate was washed with water (100 mL) and saturated physiological saline (100 mL), respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain intermediate I-136. LC-MS(ESI)[M+H] + 356.2.

[0351] Reference Example 137: Preparation of Intermediate I-137 [ka]

[0352] At room temperature, I-136 (550 mg, 1.55 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the sequential addition of sodium hydride (124 mg, 3.10 mmol, 60%), potassium iodide (514 mg, 3.10 mmol), and 3-bromo-2,6-piperidinedione (594 mg, 3.10 mmol), and the mixture was stirred at 60°C for 3 hours. Saturated ammonium chloride aqueous solution (50 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain intermediate I-137. LC-MS(ESI)[M+H] + 467.2.

[0353] Reference Example 138: Preparation of Intermediate I-138 [ka]

[0354] At room temperature, I-137 (200 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (5 mL), and the mixture was stirred for 1 hour. The mixture was directly concentrated under reduced pressure to obtain intermediate I-138, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 367.2.

[0355] Reference Example 139: Preparation of Intermediate I-139 [ka]

[0356] At room temperature, 4-fluorophthalic anhydride (4.00 g, 24.1 mmol) was dissolved in ethanol (10 mL), sulfuric acid (2 mL) was added, and the reaction mixture was stirred at 100 °C for 16 hours. The reaction solution was diluted with water (10 mL), the pH was adjusted to over 7 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-139. LCMS(ESI)[M+H] + 241.2.

[0357] Reference Example 140: Preparation of Intermediate I-140 [ka]

[0358] At 0°C, I-139 (3.50 g, 14.6 mmol) and cesium fluoride (110.65 mg, 0.73 mmol) were added to ethylene glycol dimethyl ether (50 mL). At 0°C, (trifluoromethyl)trimethylsilane (2.48 g, 17.5 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated physiological saline (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-140. LCMS(ESI)[M+H] + 265.0.

[0359] Reference Example 141: Preparation of Intermediate I-141 [ka]

[0360] At room temperature, I-140 (2.00 g, 7.57 mmol) was dissolved in ethanol (20 mL), hydrazine hydrate (758 mg, 15.1 mmol) was added, and the mixture was stirred at 80°C for 5 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated physiological saline (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain the intermediate I-140. LCMS(ESI)[M+H] + 233.0.

[0361] Reference Example 142: Preparation of Intermediate I-142 [ka]

[0362] At room temperature, I-141 (410 mg, 1.77 mmol), 1-tert-butoxycarbonylpiperazine (493 mg, 2.64 mmol), and N,N-diisopropylethylamine (460 mg, 3.54 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at 140 °C for 16 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated physiological saline (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-142. LCMS(ESI)[M+H] + 399.2.

[0363] Reference Example 143: Preparation of Intermediate I-143 [ka]

[0364] At 0°C, I-142 (444 mg, 1.11 mmol) was dissolved in N,N-dimethylformamide (30 mL), sodium hydride (222 mg, 5.55 mmol, 60%) was added, and the mixture was stirred at 0°C for 30 minutes. Then, 3-bromo-2,6-piperidinedione (320 mg, 1.66 mmol) and potassium iodide (100 mg) were added, and the reaction mixture was stirred at 70°C for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated physiological saline (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-143. LCMS(ESI)[M+H] + 510.2.

[0365] Reference Example 144: Preparation of Intermediate I-144 [ka]

[0366] At room temperature, I-143 (234 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent and obtain crude product I-144. The crude product was used directly in the next reaction without purification. LCMS(ESI)[M+H] + 410.2.

[0367] Preparation of the embodiment: Embodiment 1: Preparation of Compound 1 [ka]

[0368] Intermediate I-11 (19 mg), Reagent 1 (19 mg), and N,N-diisopropylethylamine (22.0 mg, 0.17 mmol) were dissolved in dichloromethane (4.00 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.051 mmol) was added. The reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a residue, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 1. LC-MS(ESI)[M+H] + m / z = 819.4. 1H NMR(400 MHz,DMSO-d6)δ 10.99(s,1H),8.24(s,1H),8.04(d,J=9.0 Hz,1H),7.90(d,J=8.7 Hz,1H),7.74(d,J=8.6 Hz,2H),7.54-7.43(m,2H),7.30-7.20(m,2H),7.04-6.90(m,3H),5.75(dd,J=12.1,5.4 Hz,1H),4.32(s,1H),4.05(d,J=9.2 Hz,1H),3.86(d,J=12.5 Hz,2H),3.42(t,J=5.0 Hz,4H),2.99-2.86(m,1H),2.80(t,J=12.0 Hz,2H),2.65-2.52(m,6H),2.22(d,J=6.7 Hz,2H),2.13-2.03(m,1H),1.84-1.75(m,3H),1.25-1.20(m,8H),1.13(s,6H).

[0369] Embodiment 2: Preparation of Compound 2 [ka]

[0370] At room temperature, intermediate I-15 (100 mg, 0.201 mmol) was dissolved in a mixed solvent of dichloromethane (4.00 mL) and methanol (1.00 mL), followed by the addition of intermediate I-7 (50.0 mg), sodium acetate (60.0 mg, 0.735 mmol), and sodium triacetoxyborohydride (93.0 mg, 0.441 mmol). After the additions were complete, the reaction solution was stirred overnight at room temperature. The solution was diluted with dichloromethane (10.0 mL) and saturated sodium bicarbonate solution (10.0 mL) was added; the organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL x 2); the organic phases were combined, washed with saturated physiological saline (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 2. LC-MS(ESI)[M+H] + 821.4. 1H NMR(400 MHz,CDCl3)δ 8.70(s,2H),8.25(d,J=9.0 Hz,1H),8.04(s,1H),7.97(s,1H),7.57(d,J=8.7 Hz,1H),7.38-7.28(m,2H),6.96(d,J=2.3 Hz,1H),6.89(s,1H),6.80(dd,J=8.8,2.4 Hz,1H),5.92(d,J=8.1 Hz,1H),5.82(s,1H),4.87(d,J=11.9 Hz,2H),4.13(d,J=7.9 Hz,1H),4.04(s,1H),3.51-3.34(m,4H),2.95(dd,J=27.0,16.0 Hz,3H),2.78(d,J=13.2 Hz,2H),2.61(s,4H),2.29(d,J=6.9 Hz,3H),1.92(d,J=11.3 Hz,4H),1.25(s,6H),1.21(s,6H).

[0371] Embodiment 3: Preparation of Compound 3 [ka]

[0372] Intermediate I-20 (90 mg, 0.170 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (10 mL / 10 mL), and intermediate I-7 (58 mg, 0.170 mmol) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (108 mg, 0.510 mmol) was added little by little, the system was protected with argon, and stirred at room temperature for 3 hours to allow the reaction to proceed. After concentration, the mixture was diluted with water (20 mL) and extracted using dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 3. LC-MS(ESI)[M+H] + 853.3. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.25(s,1H),8.11(d,J=8.7 Hz,1H),8.05(d,J=9.0 Hz,1H),7.75(d,J=8.8 Hz,2H),7.54-7.47(m,2H),7.40(d,J=2.4 Hz,1H),7.32-7.23(m,2H),6.96(d,J=9.0 Hz,2H),5.75(dd,J=12.0,5.3 Hz,1H),4.40(s,1H),4.08(d,J=9.1 Hz,1H),3.87(d,J=12.5 Hz,2H),3.42(d,J=4.4 Hz,6H),2.97-2.86(m,1H),2.80(t,J=11.8 Hz,2H),2.64-2.58(m,1H),2.53(d,J=4.7 Hz,3H),2.22(d,J=6.5 Hz,2H),2.14-2.04(m,1H),1.82(d,J=10.3 Hz,3H),1.23(s,6H),1.19(s,2H),1.14(s,6H).

[0373] Embodiment 4: Preparation of Compound 4 [ka]

[0374] Intermediate I-24 (100 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), followed by the sequential addition of intermediate I-7 (68 mg) and sodium acetate (49 mg, 0.60 mmol). The reaction mixture was stirred and allowed to react at room temperature for 30 minutes. Then sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. The mixture was diluted with water (10 mL), and the mixture was subjected to layering. The organic phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 4. LC-MS(ESI)[M+H] + 820.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.62(d,J=2.4 Hz,1H),8.24(s,1H),8.04(d,J=9.0 Hz,1H),7.96-7.88(m,2H),7.58(d,J=9.3 Hz,1H),7.50(dd,J=9.1,2.2 Hz,1H),7.25(d,J=2.2 Hz,1H),7.21(d,J=2.4 Hz,1H),7.01(dd,J=8.8,2.4 Hz,1H),6.86(d,J=9.2 Hz,1H),5.75(dd,J=11.9,5.3 Hz,1H),4.42(d,J=13.1 Hz,2H),4.30(s,1H),4.05(d,J=9.2 Hz,1H),3.42(s,4H),2.92(t,J=12.5 Hz,3H),2.65-2.51(m,6H),2.21(d,J=7.0 Hz,2H),2.13-2.04(m,1H),1.95-1.77(m,3H),1.22(s,6H),1.12(s,6H),1.08(s,2H).

[0375] Embodiment 5: Preparation of Compound 5 [ka]

[0376] Intermediate I-28 (110 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), followed by the sequential addition of intermediate I-7 (74 mg) and sodium acetate (53 mg, 0.65 mmol). The reaction mixture was stirred and allowed to react at room temperature for 30 minutes. Then sodium triacetoxyborohydride (137 mg, 0.65 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. The mixture was diluted with water (10 mL), and the mixture was subjected to layering. The organic phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 5. LC-MS(ESI)[M+H] + 837.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.25(s,1H),8.04(d,J=9.0 Hz,1H),7.91(d,J=8.7 Hz,1H),7.71-7.59(m,3H),7.50(d,J=9.7 Hz,1H),7.28-7.18(m,2H),7.09(t,J=8.9 Hz,1H),7.01(dd,J=8.8,2.3 Hz,1H),5.75(dd,J=12.0,5.2 Hz,1H),4.32(s,1H),4.06(d,J=9.3 Hz,1H),3.58-3.43(m,8H),3.00-2.85(m,2H),2.76(t,J=11.1 Hz,2H),2.69-2.58(m,2H),2.26(d,J=6.7 Hz,2H),2.08(d,J=4.8 Hz,1H),1.90-1.71(m,4H),1.30(d,J=10.3 Hz,2H),1.22(s,6H),1.13(s,6H).

[0377] Embodiment 6: Preparation of Compound 6 [ka]

[0378] Intermediate I-33 (50 mg, 0.097 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), and intermediate I-7 (33.1 mg, 0.097 mmol) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (61.7 mg, 0.291 mmol) was added little by little, the system was protected with argon and stirred at room temperature for 3 hours to allow the reaction to proceed. The mixture was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by silica gel chromatography to obtain compound 6. LC-MS(ESI)[M+H] + 838.2. 1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.25(s,1H),8.05(d,J=9.0 Hz,1H),7.97-7.86(m,2H),7.50(dd,J=9.1,2.1 Hz,1H),7.33(t,J=7.7 Hz,1H),7.24(dd,J=10.6,2.2 Hz,2H),7.02(dd,J=8.8,2.4 Hz,1H),6.78(dd,J=8.7,2.3 Hz,1H),5.75(dd,J=12.0,5.4 Hz,1H),4.31(d,J=12.7 Hz,3H),3.94(d,J=8.4 Hz,1H),3.46(s,5H),2.93(ddd,J=18.3,16.4,8.7 Hz,3H),2.68-2.54(m,3H),2.21(d,J=7.0 Hz,2H),2.13-2.06(m,1H),1.94-1.76(m,3H),1.24(t,J=13.1 Hz,2H),1.19(s,6H),1.12(s,6H),1.10-1.02(m,2H).

[0379] Embodiment 7: Preparation of Compound 7 [ka]

[0380] Intermediate I-37 (60 mg, 0.127 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), and intermediate I-7 (43.3 mg) was added sequentially. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (80.7 mg, 0.381 mmol) was added little by little, the system was protected with argon and stirred at room temperature for 3 hours to allow the reaction to proceed. The mixture was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was purified by silica gel chromatography to obtain target compound 7. LC-MS(ESI)[M+H] + 799.2. 1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.25(s,1H),8.05(d,J=9.0 Hz,1H),7.72(dd,J=16.6,8.7 Hz,3H),7.53-7.46(m,2H),7.25(d,J=1.9 Hz,1H),6.95(dd,J=11.3,5.5 Hz,3H),6.82(dd,J=8.6,2.4 Hz,1H),5.75(dd,J=12.0,5.3 Hz,1H),4.24(s,1H),4.04(d,J=9.1 Hz,1H),3.86(d,J=12.5 Hz,2H),3.49(d,J=31.4 Hz,4H),2.96-2.75(m,3H),2.66-2.53(m,4H),2.45(s,3H),2.22(d,J=6.5 Hz,2H),2.12-1.96(m,2H),1.82(d,J=10.5 Hz,3H),1.27(d,J=29.8 Hz,3H),1.22(s,6H),1.13(s,6H).

[0381] Embodiment 8: Preparation of Compound 8 [ka]

[0382] At room temperature, intermediates I-41 (100 mg, 0.202 mmol), I-7 (68.6 mg, 0.202 mmol), and sodium acetate (82.7 mg, 1.01 mmol) were dissolved in dichloromethane (5 mL) and methanol (1 mL). Under argon protection and stirring conditions, sodium triacetoxyborohydride (128 mg, 0.605 mmol) was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with dichloromethane (20 mL x 3). The organic phases were combined and concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 8 (containing monomolecule formate). LC-MS(ESI)[M+H] + 821.2. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.46(s,1H),8.27-8.20(m,2H),8.04(d,J=9.0 Hz,1H),7.91(d,J=8.8 Hz,1H),7.82(d,J=9.6 Hz,1H),7.50(d,J=7.2 Hz,1H),7.37(d,J=9.7 Hz,1H),7.25(d,J=2.2 Hz,2H),7.04(dd,J=8.8,2.3 Hz,1H),5.75(dd,J=12.0,5.2 Hz,1H),4.57-4.43(m,3H),4.01(d,J=9.1 Hz,1H),3.43(s,4H),3.05(t,J=12.0 Hz,3H),2.97-2.86(m,1H),2.69-2.52(m,6H),2.23(d,J=7.0 Hz,2H),2.13-1.92(m,3H),1.86(d,J=12.1 Hz,2H),1.22(s,6H),1.14(s,6H).

[0383] Embodiment 9: Preparation of Compound 9 [ka]

[0384] Intermediate I-45 (50 mg, 0.101 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), and intermediate I-7 (34.5 mg) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (64 mg, 0.303 mmol) was added little by little, the system was protected with argon and stirred at room temperature for 3 hours to allow the reaction to proceed. After concentration, the mixture was diluted with water (20 mL) and extracted using dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 9. LC-MS(ESI)[M+H] + 820.3. 1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.34(d,J=2.4 Hz,1H),8.25(s,1H),8.07(dd,J=17.5,9.0 Hz,2H),7.90(d,J=8.7 Hz,1H),7.84(d,J=8.8 Hz,1H),7.54-7.48(m,1H),7.42(dd,J=8.9,2.6 Hz,1H),7.25(d,J=2.2 Hz,2H),7.04(dd,J=8.8,2.3 Hz,1H),5.76(dd,J=11.9,5.3 Hz,1H),4.43(s,1H),3.95(d,J=9.1 Hz,3H),3.44(s,6H),2.97-2.83(m,3H),2.67-2.53(m,4H),2.22(d,J=6.4 Hz,2H),2.13-2.04(m,1H),1.83(d,J=10.2 Hz,3H),1.22(d,J=6.5 Hz,2H),1.20(s,6H),1.13(s,6H).

[0385] Embodiment 10: Preparation of Compound 10 [ka]

[0386] Intermediate I-48 (120 mg) was dissolved in dichloromethane and methanol (5 mL / 5 mL), and intermediate I-7 (82 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (102 mg, 0.481 mmol) was added, and the mixture was stirred with a stirring bar and reacted at room temperature for 16 hours. After concentration, the mixture was diluted with water (20 mL) and extracted using dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 10. LC-MS(ESI)[M+H] + 821.1. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.61(d,J=0.9 Hz,1H),8.34(s,1H),8.25(s,1H),8.04(d,J=9.0 Hz,1H),7.90(d,J=8.7 Hz,1H),7.81(d,J=9.0 Hz,1H),7.53-7.46(m,1H),7.25(d,J=2.5 Hz,2H),7.03(dd,J=8.8,2.4 Hz,1H),5.75(dd,J=12.0,5.3 Hz,1H),4.49(d,J=13.0 Hz,2H),4.43(s,1H),3.96(d,J=9.0 Hz,1H),3.43(s,6H),3.09-2.87(m,4H),2.65-2.52(m,5H),2.22(d,J=7.0 Hz,2H),2.14-2.04(m,1H),1.98-1.79(m,3H),1.19(s,6H),1.13(s,6H).

[0387] Embodiment 11: Preparation of Compound 11 [ka]

[0388] At 25°C, intermediate I-56 (80 mg, 0.162 mmol) was dissolved in dichloromethane (10 mL). Intermediate I-54 (61.2 mg), sodium acetate (13.3 mg, 0.162 mmol), and sodium triacetoxyborohydride (34.3 mg, 0.162 mmol) were added, and the reaction mixture was stirred and allowed to react at room temperature for 3 hours. The reaction system was concentrated, the residue was dissolved in N,N-dimethylformamide (3 mL), filtered, and the filtrate was separated and purified by preparative HPLC (containing formic acid) to obtain compound 11. LC-MS(ESI)[M+H] + 819.5. 1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.26(s,1H),7.91(d,J=8.8 Hz,1H),7.79(d,J=8.9 Hz,1H),7.74(d,J=8.9 Hz,2H),7.62(dd,J=9.0,2.5 Hz,1H),7.49(t,J=6.1 Hz,2H),7.21(d,J=2.4 Hz,1H),7.00(dd,J=8.8,2.4 Hz,1H),6.96(d,J=9.0 Hz,2H),5.76(dd,J=12.0,5.2 Hz,1H),4.32(s,1H),4.05(d,J=9.2 Hz,1H),3.86(d,J=12.9 Hz,2H),3.41(s,4H),2.98-2.86(m,1H),2.80(t,J=11.7 Hz,2H),2.69-2.52(m,6H),2.23(d,J=6.4 Hz,2H),2.14-2.04(m,1H),1.92-1.78(m,3H),1.28-1.18(m,8H),1.13(s,6H).

[0389] Embodiment 12: Preparation of Compound 12 [ka]

[0390] Intermediate I-56 (89.4 mg, 0.181 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (10.0 mL / 2.00 mL), followed by the addition of intermediate I-61 (80.0 mg), anhydrous sodium acetate (74.2 mg, 0.905 mmol), and sodium triacetoxyborohydride (76.7 mg, 0.362 mmol). The reaction system was protected with argon and stirred at room temperature for 2 hours. Dichloromethane (50.0 mL) was used for dilution, and water (20.0 mL x 2) was used for washing. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 12. LC-MS(ESI)[M+H] + 819.4. 1H NMR(400 MHz,DMSO-d6)δ 11.05(s,1H),8.43(s,1H),7.91(dd,J=8.2,6.3 Hz,2H),7.80(t,J=7.9 Hz,1H),7.74(d,J=8.8 Hz,2H),7.57(d,J=7.6 Hz,1H),7.48(d,J=9.2 Hz,1H),7.21(d,J=2.4 Hz,1H),7.02-6.94(m,3H),5.80(dd,J=11.9,5.2 Hz,1H),4.32(s,1H),4.05(d,J=9.1 Hz,1H),3.86(d,J=12.3 Hz,2H),3.08(s,4H),3.01-2.86(m,2H),2.79(t,J=11.7 Hz,3H),2.69-2.54(m,6H),2.27(d,J=6.4 Hz,2H),2.17-2.09(m,1H),1.82(d,J=12.3 Hz,3H),1.22(s,6H),1.13(s,6H).

[0391] Embodiment 13: Preparation of Compound 13 [ka]

[0392] Intermediate I-65 (80.0 mg) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), and intermediate I-7 (58.8 mg) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (109 mg, 0.516 mmol) was added little by little, the system was protected with argon, and stirred at room temperature for 3 hours to allow the reaction to proceed. The mixture was washed with water (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 13. LC-MS(ESI)[M+H] + 791.4. 1H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.25(s,1H),8.01(dd,J=28.8,8.2 Hz,2H),7.85(d,J=8.8 Hz,1H),7.73(d,J=8.6 Hz,2H),7.50(d,J=8.2 Hz,1H),7.37(d,J=1.9 Hz,1H),7.25(s,1H),7.16-7.11(m,1H),6.93(d,J=8.7 Hz,2H),5.75(dd,J=11.7,5.1 Hz,1H),4.53(s,1H),3.89-3.60(m,7H),2.97-2.86(m,1H),2.77(t,J=11.7 Hz,2H),2.66-2.52(m,5H),2.16(dd,J=45.6,7.3 Hz,5H),1.93-1.74(m,5H),1.51(dd,J=19.8,10.1 Hz,4H),1.27-1.10(m,3H).

[0393] Embodiment 14: Preparation of Compound 14 [ka]

[0394] At room temperature, intermediate I-67 (90.0 mg), intermediate I-7 (65.7 mg), and sodium acetate (78.9 mg, 0.962 mmol) were dissolved in dichloromethane (5 mL) and methanol (1 mL). Under argon protection and stirring conditions, sodium triacetoxyborohydride (122 mg, 0.577 mmol) was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with dichloromethane (20 mL x 3). The organic phases were combined and concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 14. LC-MS(ESI)[M+H] + 793.1. 1H NMR(400 MHz,CD3OD)δ 8.72(s,2H),8.22(s,1H),8.15(d,J=9.1 Hz,1H),7.69(d,J=8.8 Hz,1H),7.49(dd,J=9.1,2.4 Hz,1H),7.19(d,J=2.4 Hz,2H),7.03(dd,J=8.8,2.4 Hz,1H),5.79(dd,J=11.8,5.4 Hz,1H),4.50-4.40(m,1H),3.98-3.85(m,1H),3.53-3.46(m,4H),3.00(t,J=11.6 Hz,2H),2.96-2.67(m,4H),2.67-2.57(m,4H),2.32(d,J=6.9 Hz,2H),2.28-2.14(m,4H),2.10-1.88(m,6H),1.71-1.47(m,5H).

[0395] Embodiment 15: Preparation of Compound 15 [ka]

[0396] Intermediate I-71 (40 mg, 0.091 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), and intermediate I-7 (31 mg) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (58 mg, 0.273 mmol) was added little by little, the system was protected with argon, and stirred at room temperature for 3 hours to allow the reaction to proceed. After concentration, the mixture was diluted with water (20 mL) and extracted using dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 15. LC-MS(ESI)[M+H] + 763.2. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.24(s,1H),8.04(d,J=9.0 Hz,1H),7.91(d,J=7.6 Hz,1H),7.86(d,J=8.8 Hz,1H),7.72(d,J=8.6 Hz,2H),7.50(dd,J=9.1,2.1 Hz,1H),7.38(d,J=2.4 Hz,1H),7.26(d,J=2.1 Hz,1H),7.14(dd,J=8.8,2.4 Hz,1H),6.40(d,J=8.7 Hz,2H),5.75(dd,J=12.0,5.3 Hz,1H),4.53(s,1H),4.01(t,J=7.6 Hz,2H),3.80(s,1H),3.61-3.53(m,3H),3.46(s,2H),3.06-2.83(m,3H),2.64(dd,J=12.9,5.4 Hz,3H),2.55(d,J=7.7 Hz,5H),2.15-2.04(m,3H),1.89(d,J=9.1 Hz,2H),1.59-1.43(m,4H).

[0397] Embodiment 16: Preparation of Compound 16 [ka]

[0398] Intermediate I-75 (80.0 mg, 0.167 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (6.00 mL / 2.00 mL), followed by the addition of intermediate I-7 (91.1 mg) and anhydrous sodium acetate (68.5 mg, 0.835 mmol). The reaction system was protected with argon and stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (70.8 mg, 0.334 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 2 hours. Dichloromethane (50.0 mL) was used for dilution, and water (10.0 mL x 2) was used for washing. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 16. LC-MS(ESI)[M+H]+ 805.1. 1 H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.25(s,1H),8.04(d,J=9.0 Hz,1H),7.90(d,J=8.8 Hz,1H),7.74(d,J=8.8 Hz,2H),7.51(dd,J=9.2,2.2 Hz,1H),7.39(d,J=9.2 Hz,1H),7.26(d,J=2.2 Hz,1H),7.21(d,J=2.4 Hz,1H),7.00(dd,J=8.8,2.4 Hz,1H),6.55(d,J=8.9 Hz,2H),5.75(dd,J=12.1,5.5 Hz,1H),4.32(s,1H),4.05(d,J=9.1 Hz,1H),3.47-3.43(m,4H),3.06(dd,J=9.6,7.0 Hz,2H),2.99-2.83(m,2H),2.67-2.54(m,6H),2.42(d,J=5.0 Hz,2H),2.18-2.00(m,3H),1.75(dd,J=12.1,8.0 Hz,2H),1.22(s,6H),1.13(s,6H).

[0399] Embodiment 17: Preparation of Compound 17 [ka]

[0400] Intermediate I-77 (190 mg) was dissolved in a mixed solvent of dichloromethane / methanol (10.0 mL / 3.00 mL), followed by the addition of intermediate I-56 (241 mg, 0.487 mmol) and anhydrous sodium acetate (167 mg, 2.03 mmol). The reaction system was protected with argon and stirred at room temperature for 2 hours. Dichloromethane (50.0 mL) was used for dilution, and water (10.0 mL x 2) was used for washing. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 17. LC-MS(ESI)[M+H] + 831.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.19(s,1H),8.00(d,J=8.9 Hz,1H),7.90(d,J=8.8 Hz,1H),7.71(d,J=8.9 Hz,2H),7.48(d,J=9.3 Hz,1H),7.20(d,J=2.4 Hz,1H),7.13(d,J=7.5 Hz,1H),7.00(dd,J=8.8,2.4 Hz,1H),6.93(d,J=9.0 Hz,2H),6.88(s,1H),5.74(dd,J=11.9,5.2 Hz,1H),4.55(s,1H),4.31(s,1H),4.04(d,J=9.2 Hz,1H),3.81(s,2H),3.60(s,1H),3.45-3.41(m,1H),3.05-2.82(m,3H),2.81-2.52(m,5H),2.35(dd,J=10.4,4.4 Hz,2H),2.13-2.03(m,1H),1.99-1.69(m,5H),1.65-1.38(m,2H),1.21(s,6H),1.12(s,6H).

[0401] Embodiment 18: Preparation of Compound 18 [ka]

[0402] Intermediate I-79 (40.0 mg), intermediate I-56 (42.1 mg, 0.0852 mmol), and sodium acetate (34.9 mg, 0.426 mmol) were mixed in dichloromethane (0.5 mL) and methanol (1.5 mL). The reaction mixture was stirred and reacted at room temperature for 30 minutes, after which sodium triacetoxyborohydride (54.3 mg, 0.256 mmol) was added. The reaction mixture was continuously stirred and reacted at room temperature for 2 hours. The solvent was removed from the mixture under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.5 mL), filtered, and the filtrate was separated and purified by preparative HPLC (containing formic acid) to obtain compound 18. LC-MS(ESI)[M+H] + 833.2. 1H NMR(400 MHz,CDCl3)δ 8.24(d,J=9.0 Hz,1H),8.03(s,1H),8.01(s,1H),7.68(d,J=8.8 Hz,2H),7.56(d,J=8.7 Hz,1H),6.96(d,J=2.4 Hz,1H),6.92(d,J=8.9 Hz,2H),6.84(s,1H),6.81(dd,J=8.7,2.4 Hz,1H),6.11(d,J=8.1 Hz,1H),5.83(dd,J=11.1,5.3 Hz,1H),4.25-4.18(m,1H),4.15(d,J=8.1 Hz,1H),4.04(s,1H),3.86(d,J=12.6 Hz,2H),3.55(d,J=11.8 Hz,1H),3.25(t,J=11.8 Hz,1H),2.97-2.75(m,6H),2.39-2.18(m,5H),1.97-1.88(m,2H),1.86-1.51(m,5H),1.34(d,J=12.2 Hz,3H),1.26(s,6H),1.22(s,6H).

[0403] Embodiment 19: Preparation of Compound 19 [ka]

[0404] Intermediate I-81 (30.0 mg), intermediate I-56 (31.6 mg, 0.0639 mmol), and sodium acetate (26.2 mg, 0.320 mmol) were mixed in dichloromethane (0.5 mL) and methanol (1 mL). The reaction mixture was stirred and reacted at room temperature for 30 minutes, after which sodium triacetoxyborohydride (40.7 mg, 0.192 mmol) was added. The reaction mixture was continuously stirred and reacted at room temperature for 2 hours. The solvent was removed from the mixture under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL), filtered, and the filtrate was separated and purified by preparative HPLC (containing formic acid) to obtain compound 19. LC-MS(ESI)[M+H] + 833.2. 1H NMR(400 MHz,CDCl3)δ 8.24(d,J=9.0 Hz,1H),8.03(s,1H),7.99(s,1H),7.68(d,J=8.6 Hz,2H),7.56(d,J=8.8 Hz,1H),6.96(d,J=2.4 Hz,1H),6.92(d,J=8.7 Hz,2H),6.84(s,1H),6.81(dd,J=8.7,2.4 Hz,1H),6.11(d,J=8.1 Hz,1H),5.83(dd,J=11.1,5.3 Hz,1H),4.25-4.17(m,1H),4.15(d,J=8.1 Hz,1H),4.04(s,1H),3.86(d,J=12.5 Hz,2H),3.55(d,J=11.9 Hz,1H),3.25(t,J=11.9 Hz,1H),2.97-2.75(m,6H),2.39-2.19(m,5H),1.96-1.88(m,2H),1.79-1.59(m,5H),1.34(d,J=12.4 Hz,3H),1.26(s,6H),1.22(s,6H).

[0405] Embodiment 20: Preparation of Compound 20 [ka]

[0406] Intermediate I-83 (150 mg) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), and intermediate I-7 (110 mg) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to react. Sodium triacetoxyborohydride (205 mg, 0.966 mmol) was added little by little, the system was protected with argon and stirred at room temperature for 3 hours to react. The mixture was washed with water (10.0 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography, and then purified by beating with anhydrous acetonitrile (15.0 mL). The filtration was performed by suction filtration, and the filtration cake was dried. Finally, the dried filtration cake was separated and purified by preparative HPLC (containing formic acid) to obtain compound 20. LC-MS(ESI)[M+H] + 791.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.01(s,1H),8.25(s,1H),8.05(d,J=8.9 Hz,1H),7.90(d,J=8.7 Hz,1H),7.74(d,J=8.4 Hz,2H),7.48(dd,J=24.3,8.9 Hz,2H),7.28-7.18(m,2H),7.01(dd,J=8.7,1.9 Hz,1H),6.44(d,J=8.4 Hz,2H),5.75(dd,J=12.0,5.2 Hz,1H),4.32(s,1H),4.03(dd,J=16.4,8.4 Hz,3H),3.61-3.55(m,4H),3.01(s,1H),2.93(dd,J=21.7,9.0 Hz,1H),2.69-2.62(m,3H),2.57(s,5H),2.14-2.05(m,1H),1.23(s,2H),1.21(s,6H),1.13(s,6H).

[0407] Embodiment 21: Preparation of Compound 21 [ka]

[0408] At room temperature, intermediate I-88 (100 mg) was dissolved in a mixed solvent of dichloromethane (8.00 mL) and methanol (2.00 mL), followed by the addition of intermediate I-7 (94.0 mg), sodium acetate (68.0 mg, 0.828 mmol), and sodium triacetoxyborohydride (132 mg, 0.621 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted using dichloromethane (10 mL x 3); the organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 21. LC-MS(ESI)m / z[M+H] + 807.1. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.76(s,2H),8.25(s,1H),8.04(d,J=8.7 Hz,1H),7.90(d,J=8.6 Hz,1H),7.71(d,J=9.2 Hz,1H),7.51(d,J=8.8 Hz,1H),7.24(d,J=19.5 Hz,2H),7.01(d,J=8.6 Hz,1H),5.75(d,J=6.7 Hz,1H),4.29(s,1H),4.04(d,J=9.4 Hz,1H),3.75(dd,J=23.7,16.7 Hz,3H),3.53-3.41(m,7H),2.90(d,J=10.9 Hz,1H),2.65-2.55(m,6H),2.43(s,2H),2.11(s,2H),1.22(s,6H),1.11(s,6H).

[0409] Embodiment 22: Preparation of Compound 22 [ka]

[0410] Intermediate I-93 (100 mg, 0.207 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5 mL / 5 mL), and intermediate I-7 (70.6 mg) was added. The system was protected with argon and stirred at room temperature for 0.5 hours to allow the reaction to proceed. Sodium triacetoxyborohydride (131.6 mg, 0.621 mmol) was added little by little, the system was protected with argon and stirred at room temperature for 3 hours to allow the reaction to proceed. The mixture was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 22. LC-MS(ESI)[M+H]+807.4. 1H NMR(400 MHz,DMSO-d6)δ 10.92(s,1H),8.68(s,2H),8.17(s,1H),7.97(d,J=9.0 Hz,1H),7.81(d,J=8.7 Hz,1H),7.64(d,J=9.2 Hz,1H),7.43(d,J=7.3 Hz,1H),7.20-7.11(m,2H),6.92(dd,J=8.8,2.4 Hz,1H),5.66(dd,J=11.9,5.3 Hz,1H),4.21(s,1H),3.96(d,J=9.2 Hz,1H),3.73-3.56(m,3H),3.47-3.39(m,5H),3.20(dd,J=11.6,7.4 Hz,3H),2.88-2.78(m,1H),2.52(dd,J=24.8,8.2 Hz,5H),2.11-1.85(m,3H),1.65(dq,J=15.9,7.9 Hz,1H),1.13(s,6H),1.03(s,6H).

[0411] Embodiment 23: Preparation of Compound 23 [ka]

[0412] Intermediate I-100 (70 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), followed by the sequential addition of intermediate I-7 (50 mg) and sodium acetate (35 mg, 0.42 mmol). The reaction mixture was stirred and allowed to react at room temperature for 30 minutes. Then sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, the mixture was diluted with water (10 mL), and the organic phase was separated by standing for layering. The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 23. LC-MS(ESI)[M+H] + 821.5. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.76(s,2H),8.24(s,1H),8.04(d,J=9.1 Hz,1H),7.90(d,J=8.7 Hz,1H),7.69(d,J=9.3 Hz,1H),7.50(d,J=9.1 Hz,1H),7.26(s,1H),7.21(d,J=2.4 Hz,1H),7.01(dd,J=8.8,2.4 Hz,1H),5.75(dd,J=12.1,5.0 Hz,1H),4.29(s,1H),4.04(d,J=9.1 Hz,1H),3.83(dd,J=11.2,7.4 Hz,1H),3.71(t,J=8.5 Hz,1H),3.42(s,6H),3.17-3.09(m,1H),2.90(dd,J=21.4,9.1 Hz,1H),2.55(s,5H),2.42(s,2H),2.32(d,J=9.4 Hz,1H),2.10(dd,J=18.7,14.0 Hz,2H),1.71-1.60(m,3H),1.21(s,6H),1.11(s,6H).

[0413] Embodiment 24: Preparation of Compound 24 [ka]

[0414] Intermediate I-104 (55 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), and then intermediate I-7 (34 mg) and sodium acetate (24 mg, 0.29 mmol) were added sequentially. The reaction mixture was stirred and allowed to react at room temperature for 30 minutes. Then sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added. After the addition was complete, the reaction mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, the mixture was diluted with water (10 mL), and layering was performed. The organic phase was extracted with dichloromethane (10 mL x 2), the organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 24. LC-MS(ESI)[M+H]+ 835.1. 1 H NMR(400 MHz, DMSO-d6)δ 11.00(s,1H),8.75(s,2H),8.24(s,1H),8.04(d,J=9.0 Hz,1H),7.90(d,J=8.8 Hz,1H),7.70(d,J=9.2 Hz,1H),7.50(dd,J=9.2,2.3 Hz,1H),7.25(d,J=2.2 Hz,1H),7.22(d,J=2.4 Hz,1H),7.01(dd,J=8.8,2.4 Hz,1H),5.75(dd,J=11.9,5.4 Hz,1H),4.73(d,J=13.2 Hz,2H),4.29(s,1H),4.03(d,J=9.1 Hz,1H),3.40(d,J=4.4 Hz,6H),2.95(dd,J=21.7,8.3 Hz,3H),2.64-2.52(m,4H),2.42-2.36(m,2H),2.13-2.04(m,1H),1.79(d,J=12.5 Hz,2H),1.67(s,1H),1.50-1.39(m,2H),1.21(s,6H),1.11(s,6H),1.07(d,J=10.8 Hz,2H).

[0415] Mishi Form 25: Preparation of Compound 25

change

[0416] Intermediate I-112 (90.0 mg, 0.176 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (10.0 mL / 3.00 mL), followed by the addition of intermediate I-7 (96.1 mg) and anhydrous sodium acetate (72.2 mg, 0.880 mmol). The reaction system was protected with argon and stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (74.6 mg, 0.352 mmol) was added. The reaction system was protected with argon and stirred at room temperature for 16 hours. Dichloromethane (50.0 mL) was used for dilution, and water (20.0 mL x 2) was used for washing. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 25. LC-MS(ESI)[M+H] + 835.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.76(s,2H),8.23(s,1H),8.03(d,J=9.0 Hz,1H),7.90(d,J=8.8 Hz,1H),7.72(d,J=9.2 Hz,1H),7.48(dd,J=9.1,2.3 Hz,1H),7.23(dd,J=7.6,2.3 Hz,2H),7.01(dd,J=8.8,2.4 Hz,1H),5.74(dd,J=12.0,5.5 Hz,1H),4.29(s,1H),4.07-3.96(m,2H),3.90-3.73(m,2H),3.67-3.58(m,1H),3.40(s,4H), 2.97-2.85(m,1H),2.75-2.52(m,2H),2.49-2.42(m,5H),2.25-1.90(m,6H),1.84(d,J=13.7 Hz,1H),1.73-1.57(m,2H),1.22(s,6H),1.11(s,6H).

[0417] Embodiment 26: Preparation of Compound 26 [ka]

[0418] At room temperature, intermediate I-118 (80.0 mg) was dissolved in a mixed solvent of dichloromethane (8.00 mL) and methanol (2.00 mL), followed by the addition of intermediate I-7 (53.2 mg) and sodium triacetoxyborohydride (99.2 mg, 0.468 mmol), and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution (10.0 mL) was added, and the mixture was extracted using dichloromethane (15 mL x 2). The organic phases were combined, washed with saturated physiological saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 26. LC-MS(ESI)[M+H] + 838.1. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.50(s,1H),8.24(s,1H),8.04(d,J=9.0 Hz,1H),7.88(dd,J=19.9,5.3 Hz,2H),7.73(d,J=9.2 Hz,1H),7.53-7.47(m,1H),7.23(dd,J=15.2,2.3 Hz,2H),7.01(dd,J=8.8,2.4 Hz,1H),5.75(dd,J=12.1,5.4 Hz,1H),4.31(s,1H),4.21(d,J=13.1 Hz,2H),4.06(d,J=9.1 Hz,1H),3.42(s,6H),3.03-2.86(m,3H),2.64-2.57(m,1H),2.52(d,J=3.6 Hz,3H),2.22(d,J=6.9 Hz,2H),2.12-2.04(m,1H),1.84(d,J=13.1 Hz,3H),1.22(s,6H),1.17(d,J=15.4 Hz,2H),1.12(s,6H).

[0419] Embodiment 27: Preparation of Compound 27 [ka]

[0420] Intermediate I-123 (25 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), and then intermediate I-7 (17 mg) and sodium acetate (12 mg, 0.15 mmol) were added sequentially. The reaction mixture was stirred and allowed to react at room temperature for 30 minutes. Then sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added, the reaction mixture was stirred, and allowed to react overnight at room temperature. The mixture was diluted with water (10 mL), and the standing layer was performed. The aqueous phase was extracted with dichloromethane (10 mL x 2), the organic phase was combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 27. LC-MS(ESI)[M+H] + 838.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.24(s,1H),8.04(d,J=9.5 Hz,1H),7.90(d,J=8.8 Hz,1H),7.86(d,J=8.9 Hz,1H),7.78(d,J=8.8 Hz,1H),7.60(s,1H),7.53-7.48(m,1H),7.25(s,2H),7.03(d,J=8.7 Hz,1H),5.80-5.69(m,1H),4.47(s,1H),3.93(d,J=9.0 Hz,1H),3.57(s,3H),3.42(s,6H),2.83(s,3H),2.58(s,2H),2.54(s,2H),2.25 (s,2H),2.12-2.05(m,1H),1.84(s,2H),1.28(s,2H),1.20(s,6H),1.14(s,6H).

[0421] Embodiment 28: Preparation of Compound 28A and Compound 28B [ka]

[0422] Compound 1 (5g) was subjected to chiral resolution to obtain compound 28A (Rt=10.206 mins) and compound 28B (Rt=13.352 mins). Chiral cleavage method: Equipment: Shimadzu LC-20 AP HPLC Column: ChiralPak IC, 300×50mm ID, 10μm Mobile phase: A: Methanol (0.1% aqueous ammonia) B: Dichloromethane Dissolution gradient: 70%B Flow rate: 80mL / min Column temperature: Room temperature Detection wavelength: 220nm Cycle time: Approximately 6 minutes Chiral analysis methods: Equipment: Waters UPC 2 Analysis SFC (SFC-H) Column: ChiralCel OJ, 150×4.6mm ID, 3μm Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine) Dissolution gradient: 50%B Flow rate: 2.0mL / min Back pressure: 1500psi Column temperature: 35℃ Detection wavelength: 220nm Compound 28A: Rt=10.206 minutes LC-MS(ESI)[M+H] + m / z = 819.6. 1H NMR(400 MHz, DMSO-d6)δ 10.96(s,1H),8.24(s,1H),8.04(d,J=9.00 Hz,1H),7.90(d,J=8.63 Hz,1H),7.74(d,J=8.76 Hz,2H),7.44-7.55(m,2H),7.24(d,J=1.75 Hz,1H),7.19(d,J=2.38 Hz,1H),6.90-7.03(m,3H),5.76(dd,J=5.19,12.07 Hz,1H),4.31(s,1H),4.06(d,J=9.13 Hz,1H),3.85(d,J=12.26 Hz,2H),3.37-3.47(m,4H),2.85-2.99(m,1H),2.78(t,J=11.69 Hz,2H),2.50-2.65(m,8H),2.20(d,J=6.38 Hz,2H),2.04-2.13(m,1H),1.72-1.85(m,3H),1.22(s,6H),1.12(s,6H). Compound 28B: Rt=13.352 points LC-MS(ESI)[M+H] + m / z = 819.6. 1 H NMR(400 MHz, DMSO-d6)δ 10.91(s,1H),8.24(s,1H),8.04(d,J=9.01 Hz,1H),7.90(d,J=8.75 Hz,1H),7.74(d,J=8.63 Hz,2H),7.43-7.56(m,2H),7.14-7.28(m,2H),6.89-7.04(m,3H),5.70-5.81(m,1H),4.31(s,1H),4.05(d,J=9.13 Hz,1H),3.86(d,J=12.01 Hz,2H),3.37-3.52(m,4H),2.86-2.99(m,1H),2.78(t,J=11.76 Hz,2H),2.50-2.67(m,8H),2.21(d,J=6.00 Hz,2H),2.03-2.13(m,1H),1.72-1.87(m,3H),1.22(s,6H),1.12(s,6H).

[0423] Shishi Form 29: Preparation of Compound 29

change

[0424] At 25°C, a solution of I-130 (260 mg, 0.48 mmol) in N,N-dimethylacetamide (1 mL) and dichloromethane (10 mL) was sequentially mixed with I-56 (262 mg, 0.53 mmol), sodium triacetoxyborohydride (203 mg, 0.96 mmol), and glacial acetic acid (2.88 mg, 0.048 mmol), and the mixture was stirred at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by HPLC to obtain compound 29. LC-MS(ESI)[M+H] + 837.5. 1 H NMR(400 MHz,DMSO-d6)δ 11.06(s,1H),8.09(d,J=9.0 Hz,1H),7.91(d,J=8.7 Hz,1H),7.74(d,J=8.7 Hz,2H),7.62(d,J=9.0 Hz,1H),7.51(d,J=9.2 Hz,1H),7.21(d,J=2.5 Hz,1H),7.14(s,1H),7.05-6.88(m,3H),5.75(dd,J=12.5,5.5 Hz,1H),4.32(s,1H),4.05(d,J=9.1 Hz,1H),3.87(d,J=12.4 Hz,2H),3.57-3.40(m,4H),3.34-3.32(m,8H),2.99-2.87(m,1H),2.80(t,J=12.2 Hz,2H),2.66-2.57(m,1H),2.29-2.03(m,2H),1.88-1.73(m,3H),1.22(s,6H),1.13(s,6H).

[0425] Embodiment 30: Preparation of Compound 30 [ka]

[0426] At room temperature, I-135 (60.0 mg, 0.16 mmol) and I-56 (93.0 mg, 0.19 mmol) were dissolved in dichloromethane / methanol (3 mL / 1 mL), two drops of acetic acid were added dropwise, and the reaction mixture was stirred at room temperature for 0.5 hours. Then, sodium triacetoxyborohydride (66.0 mg, 0.32 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with saturated physiological saline (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by C18 reverse-phase column chromatography to obtain compound 30. LCMS(ESI)[M+H] + 859.6. 1 H NMR(400 MHz,DMSO-d6)δ 10.98(s,1H),8.08-8.06(d,J=8.8 Hz,1H),7.92-7.90(d,J=8.8 Hz,1H),7.75-7.72(d,J=8.8 Hz,2H),7.52-7.44(m,3H),7.21-7.20(d,J=2.4 Hz,1H),7.02-6.95(m,3H),5.57-5.66(d,J=9.6 Hz,1H),4.32(s,1H),4.06-4.04(d,J=8.8 Hz,1H),3.88-3.85(d,J=12.4 Hz,2H),3.46-3.35(m,4H),2.87-2.76(m,3H),2.60-2.52((m,6H),2.47-2.44(m,1H),2.24-2.22(m,2H) ,2.05-2.05(m,1H),1.83-1.81(m,3H),1.21(s,8H),1.12(s,6H),0.96-0.92(m,2H),0.82-0.80(m,2H).

[0427] Embodiment 31: Preparation of Compound 31 [ka]

[0428] At room temperature, I-138 (TFA salt, 200 mg, 0.43 mmol) was dissolved in N,N-dimethylacetamide (1 mL) and dichloromethane (10 mL). Subsequently, I-56 (234 mg, 0.47 mmol), sodium triacetoxyborohydride (182 mg, 0.86 mmol), and glacial acetic acid (2.58 mg, 0.043 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated physiological saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by C18 reversed-phase column chromatography to obtain compound 31. LC-MS(ESI)[M+H] + 844.6. 1 H NMR(400 MHz,DMSO-d6)δ 11.14(s,1H),8.12(d,J=9.0 Hz,1H),7.91(d,J=8.7 Hz,1H),7.74(d,J=8.6 Hz,2H),7.66(d,J=9.2 Hz,1H),7.51(d,J=9.3 Hz,1H),7.21(d,J=2.4 Hz,1H),7.13-6.89(m,4H),5.87(dd,J=12.7,5.3 Hz,1H),4.32(s,1H),4.06(d,J=9.0 Hz,1H),3.88(d,J=12.4 Hz,2H),3.50(s,4H),2.92(ddd,J=17.0,13.5,5.4 Hz,1H),2.80(t,J=12.1 Hz,2H),2.70-2.59(m,1H),2.55(s,8H),2.32-2.11(m,2H),1.83(d,J=12.5 Hz,3H),1.22(s,6H),1.13(s,6H).

[0429] Embodiment 32: Preparation of Compound 32 [ka]

[0430] At room temperature, I-144 (180 mg, 0.44 mmol) and I-56 (217 mg, 0.44 mmol) were dissolved in dichloromethane / methanol (10 mL / 5 mL). The reaction mixture was stirred at room temperature for 0.5 hours, 2 drops of acetic acid were added dropwise, and sodium triacetoxyborohydride (187 mg, 0.88 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (30 mL x 2), the organic phases were combined, washed with saturated physiological saline (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting residue was purified by C18 reversed-phase column chromatography to obtain compound 32. LCMS(ESI)[M+H] + 887.6. 1 H NMR(400 MHz,DMSO-d6)δ 11.11(s,1H),8.19-8.17(d,J=8.8 Hz,1H),7.92-7.90(d,J=8.8 Hz,1H),7.75-7.66(m,3H),7.52-7.49(d,J=9.2 Hz,1H),7.21-7.20(d,J=2.4 Hz,1H),7.02-6.96(m,4H),5.84-5.80(dd,J=12.0,5.2 Hz,1H),4.32(s,1H),4.06-4.04(d,J=9.2 Hz,1H),3.89-3.86(d,J=12.0 Hz,2H),3.45-3.45(m,4H),2.93-2.89(m,1H),2.82-2.76(t,J=12.4 Hz,2H),2.67-2.52(m,6H),2.19-2.17(m,3H),1.84-1.81(m,3H),1.21(s,8H),1.12(s,6H).

[0431] Experimental Example 1: Intracellular Western Assay of Androgen Receptors This assay evaluated the compound performance in VCap cells. Intracellular androgen receptors were assayed in-cell-Western according to the assay procedure described below.

[0432] Vcap cells were seeded in Vcap cell assay medium [phenol red containing DMEM (Gibco catalog number: 11995065); fetal bovine serum FBS (Gibco catalog number: 10099141C)] at a volume of 100 μL / well and a cell density of 50,000 cells / well in a 96-well cell culture plate (Corning 3599) pretreated with poly-D-lysine. The cells were cultured for at least 2 days.

[0433] 1. First, the cells were treated with the compound. The compound was gradient diluted using DMSO and cell culture medium, and the DMSO contained in the cell culture plate was diluted to 0.5%. Polypropylene plates were used according to the following protocol.

[0434] (1) (i) A 200× stock solution plate was prepared in DMSO; (ii) A 10 mM stock solution was diluted 1:4 with DMSO (10 μL stock solution + 40 μL DMSO = 2000 μM) and placed in the second row; (iii) A 1:4 gradient dilution (10 μL Protac + 40 μL DMSO) was performed from the second to the ninth row, with the first row reserved for the 2000 μM reference compound and the tenth row reserved for DMSO. (iv) A total of eight concentrations were present (the final concentrations on the 200× plate were 2000 μM, 400 μM, 80 μM, etc.). (2) (i) A 3× stock solution was prepared in culture medium; (ii) 3 μL of 200× stock solution was transferred to 197 μL of culture medium (from the first to the tenth row using a 12-channel pipette), i.e., the 3× stock solution plate. (iii) The stock solution plate was mixed uniformly. (3) (i) The medium for the Vcap cells was replaced with fresh medium in a volume of 100 μL. (ii) A homogeneously mixed 3× stock solution was transferred to a cell culture plate (50 μL of stock solution was transferred from row 1 to row 10 using a 12-channel pipette). (iii) The cells were cultured for 24 hours.

[0435] 2. The expression level of intracellular androgen receptors after compound treatment was detected, and an assay was performed according to the following method.

[0436] (1)(i) Equivalent volumes of 8% paraformaldehyde were added to the cell culture plate for cell fixation. The fixative in the cell plate was discarded and the cell plate was washed three times with PBS. (ii) Triton solution was prepared (stock solution diluted to 1:1000). The solution in the cell plate was discarded and 200 μL of Triton diluent was added to each well. (iii) 2× blocking solution was prepared (10× blocking stock solution diluted to 1:4). The solution in the cell plate was discarded and 100 μL of 2× blocking solution was added to each well. (iv) Primary antibody solution (androgen receptor rabbit mAb, Cell Signaling Technology catalog number: 5153; 1:1000 dilution) was prepared. The solution in the cell plate was discarded and 100 μL of primary antibody diluent was added to each well and incubated overnight at 4°C. (v) The primary antibody solution was discarded and the cell plate was washed with 1× wash buffer (Wash buffer in this application means washing buffer solution). (vi) A secondary antibody solution (goat anti-rabbit IgG(H+L) secondary antibody, HRP, Thermo catalog number: 31460; 1:5000 dilution) was prepared and 100 μL of the secondary antibody dilution was added to each well and incubated. (vii) The secondary antibody solution in the cell plate was discarded and the cell plate was washed with 1× wash buffer. (viii) A TMB chromogenic solution (BD catalog number: 550534) was prepared and 100 μL of the chromogenic solution was added to each well. (ix) 50 μL of stop solution (BD catalog number: 550534) was added to each well. (x) Absorption values ​​at OD 450 nm and 570 nm were read by EnVision. (2) (i) Normalized analysis was performed on the number of cells in each well. (ii) Discard the solution in the cell plate and wash it three times with washing buffer. (iii) Prepare Janus diluent (1:3 dilution). (iii) Add 50 μL of the diluent to each well for incubation. (iv) Discard the solution in the plate and wash the cell plate with deionized water. (v) Prepare 1 M hydrochloric acid (diluting concentrated hydrochloric acid to 1:24) and treat the cells by adding 200 μL of the hydrochloric acid dilution to each well.(vi) The absorption value at OD595nm was read using Flex Station. (vii) The effect of the test compound on androgen receptor expression was calculated according to the obtained readings.

[0437] The experimental results are shown in Table 1. [Table 1]

[0438] Experimental Example 2: Inhibitory effect of test compound on VCap cell proliferation The tumor cell line Vcap (ATCC catalog number CRL-2876) was cultured in DMEM (Gibco catalog number 11965-092) medium containing 10% FBS (Gibco catalog number 10099-141C). During the experiment, Vcap cells were replaced with DMEM culture medium containing 5% FBS and 0.1 nM R1881 (Sigma catalog number R0908).

[0439] The assay method was as follows:

[0440] Vcap cells were seeded in a 384-well plate (Perkin Elmer catalog no. 6007460) at a cell density of 1200 cells / well and a volume of 20 μL / well; the cells were incubated overnight in a carbon dioxide incubator (Thermo), and then compound solutions prepared at different concentrations were added at a volume of 5 μL / well; the corresponding solvents were prepared as controls; the cells were incubated in the incubator for 6 consecutive days, and then the cell plate and its contents were equilibrated to room temperature; 25 μL of Cell Titer Glor (Promega catalog no. G7573) reagent was added to each well; after vibration and homogenization, the plates were incubated in the dark for 10–30 minutes, and signal values ​​were detected using an Envision microplate reader (PerkinElmer).

[0441] Method for processing experimental data: The inhibition rate of the compound-treated wells is calculated through the solvent control wells on the plate, and the inhibition rate data corresponding to different concentrations is fitted using a GraphPad prism, and IC 50 The values ​​were calculated using the four-parameter nonlinear logistic equation. The experimental results are shown in Table 2. [Table 2]

[0442] Experimental Example 3: In vivo pharmacokinetic experiment of the compound of the present invention In this experiment, in vivo pharmacokinetics were evaluated in mice via intravenous injection and oral administration.

[0443] Experimental Method and Conditions: Male CD1 mice aged 6-8 weeks; all animals had free access to food and water; blood was collected from the orbit 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after a single intravenous injection of 1 mg / kg of the test compound (solvent 5% DMSO / 15% Solutol / 80% physiological saline) (in this application, physiological saline means physiological saline solution), or 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after oral gastric administration of 10 mg / kg (solvent 5% DMSO / 10% Solutol / 85% physiological saline), and at least 50 μL of each sample was collected, and heparin sodium was used for anticoagulation; the collected samples were placed on ice, and the plasma was centrifuged within 1 hour for testing. Drug concentrations in plasma were detected by liquid chromatography-tandem mass spectrometry (LC / MS / MS), and pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Embodiment 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 3. [Table 3]

[0444] Experimental data showed that the in vivo pharmacokinetic results of orally administered compounds of the present invention in mice were longer T 1 / 2 , higher in vivo exposure AUC 0-inf This also indicates that it represents oral bioavailability F.

[0445] Example 4: In vivo pharmacokinetic experiment of the compound of the present invention In this experiment, in vivo pharmacokinetics were evaluated in rats via intravenous injection and oral administration.

[0446] Experimental methods and conditions: Male SD rats aged 6-8 weeks; all animals had free access to food and water; blood was collected from the orbit 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours after a single intravenous injection of 1 mg / kg of the test compound (solvent 5% DMSO / 15% Solutol / 80% saline), or 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 48 hours after oral gastric administration of 10 mg / kg (solvent 5% DMSO / 10% Solutol / 85% saline), and at least 50 μL of each sample was collected, and heparin sodium was used for anticoagulation; the collected samples were placed on ice, and the plasma was centrifuged within 1 hour for testing. Drug concentrations in plasma were detected by liquid chromatography-tandem mass spectrometry (LC / MS / MS), and pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Embodiment 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 4. [Table 4]

[0447] Example 5: In vivo pharmacokinetic experiment of the compound of the present invention In this experiment, in vivo pharmacokinetic evaluations were performed in dogs via intravenous injection and oral administration.

[0448] Experimental methods and conditions: Male Beijing Marshall beagles, 12-18 months old; beagles were offered for administration 30 minutes after feeding; blood was collected from the orbit 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours after a single intravenous injection of 1 mg / kg of the test compound (solvent 5% DMSO / 10% Solutol / 85% saline), or 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours after oral gastric administration of 10 mg / kg (solvent 5% DMSO / 10% Solutol / 85% saline), and at least 50 μL of each sample was collected, and heparin sodium was used for anticoagulation; the collected samples were placed on ice, and the plasma was centrifuged within 1 hour for testing. Drug concentrations in plasma were detected by liquid chromatography-tandem mass spectrometry (LC / MS / MS), and pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Embodiment 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 5. [Table 5]

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ These are H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. Ring B is selected from phenyl and 5-6 membered heteroaryl compounds, and the phenyl or 5-6 membered heteroaryl compound is optionally substituted with 1, 2, or 3 R atoms. Ring C is C ４～６ Selected from cycloalkyl groups, R ２ is selected from H and C １～６ alkyl, and said C １～６ alkyl is optionally substituted with one, two or three Rs Ring A is selected from 6- to 12-membered aryls and 5- to 12-membered heteroaryls. R Ａ H, NO ２ , halogen, NH ２ , CN, C １～６ Alkyl and C １～６ Selected from alkoxy, the C １－６ Alkyl or C １－６ The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R Ｄ H, CN, halogen, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ Selected from cycloalkyl and 3-6 member heterocycloalkyl, the C １～６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl or 3-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms. R is independent of H, F, Cl, Br, I, OH, NH ２ and C １～６ Each is selected from alkyl groups, and the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R' atoms. Each L １ , L ２ and L ３ These are independently single bonds: O, S, NH, C(=O), S(=O), S(=O) ２ , C １～６ Alkyl, -C １～６ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～１０ Selected from cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-9 member heteroaryl, respectively, the C １～６ Alkyl, -C １～６ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～１０ Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl has 1, 2, or 3 R Ｌ It is arbitrarily replaced with, R Ｌ These are independently H, halogen, OH, and NH. ２ , CN, 【Chemistry 2】 , C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio and C １～６ Each is selected from alkylaminos, and the C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio or C １～６ Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Transformation 3】 ,CH ３ ,CH ２ F, CHF ２ and CF ３ Each is selected from the following: n is 0, 1, 2, 3, or 4. m is 0, 1, 2, 3, or 4. q is 1, 2, 3, or 4. The aforementioned 3-10 member heterocycloalkyl, 3-6 member heterocycloalkyl, 5-12 member heteroaryl, 5-6 member heteroaryl, or 5-9 member heteroaryl are O, NH, S, C(=O), C(=O)O, S(=O), S(=O) ２ (and comprising one, two, or three heteroatoms or heteroatomic groups independently selected from N) Compounds represented by , their optical isomers, and pharmacodynamically acceptable salts thereof.

2. Equation (I-A) 【Chemistry 4】 (In the formula, R １ These are H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. Ring B is selected from phenyl and 5-6 membered heteroaryl compounds, and the phenyl or 5-6 membered heteroaryl compound is optionally substituted with 1, 2, or 3 R atoms. Ring C is C ４～６ Selected from cycloalkyl groups, R ２ H and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. Each R ３ and R ４ These are H and NO, independently. ２ , halogen, NH ２ , CN, C １～６ Alkyl and C １～６ Each is selected from the alkoxy, and the C １～６ Alkyl or C １～６ The alkoxy is optionally substituted with 1, 2, or 3 R atoms. Each R Ｄ１ , R Ｄ２ and R Ｄ３ These are independently H, CN, halogen, and C １～６ Alkyl and C １～６ Each is selected from the alkoxy, and the C １～６ Alkyl or C １～６ The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R Ｄ４ is independently selected from H, CN, halogen, C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl and 3-6 member heterocycloalkyl, respectively, wherein said C １～６ alkyl, C ３－６ cycloalkyl or 3-6 member heterocycloalkyl is optionally substituted with 1, 2 or 3 R's, R is independent of H, F, Cl, Br, I, OH, NH ２ and C １～６ Each is selected from alkyl groups, and the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R' atoms. Each L １ , L ２ and L ３ is independently selected from a single bond, O, S, NH, C(=O), S(=O), S(=O) ２ , C １～６ alkyl, -C １～６ alkyl-O-, C ２～３ alkenyl, C ２～３ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 9-membered heteroaryl, respectively, wherein the C １～６ alkyl, -C １～６ alkyl-O-, C ２～３ alkenyl, C ２～３ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or 5- to 9-membered heteroaryl is optionally substituted with 1, 2 or 3 R Ｌ s, R Ｌ These are independently H, halogen, OH, and NH. ２ , CN, 【Transformation 5】 , C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio and C １～６ Each is selected from alkylaminos, and the C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio or C １～６ Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Transformation 6】 ,CH ３ ,CH ２ F, CHF ２ and CF ３ Each is selected from the following: m is 0, 1, 2, 3, or 4. The aforementioned 3-10 member heterocycloalkyl, 3-6 member heterocycloalkyl, 5-6 member heteroaryl, or 5-9 member heteroaryl is O, NH, S, C(=O), C(=O)O, S(=O), S(=O) ２ (and comprising one, two, or three heteroatoms or heteroatomic groups independently selected from N) Compounds represented by , their optical isomers, and pharmacodynamically acceptable salts thereof.

3. Formula (IB) 【Transformation 7】 (In the formula, R １ These are H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. G is H, F, Cl, Br, I and C １～６ Selected from alkyl, the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R atoms. Each R ３ and R ４ These are H and NO, independently. ２ , halogen, NH ２ , CN, C １～６ Alkyl and C １～６ Each is selected from the alkoxy, and the C １～６ Alkyl or C １～６ The alkoxy is optionally substituted with 1, 2, or 3 R atoms. Each X １ , X ２ , X ３ and X ４ These are independently selected from C(R) and N, respectively. Each R Ｄ１ , R Ｄ２ and R Ｄ３ These are independently H, CN, halogen, and C １～６ Alkyl and C １～６ Each is selected from the alkoxy, and the C １～６ Alkyl or C １～６ The alkoxy is optionally substituted with 1, 2, or 3 R atoms. R Ｄ４ These are independently H, CN, halogen, and C １～６ Alkyl, C １～６ Alkoxy, C ３～６ Selected from cycloalkyl and 3-6 membered heterocycloalkyl, respectively, C １～６ Alkyl, C ３－６ Cycloalkyl or 3-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms. R is independent of H, F, Cl, Br, I, OH, NH ２ and C １～６ Each is selected from alkyl groups, and the C １～６ The alkyl group is optionally substituted with 1, 2, or 3 R' atoms. Each L １ , L ２ and L ３ These are independently single bonds: O, S, NH, C(=O), S(=O), S(=O) ２ , C １～６ Alkyl, -C １～６ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～１０ Selected from cycloalkyl, 3-10 member heterocycloalkyl, phenyl, and 5-9 member heteroaryl, respectively, the C １～６ Alkyl, -C １～６ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～１０ Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, or 5-9 membered heteroaryl has 1, 2, or 3 R Ｌ It is arbitrarily replaced with, R Ｌ These are independently H, halogen, OH, and NH. ２ , CN, 【Transformation 8】 , C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio and C １～６ Each is selected from alkylaminos, and the C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkyl-C(=O)-, C １～６ Alkoxy, C １～６ Alkylthio or C １～６ Alkylamino is optionally substituted with 1, 2, or 3 R' atoms. R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Chemistry 9】 ,CH ３ ,CH ２ F, CHF ２ and CF ３ Each is selected from the following: The aforementioned 3-10 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-9 member heteroaryl is O, NH, S, C(=O), C(=O)O, S(=O), S(=O) ２ (and comprising one, two, or three heteroatoms or heteroatomic groups independently selected from N) Compounds represented by , their optical isomers, and pharmacodynamically acceptable salts thereof.

4. Equation (I-B-1) or Equation (I-B-2) 【Chemistry 10】 (In the formula, R １ , R ３ , R ４ , R Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , L １ , L ２ , L ３ , X １ , X ２ , X ３ , X ４ (and G is as described in claim 3) Compounds represented by , their optical isomers, and pharmacodynamically acceptable salts thereof.

5. The compound according to claim 1, wherein ring A is selected from phenyl, its optical isomers, and pharmacodynamically acceptable salts thereof.

6. Each R ３ and R ４ However, independently, H, NO ２ , F, Cl, Br, I, NH ２ ,CN,CF ３ A compound according to any one of claims 2 to 4, selected from methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof.

7. R ２ The compound according to claim 1 or 2, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof, selected from H, methyl, and ethyl.

8. The compound according to claim 1 or 2, its optical isomers, and its pharmacodynamically acceptable salts, wherein ring C is selected from cyclobutyl and cyclohexanil.

9. Components 【Chemistry 11】 but, 【Chemistry 12】 A compound according to claim 1 or 2, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof, selected from among.

10. The compound according to claim 1 or 2, optical isomers thereof, and pharmacodynamically acceptable salts thereof, wherein ring B is selected from phenyl, pyridyl, pyridadinyl, pyrimidinyl, and pyrazinyl, and the phenyl, pyridyl, pyridadinyl, pyrimidinyl, or pyrazinyl is optionally substituted with 1, 2, or 3 R atoms.

11. Components 【Chemistry 13】 but, 【Chemistry 14】 【change】 A compound according to claim 1 or 2, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof, selected from among.

12. Each L １ , L ２ and L ３ However, independently, they are single bonds, O, S, NH, C(=O), S(=O), S(=O) ２ , C １～３ Alkyl, -C １～３ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～６ The C is a cycloalkyl, a 4-8 member heterocycloalkyl, a phenyl, and a 5-6 member heteroaryl. １～３ Alkyl, -C １～３ Alkyl-O-,C ２～３ Alkenil, C ２～３ Alkinyl, C ３～６ Cycloalkyl, 4-8 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, with 1, 2, or 3 R Ｌ A compound according to any one of claims 1 to 4, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof, optionally substituted with.

13. R Ｌ However, independently, H, halogen, OH, NH ２ , CN, 【Chemistry 15】 , C １～３ Alkyl, C ３～６ Cycloalkyl, C １～３ Alkyl-C(=O)-, C １～３ Alkoxy, C １～３ Alkylthio and C １～３ Each is selected from alkylaminos, and the C １～３ Alkyl, C ３～６ Cycloalkyl, C １～３ Alkyl-C(=O)-, C １～３ Alkoxy, C １～３ Alkylthio or C １～３ The compound according to claim 12, wherein the alkylamino is optionally substituted with one, two, or three R' groups, its optical isomers, and pharmacodynamically acceptable salts thereof.

14. Each L １ , L ２ and L ３ However, independently, they are single bonds, O, S, NH, C(=O), S(=O), S(=O) ２ ,CH ２ , 【Chemistry 16】 The compound according to claim 12, its optical isomers, and its pharmacodynamically acceptable salts.

15. Components 【Chemistry 17】 but, [Chemistry 18] 【change】 【change】 A compound according to any one of claims 1 to 4, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof, selected from among.

16. R Ｄ４ However, independently, H, CN, F, Cl, Br, I, CF ３ ,CH ３ ,CH ２ CH ３ A compound, optical isomer, and pharmacodynamically acceptable salt thereof, selected from and cyclopropyl, according to any one of claims 2 to 4.

17. A compound of the following formula, its optical isomers, and its pharmacodynamically acceptable salts, 【Chemistry 19】 【change】 A compound, its optical isomers, and a pharmacodynamically acceptable salt thereof, selected from the above.

18. Use of a compound according to any one of claims 1 to 17, an optical isomer thereof, and a pharmacodynamically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of cancer or Kennedy disease.

19. The use according to claim 18, wherein the cancer is selected from prostate cancer and breast cancer.

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