Phthaloxizone compounds and preparation methods and medical uses thereof

Abstract

The present application relates to phthalazinone compounds, preparation methods and medical uses thereof, and specifically to compounds represented by formula (I) and pharmaceutically acceptable salts thereof, as well as the use of the compounds as androgen receptor (AR) degradation agents.

Description

[0001] This application is a divisional application of Chinese patent application No. 202110653817.9, filed on June 11, 2021, entitled “Phthalocyanine compounds, preparation methods and medical uses thereof”. Technical Field

[0002] The present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and application of the compound in degradation of androgen receptor (AR). Background Art

[0003] Prostate cancer (PCa) is one of the most common cancers in the world and the second leading cause of cancer death among adult men worldwide. Prostate cancer has no significant symptoms in the early stages and grows slowly. In the late stages, symptoms such as frequent urination, dysuria, hematuria, and urinary pain will appear, and it may metastasize to other parts of the body. Generally, when patients are diagnosed, the cancer is already in the late stages. In the United States, the incidence of prostate cancer has surpassed lung cancer and has become the number one cancer that endangers men's health. The incidence of prostate cancer in my country will enter a peak period.

[0004] Prostate cancer is an androgen-dependent tumor, androgen can stimulate the growth of prostate cancer cells and disease progression. Endocrine therapy is one of the conventional treatment methods. For example, the standard of treatment for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) / drug castration (such as injection of Noradrena). ADT therapy has a significant effect in the early stage of treatment, but as the disease progresses, the androgen receptor (AR) mutates, and the mutated AR is more sensitive to low levels of androgens, thereby driving the disease to castration-resistant prostate cancer (CRPC). Almost all patients with advanced prostate cancer will eventually progress to CRPC after receiving endocrine therapy. In addition, up to 30% of prostate cancer patients will transform into metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment. At present, patients diagnosed with early focal prostate cancer are usually cured clinically, but patients diagnosed with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) have no cure options in clinical practice.

[0005] Currently approved oral drugs for the treatment of metastatic castration-resistant prostate cancer mainly include abiraterone and enzalutamide. Among them, abiraterone is a new type of androgen biosynthesis inhibitor, which can block the synthesis of androgens in the testicles, adrenal glands or tumor cells. Enzalutamide is an androgen receptor inhibitor that can competitively inhibit the binding of androgens to receptors. When enzalutamide binds to AR, it can also further inhibit the nuclear transport of AR, thereby blocking the interaction between AR and DNA.

[0006] Despite being castration-resistant, CRPC still relies on the AR signaling axis to continue to grow. AR mutations reduce the activity of small molecule antagonists targeting AR, or even convert them into AR agonists, which manifests as drug resistance in the clinic. 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, bringing more benefits.

[0007] The present invention mainly relies on the protein degradation targeted chimera (PROTAC) technology to obtain a class of selective AR degraders (SARD). PROTAC technology mainly relies on the ubiquitin-proteasome system in the cell. This system is the "cleaner" in the cell, and the main function of the ubiquitination system is to ubiquitinate denatured, mutated or harmful proteins in the cell. Ubiquitinated proteins are degraded by the proteasome system inside the cell. The design idea of ​​PROTAC is that one end of the molecule is an AR interaction fragment, and the other end is a ubiquitin-proteasome interaction fragment. Through the middle connection, the two ends are connected to form a chimeric molecule. PROTAC interacts with the target protein (AR) and the proteasome system at the same time, so that the proteasome and AR protein are close to each other in space, thereby causing AR to be ubiquitinated and degraded.

[0008] The small molecule PROTAC technology was reported in 2008. Currently, only Arvinas's small molecule drug ARV-110 (currently with an unknown structure) based on AR degradation is in the first phase of clinical research and development. PROTAC technology is a cutting-edge field. In recent years, a large number of literature reports have shown that PROTAC works by binding to degradation targets and ubiquitination systems at the same time, and its mechanism of action is far more complex than that of traditional small molecule drugs: the mode of action of this type of molecule involves three-body binding kinetics and is affected by the catalyst characteristics of PROTAC itself (as well as potential hook effect problems). Therefore, the molecular design ideas of PROTAC are also completely different from those of small molecules, and there is no obvious regularity. Common pharmaceutical strategies, such as equivalent replacement of effective fragments, are not necessarily applicable in the design of such molecules.

[0009] Currently, there is still a need in the art to develop PROTAC molecules with novel structures for AR degradation. Summary of the invention

[0010] In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0011]

[0012] in:

[0013] R1 is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0014] G is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0015] Ring B is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;

[0016] Ring C is selected from C 4-6 Cycloalkyl;

[0017] R2 is selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0018] Ring A is selected from 6-12 membered aryl and 5-12 membered heteroaryl;

[0019] R A Selected from H, NO2, halogen, NH2, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0020] R D Selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0021] R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R';

[0022] Each L1, L2, and L3 are 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 3-10Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, -C 1-6 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl are optionally substituted with 1, 2 or 3 R L replace;

[0023] R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 The alkylamino group is optionally substituted with 1, 2 or 3 R';

[0024] R' is independently selected from H, halogen, C 1-6 Alkyl, OH, NH2, CH3, CH2F, CHF2 and CF3;

[0025] n is 0, 1, 2, 3 or 4;

[0026] m is 0, 1, 2, 3 or 4;

[0027] q is 1, 2, 3, or 4;

[0028] The above 3-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 5-12 membered heteroaryl, 5-6 membered heteroaryl or 5-9 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2 and N.

[0029] In another aspect of the present invention, the present invention also provides a compound represented by formula (I-X-1) or formula (I-X-2), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0030]

[0031] Among them, ring A, ring B, ring C, R1, R2, R A , RD , G, L1, L2, L3, m, n, q are as defined in the present invention.

[0032] In another aspect of the present invention, the present invention also provides a compound represented by formula (II), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0033]

[0034] in:

[0035] R1 is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0036] G is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0037] Ring B is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;

[0038] Ring C is selected from C 4-6 Cycloalkyl;

[0039] R2 is selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0040] Each R3 and R4 are independently selected from H, NO2, halogen, NH2, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0041] Each R D1 , R D2 , R D3 are independently selected from H, CN, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0042] R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R';

[0043] Each L1, L2, and L3 are 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, 3-10 membered heterocycloalkyl, phenyl and 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, -C 1-6 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl are optionally substituted with 1, 2 or 3 R L replace;

[0044] R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 The alkylamino group is optionally substituted with 1, 2 or 3 R';

[0045] R' is independently selected from H, halogen, C 1-6 Alkyl, OH, NH2, CH3, CH2F, CHF2 and CF3;

[0046] m is 0, 1, 2, 3 or 4;

[0047] The above 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-9 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2 and N.

[0048] In another aspect of the present invention, the present invention also provides a compound represented by formula (II-A-1) or formula (II-A-2), an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0049]

[0050] Among them, ring B, ring C, R1, R2, R3, R4, R D1 , R D2 , R D3 , G, L1, L2, L3, and m are as defined in the present invention.

[0051] In another aspect of the present invention, the present invention also provides a compound represented by formula (III), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0052]

[0053] in:

[0054] R1 is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0055] G is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0056] Each R3 and R4 are independently selected from H, NO2, halogen, NH2, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0057] Each X1, X2, X3, and X4 is independently selected from C(R) and N;

[0058] Each R D1 , R D2 , R D3 are independently selected from H, CN, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0059] R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R';

[0060] Each L1, L2, and L3 are 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-, C2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, -C 1-6 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl are optionally substituted with 1, 2 or 3 R L replace;

[0061] R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 The alkylamino group is optionally substituted with 1, 2 or 3 R';

[0062] R' is independently selected from H, halogen, C 1-6 Alkyl, OH, NH2, CH3, CH2F, CHF2 and CF3;

[0063] The above 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-9 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2 and N.

[0064] In another aspect of the present invention, the present invention also provides a compound represented by formula (III-A-1) or formula (III-A-2), an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0065]

[0066]

[0067] Among them, R1, R3, R4, R D1 , R D2 , R D3, G, L1, L2, L3, X1, X2, X3, and X4 are as defined in the present invention.

[0068] In another aspect of the present invention, the present invention also provides a compound represented by formula (IA), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0069]

[0070] in:

[0071] R1 is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0072] G is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0073] Ring B is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;

[0074] Ring C is selected from C 4-6 Cycloalkyl;

[0075] R2 is selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0076] Each R3 and R4 are independently selected from H, NO2, halogen, NH2, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0077] Each R D1 , R D2 , R D3 are independently selected from H, CN, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0078] R D4 are independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0079] R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R';

[0080] Each L1, L2, and L3 are 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, 3-10 membered heterocycloalkyl, phenyl and 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, -C 1-6 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl are optionally substituted with 1, 2 or 3 R L replace;

[0081] R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 The alkylamino group is optionally substituted with 1, 2 or 3 R';

[0082] R' is independently selected from H, halogen, C 1-6 Alkyl, OH, NH2, CH3, CH2F, CHF2 and CF3;

[0083] m is 0, 1, 2, 3 or 4;

[0084] The above 3-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 5-9 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2 and N.

[0085] In another aspect of the present invention, the present invention also provides a compound represented by formula (IA-1) or formula (IA-2), an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0086]

[0087] Among them, ring B, ring C, R1, R2, R3, R4, R D1 , R D2 , R D3 , R D4 , G, L1, L2, L3, and m are as defined in the present invention.

[0088] In another aspect of the present invention, the present invention also provides a compound represented by formula (IB), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0089]

[0090] in:

[0091] R1 is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0092] G is selected from H, F, Cl, Br, I and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R;

[0093] Each R3 and R4 are independently selected from H, NO2, halogen, NH2, CN, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0094] Each X1, X2, X3, and X4 is independently selected from C(R) and N;

[0095] Each R D1 , R D2 , R D3 are independently selected from H, CN, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C1-6 The alkoxy group is optionally substituted with 1, 2 or 3 R;

[0096] R D4 are independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R;

[0097] R is independently selected from H, F, Cl, Br, I, OH, NH2 and C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R';

[0098] Each L1, L2, and L3 are 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, 3-10 membered heterocycloalkyl, phenyl and 5-9 membered heteroaryl, wherein the C 1-6 Alkyl, -C 1-6 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl are optionally substituted with 1, 2 or 3 R L replace;

[0099] R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 The alkylamino group is optionally substituted with 1, 2 or 3 R';

[0100] R' is independently selected from H, halogen, C 1-6Alkyl, OH, NH2, CH3, CH2F, CHF2 and CF3;

[0101] The above 3-10 membered heterocycloalkyl, 3-6 membered heterocycloalkyl or 5-9 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2 and N.

[0102] In another aspect of the present invention, the present invention also provides a compound represented by formula (IB-1) or formula (IB-2), an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0103]

[0104] Among them, R1, R3, R4, R D1 , R D2 , R D3 , R D4 , L1, L2, L3, X1, X2, X3, X4, and G are as defined above.

[0105] In some embodiments of the present invention, the above-mentioned ring A is selected from phenyl, and other variables are as defined in the present invention.

[0106] In some embodiments of the present invention, each of R3 and R4 is independently selected from H, NO2, F, Cl, Br, I, NH2, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy and ethoxy, and other variables are as defined in the present invention.

[0107] In some embodiments of the present invention, the above R2 is selected from H, methyl and ethyl, and other variables are as defined in the present invention.

[0108] In some embodiments of the present invention, the above ring C is selected from cyclobutyl and cyclohexyl, and other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0110] In some embodiments of the present invention, the above-mentioned ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, wherein the phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl is optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0112] In some embodiments 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, C 1-3 Alkyl, -C 1-3 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, -C 1-3 Alkyl-O-, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R L The other variables are as defined in the present invention.

[0113] In some embodiments of the present invention, the above R L are independently selected from H, halogen, OH, NH2, CN, 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 Alkylamino, wherein 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 alkylamino group is optionally substituted with 1, 2 or 3 R's, and the other variables are as defined herein.

[0114] In some embodiments 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, CH2,

[0115] Other variables are as defined herein.

[0116] In some embodiments of the present invention, the above structural unit Selected from

[0117] Other variables are as defined herein.

[0118] In some embodiments of the present invention, the above R D4 Each of the following is independently selected from H, CN, F, Cl, Br, I, CF3, CH3, CH2CH3 and cyclopropyl, and other variables are as defined in the present invention.

[0119] In another aspect of the present invention, the present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:

[0120]

[0121]

[0122]

[0123] In another aspect of the present invention, the present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:

[0124]

[0125]

[0126]

[0127]

[0128] In still another aspect of the present invention, the present invention also provides use of the aforementioned compound, its optical isomers and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating cancer or Kennedy's disease.

[0129] In some embodiments of the present invention, the above-mentioned cancer is AR-related cancer, such as prostate cancer and breast cancer.

[0130] In another aspect of the present invention, the present invention also provides a method for treating cancer (such as prostate cancer and breast cancer, etc.) or Kennedy's disease, which comprises administering the aforementioned compound, its optical isomers and pharmaceutically acceptable salts thereof to a patient.

[0131] Definition and Description

[0132] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0133] As in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.

[0134] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0135] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as 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, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0136] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0137] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0138] Unless otherwise specified, the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0139] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also called prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one, or for example and They are tautomers.

[0140] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine). The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms that constitute the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be substituted for hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described later may but does not necessarily occur, and the description includes the case where the event or situation occurs and the case where the event or situation does not occur.

[0141] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be substituted for hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described later may but does not necessarily occur, and the description includes the case where the event or situation occurs and the case where the event or situation does not occur.

[0142] When the group bond is marked with a dotted line When, for example, In the example, the dashed line indicates the point of attachment of the group to the rest of the molecule. When, for example, In the example, the dashed line represents a single bond or its absence, which also means Represents a single bond or double bond

[0143] The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.

[0144] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, the group may be optionally substituted with 1 or 2 or 3 R's, and each occurrence of R' has independent options. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0145] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L1 represents a single bond, it means that the structure is actually

[0146] When the substituent is listed without indicating the atom through which it is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0147] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH2O-, in which case -CH2O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form

[0148] It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0149] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0150] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3,

[0151] wait.

[0152] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 , C 3-4 and C 2-3 Alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0153] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 The alkenyl group may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to wait.

[0154] Unless otherwise specified, “C 2-3 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-3Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to wait.

[0155] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0156] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0157] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an amino group. 1-6 Alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3,

[0158] -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0159] Unless otherwise specified, the term “C 1-3"Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an amino group. 1-3 Alkylamino groups include C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0160] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0161] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0162] Unless otherwise specified, “C 3-9 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 9 carbon atoms, which is a monocyclic or bicyclic system. 3-9 Cycloalkyl groups include C 3-8 , C 3-7 , C 3-6 , C 3-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-9 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0163] Unless otherwise specified, “C3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl groups include C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0164] Unless otherwise specified, “C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic or bicyclic system. 4-6 Cycloalkyl groups include C 4-5 , C 4-6 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0165] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl includes 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 heterocycloalkyl, etc. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl or wait.

[0166] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused and bridged rings. In addition, with respect to the "4-8 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 4-8 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thiopyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or wait.

[0167] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0168] Unless otherwise specified, the term "C 6-10 Aromatic rings" and "C 6-10 Aryl" can be used interchangeably, the term "C 6-10 Aromatic ring" or "C 6-10 "Aryl" means a cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It can be monovalent, divalent or polyvalent, C 6-10 Aryl includes C 6-9 , C9, C 10 and C6 aryl, etc. 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0169] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" are used interchangeably in the present invention. The term "5-12 membered heteroaryl" refers to a cyclic group with a conjugated π electron system consisting of 5 to 12 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-12 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-12 membered heteroaryl group includes 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, 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.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0170] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, 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.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0171] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably in the present invention. The term "5-10 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). 5-10 yuan of heteroaryl can be connected to the rest of the molecule by heteroatom or carbon atom. The 5-10 yuan of heteroaryl includes 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan of heteroaryl. The example of the 5-10 yuan of heteroaryl includes but is not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, 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, etc.), 1-H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl 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 or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl).

[0172] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including 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 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0173] 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., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0174] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". 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; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0175] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0176] The solvent used in the present invention is commercially available.

[0177] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0178] The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0179] Preparation of intermediates

[0180] Reference Example 1: Preparation of Intermediate I-1

[0181]

[0182] 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, and after removing thionyl chloride under reduced pressure, the residue was dissolved in dichloromethane (100 mL). Diethylamine (11.7 g, 159.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (30.0 mL), water (30.0 mL), saturated brine, 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 directly used in the next step without purification.

[0183] LC-MS(ESI)[M+H] + 274.0.

[0184] 1 H NMR(400MHz,Chloroform-d)δ7.30(dd,J=8.3,2.5Hz,1H),7.22(dd,J=8.5,5.8Hz,1H),7.05(td,J=8.3,2.5Hz,1H),3.78(d t,J=14.5,7.1Hz,1H),3.42–3.21(m,1H),3.12(ddt,J=17.6,10.5,7.2Hz,2H),1.24(t,J=7.1Hz,3H),1.04(t,J=7.1Hz,3H).

[0185] Reference Example 2: Preparation of Intermediate I-2

[0186]

[0187] Intermediate I-1 (8.50 g), potassium vinyl fluoroborate (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) / water (20.0 mL), and bistriphenylphosphine palladium dichloride (1.09 g, 1.55 mmol) was added. The reaction solution was stirred at 90 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (100.0 mL), washed with water (30.0 mL) and saturated brine in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product of intermediate I-2, which was directly used in the next step without purification.

[0188] LC-MS(ESI)[M+H] + 222.2.

[0189] 1 H NMR (400MHz, Chloroform-d) δ7.24(d,J=2.6Hz,1H),7.17(dd,J=8.4,5.7Hz,1H),6.97(td,J=8.3,2.5Hz,1H),6.67(ddd,J=17.4,11.0,1. 7Hz,1H),5.75(d,J=17.4Hz,1H),5.36(d,J=11.0Hz,1H),3.55(brs,2H),3.10–3.01(m,2H),1.25(t,J=7.1Hz,3H),1.00(t,J=7.1Hz,3H).

[0190] Reference Example 3: Preparation of Intermediate I-3

[0191]

[0192] Intermediate I-2 (7.00 g) was dissolved in a mixed solvent of dioxane (70.0 mL) / water (30.0 mL), and potassium osmate 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 a residue. The residue was dissolved in ethyl acetate (100.0 mL), washed with water (30.0 mL) and saturated brine in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-3.

[0193] 1 H NMR(400MHz,Chloroform-d)δ9.99(d,J=2.3Hz,1H),7.63–7.57(m,1H),7.38–7.28(m,2H), 3.59(q,J=7.1Hz,2H), 3.11(q,J=7.1Hz,2H), 1.27(t,J=7.1Hz,3H), 1.02(t,J=7.1Hz,3H).

[0194] Reference Example 4: Preparation of Intermediate I-4

[0195]

[0196] Dissolve intermediate I-3 (3.00 g, 13.4 mmol) in acetic acid (10.0 mL), add hydrazine hydrate (1.03 g, 17.4 mmol, mass fraction 85.0%). Stir the reaction solution at 145 ° C for 1 hour under microwave irradiation. Cool the reaction solution to room temperature, filter, and dry the filter cake to obtain the crude product of intermediate I-4, which is directly used in the next step without purification.

[0197] LC-MS(ESI)[M+H] + 165.0.

[0198] 1 H NMR (400MHz, DMSO-d6) δ12.69(brs,1H),8.34(s,1H),8.28(dd,J=8.8,5.5Hz,1H),7.79(dd,J=9.0,2.6Hz,1H),7.70(td,J=8.9,2.6Hz,1H).

[0199] Reference Example 5: Preparation of Intermediate I-5

[0200]

[0201] Dissolve the intermediate I-4 (200.0 mg) in N, N-dimethylformamide (5.00 mL), add sodium hydrogen (58.0 mg, 1.46 mmol, mass fraction 60.0%). The reaction solution was stirred at room temperature for half an hour under nitrogen protection, and 3-bromopiperidine-2,6-dione (280.0 mg, 1.46 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100.0 mL), and the organic phase was washed with water (30.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of the intermediate I-5, which was directly used in the next step without purification.

[0202] LC-MS(ESI)[M+H] + 276.2.

[0203] Reference Example 6: Preparation of Intermediate I-6

[0204]

[0205] 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 at 130 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100.0 mL), washed with water (30.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, and the residue was separated and purified by chromatography to obtain intermediate I-6.

[0206] LC-MS(ESI)[M+H] + 442.3.

[0207] Reference Example 7: Preparation of Intermediate I-7

[0208]

[0209] 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 a crude product of intermediate I-7, which was directly used in the next step without purification.

[0210] LC-MS(ESI)[M+H] + 342.2.

[0211] Reference Example 8: Preparation of Intermediate I-8

[0212]

[0213] Dissolve tert-butyl 4-fluorobenzoate (3.00 g, 15.3 mmol) and 4-hydroxymethylpiperidine (2.10 g, 18.2 mmol) in N,N-dimethylformamide (20.0 mL), and add potassium carbonate (2.64 g, 19.1 mmol). The reaction solution was stirred at 80 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100.0 mL). The organic phase was washed with water (30.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by silica gel chromatography to obtain intermediate I-8. LC-MS (ESI) [M+H] + 292.2.

[0214] Reference Example 9: Preparation of Intermediate I-9

[0215]

[0216] Dess-Martin periodinane (864.0 mg, 2.03 mmol) was added to a solution of intermediate I-8 (400.0 mg, 1.37 mmol) in dichloromethane (20.0 mL), and the reaction solution was stirred at room temperature overnight under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by silica gel chromatography to obtain intermediate I-9.

[0217] LC-MS(ESI)[M+H] + 290.2.

[0218] Reference Example 10: Preparation of Intermediate I-10

[0219]

[0220] Dissolve intermediate I-7 (15.0 mg) and I-9 (19.0 mg, 0.066 mmol) in 1,2-dichloroethane (3.00 mL), add potassium acetate (3.60 mg, 0.044 mmol) and sodium acetate borohydride (18.0 mg, 0.085 mmol). Stir the reaction solution at room temperature overnight under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain a residue. The residue is separated and purified by silica gel chromatography to obtain intermediate I-10.

[0221] LC-MS(ESI)[M+H-56] + 559.3.

[0222] Reference Example 11: Preparation of Intermediate I-11

[0223]

[0224] 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 at room temperature overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product of intermediate I-11, which was directly used in the next step without purification.

[0225] Reference Example 12: Preparation of Intermediate I-12

[0226]

[0227] Mix 2-chloropyrimidine-5-carboxylic acid ethyl ester (500 mg, 2.68 mmol), 4-hydroxymethylpiperidine (309 mg, 2.68 mmol) and potassium carbonate (370 mg, 2.68 mmol) and dissolve in N,N-dimethylformamide (20 mL). The reaction mixture is stirred at 50 ° C overnight. The mixture is cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases are combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to obtain a residue. The residue is separated and purified by silica gel chromatography to obtain intermediate I-12.

[0228] LC-MS(ESI)[M+H] + 266.1.

[0229] Reference Example 13: Preparation of Intermediate I-13

[0230]

[0231] At room temperature, the 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 above solution. After the addition was completed, 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. A white solid precipitated and was filtered to obtain a crude product of the intermediate I-13, which was directly used in the next step without purification.

[0232] LC-MS(ESI)[M+H] + 238.2.

[0233] Reference Example 14: Preparation of Intermediate I-14

[0234]

[0235] 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 replacement and stirring conditions, O-(7-nitrobenzotriazole)-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), extracted with ethyl acetate (50 mL×3), and 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.

[0236] LC-MS(ESI)[M+H] + 498.2.

[0237] Reference Example 15: Preparation of Intermediate I-15

[0238]

[0239] 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 completed, the reaction solution was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate solution (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added to the reaction solution, and then extracted with dichloromethane (20 mL × 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 step without purification.

[0240] Reference Example 16: Preparation of Intermediate I-16

[0241]

[0242] At room temperature, reagent 2 (777 mg, 4.11 mmol) was dissolved in N, N-dimethylformamide (15 mL), and sodium hydride (296 mg, 60% content, 7.40 mmol) was added at 0°C under nitrogen protection, stirred for 30 minutes, and 4-fluoro-2-(trifluoromethyl)benzonitrile (1.00 g, 4.11 mmol) was added. The mixture was stirred at 40°C for 3 hours, and water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. After the crude product was purified by normal column chromatography, a solution of hydrogen chloride in dioxane (15 mL, 3 M) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly spin-dried and concentrated to obtain intermediate I-16. The intermediate was directly used in the next step without purification.

[0243] Reference Example 18: Preparation of Intermediate I-18

[0244]

[0245] The 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 by argon and heated to 75 ° C. and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by slurrying with ethyl acetate (500 mL), filtered, and the filter cake was purified by slurrying with anhydrous acetonitrile (500 mL), filtered, and dried to obtain the intermediate I-18.

[0246] Reference Example 19: Preparation of Intermediate I-19

[0247]

[0248] Intermediate I-18 (200 mg) was dissolved in N, N-dimethylformamide (30 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to dilute and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-19.

[0249] Reference Example 20: Preparation of Intermediate I-20

[0250]

[0251] Dissolve the intermediate I-19 (120 mg, 0.226 mmol) in anhydrous dichloromethane (20 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (192 mg, 0.452 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (200 mL), and extract with dichloromethane (200 mL × 3). Combine the organic phases, wash with saturated brine (200 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is separated and purified by silica gel chromatography to obtain intermediate I-20.

[0252] Reference Example 21: Preparation of Intermediate I-21

[0253]

[0254] At room temperature, methyl 6-chloronicotinate (500 mg, 2.91 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 4-piperidinemethanol (402 mg, 3.50 mmol) and N, N-diisopropylethylamine (1.13 g, 8.73 mmol) were added in sequence. After the addition was completed, the reaction mixture was stirred at 80°C for 3 hours. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (10 mL × 3) was used for extraction, the combined organic phases were washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-21.

[0255] Reference Example 22: Preparation of Intermediate I-22

[0256]

[0257] At room temperature, the 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 completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, it 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.

[0258] Reference Example 23: Preparation of Intermediate I-23

[0259]

[0260] At room temperature, the intermediate I-22 (100 mg, 0.42 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 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) were added in sequence. After the addition was completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (10 mL × 3) was used for extraction, the combined organic phases were washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase silica gel chromatography to obtain the intermediate I-23.

[0261] Reference Example 24: Preparation of Intermediate I-24

[0262]

[0263] Under ice-water bath, the 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 completed, the reaction mixture was stirred at room temperature for 2 hours. Saturated sodium sulfite solution (10 mL) was added for dilution, and the layers were separated by standing. The aqueous phase was extracted with dichloromethane (10 mL × 2), and the organic phases were combined and washed with saturated sodium sulfite solution (10 mL), saturated sodium bicarbonate solution (10 mL), and water (10 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate I-24. It was directly used in the next step without further purification.

[0264] Reference Example 25: Preparation of Intermediate I-25

[0265]

[0266] At room temperature, methyl 3,4-difluorobenzoate (200 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (10 mL) solution, and 4-piperidinemethanol (133 mg, 1.16 mmol) and potassium carbonate (480 g, 3.48 mmol) were added in sequence. After the addition was completed, the reaction mixture was stirred at 100°C for 2 hours. Water (20 mL) was added for dilution, and ethyl acetate (20 mL × 3) was used for extraction. The combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain intermediate I-25.

[0267] LC-MS(ESI)[M+H] + 268.1.

[0268] Reference Example 26: Preparation of Intermediate I-26

[0269]

[0270] At room temperature, the 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 completed, the reaction mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to 4-5 with 1N hydrochloric acid aqueous solution, filtered, and the filter cake was dried to obtain the intermediate I-26.

[0271] LC-MS(ESI)[M+H] + 254.1.

[0272] Reference Example 27: Preparation of Intermediate I-27

[0273]

[0274] At room temperature, the intermediate I-26 (120 mg, 0.47 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 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) were added in sequence. After the addition was completed, the reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added for dilution, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the intermediate I-27.

[0275] LC-MS(ESI)[M+H] + 514.1.

[0276] Reference Example 28: Preparation of Intermediate I-28

[0277]

[0278] At 0°C, the 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 completed, the reaction mixture was stirred at room temperature for 2 hours. Saturated sodium sulfite solution (20 mL) was added for dilution, and the layers were separated by standing. The aqueous phase was extracted with dichloromethane (20 mL × 2), and the organic phases were combined and washed with saturated sodium sulfite solution (20 mL × 2), saturated sodium bicarbonate solution (20 mL × 3), and water (20 mL × 3) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate I-28. It was directly used in the next step without further purification.

[0279] Reference Example 29: Preparation of Intermediate I-29

[0280]

[0281] Dissolve 2,6-difluoronicotinic acid (1.0 g, 0.322 mmol) in ethanol (20 mL), add concentrated sulfuric acid (61.7 mg, 0.629 mmol), protect the system with nitrogen, and stir the mixture at 100 ° C for 16 hours. Add the mixture into water (20 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate I-29. It is used directly in the next step without further purification.

[0282] Reference Example 30: Preparation of Intermediate I-30

[0283]

[0284] The intermediate I-29 (350 mg, 2.02 mmol) was dissolved in anhydrous N, N-dimethylformamide (15 mL), and 4-hydroxymethylpiperidine (255 mg, 2.22 mmol) and potassium carbonate (558 mg, 4.04 mmol) were added in sequence. The reaction system was heated to 100 ° C for 16 hours under nitrogen protection. After the mixture was cooled to room temperature, water (20 mL) was added to the mixture, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated brine (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 the intermediate I-30.

[0285] LC-MS(ESI)[M+H] + 269.1.

[0286] Reference Example 31: Preparation of Intermediate I-31

[0287]

[0288] Dissolve the intermediate I-30 (100 mg, 0.373 mmol) in anhydrous tetrahydrofuran (5 mL), then dissolve lithium hydroxide monohydrate (78.3 mg, 1.87 mmol) in water (5.00 mL) and add dropwise to the reaction. The reaction system is protected by argon and stirred at room temperature for 2 hours. The mixture is adjusted to weak acidity with 1N hydrochloric acid, and solids are precipitated. The crude product intermediate I-31 is obtained by filtration. It is directly used in the next step without further purification.

[0289] LC-MS(ESI)[M+H] + 255.2.

[0290] Reference Example 32: Preparation of Intermediate I-32

[0291]

[0292] The intermediate I-31 (55 mg) was dissolved in N, N-dimethylformamide (10 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (5 mL × 3) and dried to obtain the intermediate I-32.

[0293] LC-MS(ESI)[M+H] + 515.2.

[0294] Reference Example 33: Preparation of Intermediate I-33

[0295]

[0296] Dissolve intermediate I-32 (80 mg, 0.155 mmol) in anhydrous dichloromethane (10 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (98.8 mg, 0.233 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (10 mL), and extract with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is purified by silica gel chromatography to obtain intermediate I-33.

[0297] Reference Example 34: Preparation of Intermediate I-34

[0298]

[0299] 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 in sequence. When the temperature dropped to 0°C, 60% sodium hydride (164 mg, 4.1 mmol) was added. The whole system was carried out under nitrogen. After the addition was completed, the system was heated to 70°C and reacted for 2 hours. Water was added to quench, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-34.

[0300] LC-MS(ESI)[M-100+H] + 259.2.

[0301] Reference Example 35: Preparation of Intermediate I-35

[0302]

[0303] The intermediate I-34 (120 mg, 0.335 mmol) was dissolved in anhydrous dioxane (10 mL), and a solution of hydrogen chloride in dioxane (15 mL, 3 M) was added. The reaction system was protected by argon and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by slurrying with ethyl acetate (20 mL), filtered with suction, and the filter cake was purified by slurrying with anhydrous acetonitrile (20 mL), filtered with suction, and the filter cake was dried to obtain the intermediate I-35.

[0304] LC-MS(ESI)[M+H] + 259.1.

[0305] Reference Example 36: Preparation of Intermediate I-36

[0306]

[0307] Intermediate I-18 (100 mg) was dissolved in N, N-dimethylformamide (15 mL), and 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 in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (5 mL × 3) and dried to obtain intermediate I-36.

[0308] LC-MS(ESI)[M+H] + 476.2.

[0309] Reference Example 37: Preparation of Intermediate I-37

[0310]

[0311] Dissolve intermediate I-36 (63 mg, 0.132 mmol) in anhydrous dichloromethane (10 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (83.9 mg, 0.198 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (10 mL), and extract with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is purified by silica gel chromatography to obtain intermediate I-37.

[0312] Reference Example 38: Preparation of Intermediate I-38

[0313]

[0314] 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 above mixture. After the addition was completed, the reaction mixture was stirred at 110 ° C overnight under argon protection. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product of intermediate I-38, which was directly used in the next step without purification.

[0315] LC-MS(ESI)[M+H] + 252.2.

[0316] Reference Example 39: Preparation of Intermediate I-39

[0317]

[0318] At room temperature, the 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 completed, the reaction mixture was stirred at room temperature overnight. 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 the intermediate I-39.

[0319] LC-MS(ESI)[M+H] + 238.2.

[0320] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=8.0Hz,1H),7.27(d,J=12.0Hz,1H),4.52(d,J=12.0Hz, 2H), 3.28 (d, J = 8.0Hz, 2H), 2.99 (t, J = 12.0Hz, 2H), 1.70-1.80 (m, 3H), 1.15-1.20 (m, 2H).

[0321] Reference Example 40: Preparation of Intermediate I-40

[0322]

[0323] 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 replacement 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 above mixture. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL×3), and the organic phase was dried and filtered. The organic solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-40.

[0324] LC-MS(ESI)[M+H] + 498.2.

[0325] Reference Example 41: Preparation of Intermediate I-41

[0326]

[0327] In an ice-water bath, the intermediate I-40 (120 mg, 0.241 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin oxidant (204 mg, 0.482 mmol) was added under argon replacement and stirring. After the addition was completed, the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched by adding saturated sodium sulfite solution (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic phases were 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 the intermediate I-41.

[0328] Reference Example 42: Preparation of Intermediate I-42

[0329]

[0330] The compound 5-fluoropyridine-2-carboxylic acid methyl ester (900mg, 5.80mmol) was dissolved in N,N-dimethylformamide (50mL), and the compound 4-methanol piperidine (670mg, 5.82mmol) and diisopropylethylamine (2.87mL, 17.4mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After concentration, water (100mL) was added for dilution, and then extracted with ethyl acetate (100mL×3). The organic phases were combined, washed with saturated brine (100mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-42.

[0331] LC-MS(ESI)[M+H] + 251.0.

[0332] Reference Example 43: Preparation of Intermediate I-43

[0333]

[0334] Dissolve the intermediate I-42 (300 mg, 1.20 mmol) in tetrahydrofuran and water (5 mL / 5 mL), and add lithium hydroxide monohydrate (403 mg, 9.60 mmol). The reaction mixture is stirred at room temperature for 18 hours. Concentrate to remove most of the tetrahydrofuran, adjust the pH value of the solution to about 5 with 1N hydrochloric acid aqueous solution, and separate and purify the solution by chromatography to obtain the intermediate I-43.

[0335] LC-MS(ESI)[M+H] + 237.0.

[0336] Reference Example 44: Preparation of Intermediate I-44

[0337]

[0338] At room temperature, the intermediate I-43 (260 mg) was dissolved in N, N-dimethylformamide (10 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 48 hours, diluted with water (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain the intermediate I-44.

[0339] LC-MS(ESI)[M+H] + 497.1.

[0340] Reference Example 45: Preparation of Intermediate I-45

[0341]

[0342] Dissolve intermediate I-44 (70 mg, 0.141 mmol) in dichloromethane (5 mL), and then slowly add Dess-Martin periodinane (120 mg, 0.282 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was quenched with sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filter, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-45.

[0343] Reference Example 46: Preparation of Intermediate I-46

[0344]

[0345] The compound 5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol) was dissolved in N, N-dimethylformamide (40 mL), and the compound 4-methanol piperidine (365 mg, 3.17 mmol) and N, N-diisopropylethylamine (1.56 mL, 9.45 mmol) were added. The reaction mixture was stirred at 100 ° C for 16 hours. After concentration, water (80 mL) was added for dilution, and then extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-46.

[0346] LC-MS(ESI)[M+H] + 238.3.

[0347] Reference Example 47: Preparation of Intermediate I-47

[0348]

[0349] Intermediate I-46 (200 mg, 0.843 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 48 hours, diluted with water (50 mL), and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a 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.

[0350] Reference Example 48: Preparation of Intermediate I-48

[0351]

[0352] The 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 at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was quenched with aqueous sodium bicarbonate solution (20 mL), and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude intermediate I-48. The crude product was used directly in the next step without further purification.

[0353] Reference Example 49: Preparation of Intermediate I-49

[0354]

[0355] 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), and N-bromosuccinimide (1.59 g, 8.95 mmol) was added under stirring under argon protection, and nitrogen was replaced again. Under nitrogen protection, the mixture was stirred at 80 ° C for 16 hours. After the mixture was cooled to room temperature, it was poured into water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was separated and purified by silica gel chromatography to obtain intermediate I-49.

[0356] 1H NMR (400MHz, CDCl3) δ8.06(d,J=1.5Hz,1H),7.81(dd,J=8.1,1.7Hz,1H),7.40(dd,J=8.1,0.4Hz,1H),5.29(s,2H).

[0357] Reference Example 50: Preparation of Intermediate I-50

[0358]

[0359] At 25°C, the intermediate I-49 (700 mg, 3.29 mmol) was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (702 mg, 3.95 mmol) and benzoyl peroxide (79.7 mg, 0.329 mmol) were added. The mixture was then reacted at 60°C for 3 hours, the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (10 mL) was added, and dichloromethane (10 mL×3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure to remove the organic solvent, it was separated and purified by silica gel chromatography to obtain the intermediate I-50.

[0360] 1 H NMR (400MHz, CDCl3) δ8.05 (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).

[0361] Reference Example 51: Preparation of Intermediate I-51

[0362]

[0363] Dissolve intermediate I-50 (700 mg, 2.40 mmol) in ethanol (10 mL) at 25 °C, then lower the temperature to 0 °C and add 85% hydrazine hydrate (600.7 mg). Under nitrogen protection, the reaction mixture is stirred under reflux for 2 hours. Pour the reaction system into water (10 mL) and filter. Wash the filter cake with water (10 mL × 3) to obtain intermediate I-51.

[0364] 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.40(s,1H),8.32(d,J=1.9Hz,1H),8.13(dd,J=8.4,2.0Hz,1H),7.92(d,J=8.4Hz,1H).

[0365] Reference Example 52: Preparation of Intermediate I-52

[0366]

[0367] At 25°C, the 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, the nitrogen was replaced, and chloro(2-dicyclohexylphosphino-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 at 100°C overnight. The reaction system was filtered and concentrated under reduced pressure to remove the organic solvent to obtain a crude product, and the crude product residue was separated and purified by silica gel chromatography to obtain the intermediate I-52.

[0368] LC-MS(ESI)[M+H] + 331.1.

[0369] Reference Example 53: Preparation of Intermediate I-53

[0370]

[0371] At 25°C, the intermediate I-52 (400 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL), and 60% sodium hydrogen sulfide (96.8 mg, 2.42 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. 3-Bromopiperidine-2,6-dione (464.6 mg, 2.42 mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise. The mixture was stirred at room temperature for 16 hours. Water (20 mL) was poured into the reaction solution, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was separated and purified by silica gel chromatography to obtain the intermediate I-53.

[0372] LC-MS(ESI)[M+H-56] + 386.1.

[0373] Reference Example 54: Preparation of Intermediate I-54

[0374]

[0375] At 25°C, the 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 at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain the intermediate I-54. The crude product was used directly in the next step without further purification.

[0376] LC-MS(ESI)[M+H] + 342.2.

[0377] Reference Example 55: Preparation of Intermediate I-55

[0378]

[0379] Dissolve intermediate I-18 (38.8 g) in N, N-dimethylformamide (300 mL), and add 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) in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL × 3) and dried to obtain intermediate I-55.

[0380] LC-MS(ESI)[M+H] + 496.2.

[0381] Reference Example 56: Preparation of Intermediate I-56

[0382]

[0383] Dissolve the intermediate I-55 (32g, 64.52mmol) in anhydrous dichloromethane (200.0mL), cool the system to 0℃, and add Dess-Martin oxidant (41g, 96.77mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. The filtrate is quenched with saturated sodium bicarbonate aqueous solution (200mL) and extracted with dichloromethane (200mL×3). Combine the organic phases, wash with saturated brine (200mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is separated and purified by silica gel chromatography to obtain intermediate I-56.

[0384] Reference Example 57: Preparation of Intermediate I-57

[0385]

[0386] Dissolve 2,2,6,6-tetramethylpiperidine (4.42 g, 31.3 mmol) in anhydrous tetrahydrofuran (150 mL), and add butyl lithium (1.6 M) (19.6 mL, 31.3 mmol) dropwise at -60°C. After the addition is complete, the mixture is stirred and reacted at -60°C under argon protection for 1 hour. Add a solution of m-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (50 mL) dropwise at -60°C, and the mixture is stirred and reacted at -60°C under argon protection for 1 hour. Add N,N-dimethylformamide (4.36 g, 59.6 mmol) dropwise at -60°C. After the addition is complete, the mixture is slowly warmed to room temperature and stirred and reacted at room temperature for 0.5 hours. The reaction was quenched with water (500 mL) at 0°C, and the product was extracted with ethyl acetate (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-57.

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.99(dd,J=7.9,0.7Hz,1H),7.88–7.81(m,1H),7.60(t,J=7.7Hz,1H),6.62(s,1H).

[0388] Reference Example 58: Preparation of Intermediate I-58

[0389]

[0390] The intermediate I-57 (700 mg, 3.06 mmol) was dissolved in glacial acetic acid (10.0 mL), the system was protected by argon, the temperature was raised to 90°C, 85% hydrazine hydrate (460 mg) was added dropwise, after the addition, the mixture was stirred at 90°C for 4 hours, and the preheated hot water (20.0 mL) at 80°C was slowly added dropwise while maintaining the temperature at 80°C. After the addition, the mixture was slowly cooled to room temperature, solids were precipitated, filtered, the filter cake was washed with water (10.0 mL), and dried under vacuum to obtain the intermediate I-58.

[0391] LC-MS(ESI)[M+H] + 225.0.

[0392] Reference Example 59: Preparation of Intermediate I-59

[0393]

[0394] The intermediate I-58 (510 mg, 2.27 mmol) was dissolved in anhydrous dioxane (50.0 mL), and tert-butyl piperazine-1-carboxylate (635 mg, 3.41 mmol), sodium tert-butoxide (654 mg, 6.81 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (87.8 mg, 0.227 mmol) were added. The reaction system was protected by 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 to obtain a crude product, which was separated and purified by silica gel chromatography to obtain the intermediate I-59. LC-MS(ESI)[M+H] + 331.2.

[0395] Reference Example 60: Preparation of Intermediate I-60

[0396]

[0397] Dissolve the intermediate I-59 (150 mg, 0.454 mmol) in a mixed solvent of dimethyl sulfoxide / tetrahydrofuran (2.00 mL / 2.00 mL), and add sodium hydride (60%, 90.8 mg, 2.27 mmol). The reaction system was protected by 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, the mixture was stirred at room temperature for 0.5 hours. The mixture was quenched with citric acid (100 mg). Pour into water (20.0 mL), extract the product with ethyl acetate (20.0 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-60.

[0398] LC-MS(ESI)[M+H] + 442.1.

[0399] Reference Example 61: Preparation of Intermediate I-61

[0400]

[0401] Dissolve intermediate I-60 (120 mg, 0.272 mmol) in anhydrous dichloromethane (2.00 mL) and add trifluoroacetic acid (0.50 mL). The reaction system is protected by argon and stirred at room temperature for 16 hours. The mixture is concentrated to remove the organic solvent to obtain a crude product, which is separated and purified by silica gel chromatography to obtain intermediate I-61.

[0402] LC-MS(ESI)[M+H] + 342.1.

[0403] Reference Example 62: Preparation of Intermediate I-62

[0404]

[0405] In an ice-water bath, trans-4-Boc-aminocyclohexanol (5.00 g, 23.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), and sodium hydrogen (1.11 g, 27.9 mmol, 60% mass fraction) was added under argon protection and stirring. The reaction mixture was stirred in an ice-water bath for 1 hour, and then 2-chloro-4-fluorobenzonitrile (3.65 g, 23.5 mmol) was added. After the addition was completed, 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 × 3), and the organic phase was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain a white solid intermediate I-62.

[0406] LC-MS(ESI)[M-56+H] + 295.1.

[0407] Reference Example 63: Preparation of Intermediate I-63

[0408]

[0409] At room temperature, the intermediate I-62 (6.00 g, 17.1 mmol) was dissolved in a solution of hydrogen chloride in dioxane (100 mL, 4 M). After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product of the intermediate I-63, which was directly used in the next step without purification.

[0410] LC-MS(ESI)[M+H] + 251.2.

[0411] Reference Example 64: Preparation of Intermediate I-64

[0412]

[0413] Dissolve intermediate I-18 (1.40 g, 5.95 mmol) in N, N-dimethylformamide (20.0 mL), and add 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) in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (15 mL × 3) and dried to obtain intermediate I-64.

[0414] LC-MS(ESI)[M+H] + 468.1.

[0415] Reference Example 65: Preparation of Intermediate I-65

[0416]

[0417] Dissolve the intermediate I-64 (100 mg, 0.214 mmol) in anhydrous dichloromethane (10.0 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (181 mg, 0.428 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (10.0 mL), and extract with dichloromethane (10.0 mL × 3). Combine the organic phases, wash with saturated brine (10.0 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain the crude product intermediate I-65. The crude product is directly used in the next step without purification.

[0418] Reference Example 66: Preparation of Intermediate I-66

[0419]

[0420] The intermediate I-63 (700 mg) was dissolved in N, N-dimethylformamide (10 mL), and the 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) were added in sequence. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (50 mL), and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain the intermediate I-66. LC-MS (ESI) [M+H] + 470.0.

[0421] Reference Example 67: Preparation of Intermediate I-67

[0422]

[0423] Dissolve intermediate I-66 (150 mg, 0.319 mmol) in dimethyl sulfoxide (10 mL), and then slowly add 2-iodoacylbenzoic acid (270 mg, 0.964 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filter, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-67.

[0424] Reference Example 68: Preparation of Intermediate I-68

[0425]

[0426] Methyl p-fluorobenzoate (5.00 g, 32.4 mmol) was dissolved in anhydrous N, N-dimethylformamide (20.0 mL), and 3-methylhydroxyazetidine hydrochloride (4.81 g, 38.9 mmol) and anhydrous potassium carbonate (11.2 g, 81.1 mmol) were added in sequence. The reaction system was protected by 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 × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-68.

[0427] LC-MS(ESI)[M+H] + 222.2.

[0428] Reference Example 69: Preparation of Intermediate I-69

[0429]

[0430] Dissolve the intermediate I-68 (200 mg, 0.904 mmol) in anhydrous tetrahydrofuran (5.00 mL), then dissolve lithium hydroxide monohydrate (190 mg, 4.52 mmol) in (5.00 mL) water and add dropwise to the reaction. The reaction system is protected by argon and stirred at room temperature for 2 hours. The mixture is adjusted to weak acidity with 1N hydrochloric acid, and solids are precipitated. Filter to obtain the crude product intermediate I-69. The crude product is directly used in the next step without purification.

[0431] LC-MS(ESI)[M+H] + 208.0.

[0432] Reference Example 70: Preparation of Intermediate I-70

[0433]

[0434] Intermediate I-69 (160 mg) was dissolved in N, N-dimethylformamide (20.0 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (2 mL × 3) and dried to obtain intermediate I-70.

[0435] LC-MS(ESI)[M+H] + 440.0.

[0436] Reference Example 71: Preparation of Intermediate I-71

[0437]

[0438] Dissolve the intermediate I-70 (100 mg, 0.227 mmol) in anhydrous dichloromethane (10.0 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (193 mg, 0.454 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (10.0 mL), and extract with dichloromethane (10.0 mL × 3). Combine the organic phases, wash with saturated brine (10.0 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is separated and purified by silica gel chromatography to obtain intermediate I-71.

[0439] Reference Example 72: Preparation of Intermediate I-72

[0440]

[0441] Dissolve 3-hydroxymethylpyrrole hydrochloride (1.20 g, 8.72 mmol) in anhydrous N, N-dimethylformamide (20.0 mL), add methyl p-fluorobenzoate (1.48 g, 9.59 mmol) and anhydrous potassium carbonate (3.62 g, 26.2 mmol). The reaction system is protected by argon and stirred at 120 ° C for 16 hours. The reaction solution is cooled to room temperature, water (100 mL) is added, and the product is extracted with ethyl acetate (50.0 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is separated and purified by silica gel chromatography to obtain intermediate I-72.

[0442] LC-MS(ESI)[M+H] + 236.2.

[0443] Reference Example 73: Preparation of Intermediate I-73

[0444]

[0445] Dissolve the intermediate I-72 (400 mg, 1.70 mmol) in a mixed solvent of tetrahydrofuran / methanol (2.00 mL / 2.00 mL), and add a solution of sodium hydroxide (204 mg, 5.10 mmol) in water (2.00 mL). The reaction system is protected by argon and stirred at 70 ° C for 4 hours. Adjust the pH of the system to 6.0 with dilute hydrochloric acid (1N), precipitate a large amount of solid, filter, and dry the filter cake to obtain the intermediate I-73.

[0446] LC-MS(ESI)[M+H] + 222.2.

[0447] Reference Example 74: Preparation of Intermediate I-74

[0448]

[0449] The intermediate I-73 (350 mg, 1.58 mmol) was dissolved in anhydrous N, N-dimethylformamide (20.0 mL), and 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) were added. The reaction system was protected by argon and stirred at room temperature for 16 hours. The mixture was poured into water (100 mL), solids were precipitated, filtered, and the solids were dried. The solids were washed with ethyl acetate (25 mL), filtered, and the filter cake was dried to obtain the intermediate I-74.

[0450] LC-MS(ESI)[M+H] + 482.3.

[0451] Reference Example 75: Preparation of Intermediate I-75

[0452]

[0453] 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 by argon and stirred at 20°C for 16 hours. The mixture was diluted with dichloromethane (50.0 mL), washed with water (20.0 mL×2), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-75.

[0454] LC-MS(ESI)[M+H] + 480.1.

[0455] Reference Example 76: Preparation of Intermediate I-76

[0456]

[0457] The intermediate I-5 (230 mg) was dissolved in anhydrous dimethyl sulfoxide (10.0 mL), and 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) were added. The reaction system was protected by 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×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain the intermediate I-76.

[0458] LC-MS(ESI)[M+H] + 454.1.

[0459] Reference Example 77: Preparation of Intermediate I-77

[0460]

[0461] Dissolve intermediate I-76 (234 mg, 0.516 mmol) in anhydrous dichloromethane (3.00 mL) and add trifluoroacetic acid (1.00 mL). The reaction system was protected by argon and stirred at room temperature for 16 hours. The mixture was wet loaded and separated and purified by silica gel chromatography to obtain intermediate I-77. LC-MS (ESI) [M+H] + 354.1.

[0462] Reference Example 78: Preparation of Intermediate I-78

[0463]

[0464] 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 at 130 ° C for 3 days. After the mixture was cooled to room temperature, it was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, 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.

[0465] LC-MS(ESI)[M+H] + 456.1.

[0466] Reference Example 79: Preparation of Intermediate I-79

[0467]

[0468] Intermediate I-78 (50.0 mg, 0.110 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature. 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.

[0469] Reference Example 80: Preparation of Intermediate I-80

[0470]

[0471] 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 at 130 ° C for 3 days. After the mixture was cooled to room temperature, it was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, 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.

[0472] LC-MS(ESI)[M+H] + 456.1.

[0473] Reference Example 81: Preparation of Intermediate I-81

[0474]

[0475] Intermediate I-80 (30.0 mg, 0.0659 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature. 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 step without further purification.

[0476] LC-MS(ESI)[M+H] + 356.1.

[0477] Reference Example 82: Preparation of Intermediate I-82

[0478]

[0479] Intermediate I-69 (150 mg) was dissolved in N, N-dimethylformamide (20.0 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed three times with ethyl acetate (2 mL × 3) and dried to obtain intermediate I-82.

[0480] Reference Example 83: Preparation of Intermediate I-83

[0481]

[0482] Dissolve the intermediate I-82 (200 mg, 0.43 mmol) in anhydrous dichloromethane (10.0 mL), cool the system to 0 ° C, and add Dess-Martin periodinant (274 mg, 0.645 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. The filtrate is quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10.0 mL × 3). The organic phases are combined, washed with saturated brine (10.0 mL), and dried over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure to remove the organic solvent to obtain the crude product intermediate I-83. The crude product is directly used in the next step without further purification.

[0483] Reference Example 84: Preparation of Intermediate I-84

[0484]

[0485] At room temperature, (R)-1-BOC-3-hydroxymethylpyrrolidine (1.60 g, 8.00 mmol) was dissolved in dioxane (2.00 mL), followed by addition of a solution of hydrogen chloride in dioxane (20.0 mL, 4 M), and stirred overnight at room temperature. The reaction solution was concentrated to obtain a crude intermediate I-84. The crude product was directly used for the next step without purification.

[0486] Reference Example 85: Preparation of Intermediate I-85

[0487]

[0488] 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), and stirred at 50°C for 2 hours. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-85.

[0489] LC-MS(ESI)[M+H] + 252.2.

[0490] Reference Example 86: Preparation of Intermediate I-86

[0491]

[0492] At room temperature, the intermediate I-85 (520 mg, 2.06 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8.00 mL) and water (2.00 mL), followed by the addition of lithium hydroxide monohydrate (433 mg, 10.3 mmol), and stirred overnight at room temperature. Water (6.00 mL) was added first, and then extracted with ethyl acetate (5.00 mL). The aqueous phase was adjusted to a pH of about 1.0 with 2N dilute hydrochloric acid, and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10.0 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness to obtain the intermediate I-86.

[0493] LC-MS(ESI)[M+H] + 224.1.

[0494] Reference Example 87: Preparation of Intermediate I-87

[0495]

[0496] At room temperature, the 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), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mmol), and stirred at room temperature for 1 hour. First, water (10.0 mL) was added, and a large amount of solid precipitated. The solid was filtered and the filtrate was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, combined with the filter residue, and dried to obtain the intermediate I-87. LC-MS (ESI) [M+H] + 484.1.

[0497] Reference Example 88: Preparation of Intermediate I-88

[0498]

[0499] At room temperature, the intermediate I-87 (150 mg, 0.310 mmol) was dissolved in dimethyl sulfoxide (5.00 mL), followed by the addition of 2-iodobenzoic acid (434 mg, 1.55 mmol), argon replacement three times, and stirring at 80 ° C for 30 minutes. Cool to room temperature, add water (10.0 mL) to dilute, and extract with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated brine (10.0 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain the crude intermediate I-88. The crude product was used directly in the next step without further purification.

[0500] Reference Example 89: Preparation of Intermediate I-89

[0501]

[0502] (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 by argon and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by slurrying with ethyl acetate (20 mL), filtered with suction, and the filter cake was purified by slurrying with anhydrous acetonitrile (20 mL), filtered with suction, and the filter cake was dried to obtain intermediate I-89.

[0503] LC-MS(ESI)[M+H] + 102.4.

[0504] Reference Example 90: Preparation of Intermediate I-90

[0505]

[0506] Dissolve the intermediate I-89 (500 mg, 3.61 mmol) in dimethyl sulfoxide (10 mL), add ethyl 2-chloropyrimidine-5-carboxylate (670 mg, 3.61 mmol), N,N-diisopropylethylamine (1.78 mL, 10.8 mmol) in turn, replace argon gas at room temperature for 3 times, and stir the reaction mixture at 50 ° C under argon protection for 3 hours. After the mixture is cooled to room temperature, the liquid is separated, and the organic phase is concentrated to dryness under reduced pressure. Add water (10 mL) to the residue and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. The residue is separated and purified by silica gel chromatography to obtain intermediate I-90.

[0507] LC-MS(ESI)[M+H] + 252.0.

[0508] Reference Example 91: Preparation of Intermediate I-91

[0509]

[0510] The intermediate I-90 (700 mg, 2.79 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and 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 by argon and stirred at room temperature for 2 hours. The mixture was adjusted to weak acidity with 1N hydrochloric acid, and solids precipitated. The crude intermediate I-91 was obtained by filtration. The crude product was directly used in the next step without further purification.

[0511] LC-MS(ESI)[M+H] + 224.1.

[0512] Reference Example 92: Preparation of Intermediate I-92

[0513]

[0514] Intermediate I-91 (200 mg) was dissolved in N, N-dimethylformamide (10 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (5 mL × 3) and dried to obtain intermediate I-92.

[0515] LC-MS(ESI)[M+H] + 484.0.

[0516] Reference Example 93: Preparation of Intermediate I-93

[0517]

[0518] Dissolve the intermediate I-92 (150 mg, 0.31 mmol) in anhydrous dichloromethane (10 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (197 mg, 0.465 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. The filtrate is quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (10 mL × 3). Combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is separated and purified by silica gel chromatography to obtain intermediate I-93.

[0519] Reference Example 94: Preparation of Intermediate I-94

[0520]

[0521] At 0°C, sodium hydride (mass fraction 60%) (438 mg, 11.0 mmol) was added to tetrahydrofuran (10 mL), argon was replaced, and after stirring at 0°C for 5 minutes, a solution of triethylphosphonoacetate (2.66 g, 11.9 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, and the reaction 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 completed, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was concentrated under reduced pressure. The residual liquid was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-94.

[0522] LC-MS(ESI)[M+H] + 290.2.

[0523] Reference Example 95: Preparation of Intermediate I-95

[0524]

[0525] At room temperature, the intermediate I-94 (1.84 g, 6.37 mmol) was dissolved in methanol (20 mL), and palladium / carbon (mass fraction 10%) (1.35 g, 1.27 mmol) was added. After the addition was completed, the hydrogen was replaced, and the reaction mixture was stirred at room temperature in a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate I-95. The crude product was directly used in the next step without further purification.

[0526] 1 H NMR (400MHz, DMSO-d6) δ4.09–4.01(m,2H),3.40(d,J=8.4Hz,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=7.1Hz,3H).

[0527] Reference Example 96: Preparation of Intermediate I-96

[0528]

[0529] The intermediate I-95 (900 mg, 5.73 mmol) was dissolved in tetrahydrofuran (20 mL), argon was replaced, and lithium aluminum tetrahydride (435 mg, 11.5 mmol) was slowly added in batches at 0°C. After the addition was completed, the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, water (0.9 mL) was added, stirred for 5 minutes, and then anhydrous sodium sulfate was added and stirred, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate I-96. The crude product was directly used in the next reaction without further purification.

[0530] LC-MS(ESI)[M+H] + 116.1.

[0531] Reference Example 97: Preparation of Intermediate I-97

[0532]

[0533] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (730 mg, 3.9 mmol) was dissolved in dimethyl sulfoxide (5 mL), and intermediate I-96 (450 mg) and N,N-diisopropylethylamine (1.5 g, 11.7 mmol) were added. After the addition was completed, the reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the reaction mixture was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-97.

[0534] LC-MS(ESI)[M+H] + 266.0.

[0535] Reference Example 98: Preparation of Intermediate I-98

[0536]

[0537] At room temperature, the 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 completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid solution, and then diluted with saturated brine (10 mL), extracted with ethyl acetate (10 mL×5), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude intermediate I-98. The crude product was directly used in the next step without further purification.

[0538] LC-MS(ESI)[M+H] + 238.1.

[0539] Reference Example 99: Preparation of Intermediate I-99

[0540]

[0541] At room temperature, the intermediate I-98 (120 mg, 0.51 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 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) were added in sequence. After the addition was completed, the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (20 mL × 3) was used for extraction, the combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain the intermediate I-99.

[0542] LC-MS(ESI)[M+H] + 498.1.

[0543] Reference Example 100: Preparation of Intermediate I-100

[0544]

[0545] At room temperature, the intermediate I-99 (80 mg, 0.16 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodoacylbenzoic acid (224 mg, 0.80 mmol) was added. After the addition was completed, the reaction mixture was stirred at 80°C for 30 minutes. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (20 mL × 3) was extracted, the combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate I-100. The crude product was directly used in the next step without further purification.

[0546] Reference Example 101: Preparation of Intermediate I-101

[0547]

[0548] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.07 mmol) was dissolved in dimethyl sulfoxide (5 mL), 4-piperidineethanol (165 mg, 1.28 mmol) and N,N-diisopropylethylamine (414 g, 3.21 mmol) were added, and the reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (20 mL × 3) was used for extraction, the combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-101.

[0549] LC-MS(ESI)[M+H] + 280.1.

[0550] Reference Example 102: Preparation of Intermediate I-102

[0551]

[0552] At room temperature, the 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 completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid solution, filtered, and the filter cake was dried to obtain the intermediate I-102.

[0553] LC-MS(ESI)[M+H] + 252.1.

[0554] Reference Example 103: Preparation of Intermediate I-103

[0555]

[0556] At room temperature, the intermediate I-102 (140 mg, 0.56 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 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) were added in sequence. After the addition was completed, the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (20 mL × 3) was used for extraction, the organic phases were combined, washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain the intermediate I-103.

[0557] LC-MS(ESI)[M+H] + 512.3.

[0558] Reference Example 104: Preparation of Intermediate I-104

[0559]

[0560] At 0°C, the intermediate I-103 (60 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin periodinant (102 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated sodium sulfite solution (10 mL) was added for dilution, and the mixture was allowed to stand for stratification. The aqueous phase was extracted with dichloromethane (10 mL × 2), and the organic phases were combined and washed with a saturated sodium sulfite solution (10 mL × 2), a saturated sodium bicarbonate solution (10 mL × 3) and water (10 mL × 3) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude intermediate I-104. The crude product was used directly in the next step without further purification.

[0561] Reference Example 105: Preparation of Intermediate I-105

[0562]

[0563] At room temperature, hydroxylamine hydrochloride (8.69 g, 125 mmol) was dissolved in water (130 mL), anhydrous sodium acetate (13.6 g, 166 mmol) was added, the mixture was stirred at room temperature for 10 minutes, and ethyl cyclohexanone formate (13.0 g, 83.2 mmol) was added dropwise. The reaction system was protected by argon and 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 × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-105.

[0564] LC-MS(ESI)[M+H] + 186.1.

[0565] Reference Example 106: Preparation of Intermediate I-106

[0566]

[0567] At room temperature, the intermediate I-105 (11.2 g, 60.5 mmol) was dissolved in anhydrous pyridine (50.0 mL), the reaction system was protected by argon, the temperature was lowered to -15 ° C, and 4-toluenesulfonyl chloride (17.3 g, 90.8 mmol) was added. The reaction mixture was stirred at -15 ° C for 2 hours. The mixture was poured into ice water, solid precipitated, stirred at 5 ° C for 20 minutes, filtered, and the filter cake was dried to obtain the intermediate I-106.

[0568] LC-MS(ESI)[M+H] + 340.2.

[0569] Reference Example 107: Preparation of Intermediate I-107

[0570]

[0571] At room temperature, the intermediate I-106 (12.5 g, 36.8 mmol) was dissolved in glacial acetic acid (30.0 mL), the reaction system was protected by argon, and the reaction was stirred at room temperature for 16 hours. The glacial acetic acid was removed by vacuum concentration, and a saturated sodium bicarbonate aqueous solution (40.0 mL) was added to the residue, stirred for 15 minutes, and the product was extracted with ethyl acetate (30.0 mL × 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 to obtain a crude product, which was separated and purified by silica gel chromatography to obtain the intermediate I-107.

[0572] LC-MS(ESI)[M+H] + 186.2.

[0573] Reference Example 108: Preparation of Intermediate I-108

[0574]

[0575] Dissolve lithium aluminum hydride (2.56 g, 67.5 mmol) in anhydrous tetrahydrofuran (100 mL), and add a solution of intermediate I-107 (2.50 g, 13.5 mmol) in anhydrous tetrahydrofuran (20.0 mL) dropwise at 0°C. Protect the reaction system with argon and stir at room temperature for 2 hours. Then heat to 60°C and stir for 4 hours. Cool the mixture to room temperature, add sodium sulfate decahydrate (10.0 g) at 0°C, and stir for 0.5 hours. Filter with suction, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain intermediate I-108.

[0576] LC-MS(ESI)[M+H] + 130.1.

[0577] Reference Example 109: Preparation of Intermediate I-109

[0578]

[0579] At room temperature, the intermediate I-108 (560 mg, 4.33 mmol) was dissolved in anhydrous dichloromethane (50.0 mL), and ethyl 2-chloropyrimidine-5-carboxylate (970 mg, 5.20 mmol) and N,N-diisopropylethylamine (1.68 g, 13.0 mmol) were added. The reaction system was protected by argon and stirred at room temperature for 16 hours. The mixture was separated and purified by silica gel chromatography to obtain the intermediate I-109.

[0580] LC-MS(ESI)[M+H] + 280.2.

[0581] Reference Example 110: Preparation of Intermediate I-110

[0582]

[0583] At room temperature, the 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 by argon and stirred at room temperature for 16 hours. The mixture was adjusted to pH 6.0 with 1N hydrochloric acid, and the solid was precipitated, filtered, and the filter cake was dried to obtain the intermediate I-110.

[0584] LC-MS(ESI)[M+H] + 252.2.

[0585] Reference Example 111: Preparation of Intermediate I-111

[0586]

[0587] At room temperature, the intermediate I-110 (180 mg, 0.716 mmol) was dissolved in anhydrous N, N-dimethylformamide (20.0 mL), and reagent 1 (293 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (274 mg, 1.43 mmol), 1-hydroxybenzotriazole (193 mg, 1.43 mmol), N, N-diisopropylethylamine (370 mg, 2.86 mmol) were added. The reaction system was protected by 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 the intermediate I-111.

[0588] LC-MS(ESI)[M+H] + 512.2.

[0589] Reference Example 112: Preparation of Intermediate I-112

[0590]

[0591] Dissolve the intermediate I-111 (200 mg, 0.391 mmol) in anhydrous dichloromethane (20.0 mL), and add Dess-Martin periodinane (249 mg, 0.587 mmol) at 0°C. Protect the reaction system with argon and stir at room temperature for 2 hours. The mixture is separated and purified by silica gel chromatography to obtain the intermediate I-112.

[0592] LC-MS(ESI)[M+H] + 510.1.

[0593] Reference Example 113: Preparation of Intermediate I-113

[0594]

[0595] At room temperature, 2-chloro-3-fluoro-5-methylpyridine (1.00 g, 6.87 mmol) was added to water (5.00 mL), followed by potassium permanganate (2.17 g, 13.7 mmol) and pyridine (5.52 mL, 68.7 mmol). Stir at 100 ° C for 1 hour, then add potassium permanganate (4.34 g, 27.4 mmol) and stir at 100 ° C overnight. Add water (10.0 mL), extract with ethyl acetate (20.0 mL × 2), adjust the pH of the aqueous phase to about 2.0 with 2N dilute hydrochloric acid, extract with ethyl acetate (20.0 mL × 2), wash the combined organic phase with saturated brine (20 mL), and concentrate to obtain the crude intermediate I-113. The crude product was used directly in the next step without purification.

[0596] LC-MS(ESI)[2M-H] - 349.0.

[0597] Reference Example 114: Preparation of Intermediate I-114

[0598]

[0599] At room temperature, the intermediate I-113 (650 mg) was dissolved in ethanol (10.0 mL), cooled to 0°C in an ice-water bath, and thionyl chloride (0.676 mL, 9.26 mmol) was slowly added with a syringe, and the temperature was slowly raised to room temperature, and then heated under reflux for 4 hours. Concentrated, saturated sodium bicarbonate solution (10.0 mL) was added to the residual liquid, and then extracted with ethyl acetate (30.0 mL × 2), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-114.

[0600] LC-MS(ESI)[M+H] + 204.1.

[0601] Reference Example 115: Preparation of Intermediate I-115

[0602]

[0603] At room temperature, the 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 stirred overnight at 50°C. The reaction solution was cooled to room temperature, and water (10.0 mL) was added first, and then extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel chromatography to obtain the intermediate I-115.

[0604] LC-MS(ESI)[M+H] + 283.1.

[0605] Reference Example 116: Preparation of Intermediate I-116

[0606]

[0607] At room temperature, the 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 stirred overnight at room temperature. Water (5.00 mL) was added first, followed by washing with ethyl acetate (3.00 mL), the aqueous phase was adjusted to pH 2.0 with 2N dilute hydrochloric acid, and then extracted with ethyl acetate (8 mL × 2), the combined extracts were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude intermediate I-116. The crude product was used directly in the next step without purification.

[0608] LC-MS(ESI)[M+H] + 255.1.

[0609] Reference Example 117: Preparation of Intermediate I-117

[0610]

[0611] The intermediate I-116 (130 mg) was dissolved in N, N-dimethylformamide (10 mL), and 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) were added in sequence. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (2 mL × 3) and dried to obtain the intermediate I-117.

[0612] LC-MS(ESI)[M+H] + 515.0.

[0613] Reference Example 118: Preparation of Intermediate I-118

[0614]

[0615] Dissolve the intermediate I-117 (100 mg, 0.194 mmol) in anhydrous dichloromethane (15.0 mL), cool the system to 0 ° C, and add Dess-Martin oxidant (123 mg, 0.291 mmol). The reaction system is protected by argon and stirred at room temperature for 2 hours. Filter, quench the filtrate with saturated sodium bicarbonate aqueous solution (20.0 mL), and extract with dichloromethane (15.0 mL × 3). Combine the organic phases, wash with saturated brine (10.0 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain the crude product intermediate I-118. The crude product is used directly in the next step without purification.

[0616] Reference Example 119: Preparation of Intermediate I-119

[0617]

[0618] 5-Bromopyridine-2-carboxylic acid methyl ester (10.0 g, 46.3 mmol) was dissolved in anhydrous toluene (200 mL), and 4-piperidinol (10.7 g, 92.6 mmol), anhydrous potassium carbonate (19.2 g, 139 mmol), tris(dibenzylideneacetone)dipalladium (848 mg, 0.926 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (864 mg, 1.85 mmol) were added in sequence, and the mixture was stirred at 100°C under argon protection for 16 hours. The mixture was cooled and filtered, the filter cake was washed with dichloromethane (100 mL), the filtrate was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-119.

[0619] LC-MS(ESI)[M+H] + 251.2.

[0620] Reference Example 120: Preparation of Intermediate I-120

[0621]

[0622] Dissolve the intermediate I-119 (300 mg, 1.20 mmol) in anhydrous tetrahydrofuran (30.0 mL), add N-bromosuccinimide (214 mg, 1.20 mmol), and stir at room temperature for 16 hours under argon protection. The reaction solution is concentrated and separated and purified by silica gel chromatography to obtain the intermediate I-120.

[0623] Reference Example 121: Preparation of Intermediate I-121

[0624]

[0625] Dissolve the intermediate I-120 (220 mg, 0.668 mmol) in anhydrous dimethyl sulfoxide (10.0 mL), and add potassium fluoride (116 mg, 2.00 mmol). The reaction system is protected by argon and stirred at 150°C for 3 days. The mixture is cooled to room temperature, filtered, and separated and purified by preparative high performance liquid chromatography (formic acid conditions) to obtain intermediate I-121.

[0626] LC-MS(ESI)[M+H] + 255.2.

[0627] Reference Example 122: Preparation of Intermediate I-122

[0628]

[0629] At room temperature, the intermediate I-121 (35 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (5 mL) solution, and 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) were added in sequence, and the reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added for dilution, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain the intermediate I-122.

[0630] LC-MS(ESI)[M+H] + 515.0.

[0631] Reference Example 123: Preparation of Intermediate I-123

[0632]

[0633] At room temperature, the intermediate I-122 (30 mg, 0.058 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodoacylbenzoic acid (81 mg, 0.29 mmol) was added. After the addition was completed, the reaction mixture was stirred at 80°C for 1 hour. Water (10 mL) was added for dilution, and ethyl acetate (20 mL × 3) was used for extraction. The combined organic phases were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate I-123. The crude product was used directly in the next step without further purification.

[0634] Reference Example 124: Preparation of Intermediate I-124

[0635]

[0636] At 25°C, 4-bromophthalic anhydride (20.0 g, 88.1 mmol) was dissolved in glacial acetic acid (200 mL), 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 generate a large amount of white solid, and the temperature was raised to 120°C for reaction for 1 hour. After cooling to room temperature, the mixture was filtered and the filter cake was rinsed with water (200 mL) and ethyl acetate (200 mL) respectively. The filter cake was collected and dried to obtain intermediate I-124.

[0637] LC-MS(ESI)[M+H] + 243.0.

[0638] Reference Example 125: Preparation of Intermediate I-125

[0639]

[0640] At 25°C, I-124 (16.2 g, 67.2 mmol) was dissolved in phosphorus oxychloride (100 mL), heated to 100°C and reacted for 3 hours. After cooling, the crude product was spin-dried and dissolved in ethyl acetate (200 mL), added to water (200 mL), and a white solid precipitated. The filter cake was filtered and rinsed with ethyl acetate (200 mL) and dried. The organic phase of the filtrate was separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained by combining the filter cake and the organic phase concentration was obtained to obtain the intermediate I-125.

[0641] LC-MS(ESI)[M+H] + 277.0.

[0642] Reference Example 126: Preparation of Intermediate I-126

[0643]

[0644] At 25°C, I-125 (8.00 g, 28.8 mmol) was dissolved in N, N-dimethylacetamide (100 mL), potassium fluoride (8.36 g, 143.9 mmol), 18-crown ether-6 (3.04 g, 11.5 mmol) were added, and the temperature was raised to 120°C for 16 hours. After cooling, water (200 mL) was added. The above reaction solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate I-126.

[0645] LC-MS(ESI)[M+H] + 247.0.

[0646] Reference Example 127: Preparation of Intermediate I-127

[0647]

[0648] At 25°C, I-126 (1.50 g, 6.12 mmol) was dissolved in dimethyl sulfoxide (25 mL) and water (5 mL), and the temperature was raised to 100°C for 5 hours. After cooling, water (200 mL) was added to the reaction solution, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-127.

[0649] LC-MS(ESI)[M+H] + 245.0.

[0650] Reference Example 128: Preparation of Intermediate I-128

[0651]

[0652] At 25°C, N-tert-butyloxycarbonylpiperazine (1.50 g, 8.03 mmol), tris(dibenzylideneacetone)dipalladium (494.49 mg, 0.54 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (666.28 mg, 1.07 mmol), sodium tert-butoxide (1.29 g, 13.38 mmol) were added to a solution of I-127 (1.30 g, 5.35 mmol) in N,N-dimethylacetamide (20 mL) in sequence. The temperature was raised to 85°C and the reaction was continued for 2 hours. After cooling, water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-128.

[0653] LC-MS(ESI)[M+H] + 349.2.

[0654] Reference Example 129: Preparation of Intermediate I-129

[0655]

[0656] At 25°C, I-128 (330 mg, 0.95 mmol) was dissolved in tetrahydrofuran (10 mL), and 3-bromo-2,6-piperidindione (364 mg, 1.89 mmol), sodium hydrogen hydride (75.8 mg, 1.89 mmol, 60%), and potassium iodide (314 mg, 1.89 mmol) were added to the above solution in sequence, and the temperature was raised to 60°C for reaction for 3 hours. After cooling, saturated aqueous ammonium chloride solution (20 mL) was added to the above reaction solution, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate I-129.

[0657] LC-MS(ESI)[M+H] + 460.2.

[0658] Reference Example 130: Preparation of Intermediate I-130

[0659]

[0660] Trifluoroacetic acid (5 mL) was added to a solution of I-129 (220 mg, 0.48 mmol) in dichloromethane (10 mL) at 25°C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain intermediate I-130.

[0661] LC-MS(ESI)[M+H] + 360.2.

[0662] Reference Example 131: Preparation of Intermediate I-131

[0663]

[0664] The intermediate I-4 (22.0 g, 134 mmol) was dissolved in anhydrous DMSO (500 mL), and 1-tert-butyloxycarbonylpiperazine (37.4 g, 201 mmol) and diisopropylethylamine (52.0 g, 402 mmol) were added in sequence. The reaction system was heated to 140 ° C and stirred for 24 hours under argon protection. The mixture was cooled to room temperature and poured into water (1000 mL). A large amount of solid was precipitated, filtered, and the filter cake was collected and purified by slurrying with ethyl acetate (300 mL) for 16 hours. Filtered and dried to obtain the intermediate compound I-131.

[0665] LC-MS(ESI)[M+H] + 331.1.

[0666] Reference Example 132: Preparation of Intermediate I-132

[0667]

[0668] 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 was stirred at 40 ° C for 48 hours. After cooling to room temperature, water (10 mL) was added for dilution and extraction was performed with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 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.

[0669] LCMS(ESI)[M+H] + 409.2.

[0670] Reference Example 133: Preparation of Intermediate I-133

[0671]

[0672] 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. 3-bromo-2,6-piperidindione (422 mg, 2.20 mmol) and potassium iodide (200 mg) were added, and the reaction was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution to dilute it, and it was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 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.

[0673] LCMS(ESI)[M+H] + 520.2.

[0674] Reference Example 134: Preparation of Intermediate I-134

[0675]

[0676] I-134 (134 mg, 0.26 mmol), potassium cyclopropyl fluoroborate (114 mg, 0.78 mmol), 1,1'-bis(diphenylphosphinoferrocene)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 subjected to microwave reaction at 100 °C for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 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.

[0677] LCMS(ESI)[M+H] + 482.2.

[0678] Reference Example 135: Preparation of Intermediate I-135

[0679]

[0680] 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 was stirred at room temperature for 3 hours. The organic solvent was removed by concentration under reduced pressure to obtain the intermediate compound I-135, which was directly used for the next step without purification.

[0681] LCMS(ESI)[M+H] + 382.2.

[0682] Reference Example 136: Preparation of Intermediate I-136

[0683]

[0684] At room temperature, I-132 (1.00 g, 2.44 mmol) was dissolved in N, N-dimethylacetamide (15 mL), and cuprous cyanide (656 mg, 7.33 mmol) was added, and microwave reaction was performed at 140°C for 16 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (100 mL), and the filtrate was collected. The filtrate was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate I-136.

[0685] LC-MS(ESI)[M+H] + 356.2.

[0686] Reference Example 137: Preparation of Intermediate I-137

[0687]

[0688] At room temperature, I-136 (550 mg, 1.55 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydrogen (124 mg, 3.10 mmol, 60%), potassium iodide (514 mg, 3.10 mmol), 3-bromo-2,6-piperidindione (594 mg, 3.10 mmol) were added in sequence, and stirred at 60°C for 3 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain intermediate I-137.

[0689] LC-MS(ESI)[M+H] + 467.2.

[0690] Reference Example 138: Preparation of Intermediate I-138

[0691]

[0692] At room temperature, I-137 (200 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and stirred for 1 hour. The mixture was directly concentrated under reduced pressure to obtain intermediate I-138, which was directly used in the next step without purification.

[0693] LC-MS(ESI)[M+H] + 367.2.

[0694] Reference Example 139: Preparation of Intermediate I-139

[0695]

[0696] 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 was stirred at 100 ° C for 16 hours. Water (10 mL) was added to the reaction solution to dilute it, and the pH was adjusted to greater than 7 with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography as intermediate I-139.

[0697] LCMS(ESI)[M+H] + 241.2.

[0698] Reference Example 140: Preparation of Intermediate I-140

[0699]

[0700] 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), and (trifluoromethyl) trimethylsilane (2.48 g, 17.5 mmol) was added dropwise at 0°C. The reaction was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-140.

[0701] LCMS(ESI)[M+H] + 265.0.

[0702] Reference Example 141: Preparation of Intermediate I-141

[0703]

[0704] 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 reaction was stirred at 80 ° C for 5 hours. Water (10 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (20 mL × 3). After the organic phase was combined, it was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-140.

[0705] LCMS(ESI)[M+H] + 233.0.

[0706] Reference Example 142: Preparation of Intermediate I-142

[0707]

[0708] At room temperature, I-141 (410 mg, 1.77 mmol), 1-tert-butyloxycarbonylpiperazine (493 mg, 2.64 mmol) and N,N-diisopropylethylamine (460 mg, 3.54 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the reaction was stirred at 140 ° C for 16 hours. Water (10 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-142. LCMS (ESI) [M + H] + 399.2.

[0709] Reference Example 143: Preparation of Intermediate I-143

[0710]

[0711] 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. 3-bromo-2,6-piperidindione (320 mg, 1.66 mmol) and potassium iodide (100 mg) were added, and the reaction was stirred at 70°C for 24 hours. Water (10 mL) was added to the reaction solution to dilute it, and it was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-143.

[0712] LCMS(ESI)[M+H] + 510.2.

[0713] Reference Example 144: Preparation of Intermediate I-144

[0714]

[0715] 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 was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain the crude product I-144. It was used directly in the next step without purification.

[0716] LCMS(ESI)[M+H] + 410.2.

[0717] Preparation of Example:

[0718] Example 1: Preparation of Compound 1

[0719]

[0720] 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-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (19 mg, 0.051 mmol) was added. The reaction solution was stirred at room temperature overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was separated and purified by preparative HPLC (containing formic acid) to obtain compound 1.

[0721] LC-MS(ESI)[M+H] + m / z = 819.4.

[0722] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.24(s,1H),8.04(d,J=9.0Hz,1H),7.90(d,J=8.7Hz,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=12.1,5.4Hz,1H),4.32(s,1H),4. 05(d,J=9.2Hz,1H),3.86(d,J=12.5Hz,2H),3.42(t,J=5.0Hz,4H),2.99–2.86(m,1H),2.80(t,J=12.0Hz,2H),2 .65–2.52(m,6H),2.22(d,J=6.7Hz,2H),2.13–2.03(m,1H),1.84–1.75(m,3H),1.25–1.20(m,8H),1.13(s,6H).

[0723] Example 2: Preparation of Compound 2

[0724]

[0725] At room temperature, the 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 the intermediate I-7 (50.0 mg), sodium acetate (60.0 mg, 0.735 mmol) and sodium acetate borohydride (93.0 mg, 0.441 mmol). After the addition was completed, the mixture was stirred at room temperature overnight. Diluted with dichloromethane (10.0 mL), saturated sodium bicarbonate solution (10.0 mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (20 mL × 2), the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 2.

[0726] LC-MS(ESI)[M+H] + 821.4.

[0727] 1H NMR (400MHz, CDCl3) δ8.70(s,2H),8.25(d,J=9.0Hz,1H),8.04(s,1H),7.97(s,1H),7.57(d,J=8.7Hz,1H),7.38 –7.28(m,2H),6.96(d,J=2.3Hz,1H),6.89(s,1H),6.80(dd,J=8.8,2.4Hz,1H),5.92(d,J=8.1Hz,1H),5.82(s,1 H),4.87(d,J=11.9Hz,2H),4.13(d,J=7.9Hz,1H),4.04(s,1H),3.51–3.34(m,4H),2.95(dd,J=27.0,16.0Hz,3H ),2.78(d,J=13.2Hz,2H),2.61(s,4H),2.29(d,J=6.9Hz,3H),1.92(d,J=11.3Hz,4H),1.25(s,6H),1.21(s,6H).

[0728] Example 3: Preparation of Compound 3

[0729]

[0730]

[0731] Dissolve the intermediate I-20 (90 mg, 0.170 mmol) in a mixed solvent of anhydrous dichloromethane and methanol (10 mL / 10 mL), add the intermediate I-7 (58 mg, 0.170 mmol), protect the system with argon, and stir at room temperature for 0.5 hours. Add sodium acetate borohydride (108 mg, 0.510 mmol) in batches, protect the system with argon, and stir at room temperature for 3 hours. After concentration, add water (20 mL) to dilute and extract with dichloromethane (20 mL×3). Combine the organic phases, wash with saturated brine (30 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is then separated and purified by preparative HPLC (containing formic acid) to obtain compound 3.

[0732] LC-MS(ESI)[M+H] + 853.3.

[0733] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.25(s,1H),8.11(d,J=8.7Hz,1H),8.05(d,J=9.0Hz,1H),7.75(d,J=8.8Hz,2H),7.54– 7.47(m,2H),7.40(d,J=2.4Hz,1H),7.32–7.23(m,2H),6.96(d,J=9.0Hz,2H),5.75(dd,J=12.0,5.3Hz,1H),4.40(s,1H),4.08( d,J=9.1Hz,1H),3.87(d,J=12.5Hz,2H),3.42(d,J=4.4Hz,6H),2.97–2.86(m,1H),2.80(t,J=11.8Hz,2H),2.64–2.58(m,1H),2 .53(d,J=4.7Hz,3H),2.22(d,J=6.5Hz,2H),2.14–2.04(m,1H),1.82(d,J=10.3Hz,3H),1.23(s,6H),1.19(s,2H),1.14(s,6H).

[0734] Example 4: Preparation of Compound 4

[0735]

[0736] The intermediate I-24 (100 mg) was dissolved in dichloromethane and methanol (5 mL / 1 mL), and the intermediate I-7 (68 mg) and sodium acetate (49 mg, 0.60 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 30 minutes, and sodium acetate borohydride (127 mg, 0.60 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature for overnight reaction. Water (10 mL) was added for dilution, and the layers were separated and separated. The organic phase was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with water (10 mL × 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.

[0737] LC-MS(ESI)[M+H] + 820.2.

[0738] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.62(d,J=2.4Hz,1H),8.24(s,1H),8.04(d,J=9.0Hz,1H),7.96–7.88(m,2H),7.58(d,J= 9.3Hz,1H),7.50(dd,J=9.1,2.2Hz,1H),7.25(d,J=2.2Hz,1H),7.21(d,J=2.4Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),6.86(d,J=9. 2Hz,1H),5.75(dd,J=11.9,5.3Hz,1H),4.42(d,J=13.1Hz,2H),4.30(s,1H),4.05(d,J=9.2Hz,1H),3.42(s,4H),2.92(t,J=12.5 Hz,3H),2.65–2.51(m,6H),2.21(d,J=7.0Hz,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).

[0739] Example 5: Preparation of Compound 5

[0740]

[0741] The intermediate I-28 (110 mg) was dissolved in dichloromethane and methanol (5 mL / 1 mL), and the intermediate I-7 (74 mg) and sodium acetate (53 mg, 0.65 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 30 minutes, and sodium acetate borohydride (137 mg, 0.65 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature for overnight reaction. Water (10 mL) was added for dilution, and the layers were separated and separated. The organic phase was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with water (10 mL × 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.

[0742] LC-MS(ESI)[M+H] + 837.2.

[0743] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.25(s,1H),8.04(d,J=9.0Hz,1H),7.91(d,J=8.7Hz,1H),7.71–7.59(m,3H),7 .50(d,J=9.7Hz,1H),7.28–7.18(m,2H),7.09(t,J=8.9Hz,1H),7.01(dd,J=8.8,2.3Hz,1H),5.75(dd,J=12.0,5.2Hz,1 H),4.32(s,1H),4.06(d,J=9.3Hz,1H),3.58–3.43(m,8H),3.00–2.85(m,2H),2.76(t,J=11.1Hz,2H),2.69–2.58(m,2 H),2.26(d,J=6.7Hz,2H),2.08(d,J=4.8Hz,1H),1.90–1.71(m,4H),1.30(d,J=10.3Hz,2H),1.22(s,6H),1.13(s,6H).

[0744] Example 6: Preparation of Compound 6

[0745]

[0746] The intermediate I-33 (50 mg, 0.097 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), and the intermediate I-7 (33.1 mg, 0.097 mmol) was added. The system was protected by argon and stirred at room temperature for 0.5 hours. Sodium acetate borohydride (61.7 mg, 0.291 mmol) was added in batches, the system was protected by argon, and stirred at room temperature for 3 hours. The mixture was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by silica gel chromatography to obtain compound 6.

[0747] LC-MS(ESI)[M+H] + 838.2.

[0748] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.25(s,1H),8.05(d,J=9.0Hz,1H),7.97–7.86(m,2H),7.50(dd,J=9.1,2.1Hz,1H),7.33 (t,J=7.7Hz,1H),7.24(dd,J=10.6,2.2Hz,2H),7.02(dd,J=8.8,2.4Hz,1H),6.78(dd,J=8.7,2.3Hz,1H),5.75(dd,J=12.0,5.4 Hz,1H),4.31(d,J=12.7Hz,3H),3.94(d,J=8.4Hz,1H),3.46(s,5H),2.93(ddd,J=18.3,16.4,8.7Hz,3H),2.68–2.54(m,3H),2. 21(d,J=7.0Hz,2H),2.13–2.06(m,1H),1.94–1.76(m,3H),1.24(t,J=13.1Hz,2H),1.19(s,6H),1.12(s,6H),1.10–1.02(m,2H).

[0749] Example 7: Preparation of Compound 7

[0750]

[0751] The intermediate I-37 (60 mg, 0.127 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), and the intermediate I-7 (43.3 mg) was added in sequence, the system was protected by argon, and the reaction was stirred at room temperature for 0.5 hours. Sodium acetate borohydride (80.7 mg, 0.381 mmol) was added in batches, the system was protected by argon, and the reaction was stirred at room temperature for 3 hours. The mixture was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by silica gel chromatography to obtain the target compound 7.

[0752] LC-MS(ESI)[M+H] + 799.2.

[0753] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.25(s,1H),8.05(d,J=9.0Hz,1H),7.72(dd,J=16.6,8.7Hz,3H),7.53–7.46(m,2H ),7.25(d,J=1.9Hz,1H),6.95(dd,J=11.3,5.5Hz,3H),6.82(dd,J=8.6,2.4Hz,1H),5.75(dd,J=12.0,5.3Hz,1H),4.24(s, 1H),4.04(d,J=9.1Hz,1H),3.86(d,J=12.5Hz,2H),3.49(d,J=31.4Hz,4H),2.96–2.75(m,3H),2.66–2.53(m,4H),2.45(s ,3H),2.22(d,J=6.5Hz,2H),2.12–1.96(m,2H),1.82(d,J=10.5Hz,3H),1.27(d,J=29.8Hz,3H),1.22(s,6H),1.13(s,6H).

[0754] Example 8: Preparation of Compound 8

[0755]

[0756] At room temperature, intermediate I-41 (100 mg, 0.202 mmol), intermediate 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). Sodium acetate borohydride (128 mg, 0.605 mmol) was added under stirring under argon protection. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with dichloromethane (20 mL×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 one molecule of formate).

[0757] LC-MS(ESI)[M+H] + 821.2.

[0758] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.46(s,1H),8.27-8.20(m,2H),8.04(d,J=9.0Hz,1H) ,7.91(d,J=8.8Hz,1H),7.82(d,J=9.6Hz,1H),7.50(d,J=7.2Hz,1H),7.37(d,J=9.7Hz,1H), 7.25(d,J=2.2Hz,2H),7.04(dd,J=8.8,2.3Hz,1H),5.75(dd,J=12.0,5.2Hz,1H),4.57–4.43 (m,3H),4.01(d,J=9.1Hz,1H),3.43(s,4H),3.05(t,J=12.0Hz,3H),2.97–2.86(m,1H),2.69 -2.52(m,6H),2.23(d,J=7.0Hz,2H),2.13-1.92(m,3H),1.86(d,J=12.1Hz,2H),1.22(s,6H),1.14(s,6H).

[0759] Example 9: Preparation of Compound 9

[0760]

[0761] Dissolve the intermediate I-45 (50 mg, 0.101 mmol) in a mixed solvent of anhydrous dichloromethane and methanol (5 mL / 5 mL), add the intermediate I-7 (34.5 mg), protect the system with argon, and stir at room temperature for 0.5 hours. Add sodium acetate borohydride (64 mg, 0.303 mmol) in batches, protect the system with argon, and stir at room temperature for 3 hours. After concentration, add water (20 mL) to dilute and extract with dichloromethane (20 mL×3). Combine the organic phases, wash with saturated brine (30 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is then separated and purified by preparative HPLC (containing formic acid) to obtain compound 9.

[0762] LC-MS(ESI)[M+H] + 820.3.

[0763] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.34(d,J=2.4Hz,1H),8.25(s,1H),8.07(dd,J=17.5,9.0Hz,2H),7.90(d,J=8.7H z,1H),7.84(d,J=8.8Hz,1H),7.54–7.48(m,1H),7.42(dd,J=8.9,2.6Hz,1H),7.25(d,J=2.2Hz,2H),7.04(dd,J=8.8,2.3 Hz,1H),5.76(dd,J=11.9,5.3Hz,1H),4.43(s,1H),3.95(d,J=9.1Hz,3H),3.44(s,6H),2.97–2.83(m,3H),2.67–2.53(m ,4H),2.22(d,J=6.4Hz,2H),2.13–2.04(m,1H),1.83(d,J=10.2Hz,3H),1.22(d,J=6.5Hz,2H),1.20(s,6H),1.13(s,6H).

[0764] Example 10: Preparation of Compound 10

[0765]

[0766] 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, and then sodium acetate borohydride (102 mg, 0.481 mmol) was added, and then the mixture was stirred at room temperature for 16 hours. After concentration, water (20 mL) was added for dilution, and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was then separated and purified by preparative HPLC (containing formic acid) to obtain compound 10.

[0767] LC-MS(ESI)[M+H] + 821.1.

[0768] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.61(d,J=0.9Hz,1H),8.34(s,1H),8.25(s,1H),8.04(d,J=9.0Hz,1H),7.9 0(d,J=8.7Hz,1H),7.81(d,J=9.0Hz,1H),7.53–7.46(m,1H),7.25(d,J=2.5Hz,2H),7.03(dd,J=8.8,2.4Hz,1H),5 .75(dd,J=12.0,5.3Hz,1H),4.49(d,J=13.0Hz,2H),4.43(s,1H),3.96(d,J=9.0Hz,1H),3.43(s,6H),3.09–2.87( m,4H),2.65–2.52(m,5H),2.22(d,J=7.0Hz,2H),2.14–2.04(m,1H),1.98–1.79(m,3H),1.19(s,6H),1.13(s,6H).

[0769] Example 11: Preparation of Compound 11

[0770]

[0771] 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 acetate borohydride (34.3 mg, 0.162 mmol) were added and the reaction mixture was stirred at room temperature for 3 hours. The reaction system was concentrated, and 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.

[0772] LC-MS(ESI)[M+H] + 819.5.

[0773] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.26(s,1H),7.91(d,J=8.8Hz,1H),7.79(d,J=8.9Hz,1H),7.74(d,J=8.9Hz,2H),7.62( dd,J=9.0,2.5Hz,1H),7.49(t,J=6.1Hz,2H),7.21(d,J=2.4Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),6.96(d,J=9.0Hz,2H),5.76( dd,J=12.0,5.2Hz,1H),4.32(s,1H),4.05(d,J=9.2Hz,1H),3.86(d,J=12.9Hz,2H),3.41(s,4H),2.98–2.86(m,1H),2.80(t,J =11.7Hz,2H),2.69–2.52(m,6H),2.23(d,J=6.4Hz,2H),2.14–2.04(m,1H),1.92-1.78(m,3H),1.28-1.18(m,8H),1.13(s,6H).

[0774] Example 12: Preparation of Compound 12

[0775]

[0776] Dissolve the intermediate I-56 (89.4 mg, 0.181 mmol) in a mixed solvent of dichloromethane / methanol (10.0 mL / 2.00 mL), add the intermediate I-61 (80.0 mg), anhydrous sodium acetate (74.2 mg, 0.905 mmol), sodium acetate borohydride (76.7 mg, 0.362 mmol). The reaction system was protected by argon and stirred at room temperature for 2 hours. Dilute with dichloromethane (50.0 mL), wash with water (20.0 mL × 2), separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 12.

[0777] LC-MS(ESI)[M+H] + 819.4.

[0778] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.43(s,1H),7.91(dd,J=8.2,6.3Hz,2H),7.80(t,J=7.9Hz,1H),7.74(d,J=8.8 Hz,2H),7.57(d,J=7.6Hz,1H),7.48(d,J=9.2Hz,1H),7.21(d,J=2.4Hz,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=9.1Hz,1H),3.86(d,J=12.3Hz,2H),3.08(s,4H),3.01–2.86(m,2H),2.79(t,J=11.7H z,3H),2.69–2.54(m,6H),2.27(d,J=6.4Hz,2H),2.17–2.09(m,1H),1.82(d,J=12.3Hz,3H),1.22(s,6H),1.13(s,6H).

[0779] Example 13: Preparation of Compound 13

[0780]

[0781] The intermediate I-65 (80.0 mg) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), and the intermediate I-7 (58.8 mg) was added. The system was stirred at room temperature for 0.5 hours under argon protection. Sodium acetate borohydride (109 mg, 0.516 mmol) was added in batches, the system was argon protected, and the reaction was stirred at room temperature for 3 hours. The mixture was washed with water (15.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was separated and purified by preparative HPLC (containing formic acid) to obtain compound 13.

[0782] LC-MS(ESI)[M+H] + 791.4.

[0783] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.25(s,1H),8.01(dd,J=28.8,8.2Hz,2H),7.85(d,J=8.8Hz,1H),7.73(d, J=8.6Hz,2H),7.50(d,J=8.2Hz,1H),7.37(d,J=1.9Hz,1H),7.25(s,1H),7.16–7.11(m,1H),6.93(d,J=8.7Hz,2H ),5.75(dd,J=11.7,5.1Hz,1H),4.53(s,1H),3.89–3.60(m,7H),2.97–2.86(m,1H),2.77(t,J=11.7Hz,2H),2.66 –2.52(m,5H),2.16(dd,J=45.6,7.3Hz,5H),1.93–1.74(m,5H),1.51(dd,J=19.8,10.1Hz,4H),1.27–1.10(m,3H).

[0784] Example 14: Preparation of Compound 14

[0785]

[0786] 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). Sodium acetate borohydride (122 mg, 0.577 mmol) was added under stirring under argon protection. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with dichloromethane (20 mL×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.

[0787] LC-MS(ESI)[M+H] + 793.1.

[0788] 1H NMR (400MHz, CD3OD) δ8.72(s,2H),8.22(s,1H),8.15(d,J=9.1Hz,1H),7.69(d,J=8.8Hz ,1H),7.49(dd,J=9.1,2.4Hz,1H),7.19(d,J=2.4Hz,2H),7.03(dd,J=8.8,2.4Hz,1H),5 .79(dd,J=11.8,5.4Hz,1H),4.50-4.40(m,1H),3.98-3.85(m,1H),3.53-3.46(m,4H),3 .00(t,J=11.6Hz,2H),2.96-2.67(m,4H),2.67-2.57(m,4H),2.32(d,J=6.9Hz,2H),2.28 -2.14(m,4H),2.10-1.88(m,6H),1.71-1.47(m,5H).

[0789] Example 15: Preparation of Compound 15

[0790]

[0791] Dissolve the intermediate I-71 (40 mg, 0.091 mmol) in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), add the intermediate I-7 (31 mg), protect the system with argon, and stir at room temperature for 0.5 hours. Add sodium acetate borohydride (58 mg, 0.273 mmol) in batches, protect the system with argon, and stir at room temperature for 3 hours. After concentration, add water (20 mL) to dilute and extract with dichloromethane (20 mL×3). Combine the organic phases, wash with saturated brine (30 mL), and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product. The crude product is then separated and purified by preparative HPLC (containing formic acid) to obtain compound 15.

[0792] LC-MS(ESI)[M+H] + 763.2.

[0793] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.24(s,1H),8.04(d,J=9.0Hz,1H),7.91(d,J=7.6Hz,1H),7.86(d,J=8.8Hz,1H),7.72(d, J=8.6Hz,2H),7.50(dd,J=9.1,2.1Hz,1H),7.38(d,J=2.4Hz,1H),7.26(d,J=2.1Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),6.40(d,J= 8.7Hz,2H),5.75(dd,J=12.0,5.3Hz,1H),4.53(s,1H),4.01(t,J=7.6Hz,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=12.9,5.4Hz,3H),2.55(d,J=7.7Hz,5H),2.15–2.04(m,3H),1.89(d,J=9.1Hz,2H),1.59–1.43(m,4H).

[0794] Example 16: Preparation of Compound 16

[0795]

[0796] The intermediate I-75 (80.0 mg, 0.167 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (6.00 mL / 2.00 mL), and the intermediate I-7 (91.1 mg) and anhydrous sodium acetate (68.5 mg, 0.835 mmol) were added. The reaction system was protected by argon and stirred at room temperature for 0.5 hours. Sodium acetate borohydride (70.8 mg, 0.334 mmol) was added. The reaction system was protected by argon and stirred at room temperature for 2 hours. Diluted with dichloromethane (50.0 mL), washed with water (10.0 mL×2), separated the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 16.

[0797] LC-MS(ESI)[M+H] + 805.1.

[0798] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.25(s,1H),8.04(d,J=9.0Hz,1H),7.90(d,J=8.8Hz,1H),7.74(d,J=8.8Hz,2H),7.51(dd, J=9.2,2.2Hz,1H),7.39(d,J=9.2Hz,1H),7.26(d,J=2.2Hz,1H),7.21(d,J=2.4Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),6.55(d,J=8. 9Hz,2H),5.75(dd,J=12.1,5.5Hz,1H),4.32(s,1H),4.05(d,J=9.1Hz,1H),3.47–3.43(m,4H),3.06(dd,J=9.6,7.0Hz,2H),2.99– 2.83(m,2H),2.67–2.54(m,6H),2.42(d,J=5.0Hz,2H),2.18–2.00(m,3H),1.75(dd,J=12.1,8.0Hz,2H),1.22(s,6H),1.13(s,6H).

[0799] Example 17: Preparation of Compound 17

[0800]

[0801] The intermediate I-77 (190 mg) was dissolved in a mixed solvent of dichloromethane / methanol (10.0 mL / 3.00 mL), and the intermediate I-56 (241 mg, 0.487 mmol) and anhydrous sodium acetate (167 mg, 2.03 mmol) were added. The reaction system was protected by argon and stirred at room temperature for 2 hours. Diluted with dichloromethane (50.0 mL), washed with water (10.0 mL × 2), separated the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 17.

[0802] LC-MS(ESI)[M+H] + 831.2.

[0803] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.19(s,1H),8.00(d,J=8.9Hz,1H),7.90(d,J=8.8Hz,1H),7.71(d,J=8.9Hz,2H),7.48(d,J=9 .3Hz,1H),7.20(d,J=2.4Hz,1H),7.13(d,J=7.5Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),6.93(d,J=9.0Hz,2H),6.88(s,1H),5.74(dd,J= 11.9,5.2Hz,1H),4.55(s,1H),4.31(s,1H),4.04(d,J=9.2Hz,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=10.4,4.4Hz,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).

[0804] Example 18: Preparation of Compound 18

[0805]

[0806] 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). After the reaction mixture was stirred at room temperature for half an hour, sodium triacetyl borohydride (54.3 mg, 0.256 mmol) was added. The reaction mixture was stirred at room temperature for two 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.

[0807] LC-MS(ESI)[M+H] + 833.2.

[0808] 1H NMR (400MHz, CDCl3) δ8.24(d,J=9.0Hz,1H),8.03(s,1H),8.01(s,1H),7.68(d,J=8.8Hz,2H),7.56(d,J=8.7Hz,1H),6.96(d,J= 2.4Hz,1H),6.92(d,J=8.9Hz,2H),6.84(s,1H),6.81(dd,J=8.7,2.4Hz,1H),6.11(d,J=8.1Hz,1H),5.83(dd,J=11.1,5.3Hz,1H) ,4.25–4.18(m,1H),4.15(d,J=8.1Hz,1H),4.04(s,1H),3.86(d,J=12.6Hz,2H),3.55(d,J=11.8Hz,1H),3.25(t,J=11.8Hz,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=12.2Hz,3H),1.26(s,6H),1.22(s,6H).

[0809] Example 19: Preparation of Compound 19

[0810]

[0811] 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). After the reaction mixture was stirred at room temperature for half an hour, sodium triacetyl borohydride (40.7 mg, 0.192 mmol) was added. The reaction mixture was stirred at room temperature for two 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.

[0812] LC-MS(ESI)[M+H] + 833.2.

[0813] 1H NMR (400MHz, CDCl3) δ8.24(d,J=9.0Hz,1H),8.03(s,1H),7.99(s,1H),7.68(d,J=8.6Hz,2H),7.56(d,J=8.8Hz,1H),6.96(d,J= 2.4Hz,1H),6.92(d,J=8.7Hz,2H),6.84(s,1H),6.81(dd,J=8.7,2.4Hz,1H),6.11(d,J=8.1Hz,1H),5.83(dd,J=11.1,5.3Hz,1H) ,4.25–4.17(m,1H),4.15(d,J=8.1Hz,1H),4.04(s,1H),3.86(d,J=12.5Hz,2H),3.55(d,J=11.9Hz,1H),3.25(t,J=11.9Hz,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=12.4Hz,3H),1.26(s,6H),1.22(s,6H).

[0814] Example 20: Preparation of Compound 20

[0815]

[0816] The intermediate I-83 (150 mg) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5.00 mL / 5.00 mL), and the intermediate I-7 (110 mg) was added. The system was protected by argon and stirred at room temperature for 0.5 hours. Sodium acetate borohydride (205 mg, 0.966 mmol) was added in batches, the system was protected by argon, and the reaction was stirred at room temperature for 3 hours. The mixture was washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was first separated and purified by silica gel chromatography, and then purified by slurrying with anhydrous acetonitrile (15.0 mL), filtered, and the filter cake was dried. Finally, it was separated and purified by preparative HPLC (containing formic acid) to obtain compound 20.

[0817] LC-MS(ESI)[M+H] + 791.2.

[0818] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.25(s,1H),8.05(d,J=8.9Hz,1H),7.90(d,J=8.7Hz,1H),7.74(d,J=8.4 Hz,2H),7.48(dd,J=24.3,8.9Hz,2H),7.28–7.18(m,2H),7.01(dd,J=8.7,1.9Hz,1H),6.44(d,J=8.4Hz,2H),5. 75(dd,J=12.0,5.2Hz,1H),4.32(s,1H),4.03(dd,J=16.4,8.4Hz,3H),3.61–3.55(m,4H),3.01(s,1H),2.93(dd ,J=21.7,9.0Hz,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).

[0819] Example 21: Preparation of Compound 21

[0820]

[0821] At room temperature, the 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 the intermediate I-7 (94.0 mg), sodium acetate (68.0 mg, 0.828 mmol) and sodium acetate borohydride (132 mg, 0.621 mmol), and stirred at room temperature overnight. Saturated sodium bicarbonate solution (10 mL) was added for dilution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (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.

[0822] LC-MS (ESI) m / z [M+H] + 807.1.

[0823] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.76(s,2H),8.25(s,1H),8.04(d,J=8.7Hz,1H),7.90(d,J=8.6 Hz,1H),7.71(d,J=9.2Hz,1H),7.51(d,J=8.8Hz,1H),7.24(d,J=19.5Hz,2H),7.01(d,J=8.6Hz,1H),5 .75(d,J=6.7Hz,1H),4.29(s,1H),4.04(d,J=9.4Hz,1H),3.75(dd,J=23.7,16.7Hz,3H),3.53–3.41(m ,7H),2.90(d,J=10.9Hz,1H),2.65–2.55(m,6H),2.43(s,2H),2.11(s,2H),1.22(s,6H),1.11(s,6H).

[0824] Example 22: Preparation of Compound 22

[0825]

[0826] The intermediate I-93 (100 mg, 0.207 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane / methanol (5 mL / 5 mL), and the intermediate I-7 (70.6 mg) was added. The system was protected by argon and stirred at room temperature for 0.5 hours. Sodium acetate borohydride (131.6 mg, 0.621 mmol) was added in batches, the system was protected by argon, and stirred at room temperature for 3 hours. The mixture was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain compound 22.

[0827] LC-MS (ESI) [M+H] + 807.4.

[0828] 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.68(s,2H),8.17(s,1H),7.97(d,J=9.0Hz,1H),7.81(d,J=8.7Hz,1H),7.64 (d,J=9.2Hz,1H),7.43(d,J=7.3Hz,1H),7.20–7.11(m,2H),6.92(dd,J=8.8,2.4Hz,1H),5.66(dd,J=11.9,5.3Hz,1H ),4.21(s,1H),3.96(d,J=9.2Hz,1H),3.73–3.56(m,3H),3.47–3.39(m,5H),3.20(dd,J=11.6,7.4Hz,3H),2.88–2. 78(m,1H),2.52(dd,J=24.8,8.2Hz,5H),2.11–1.85(m,3H),1.65(dq,J=15.9,7.9Hz,1H),1.13(s,6H),1.03(s,6H).

[0829] Example 23: Preparation of Compound 23

[0830]

[0831] The intermediate I-100 (70 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), and the intermediate I-7 (50 mg) and sodium acetate (35 mg, 0.42 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 30 minutes, and sodium acetate borohydride (89 mg, 0.42 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature for overnight reaction. After the reaction was completed, water (10 mL) was added for dilution, and the layers were allowed to stand to separate the organic phase. The aqueous phase was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with water (10 mL × 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.

[0832] LC-MS(ESI)[M+H] + 821.5.

[0833] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.76(s,2H),8.24(s,1H),8.04(d,J=9.1Hz,1H),7.90(d,J=8.7Hz,1H),7.69(d,J=9.3Hz,1H) ,7.50(d,J=9.1Hz,1H),7.26(s,1H),7.21(d,J=2.4Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),5.75(dd,J=12.1,5.0Hz,1H),4.29(s,1H), 4.04(d,J=9.1Hz,1H),3.83(dd,J=11.2,7.4Hz,1H),3.71(t,J=8.5Hz,1H),3.42(s,6H),3.17–3.09(m,1H),2.90(dd,J=21.4,9.1Hz ,1H),2.55(s,5H),2.42(s,2H),2.32(d,J=9.4Hz,1H),2.10(dd,J=18.7,14.0Hz,2H),1.71–1.60(m,3H),1.21(s,6H),1.11(s,6H).

[0834] Example 24: Preparation of Compound 24

[0835]

[0836] The intermediate I-104 (55 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), and the intermediate I-7 (34 mg) and sodium acetate (24 mg, 0.29 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 30 minutes, and sodium acetate borohydride (61 mg, 0.29 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature for overnight reaction. After the reaction was completed, water (10 mL) was added for dilution, and the organic phase was extracted with dichloromethane (10 mL × 2), and the organic phases were combined and washed with water (10 mL × 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.

[0837] LC-MS(ESI)[M+H] + 835.1.

[0838] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.75(s,2H),8.24(s,1H),8.04(d,J=9.0Hz,1H),7.90(d,J=8.8Hz,1H),7.70(d,J=9.2Hz,1H),7. 50(dd,J=9.2,2.3Hz,1H),7.25(d,J=2.2Hz,1H),7.22(d,J=2.4Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),5.75(dd,J=11.9,5.4Hz,1H),4.73 (d,J=13.2Hz,2H),4.29(s,1H),4.03(d,J=9.1Hz,1H),3.40(d,J=4.4Hz,6H),2.95(dd,J=21.7,8.3Hz,3H),2.64–2.52(m,4H),2.42–2. 36(m,2H),2.13–2.04(m,1H),1.79(d,J=12.5Hz,2H),1.67(s,1H),1.50–1.39(m,2H),1.21(s,6H),1.11(s,6H),1.07(d,J=10.8Hz,2H).

[0839] Example 25: Preparation of Compound 25

[0840]

[0841] The intermediate I-112 (90.0 mg, 0.176 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (10.0 mL / 3.00 mL), and the intermediate I-7 (96.1 mg) and anhydrous sodium acetate (72.2 mg, 0.880 mmol) were added. The reaction system was protected by argon and stirred at room temperature for 0.5 hours. Sodium acetate borohydride (74.6 mg, 0.352 mmol) was added. The reaction system was protected by argon and stirred at room temperature for 16 hours. Diluted with dichloromethane (50.0 mL), washed with water (20.0 mL × 2), separated the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by preparative HPLC (containing formic acid) to obtain compound 25.

[0842] LC-MS(ESI)[M+H] + 835.2.

[0843] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.76(s,2H),8.23(s,1H),8.03(d,J=9.0Hz,1H),7.90(d,J=8.8Hz,1H),7.72(d,J =9.2Hz,1H),7.48(dd,J=9.1,2.3Hz,1H),7.23(dd,J=7.6,2.3Hz,2H),7.01(dd,J=8.8,2.4Hz,1H),5.74(dd,J=12.0,5. 5Hz,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=13.7Hz,1H),1.73–1.57(m,2H),1.22(s,6H),1.11(s,6H).

[0844] Example 26: Preparation of Compound 26

[0845]

[0846] At room temperature, the 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 the intermediate I-7 (53.2 mg) and sodium acetate borohydride (99.2 mg, 0.468 mmol), and stirred at room temperature overnight. A saturated sodium bicarbonate solution (10.0 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated brine (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.

[0847] LC-MS(ESI)[M+H] + 838.1.

[0848] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.50(s,1H),8.24(s,1H),8.04(d,J=9.0Hz,1H),7.88(dd,J=19.9,5.3Hz,2H),7.73(d ,J=9.2Hz,1H),7.53–7.47(m,1H),7.23(dd,J=15.2,2.3Hz,2H),7.01(dd,J=8.8,2.4Hz,1H),5.75(dd,J=12.1,5.4Hz,1H),4 .31(s,1H),4.21(d,J=13.1Hz,2H),4.06(d,J=9.1Hz,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=6.9Hz,2H),2.12–2.04(m,1H),1.84(d,J=13.1Hz,3H),1.22(s,6H),1.17(d,J=15.4Hz,2H),1.12(s,6H).

[0849] Example 27: Preparation of Compound 27

[0850]

[0851] The intermediate I-123 (25 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), and the intermediate I-7 (17 mg) and sodium acetate (12 mg, 0.15 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 30 minutes, and then sodium acetate borohydride (32 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added for dilution, and the layers were separated and separated. The aqueous phase was extracted with dichloromethane (10 mL × 2), and the organic phases were combined and washed with water (10 mL × 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.

[0852] LC-MS(ESI)[M+H] + 838.2.

[0853] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.24(s,1H),8.04(d,J=9.5Hz,1H),7.90(d,J=8.8Hz,1H),7.86(d ,J=8.9Hz,1H),7.78(d,J=8.8Hz,1H),7.60(s,1H),7.53–7.48(m,1H),7.25(s,2H),7.03(d,J=8.7Hz,1H ),5.80–5.69(m,1H),4.47(s,1H),3.93(d,J=9.0Hz,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).

[0854] Example 28: Preparation of Compound 28A and Compound 28B

[0855]

[0856] Compound 1 (5 g) was subjected to chiral separation to give Compound 28A (Rt=10.206 min) and Compound 28B (Rt=13.352 min).

[0857] Chiral separation method:

[0858] Instrument: Shimadzu LC-20AP HPLC

[0859] Chromatographic column: ChiralPak IC, 300×50mm ID, 10μm

[0860] Mobile phase: A: methanol (0.1% ammonia) B: dichloromethane

[0861] Elution gradient: 70% B

[0862] Flow rate: 80mL / min

[0863] Column temperature: room temperature

[0864] Detection wavelength: 220nm

[0865] Cycle time: ~6min

[0866] Chiral analysis method:

[0867] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0868] Column: ChiralCel OJ, 150×4.6mm ID, 3μm

[0869] Mobile phase: A: Carbon dioxide B: Ethanol (0.05% diethylamine)

[0870] Elution gradient: 50% B

[0871] Flow rate: 2.0 mL / min

[0872] Back pressure: 1500psi

[0873] Column temperature: 35°C

[0874] Detection wavelength: 220nm

[0875] Compound 28A:

[0876] Rt=10.206min

[0877] LC-MS(ESI)[M+H] + m / z = 819.6.

[0878] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.24(s,1H),8.04(d,J=9.00Hz,1H),7.90(d,J=8.63Hz,1H),7.74(d,J=8.76Hz, 2H),7.44-7.55(m,2H),7.24(d,J=1.75Hz,1H),7.19(d,J=2.38Hz,1H),6.90-7.03(m,3H),5.76(dd,J=5.19,12.07Hz, 1H),4.31(s,1H),4.06(d,J=9.13Hz,1H),3.85(d,J=12.26Hz,2H),3.37-3.47(m,4H),2.85-2.99(m,1H),2.78(t,J=11 .69Hz,2H),2.50-2.65(m,8H),2.20(d,J=6.38Hz,2H),2.04-2.13(m,1H),1.72-1.85(m,3H),1.22(s,6H),1.12(s,6H).

[0879] Compound 28B:

[0880] Rt=13.352min

[0881] LC-MS(ESI)[M+H] + m / z = 819.6.

[0882] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.24(s,1H),8.04(d,J=9.01Hz,1H),7.90(d,J=8.75Hz,1H),7.74(d, J=8.63Hz,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),4.0 5(d,J=9.13Hz,1H),3.86(d,J=12.01Hz,2H),3.37-3.52(m,4H),2.86-2.99(m,1H),2.78(t,J=11.76Hz,2H) ,2.50-2.67(m,8H),2.21(d,J=6.00Hz,2H),2.03-2.13(m,1H),1.72-1.87(m,3H),1.22(s,6H),1.12(s,6H).

[0883] Example 29: Preparation of Compound 29

[0884]

[0885] At 25°C, I-56 (262 mg, 0.53 mmol), sodium triacetoxyborohydride (203 mg, 0.96 mmol), and glacial acetic acid (2.88 mg, 0.048 mmol) were added to a solution of I-130 (260 mg, 0.48 mmol) in N, N-dimethylacetamide (1 mL) and dichloromethane (10 mL) in sequence, and stirred at 25°C for 2 hours. Water (20 mL) was added to the above reaction solution, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by HPLC to obtain compound 29.

[0886] LC-MS(ESI)[M+H] + 837.5.

[0887] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.09(d,J=9.0Hz,1H),7.91(d,J=8.7Hz,1H),7.74(d,J=8.7Hz,2H),7.62(d, J=9.0Hz,1H),7.51(d,J=9.2Hz,1H),7.21(d,J=2.5Hz,1H),7.14(s,1H),7.05–6.88(m,3H),5.75(dd,J=12.5,5.5Hz ,1H),4.32(s,1H),4.05(d,J=9.1Hz,1H),3.87(d,J=12.4Hz,2H),3.57–3.40(m,4H),3.34–3.32(m,8H),2.99–2.87 (m,1H),2.80(t,J=12.2Hz,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).

[0888] Example 30: Preparation of Compound 30

[0889]

[0890] 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), 2 drops of acetic acid were added, and the reaction was stirred at room temperature for 0.5 hours, and then sodium triacetoxyborohydride (66.0 mg, 0.32 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. Water (10 mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The obtained residue was purified by C18 reverse phase column to obtain compound 30.

[0891] LCMS(ESI)[M+H] + 859.6.

[0892] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.08-8.06(d,J=8.8Hz,1H),7.92-7.90(d,J=8.8Hz,1H),7.75-7.72(d,J=8.8Hz,2H ),7.52-7.44(m,3H),7.21-7.20(d,J=2.4Hz,1H),7.02-6.95(m,3H),5.57-5.66(d,J=9.6Hz,1H),4.32(s,1H),4.06-4.04( d,J=8.8Hz,1H),3.88-3.85(d,J=12.4Hz,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).

[0893] Example 31: Preparation of Compound 31

[0894]

[0895] At room temperature, I-138 (TFA salt, 200 mg, 0.43 mmol) was dissolved in N, N-dimethylacetamide (1 mL) and dichloromethane (10 mL), and 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 in sequence, and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography to obtain compound 31.

[0896] LC-MS(ESI)[M+H] + 844.6.

[0897] 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.12(d,J=9.0Hz,1H),7.91(d,J=8.7Hz,1H),7.74(d,J=8.6Hz,2H),7.66(d, J=9.2Hz,1H),7.51(d,J=9.3Hz,1H),7.21(d,J=2.4Hz,1H),7.13–6.89(m,4H),5.87(dd,J=12.7,5.3Hz,1H),4.32( s,1H),4.06(d,J=9.0Hz,1H),3.88(d,J=12.4Hz,2H),3.50(s,4H),2.92(ddd,J=17.0,13.5,5.4Hz,1H),2.80(t,J= 12.1Hz,2H),2.70–2.59(m,1H),2.55(s,8H),2.32–2.11(m,2H),1.83(d,J=12.5Hz,3H),1.22(s,6H),1.13(s,6H).

[0898] Example 32: Preparation of Compound 32

[0899]

[0900] 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), and the reaction was stirred at room temperature for 0.5 hours. Two drops of acetic acid were added, and sodium triacetoxyborohydride (187 mg, 0.88 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. Water (10 mL) was added to dilute the reaction solution, and it was extracted with dichloromethane (30 mL × 2). After the organic phases were combined, they were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was purified by C18 reverse phase column chromatography to obtain compound 32.

[0901] LCMS(ESI)[M+H] + 887.6.

[0902] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.19-8.17(d,J=8.8Hz,1H),7.92-7.90(d,J=8.8Hz,1H),7.75-7.66(m,3H ),7.52-7.49(d,J=9.2Hz,1H),7.21-7.20(d,J=2.4Hz,1H),7.02-6.96(m,4H),5.84-5.80(dd,J=12.0,5.2Hz,1H ),4.32(s,1H),4.06-4.04(d,J=9.2Hz,1H),3.89-3.86(d,J=12.0Hz,2H),3.45-3.45(m,4H),2.93-2.89(m,1H), 2.82-2.76(t,J=12.4Hz,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).

[0903] Experimental Example 1: Androgen Receptor In-Cell-Western Assay

[0904] This assay evaluates compound performance in VCap cells. Intracellular androgen receptor was measured by In-Cell-Western according to the following assay procedure.

[0905] Vcap cells were seeded at 50,000 cells / well in a poly-D-Lysin pretreated 96-well cell culture plate (Corning 3599) in a volume of 100 μL / well in Vcap cell assay medium [DMEM containing phenol red (Gibco catalog number: 11995065); fetal bovine serum FBS (Gibco catalog number: 10099141C)]. The cells were cultured for at least two days.

[0906] 1. First, treat the cells with the compound. Use DMSO and cell culture medium to make a gradient dilution of the compound so that the DMSO contained in the cell culture plate is diluted to 0.5% - use polypropylene plates according to the following protocol:

[0907] (1)(i) Prepare a 200× stock solution plate in DMSO; (ii) Dilute the 10mM stock solution 1:4 with DMSO (10μL stock solution + 40μL DMSO) = 2000uM and enter the second row; (iii) Perform a 1:4 gradient dilution from row 2 to row 9 (10μL protac + 40μL DMSO), leaving row 1 for 2000uM reference compound and row 10 for DMSO. (iv) A total of 8 concentrations (the final concentration on the 200× plate is 2000uM, 400uM, 80uM, etc.). (2)(i) Prepare a 3× stock solution in culture medium; (ii) Transfer 3μL of the 200× stock solution to 197μL culture medium (using a 12-channel pipette, from row 1 to row 10), i.e., a 3× stock solution plate. (iii) Mix the stock solution plate evenly. (3) (i) Replace the culture medium of Vcap cells with fresh culture medium, 100 μL volume of culture medium. (ii) Transfer the mixed 3× stock solution to the cell culture plate (use a 12-channel pipette to transfer 50 μL of stock solution from row 1 to row 10). (iii) Culture the cells for 24 hours.

[0908] 2. Detect the expression level of androgen receptor in cells after compound treatment, and measure it according to the following method.

[0909] (1)(i) Add an equal volume of 8% paraformaldehyde to the cell culture plate to fix the cells. Discard the fixative in the cell plate and wash three times with PBS. (ii) Prepare Triton solution (dilute the stock solution 1:1000). Discard the solution in the cell plate and add 200μL of Triton dilution to each well. (iii) Prepare 2× blocking solution (10× blocking stock solution diluted 1:4). Discard the solution in the cell plate and add 100μL of 2× blocking solution to each well. (iv) Prepare primary antibody solution (Androgen receptor Rabbit mAb, Cell Signaling Technology catalog number: 5153; 1:1000 dilution). Discard the solution in the cell plate, add 100μL of primary antibody dilution to each well and incubate overnight at 4 degrees. (v) Discard the primary antibody solution and wash the cell plate with 1× Wash buffer. (vi) Prepare secondary antibody solution (Goat anti Rabbit IgG (H+L) Secondary Antibody, HRP, Thermo catalog number: 31460; 1:5000 dilution), add 100 μL of secondary antibody dilution solution to each well for incubation. (vii) Discard the secondary antibody solution in the cell plate and wash the cell plate with 1× Wash buffer. (viii) Prepare TMB colorimetric solution (BD catalog number: 550534) and add 100 μL of colorimetric solution to each well. (ix) Add 50 μL of stop solution (BD catalog number: 550534) to each well. (x) Read the absorbance values ​​at OD 450nm and 570nm using EnVision. (2) (i) Standardize the number of cells in each well. Discard the solution in the cell plate and wash three times with wash buffer. (ii) Prepare Janus dilution solution (1:3 dilution). (iii) Add 50 μL of dilution solution to each well for incubation. (iv) Discard the solution in the plate and wash with deionized water. (v) Prepare 1M hydrochloric acid (concentrated hydrochloric acid is diluted at 1:24) and add 200 μL of the hydrochloric acid dilution to each well to treat the cells. (vi) Read the absorbance value at OD 595nm using the Flex Station. (vii) Based on the obtained reading, calculate the effect of the tested compound on androgen receptor expression.

[0910] The experimental results are shown in Table 1.

[0911] Table 1: Evaluation of the compounds' activity on androgen receptor degradation in VCaP cells

[0912] Example No. <![CDATA[DC 50 (nM)]]> <![CDATA[D max (%)]]> Example No. <![CDATA[DC 50 (nM)]]> <![CDATA[D max (%) <!-- 78 -->]]> 1 10 97 2 5.3 114 3 12 104 4 6.8 98 5 8.4 105 7 15 92 8 8.9 75 10 35 87 11 38 80 13 9.6 94 14 11 91 15 16 84 16 5.7 92 17 6.9 88 23 6.9 98 24 6.8 106 25 10 116 26 32 109 28A 2.7 126 28B 7.2 101 29 8.9 169 32 5.2 145

[0913] D max:The maximum degradation degree of AR in VCaP cells. DC 50 : The concentration of compound required to achieve half of the maximum degradation of AR in VCaP cells.

[0914] Experimental Example 2: Inhibitory effect of test compounds on VCap cell proliferation

[0915] 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). When tested, Vcap cells were cultured in DMEM medium containing 5% FBS and 0.1 nM R1881 (Sigma catalog number R0908).

[0916] The determination method is as follows:

[0917] Vcap cells were seeded in a 384-well plate (Perkin Elmer catalog number 6007460) at a cell density of 1200 cells / well and a volume of 20 μL / well, and then cultured overnight in a carbon dioxide incubator (Thermo). The prepared compound solutions of different concentrations were added at a volume of 5 μL / well, and corresponding solvent controls were set up. After continuing to culture in the incubator for 6 days, the cell plate and its contents were equilibrated to room temperature, 25 μL of Cell Titer Glor (Promega catalog number G7573) reagent was added to each well, and after oscillation mixing, the plates were incubated in the dark for 10-30 minutes, and the signal values ​​were detected using an Envision microplate reader (PerkinElmer).

[0918] Experimental data processing method:

[0919] The percentage inhibition rate of the compound-treated wells was calculated by the solvent control wells on the plate, and the percentage inhibition rate data corresponding to different concentrations were fitted using GraphPad prism and the IC was calculated using a 4-parameter nonlinear logistic formula. 50 value.

[0920] Table 2: Evaluation of the inhibitory activity of compounds on VCaP cell proliferation

[0921] Example No. <![CDATA[IC 50 (nM)]]> <![CDATA[E max (%)]]> Example No. <![CDATA[IC 50 (nM)]]> <![CDATA[E max (%)]]> 2 11 60 4 33 69 5 37 62 14 20 61 20 42 60 23 20 56 24 18 53 25 27 62 26 45 60 28A 9.7 74 28B 33 71 29 56 66

[0922] E max :The maximum degree of inhibition of VCaP cell proliferation. IC 50 : The concentration of compound required to achieve half of the maximal inhibition of VCaP cell proliferation.

[0923] Experimental Example 3: In vivo pharmacokinetic study of the compounds of the present invention

[0924] In this study, the pharmacokinetics of the drug were evaluated in mice by intravenous and oral administration.

[0925] Experimental methods and conditions: Male CD1 mice, 6-8 weeks old, were given free access to food and water. The test compound was injected intravenously once at 1 mg / kg (solvent 5% DMSO / 15% Solutol / 80% Saline). Blood was collected from the eye sockets 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr, 24hr after administration or 10mg / kg (solvent 5% DMSO / 10% Solutol / 85% Saline) was administered orally by gavage. Blood was collected from the eye sockets 15min, 30min, 1hr, 2hr, 4hr, 6h, 8hr, 24hr after administration. Each sample was collected with no less than 50μL, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged within 1 hour to separate the plasma for testing. The blood drug concentration in plasma was detected by liquid phase tandem mass spectrometry (LC / MS / MS), and the measured concentration was used to calculate the pharmacokinetic parameters using Phoenix WinNonlin software. Example 82 in CN110612294 A was used as reference substance 1, and the experimental results are shown in Table 3.

[0926] Table 3: Pharmacokinetics of oral administration (10 mg / kg)

[0927] Compound <![CDATA[T 1 / 2 (hr)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-inf (ng*hr / mL)]]> F(％) Compound 1 6.22 1260 18896 68.8 Compound 29 7.91 677 13404 24.1 Reference 1 4.58 660 7696 16.5

[0928] Experimental data show that the pharmacokinetic results of oral administration of the compound of the present invention in mice show a longer T 1 / 2 , higher in vivo exposure AUC 0-inf and oral bioavailability F.

[0929] Experimental Example 4: In vivo pharmacokinetic study of the compounds of the present invention

[0930] In this study, the pharmacokinetics of the drug were evaluated in rats by intravenous and oral administration.

[0931] Experimental methods and conditions: Male SD rats, 6-8 weeks old, were given free access to food and water. The test compound was intravenously injected once at 1 mg / kg (solvent 5% DMSO / 15% Solutol / 80% Saline), and blood was collected from the eye sockets 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr, 24hr, 48h after administration, or 10 mg / kg (solvent 5% DMSO / 10% Solutol / 85% Saline) was administered orally by gavage. Blood was collected from the eye sockets 15min, 30min, 1hr, 2hr, 4hr, 6h, 8hr, 24hr, 48h after administration. Each sample was collected with no less than 50 μL, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged within 1 hour to separate the plasma for testing. The blood drug concentration in plasma was detected by liquid phase tandem mass spectrometry (LC / MS / MS), and the measured concentration was used to calculate the pharmacokinetic parameters using Phoenix WinNonlin software. Example 82 in CN110612294 A was used as reference substance 1, and the experimental results are shown in Table 4.

[0932] Table 4: Pharmacokinetics of oral administration (10 mg / kg)

[0933] Compound <![CDATA[T 1 / 2 (hr)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-inf (ng*hr / mL)]]> F(％) Compound 1 7.62 147 2646 11.9 Compound 28A 8.28 173 3212 5.13 Compound 29 13.4 253 6197 11.9 Reference 1 5.87 43.6 603 0.82

[0934] Experimental data show that the pharmacokinetic results of the compound of the present invention in rats after oral administration show a longer T 1 / 2 , higher in vivo exposure AUC 0-inf and oral bioavailability F.

[0935] Experimental Example 5: In vivo pharmacokinetic study of the compounds of the present invention

[0936] In this study, the pharmacokinetics of the drug were evaluated in dogs by intravenous and oral administration.

[0937] Experimental methods and conditions: Male Pekingese beagle dogs, 12 to 18 months old, were dosed half an hour after feeding, with a single intravenous injection of the test compound 1 mg / Kg (solvent 5% DMSO / 10% Solutol / 85% Saline), and blood was collected through the eye socket 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr, 24hr, 48h, 72h after administration or oral gavage of 10 mg / kg (solvent 5% DMSO / 10% Solutol / 85% Saline) 15min, 30min, 1hr, 2hr, 4hr, 6h, 8hr, 24hr, 48h, 72h after administration, with each sample collected not less than 50μL, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged within 1 hour to separate the plasma for testing. The blood drug concentration in plasma was detected by liquid phase tandem mass spectrometry (LC / MS / MS), and the pharmacokinetic parameters were calculated using PhoenixWinNonlin software. Example 82 in CN110612294 A was used as reference substance 1, and the experimental results are shown in Table 5.

[0938] Table 5: Pharmacokinetics of oral administration (10 mg / kg)

[0939] Compound <![CDATA[T 1 / 2 (hr)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-inf (ng*hr / mL)]]> F(％) Compound 1 19.9 482 14074 44.1 Compound 28A 34.3 868 15420 33.9 Reference 1 14.9 303 7841 12.0

[0940] Experimental data show that the pharmacokinetic results of the compound of the present invention in dogs after oral administration show a longer T 1 / 2 , higher in vivo exposure AUC 0-inf and oral bioavailability F.

Claims

1. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

2. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

3. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

4. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

5. The compound according to claim 4, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

6. The compound according to claim 4, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

7. The compound according to claim 4, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

8. The compound according to claim 4, its optical isomer or a pharmaceutically acceptable salt thereof, which has the following formula:

9. Use of the compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating Kennedy's disease.

10. Use of the compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

11. The use according to claim 10, wherein the cancer is prostate cancer.

12. The use according to claim 10, wherein the cancer is breast cancer.

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