Phthalazinone compounds, their preparation methods and their medical uses

Abstract

Disclosed are phthalazinone compounds, methods for their preparation, and medical uses. In particular, disclosed are compounds of formula (I) and pharmacodynamically acceptable salts thereof, and the use of the compounds as androgen receptor (AR) inhibitors for degradation. TIFF2023531390000270.tif43170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. CN202010536221.6 filed on June 12, 2020, Chinese Patent Application No. CN202011147078.8 filed on October 23, 2020, Chinese Patent Application No. CN202011261665.X filed on November 12, 2020, Chinese Patent Application No. CN202110485680.0 filed on April 30, 2021, and Chinese Patent Application No. CN202110614030.1 filed on June 2, 2021. The above-mentioned Chinese patent applications are incorporated herein by reference in their entireties.

[0002] The present invention relates to compounds of formula (I) and pharmacodynamically acceptable salts thereof, and the use of said compounds as androgen receptor (AR) inhibitors for degradation. [Background technology]

[0003] Background technology Prostate cancer (PCa) is one of the most common cancers worldwide and the second most common fatal cancer in adult men worldwide. Prostate cancer grows relatively slowly in the early stages without noticeable symptoms, and in the later stages, it manifests with symptoms such as frequent urination, dysuria, hematuria, and painful urination (odynuria), possibly metastasizing to other parts of the body. Therefore, patients generally present with advanced cancer. In the United States, prostate cancer, with an incidence rate exceeding that of lung cancer, is the leading risk to men's health. In 2016, there were 120,000 new cases of prostate cancer in China, which is estimated to reach 237,000 by 2030, representing a compound annual growth rate of 5%. This means that the incidence of prostate cancer in China will enter a peak period over the next decade, making it the leading cause of death in men. Due to the low rate of early diagnosis, the mortality rate of prostate cancer patients in China is much higher than that in developed countries. In the United States, the five-year survival rate for patients with the disease is over 98%, while in China the survival rate for those same patients is only 50%.

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

[0005] Oral drugs currently approved for the treatment of metastatic castration-resistant prostate cancer mainly include abiraterone and enzalutamide.Among them, abiraterone is a novel androgen biosynthesis inhibitor that can block the synthesis of androgens in the testes, adrenal glands, or tumor cell environment.However, enzalutamide is an androgen receptor inhibitor that can competitively inhibit the binding of androgens to receptors.After binding to AR, enzalutamide can 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 for continued growth. AR mutations reduce the small molecule antagonist activity of targeting the AR and even convert it into an AR agonist, which manifests clinically as drug resistance. Therefore, selective androgen receptor degrading drugs (SARDs) not only inhibit the androgen receptor and block the androgen receptor signaling process, but also degrade the receptor itself, thus providing more benefits.

[0007] The present invention primarily relies on proteolysis-targeting chimera (PROTAC) technology to obtain a type of selective AR degrading drug (SARD). PROTAC technology primarily relies on the intracellular ubiquitin-proteasome system. This system is an intracellular "vacuum cleaner," and the main role of the ubiquitination system is to ubiquitinate degenerated, mutated, or harmful proteins within the cell. Ubiquitinated proteins are degraded by the intracellular proteasome system. The design concept of reconstructed PROTAC is that one end of the molecule is an AR-interacting fragment and the other end is a ubiquitin-proteasome-interacting fragment, and the two ends are linked by an intermediate bond to form a chimeric molecule. PROTAC simultaneously interacts with the target protein (AR) and the proteasome system, resulting in the proteasome and AR proteins being spatially close to each other, and therefore AR is degraded by ubiquitination.

[0008] Small molecule PROTAC technology was reported in 2008. Currently, only one small molecule drug, ARV-110 (whose structure is currently unknown) based on AR degradation from Albinus is in Phase I clinical development. PROTAC technology is at the forefront of research. In recent years, PROTACs have been shown to act by simultaneously binding degradation targets and ubiquitination systems, as shown in numerous literature reports. Their mechanism of action is much more complex than that of conventional small molecule drugs: the mechanism of action of such molecules involves three-body binding kinetics and is influenced by the catalytic properties of the PROTAC itself (as well as potential issues with the hook effect). Therefore, the molecular design concept of PROTACs is completely different from that of small molecules and has no obvious rules. Common drug-chemistry strategies, such as effective fragment-equivalent substitution, are not necessarily applicable to the design of such molecules.

[0009] Currently, there remains a need to develop PROTAC molecules with novel structures and for use in AR degradation. Summary of the Invention

[0010] Summary of the Invention In one aspect of the invention, the present invention provides a compound of formula (I): [ka] (Wherein R1 is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; G is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Ring B is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R; Ring C is C 4~6 cycloalkyl; R2 is H and C 1~6 alkyl, C 1~6alkyl is optionally substituted with 1, 2 or 3 R; Ring A is selected from 6- to 12-membered aryl and 5- to 12-membered heteroaryl; R A are H, NO2, halogens, NH2, CN, C 1~6 Alkyl and C 1~6 alkoxy, C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; R D H, CN, halogens, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 cycloalkyl and 3- to 6-membered heterocycloalkyl; 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; R is independently H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with 1, 2 or 3 R'; Each L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 each selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl may be selected from 1, 2, or 3 R L optionally replaced by R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 alkylamino, 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is independently H, halogen, C 1~6 Alkyl, OH, NH2, [ka] are each selected from CH3, CH2F, CHF2 and CF3; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; q is 1, 2, 3, or 4; The 3- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 12-membered heteroaryl, 5- to 6-membered heteroaryl, or 5- to 9-membered heteroaryl contains 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. The present invention proposes a compound represented by the formula:

[0011] In another aspect of the present invention, the present invention provides a compound of formula (IX-1) or formula (IX-2): [ka] TIFF0007797421000005.tif40170 (in the formula, ring A, ring B, ring C, R1, R2, RA , R D , G, L1, L2, L3, m, n and q are as described in the present invention). The present invention further proposes a compound represented by the formula:

[0012] In another aspect of the present invention, the present invention provides a compound of formula (II) [ka] (Wherein R1 is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; G is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Ring B is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R; Ring C is C 4~6 cycloalkyl; R2 is H and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Each R3 and R4 is independently H, NO2, halogen, NH2, CN, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; Each R D1 , R D2 and R D3 are independently H, CN, halogen, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; R is independently H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with 1, 2 or 3 R'; Each L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 each selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl may be selected from 1, 2, or 3 R L optionally replaced by R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 alkylamino, 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is independently H, halogen, C 1~6 Alkyl, OH, NH2, [ka] , CH3, CH2F, CHF2, and CF3, m is 0, 1, 2, 3 or 4; The 3- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 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. The present invention further proposes a compound represented by the formula:

[0013] In another aspect of the present invention, the present invention provides a compound of formula (II-A-1) or formula (II-A-2): [ka] TIFF0007797421000010.tif40170 (in the formula, ring B, ring C, R1, R2, R3, R4, R D1 , R D2 , R D3 , G, L1, L2, L3 and m are as described in the present invention. The present invention further proposes a compound represented by the formula:

[0014] In another aspect of the present invention, the present invention provides a compound of formula (III) [ka] (Wherein R1 is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; G is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Each R3 and R4 is independently H, NO2, halogen, NH2, CN, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; each X1, X2, X3, and X4 is independently selected from C(R) and N; Each R D1 , R D2 and R D3 are independently H, CN, halogen, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; R is independently H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with 1, 2 or 3 R'; Each L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 each selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl may be selected from 1, 2, or 3 R L optionally replaced by R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C1~6 alkylamino, 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is independently H, halogen, C 1~6 Alkyl, OH, NH2, [ka] , CH3, CH2F, CHF2, and CF3, The 3- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 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. The present invention further proposes a compound represented by the formula:

[0015] In yet another aspect of the present invention, the present invention provides a compound of formula (III-A-1) or formula (III-A-2): [ka] TIFF0007797421000015.tif46170 (in the formula, R1, R3, R4, R D1 , R D2 , R D3 , G, L1, L2, L3, X1, X2, X3 and X4 are as described in the present invention). The present invention further proposes a compound represented by the formula:

[0016] In yet another aspect of the present invention, the present invention provides a compound of formula (IA) [ka] (Wherein R1 is H, F, Cl, Br, I and C1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; G is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Ring B is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R; Ring C is C 4~6 cycloalkyl; R2 is H and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Each R3 and R4 is independently H, NO2, halogen, NH2, CN, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; Each R D1 , R D2 and R D3 are independently H, CN, halogen, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; R D4 are independently H, CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 cycloalkyl and 3- to 6-membered heterocycloalkyl; 1~6 Alkyl, C 3~6 the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; R is independently H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, and C 1~6alkyl is optionally substituted with 1, 2 or 3 R'; Each L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 each selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl may be selected from 1, 2, or 3 R L optionally replaced by R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 alkylamino, 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is independently H, halogen, C 1~6 Alkyl, OH, NH2, [ka] , CH3, CH2F, CHF2, and CF3, m is 0, 1, 2, 3 or 4; The 3- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 9-membered heteroaryl contains 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. The present invention further proposes a compound represented by the formula:

[0017] In yet another aspect of the present invention, the present invention provides a compound of formula (II-A-1) or formula (II-A-2): [ka] TIFF0007797421000020.tif50170 (in the formula, ring B, ring C, R1, R2, R3, R4, R D1 , R D2 , R D3 , R D4 , G, L1, L2, L3 and m are as described in the present invention. The present invention further provides a compound represented by the formula:

[0018] In yet another aspect of the present invention, the present invention provides a compound of formula (IB) [ka] (Wherein R1 is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; G is H, F, Cl, Br, I and C 1~6 alkyl, C 1~6 alkyl is optionally substituted with 1, 2 or 3 R; Each R3 and R4 is independently H, NO2, halogen, NH2, CN, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; each X1, X2, X3, and X4 is independently selected from C(R) and N; Each R D1 , R D2 and R D3 are independently H, CN, halogen, C 1~6 Alkyl and C 1~6 alkoxy, and C 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with 1, 2 or 3 R; R D4 are independently H, CN, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 cycloalkyl and 3- to 6-membered heterocycloalkyl; 1~6 Alkyl, C 3~6 the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; R is independently H, F, Cl, Br, I, OH, NH2, and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with 1, 2 or 3 R'; Each L1, L2 and L3 is independently a single bond, O, S, NH, C(=O), S(=O), S(=O)2, C 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 each selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 9-membered heteroaryl; 1~6 Alkyl, -C 1~6 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or 5- to 9-membered heteroaryl may be selected from 1, 2, or 3 R L optionally replaced by R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio and C 1~6 alkylamino, 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkyl-C(=O)-, C 1~6 Alkoxy, C 1~6 Alkylthio or C 1~6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is independently H, halogen, C 1~6 Alkyl, OH, NH2, [ka] , CH3, CH2F, CHF2, and CF3, The 3- to 10-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 9-membered heteroaryl contains 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N. The present invention further proposes a compound represented by the formula:

[0019] In yet another aspect of the present invention, the present invention provides a compound of formula (IB-1) or formula (IB-2): [ka] TIFF0007797421000025.tif45170 (in the formula, R1, R3, R4, R D1 , R D2 , R D3 , R D4 , L1, L2, L3, X1, X2, X3, X4 and G are as described in the present invention. The present invention further provides a compound represented by the formula:

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

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

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

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

[0024] In some schemes of the present invention, the above-mentioned building blocks [ka] teeth, [ka] and other variables are as described herein.

[0025] In some schemes of the present invention, Ring B above is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl is optionally substituted with one, two, or three R, and the other variables are as described herein.

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

[0027] In some schemes of the present invention, each of L1, L2, and L3 independently represents 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- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; C 1~3 Alkyl, -C 1~3 Alkyl-O-, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is 1, 2, or 3 R L and other variables are as described herein.

[0028] In some schemes of the present invention, the R L are independently H, halogen, OH, NH2, CN, [ka] , C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkyl-C(=O)-, C 1~3 Alkoxy, C 1~3 Alkylthio and C 1~3 alkylamino; 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3 Alkyl-C(=O)-, C 1~3 Alkoxy, C 1~3 Alkylthio or C1~3 The alkylamino is optionally substituted with 1, 2, or 3 R', and the other variables are as described herein.

[0029] In some schemes of the present invention, L1, L2 and L3 are independently a single bond, O, S, NH, C(=O), S(=O)2, CH2, [ka] and other variables are as described in the present invention.

[0030] In some schemes of the present invention, the above-mentioned components [ka] teeth, [ka] TIFF0007797421000034.tif111170, with other variables as described in the present invention.

[0031] In some schemes of the present invention, the R D4 are each independently selected from H, CN, F, Cl, Br, I, CF, CH, CHCH, and cyclopropyl, and other variables are as described herein.

[0032] In yet another aspect, the present invention further provides compounds of the following formula, their optical isomers and pharmacodynamically acceptable salts thereof, which are [ka] Selected from TIFF0007797421000036.tif240170.

[0033] In yet another aspect, the present invention further provides compounds of the following formula, their optical isomers and pharmacodynamically acceptable salts thereof, which are [ka] TIFF0007797421000038.tif255170TIFF0007797421000039.tif143170 is selected from.

[0034] In yet another aspect of the present invention, the present invention further proposes the use of the above compounds, their optical isomers and their pharmacodynamically acceptable salts in the preparation of a medicament for the prevention and / or treatment of cancer or Kennedy's disease.

[0035] In some schemes of the present invention, the cancer is an AR-associated cancer such as prostate cancer or breast cancer.

[0036] In yet another aspect, the present invention further provides a method for treating cancer (e.g., prostate cancer, breast cancer, etc.) or Kennedy's disease, which method comprises administering to a patient the aforementioned compound, its optical isomers, and its pharmacodynamically acceptable salts. DETAILED DESCRIPTION OF THE INVENTION

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

[0038] As used herein, the phrase "at least one," when referring to a list of one or more elements, is intended to mean at least one element selected from any one or more elements in the list of elements, but it should be understood that this does not necessarily include at least one of each element specifically listed in the list of elements, nor does it exclude any combinations of elements in the list of elements. This definition further allows for elements other than those specifically determined in the list of elements to which the phrase "at least one" refers, to optionally be present, whether related to those specifically determined elements or not.

[0039] As used herein, the term "pharmacodynamically acceptable" covers compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation and allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0040] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having specific substituents discovered by this invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in solution or in a suitable inert solvent. Examples of pharmacodynamically 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, and phosphorous acid; organic acid salts, including organic acids 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 examples of these salts also include salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either base or acid addition salts.

[0041] The pharmacodynamically acceptable salts of the present invention can be synthesized from a parent compound that contains an acid radical or a basic group by conventional chemical methods. In general, the preparation of such salts is as follows: the free acid or free base form of the compound is reacted with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0042] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are intended to be within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are encompassed within the scope of the present invention as claimed.

[0043] Unless otherwise stated, solid wedge bonds ( [ka] ) and dotted wedge bond ( [ka] ) is used to denote the absolute configuration of a stereocenter.

[0044] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted at room temperature. When tautomers are possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called protic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via recombination of some bonding electrons. Here, a specific example of keto-enol tautomerization is the interconversion between the two tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one, or, for example, [ka] and [ka] is a tautomer.

[0045] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a particular compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary to obtain the pure desired enantiomer. Alternatively, if the molecule contains an alkaline (e.g., amino) or acidic (e.g., carboxyl) functional group, diastereoisomeric salts can be formed with an appropriate optically active acid or alkali, followed by separation of the diastereoisomers by conventional methods known in the art, followed by recovery of the pure enantiomer. Furthermore, enantiomers and diastereomers are typically separated by chromatography using chiral stationary phases, optionally in combination with chemical derivatization (e.g., carbamates are generated from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) or C-14( 14

[0013] The compounds of the present invention can be labeled with radioactive isotopes such as HCl, HCl, and HCl. As another example, deuterated drugs can be formed by substituting deuterium for hydrogen, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. All isotopic variations of the compounds of the present invention are within the scope of the present invention, regardless of radioactivity. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, including cases where the event or circumstance occurs or does not occur.

[0046] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, the compounds may contain unnatural proportions of tritium ( 3 H), iodine-125( 125 I) or C-14( 14

[0013] The compounds of the present invention can be labeled with radioactive isotopes such as HCl, HCl, and HCl. As another example, deuterated drugs can be formed by substituting deuterium for hydrogen, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. All isotopic variations of the compounds of the present invention are within the scope of the present invention, regardless of radioactivity. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, including cases where the event or circumstance occurs or does not occur.

[0047] The valence bond of the group is dotted [ka] For example, [ka] In the formula, the dotted line represents the point of attachment of the group to the rest of the molecule. [ka] For example, [ka] In the formula, the dotted line represents a single bond or absence, [ka] is a single bond [ka] or double bond [ka] It also means to represent.

[0048] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on the specified atom are replaced with substituents, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted with" means that it may or may not be substituted; unless otherwise specified, the type and number of substituents may be selected on a chemically achievable basis.

[0049] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 1, 2, or 3 R', then that group may also be optionally substituted with 1, 2, or 3 R', and each occurrence is an independent alternative of R'. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0050] When one of the variables is selected from a single bond, it represents a direct bond between the two groups attached thereto, e.g., [ka] In the case where L1 represents a single bond, it means that the structure is actually [ka] This means that

[0051] When a recited substituent does not indicate through which atom it is bonded, such substituent may be bonded through any atom thereof; for example, pyridyl as a substituent may be bonded to the substituent through any one of the carbon atoms on the pyridine ring.

[0052] When the listed linking group does not indicate the direction of the link, the direction of the link is arbitrary, for example, [ka] In the formula, the linker group L is -CHO, and the -CHO- is attached to the phenyl and cyclopentyl in the same direction as the left-to-right reading sequence. [ka] can be formed by attaching the phenyl and cyclopentyl in the opposite direction to the left-to-right reading sequence. [ka] Combinations of linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

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

[0054] Unless otherwise stated, "C 1~6 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. 1~6 Alkyl has C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 , C6 and C5 alkyl, etc., which may be monovalent (e.g., CH3), divalent (-CH2-) or polyvalent (e.g., hypo- [ka] ) can be. C 1~6 Examples of alkyl include, but are not limited to, CH3, [ka] etc.

[0055] Unless otherwise stated, "C 1~4 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms. 1~4 Alkyl has C 1~2 , C 1~3 , C 3~4 and C 2~3 alkyl, etc., which may be monovalent (e.g., CH3), divalent (e.g., -CH2-) or polyvalent (e.g., sec- [ka] ) can be. C 1~4 Examples of alkyl include, but are not limited to, CH3, [ka] Examples include TIFF0007797421000060.tif15170.

[0056] Unless otherwise stated, "C 2~3 "Alkenyl" is used to refer to a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position in the group. 2~3 Alkenyl includes C3 and C2 alkenyl, 2~3 Alkenyl can be monovalent, divalent or polyvalent. 2~3 Examples of alkenyl include, but are not limited to, [ka] etc.

[0057] Unless otherwise stated, "C 2~3"Alkynyl" is used to refer to a straight or branched chain hydrocarbon group 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. 2~3 Alkynyl includes C3 and C2 alkynyl. 2~3 Examples of alkynyl include, but are not limited to, [ka] Examples include TIFF0007797421000063.tif23170.

[0058] Unless otherwise stated, "C 1~6 The term "alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms and attached to the remainder of the molecule through 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 include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0059] Unless otherwise stated, "C 1~3 The term "alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule through an oxygen atom. 1~3 Alkoxy includes C 1~3 , C 1~2 , C 2~3 , C1, C2 and C3 alkoxy, etc. 1~3Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0060] Unless otherwise stated, "C 1~6 The term "alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms and attached to the remainder of the molecule through an amino group. 1~6 Alkylamino has 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 include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3.

[0061] Unless otherwise stated, "C 1~3 The term "alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule through an amino group. 1~3 Alkoxy includes C 1~3 , C 1~2 , C 2~3 , C1, C2 and C3 alkylamino, etc. 1~3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0062] Unless otherwise stated, "C 1~6 The term "alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms and attached to the remainder of the molecule through 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 include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0063] Unless otherwise stated, "C 1~3 The term "alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule through 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 include -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0064] Unless otherwise stated, "C 3~9 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 9 carbon atoms, which may be monocyclic or bicyclic; 3~9 Cycloalkyl includes C 3~8 , C 3~7 , C 3~6 , C 3~5 and C 5~6 Cycloalkyl is included, which can be monovalent, divalent or polyvalent. 3~9 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0065] Unless otherwise stated, "C 3~6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, which may be monocyclic or bicyclic; 3~6 Cycloalkyl includes C 3~5 , C 4~5 and C 5~6 Cycloalkyl is included, which can be monovalent, divalent or polyvalent. 3~6Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0066] Unless otherwise stated, "C 4~6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 4 to 6 carbon atoms, both monocyclic and bicyclic; 4~6 Cycloalkyl includes C 4~5 , C 4~6 and C 5~6 Cycloalkyl is included, which can be monovalent, divalent or polyvalent. 4~6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0067] Unless otherwise stated, the term "3 to 10-membered heterocycloalkyl," alone or in combination with other terms, refers to saturated cyclic groups each consisting of 3 to 10 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and in which the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). This includes monocyclic, bicyclic, and tricyclic ring systems, and bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Additionally, for "3- to 10-membered heterocycloalkyl," a heteroatom can occupy the point of attachment of the heterocycloalkyl to the remainder of the molecule. 3- to 10-membered heterocycloalkyl includes 3- to 9-membered, 3- to 8-membered, 3- to 6-membered, 3- to 5-membered, 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl, etc. Examples of 3- to 10-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, 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, homopiperidyl, dioxepanyl, or [ka] etc.

[0068] Unless otherwise stated, the term "4 to 8-membered heterocycloalkyl," alone or in combination with other terms, refers to saturated cyclic groups each consisting of 4 to 8 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and in which the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). It includes monocyclic and bicyclic ring systems, which include spirocyclic, fused, and bridged rings. Additionally, for "4- to 8-membered heterocycloalkyl," a heteroatom can occupy the point of attachment of the heterocycloalkyl to the remainder of the molecule. 4- to 8-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, 6-membered, 7-membered, and 8-membered heterocycloalkyl, etc. Examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, 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, homopiperidyl, or [ka] etc.

[0069] Unless otherwise stated, the term "3- to 6-membered heterocycloalkyl," alone or in combination with other terms, refers to saturated cyclic groups each consisting of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, with the nitrogen atom optionally being quaternized, and the nitrogen and sulfur heteroatoms optionally being oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). It includes monocyclic and bicyclic ring systems, which include spirocyclic, fused, and bridged rings. Additionally, for "3- to 6-membered heterocycloalkyl," a heteroatom can occupy the point of attachment of the heterocycloalkyl to the remainder of the molecule. 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl, etc. Examples of 3- to 6-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, 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 homopiperidyl, etc.

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

[0071] Unless otherwise specified, the terms "5-12-membered heteroaromatic ring" and "5-12-membered heteroaryl" can be used interchangeably in the present invention; "5-12-membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms and having a conjugated π-electron system, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, in which each ring is aromatic. Therein, the nitrogen atom can be optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). The 5- to 12-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 12-membered heteroaryl includes 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5- and 6-membered heteroaryl, etc. Examples of 5- to 12-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3 triazolyl, 2H-1,2,3 triazolyl, 1H-1,2,4 triazolyl, and 4H-1,2,4 triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, and 5-isoxazolyl), and 5-thiazolyl), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 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.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0072] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" can be used interchangeably herein; "5- to 6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms and having a conjugated π-electron system, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryl. Examples of 5- to 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-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3 triazolyl, 2H-1,2,3 triazolyl, and 1H-1,2,4 triazolyl). and 4H-1,2,4 triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

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

[0074] Unless otherwise stated, C n~n+m or C n ~C n+m includes any specific example of n to n+m carbons, such as 1~12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11and C 12 and any range from n to n+m, for example, C 1~12 is 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 and the like; similarly, n to n+m members means that the number of atoms on the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 5- to 10-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0075] The term "leaving group" refers to a functional group or atom that can be replaced with another functional group or atom by a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include: triflate; chloro, bromo, iodo; sulfonic acid groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, etc.

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

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

[0078] The solvents used in the present invention are commercially available.

[0079] Compounds were named according to conventional nomenclature in the art or by using ChemDraw® software, commercially available compounds were named in supplier catalogues.

[0080] Detailed Description of the Embodiments The present application will be described in detail below with reference to embodiments, but this does not mean that there are any undesirable limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed. 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.

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

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

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

[0084] Intermediate I-1 (8.50 g), potassium vinylfluoroborate (4.98 g, 37.2 mmol), and potassium carbonate (10.7 g, 77.5 mmol) were dissolved in a mixture of dioxane (80 mL) and water (20 mL), and bistriphenylphosphinepalladium dichloride (1.09 g, 1.55 mmol) was added. The reaction solution was stirred overnight at 90 °C under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 mL), washed successively with water (30 mL) and saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate I-2, which was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 222.2. 1 H NMR(400 MHz,Chloroform-d)δ 7.24(d,J=2.6 Hz,1H),7.17(dd,J=8.4,5.7 Hz,1H),6.97(td,J=8.3,2.5 Hz,1H),6.67(ddd,J=17.4,11.0,1.7 Hz,1H),5.75(d,J=17.4 Hz,1H),5.36(d,J=11.0 Hz,1H),3.55(brs,2H),3.10-3.01(m,2H),1.25(t,J=7.1 Hz,3H),1.00(t,J=7.1 Hz,3H).

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

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

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

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

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

[0090] Intermediate I-4 (200.0 mg) was dissolved in N,N-dimethylformamide (5.00 mL), and sodium hydride (58.0 mg, 1.46 mmol, mass fraction 60.0%) was added. The reaction solution was stirred at room temperature for 30 minutes 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) and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate I-5, which was used directly in the next reaction without purification. LC-MS(ESI)[M+H] + 276.2.

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

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

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

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

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

[0096] tert-Butyl 4-fluorobenzoate (3.00 g, 15.3 mmol) and 4-hydroxymethylpiperidine (2.10 g, 18.2 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.64 g, 19.1 mmol) was added. The reaction solution was stirred overnight at 80 °C under nitrogen protection. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with water (30 mL) and saturated saline, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a residue, which was isolated and purified by silica gel chromatography to give intermediate I-8. LC-MS(ESI)[M+H] + 292.2.

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

[0098] To a solution of intermediate I-8 (400 mg, 1.37 mmol) in dichloromethane (20 mL), Dess-Martin periodinane (864 mg, 2.03 mmol) was added, and the reaction mixture was stirred overnight at room temperature under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was isolated and purified by silica gel chromatography to give intermediate I-9. LC-MS(ESI)[M+H] + 290.2.

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

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

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

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

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

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

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

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

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

[0108] 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) at room temperature. Under argon purging and stirring, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (6.01 g, 15.8 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel chromatography to give Intermediate I-14. LC-MS(ESI)[M+H] + 498.2.

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

[0110] Intermediate I-14 (400 mg, 0.803 mmol) and Dess-Martin periodinane (681 mg, 1.606 mmol) were dissolved in dichloromethane (10 mL) at room temperature. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium bicarbonate (10 mL) were added to the reaction solution, and the mixture was 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 give intermediate I-15. This intermediate was used directly in the next reaction without further purification.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0134] Intermediate I-27 (122 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL) at 0 °C, and Dess-Martin periodinane (204 mg, 0.48 mmol) was added. After the addition was complete, the reaction mixture was stirred and reacted at room temperature for 2 h. Saturated sodium sulfite solution (20 mL) was added and diluted, and the resulting mixture was layered. The aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed sequentially with saturated sodium sulfite solution (20 mL × 2), saturated sodium bicarbonate solution (20 mL × 3), and water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate I-28. This intermediate was used directly in the next reaction without further purification.

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

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

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

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

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

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

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

[0142] Intermediate I-31 (55 mg) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 1-hydroxybenzotriazole (58.6 mg, 0.434 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (83.3 mg, 0.434 mmol), N,N-diisopropylethylamine (0.107 mL, 0.651 mmol), and reagent 1 (60.5 mg). The reaction mixture was stirred and reacted 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 give Intermediate I-32. LC-MS(ESI)[M+H] + 515.2.

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

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

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

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

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

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

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

[0150] Intermediate I-18 (100 mg) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of 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). The reaction mixture was stirred and reacted 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 give intermediate I-36. LC-MS(ESI)[M+H] + 476.2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0182] Intermediate I-51 (400 mg, 1.77 mmol) was dissolved in 1,4-dioxane (15 mL) at 25 °C. N-BOC piperazine (330 mg, 1.77 mmol) and sodium tert-butoxide (510 mg, 5.31 mmol) were added to displace the nitrogen. 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 mixture was filtered and then concentrated under reduced pressure to remove the organic solvent to give the crude product. The crude residue was separated and purified by silica gel chromatography to give Intermediate I-52. LC-MS(ESI)[M+H] + 331.1.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0196] Intermediate I-58 (510 mg, 2.27 mmol) was dissolved in anhydrous dioxane (50.0 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (635 mg, 3.41 mmol), sodium tert-butoxide (654 mg, 6.81 mmol), and 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). The reaction was protected with argon and stirred at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent, affording the crude product; the crude product was isolated and purified by silica gel chromatography to afford intermediate I-59. LC-MS(ESI)[M+H] + 331.2.

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

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

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

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

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

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

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

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

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

[0206] Intermediate I-18 (1.40 g, 5.95 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the addition of 1-hydroxybenzotriazole (1.21 g, 8.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g, 8.93 mmol), N,N-diisopropylethylamine (2.31 g, 17.9 mmol), and Intermediate I-63 (1.71 g). The reaction mixture was stirred and reacted 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 give Intermediate I-64. LC-MS(ESI)[M+H] + 468.1.

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

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

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

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

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

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

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

[0214] Methyl p-fluorobenzoate (5.00 g, 32.4 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), followed by the sequential addition of 3-azetidinemethanol hydrochloride (4.81 g, 38.9 mmol) and anhydrous potassium carbonate (11.2 g, 81.1 mmol). The reaction mixture was protected with argon and stirred at 80 °C for 16 h. The mixture was cooled to room temperature, water (20 mL) was added, and the product was extracted with ethyl acetate (20 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 and obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-68. LC-MS(ESI)[M+H] + 222.2.

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

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

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

[0218] Intermediate I-69 (160 mg) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the addition of 1-hydroxybenzotriazole (209 mg, 1.546 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg, 1.546 mmol), N,N-diisopropylethylamine (0.380 mL, 2.17 mmol), and Intermediate I-63 (194 mg, 0.773 mmol). The reaction mixture was stirred and reacted 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 give Intermediate I-70. LC-MS(ESI)[M+H] + 440.0.

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

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

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

[0222] 3-Hydroxymethylpyrrole hydrochloride (1.20 g, 8.72 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), followed by the addition of methyl p-fluorobenzoate (1.48 g, 9.59 mmol) and anhydrous potassium carbonate (3.62 g, 26.2 mmol). The reaction system was protected with argon and stirred at 120 °C for 16 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the product was extracted with ethyl acetate (50 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 and obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-72. LC-MS(ESI)[M+H] + 236.2.

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

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

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

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

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

[0228] Intermediate I-74 (150 mg, 0.311 mmol) was dissolved in anhydrous dichloromethane (20 mL) and Dess-Martin periodinane (198 mg, 0.467 mmol) was added at 0 °C. The reaction mixture was protected with argon and stirred at 20 °C for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with water (20 mL × 2). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-75. LC-MS(ESI)[M+H] + 480.1.

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

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

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

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

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

[0234] Intermediate I-5 (200 mg), (R)-1-Boc-3-methylpiperazine (729 mg, 3.64 mmol), and N,N-diisopropylethylamine (2 mL) were mixed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred and reacted at 130 °C for 3 days. The mixture was cooled to room temperature, then poured into water (100 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated aqueous sodium chloride 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 give intermediate I-78. LC-MS(ESI)[M+H] + 456.1.

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

[0236] Intermediate I-78 (50.0 mg, 0.110 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise with 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 isolated and purified by silica gel chromatography to give intermediate I-79. LC-MS(ESI)[M+H] + 356.1.

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

[0238] Intermediate I-5 (200 mg), (S)-1-Boc-3-methylpiperazine (729 mg, 3.64 mmol), and N,N-diisopropylethylamine (2 mL) were mixed in dimethyl sulfoxide (10 mL). The reaction mixture was stirred and reacted at 130 °C for 3 days. The mixture was cooled to room temperature, then poured into water (100 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated aqueous sodium chloride 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 give intermediate I-80. LC-MS(ESI)[M+H] + 456.1.

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

[0240] Intermediate I-80 (30.0 mg, 0.0659 mmol) was mixed in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise with 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 give intermediate I-81, and the crude product was used directly in the next reaction without further purification. LC-MS(ESI)[M+H] + 356.1.

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

[0242] Intermediate I-69 (150 mg) was dissolved in N,N-dimethylformamide (20.0 mL), followed by the addition of 1-hydroxybenzotriazole (147 mg, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (208 mg, 1.09 mmol), N,N-diisopropylethylamine (0.400 mL, 2.17 mmol), and reagent 1 (202 mg). The reaction mixture was stirred and reacted 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 give intermediate I-82.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0272] At room temperature, ethyl 2-chloropyrimidine-5-carboxylate (730 mg, 3.9 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of intermediate I-96 (450 mg) and N,N-diisopropylethylamine (1.5 g, 11.7 mmol); after the addition was completed, the reaction mixture was stirred and reacted 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. LC-MS(ESI)[M+H] + 266.0.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0288] Hydroxylamine hydrochloride (8.69 g, 125 mmol) was dissolved in water (130 mL) at room temperature, and anhydrous sodium acetate (13.6 g, 166 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then p-cyclohexanone ethyl formate (13.0 g, 83.2 mmol) was added dropwise. The reaction system was protected with 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, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-105. LC-MS(ESI)[M+H] + 186.1.

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

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

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

[0292] Intermediate I-106 (12.5 g, 36.8 mmol) was dissolved in glacial acetic acid (30 mL) at room temperature. The reaction system was protected with argon and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to remove the glacial acetic acid. Saturated aqueous sodium bicarbonate solution (40 mL) was added to the residue and stirred for 15 minutes. The product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent and obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-107. LC-MS(ESI)[M+H] + 186.2.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0306] Intermediate I-113 (650 mg) was dissolved in ethanol (10 mL) at room temperature and cooled to 0 °C in an ice-water bath. Thionyl chloride (0.676 mL, 9.26 mmol) was slowly added via injector, and the mixture was slowly warmed to room temperature and heated under reflux for 4 hours. After concentration, saturated sodium bicarbonate solution (10 mL) was added and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was isolated and purified by silica gel chromatography to obtain intermediate I-114. LC-MS(ESI)[M+H] + 204.1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0326] At 25°C, 4-bromophthalic anhydride (20.0 g, 88.1 mmol) was dissolved in glacial acetic acid (200 mL), and the mixture was heated to 120°C and stirred for 1 hour. After cooling to room temperature, hydrazine hydrate (4.85 g, 96.9 mmol) was added dropwise to generate a large amount of white solid, and the mixture was heated to 120°C and reacted 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. LC-MS(ESI)[M+H] + 243.0.

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

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

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

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

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

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

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

[0334] To a solution of I-127 (1.30 g, 5.35 mmol) in N,N-dimethylacetamide (20 mL) at 25 °C, N-tert-butoxycarbonylpiperazine (1.50 g, 8.03 mmol), tris(dibenzylideneacetone)dipalladium (494.49 mg, 0.54 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (666.28 mg, 1.07 mmol), and sodium tert-butoxide (1.29 g, 13.38 mmol) were added sequentially. The mixture was heated to 85 °C and reacted for 2 hours. After cooling, water (50 mL) was added to the reaction solution, and the mixture was 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 provide intermediate I-128. LC-MS(ESI)[M+H] + 349.2.

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

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

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

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

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

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

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

[0342] I-131 (5.00 g, 15.15 mmol) and potassium carbonate (4.18 g, 30.30 mmol) were dissolved in N,N-dimethylformamide (300 mL), and benzyltrimethylammonium tribromide (11.78 g, 30.30 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 48 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated saline (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 isolated and purified by silica gel chromatography to give intermediate I-132. LCMS(ESI)[M+H] + 409.2.

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

[0344] I-132 (600 mg, 1.47 mmol) was dissolved in N,N-dimethylformamide (50 mL) at 0° C., sodium hydride (294 mg, 7.35 mmol, 60%) was added, and after stirring at 0° C. for 30 minutes, 3-bromo-2,6-piperidinedione (422 mg, 2.20 mmol) and potassium iodide (200 mg) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated saline (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 give intermediate I-133. LCMS(ESI)[M+H] + 520.2.

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

[0346] I-134 (134 mg, 0.26 mmol), potassium cyclopropylfluoroborate (114 mg, 0.78 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (19.0 mg, 0.026 mmol), and potassium carbonate (106.6 mg, 0.78 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL), and the reaction solution was subjected to a 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 organic phases were combined, washed with saturated saline (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 give intermediate I-134. LCMS(ESI)[M+H] + 482.2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0382] 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) at room temperature. Under argon protection and stirring, sodium triacetoxyborohydride (128 mg, 0.605 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and 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. The residue was separated and purified by preparative HPLC (containing formic acid) to give compound 8 (containing monomolecular formate). LC-MS(ESI)[M+H] + 821.2. 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.46(s,1H),8.27-8.20(m,2H),8.04(d,J=9.0 Hz,1H),7.91(d,J=8.8 Hz,1H),7.82(d,J=9.6 Hz,1H),7.50(d,J=7.2 Hz,1H),7.37(d,J=9.7 Hz,1H),7.25(d,J=2.2 Hz,2H),7.04(dd,J=8.8,2.3 Hz,1H),5.75(dd,J=12.0,5.2 Hz,1H),4.57-4.43(m,3H),4.01(d,J=9.1 Hz,1H),3.43(s,4H),3.05(t,J=12.0 Hz,3H),2.97-2.86(m,1H),2.69-2.52(m,6H),2.23(d,J=7.0 Hz,2H),2.13-1.92(m,3H),1.86(d,J=12.1 Hz,2H),1.22(s,6H),1.14(s,6H).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0415] Mishi Form 25: Preparation of Compound 25

change

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

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

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

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

[0420] Intermediate I-123 (25 mg) was dissolved in dichloromethane / methanol (5 mL / 1 mL), followed by the addition of intermediate I-7 (17 mg) and sodium acetate (12 mg, 0.15 mmol). The reaction mixture was stirred and reacted at room temperature for 30 minutes. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was then added, and the reaction mixture was stirred and reacted at room temperature overnight. Water (10 mL) was added for dilution, and the aqueous phase was extracted with dichloromethane (10 mL × 2). The combined organic phase was 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 give compound 27. LC-MS(ESI)[M+H] + 838.2. 1 H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),8.24(s,1H),8.04(d,J=9.5 Hz,1H),7.90(d,J=8.8 Hz,1H),7.86(d,J=8.9 Hz,1H),7.78(d,J=8.8 Hz,1H),7.60(s,1H),7.53-7.48(m,1H),7.25(s,2H),7.03(d,J=8.7 Hz,1H),5.80-5.69(m,1H),4.47(s,1H),3.93(d,J=9.0 Hz,1H),3.57(s,3H),3.42(s,6H),2.83(s,3H),2.58(s,2H),2.54(s,2H),2.25 (s,2H),2.12-2.05(m,1H),1.84(s,2H),1.28(s,2H),1.20(s,6H),1.14(s,6H).

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

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

[0423] Shishi Form 29: Preparation of Compound 29

change

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

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

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

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

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

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

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

[0431] Experimental Example 1: Intracellular Western Assay of Androgen Receptor This assay evaluated compound performance in VCap cells. Intracellular androgen receptor was assayed by In-Cell-Western according to the assay procedure described below.

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

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

[0434] (1) (i) A 200x stock solution plate was prepared in DMSO; (ii) a 10 mM stock solution was diluted 1:4 with DMSO (10 μL stock solution + 40 μL DMSO = 2000 μM) and placed in row 2; (iii) a 1:4 gradient dilution (10 μL Protac + 40 μL DMSO) was performed from row 2 to row 9, reserving row 1 for the 2000 μM reference compound and row 10 for DMSO. (iv) A total of eight concentrations were present (final concentrations on the 200x plate were 2000 μM, 400 μM, 80 μM, etc.). (2) (i) A 3x stock solution was prepared in culture medium; (ii) 3 μL of the 200x stock solution was transferred to 197 μL of culture medium (rows 1 to 10) using a 12-channel pipette, i.e., the 3x stock solution plate. (iii) The stock solution plate was mixed uniformly. (3) (i) The medium of Vcap cells was replaced with fresh medium with a medium volume of 100 μL. (ii) The homogeneously mixed 3× stock solution was transferred to a cell culture plate (50 μL of the stock solution was transferred to rows 1 to 10 using a 12-channel pipette). (iii) The cells were cultured for 24 hours.

[0435] 2. The expression level of intracellular androgen receptor after compound treatment was detected and assayed according to the following method.

[0436] (1) (i) An equal volume of 8% paraformaldehyde was added to a cell culture plate for cell fixation. The fixative solution in the cell plate was discarded, and the cell plate was washed three times with PBS. (ii) A Triton solution was prepared (the stock solution was diluted 1:1000). The solution in the cell plate was discarded, and 200 μL of Triton diluent was added to each well. (iii) A 2× blocking solution was prepared (10× blocking stock solution was diluted 1:4). The solution in the cell plate was discarded, and 100 μL of 2× blocking solution was added to each well. (iv) A primary antibody solution (androgen receptor rabbit mAb, Cell Signaling Technology catalog number: 5153; 1:1000 dilution) was prepared. The solution in the cell plate was discarded, and 100 μL of the primary antibody diluent was added to each well and incubated overnight at 4°C. (v) The primary antibody solution was discarded, and the cell plate was washed with 1x wash buffer (wash buffer in this application refers to washing buffer solution). (vi) A secondary antibody solution (goat anti-rabbit IgG (H+L) secondary antibody, HRP, Thermo Catalog No.: 31460; 1:5000 dilution) was prepared, and 100 μL of the secondary antibody dilution was added to each well and incubated. (vii) The secondary antibody solution in the cell plate was discarded, and the cell plate was washed with 1x wash buffer. (viii) A TMB color development solution (BD Catalog No.: 550534) was prepared, and 100 μL of the color development solution was added to each well. (ix) 50 μL of stop solution (BD Catalog No.: 550534) was added to each well. (x) The absorbance values ​​at OD 450 nm and 570 nm were read using EnVision. (2)(i) Normalization analysis was performed for the number of cells in each well. The solution in the cell plate was discarded and the plate was washed three times with wash buffer. (ii) Janus diluent (1:3 dilution) was prepared. (iii) 50 μL of diluent was added to each well for incubation. (iv) The solution in the plate was discarded and the plate was washed with deionized water. (v) 1 M hydrochloric acid was prepared (concentrated hydrochloric acid was diluted 1:24), and 200 μL of the diluted hydrochloric acid solution was added to each well to treat the cells.(vi) The absorbance value at OD595nm was read on a Flex Station. (vii) According to the obtained readings, the effect of the test compound on the androgen receptor expression was calculated.

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

[0438] Experimental Example 2: Inhibitory effect of test compounds on VCap cell proliferation The tumor cell line Vcap (ATCC Catalog No. CRL-2876) was cultured in DMEM (Gibco Catalog No. 11965-092) medium containing 10% FBS (Gibco Catalog No. 10099-141C), respectively. During the study, the Vcap cells were replaced with DMEM medium containing 5% FBS and 0.1 nM R1881 (Sigma Catalog No. R0908).

[0439] The assay method was as follows.

[0440] Vcap cells were seeded into a 384-well plate (PerkinElmer catalog number 6007460) at a cell density of 1200 cells / well and a volume of 20 μL / well. After incubating the cells overnight in a carbon dioxide incubator (Thermo), compound solutions prepared at different concentrations were added at a volume of 5 μL / well; meanwhile, the corresponding solvent was prepared as a control. After incubating the cells continuously for 6 days in the incubator, 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. After shaking and uniform mixing, the plate was incubated in the dark for 10 to 30 minutes, and the signal value was detected using an Envision microplate reader (PerkinElmer).

[0441] How to process experimental data: The inhibition percentage of compound-treated wells was calculated through the solvent control wells on the plate, and the inhibition percentage data corresponding to different concentrations was fitted using GraphPad Prism to obtain the IC 50 The values ​​were calculated using a four-parameter nonlinear logistic formula. The experimental results are shown in Table 2. [Table 2]

[0442] Experimental Example 3: In vivo pharmacokinetics of the compounds of the present invention In this example, in vivo pharmacokinetic evaluation was performed in mice by intravenous injection and oral administration.

[0443] Experimental methods and conditions: 6-8 week old male CD1 mice; all animals had free access to food and water; mice were given a single intravenous injection of 1 mg / kg of the test compound (solvent 5% DMSO / 15% solutol / 80% saline) (in this application, saline refers to saline solution), 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours later, or mice were given an oral intragastric administration of 10 mg / kg (solvent 5% DMSO / 10% solutol / 85% saline), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours later, blood was collected from the orbit, and more than 50 μL of each sample was collected. Sodium heparin was used for anticoagulation; the collected samples were placed on ice, and the plasma was centrifuged within 1 hour for testing. The plasma drug concentration was detected by liquid chromatography tandem mass spectrometry (LC / MS / MS), and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software. Example 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 3. [Table 3]

[0444] Experimental data show that the in vivo pharmacokinetic results of oral administration of the compounds of the present invention in mice show a longer T 1 / 2 , higher in vivo exposure AUC 0-inf and oral bioavailability F.

[0445] Example 4: In vivo pharmacokinetic studies of compounds of the present invention In this example, in vivo pharmacokinetics was evaluated in rats by intravenous injection and oral administration.

[0446] Experimental methods and conditions: Male SD rats, 6-8 weeks old; all animals had free access to food and water. Rats were given a single intravenous injection of 1 mg / kg of the test compound (solvent: 5% DMSO / 15% solutol / 80% saline) at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours after the injection. Alternatively, rats were given a single oral intragastric injection of 10 mg / kg of the test compound (solvent: 5% DMSO / 10% solutol / 85% saline) at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 48 hours after the injection. Blood was collected via the orbital cavity at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 48 hours after the injection. At least 50 μL of blood was collected per sample. Sodium heparin was used for anticoagulation. The collected samples were placed on ice, and plasma was centrifuged within 1 hour for testing. The plasma drug concentration was detected by liquid chromatography tandem mass spectrometry (LC / MS / MS), and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software. Example 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 4. [Table 4]

[0447] Example 5: In vivo pharmacokinetic studies of compounds of the present invention In this example, in vivo pharmacokinetic evaluation was performed in dogs by intravenous injection and oral administration.

[0448] Experimental methods and conditions: Male Beijing Marshall beagles, aged 12-18 months, were administered 30 minutes after feeding. Five minutes, 15 minutes, 30 minutes, one hour, two hours, four hours, eight hours, 24 hours, 48 ​​hours, and 72 hours after a single intravenous injection of 1 mg / kg of the test compound (solvent: 5% DMSO / 10% solutol / 85% saline), or 15 minutes, 30 minutes, one hour, two hours, four hours, six hours, eight hours, 24 hours, 48 ​​hours, and 72 hours after oral intragastric administration of 10 mg / kg (solvent: 5% DMSO / 10% solutol / 85% saline), were used to collect blood via the orbit. At least 50 μL of each sample was collected, and sodium heparin was used for anticoagulation. The collected samples were placed on ice, and the plasma was centrifuged within one hour for testing. The plasma drug concentration was detected by liquid chromatography tandem mass spectrometry (LC / MS / MS), and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software. Example 82 of Chinese Patent Application Publication No. 110612294A was used as control sample 1. The experimental results are shown in Table 5. [Table 5]

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is H, G is H, Ring B is selected from phenyl and 6-membered heteroaryl, wherein said phenyl or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R; Ring C is C ４～６ is cycloalkyl, Each R ２ are independently H and C １～６ alkyl, wherein C １～６ alkyl is optionally substituted with 1, 2 or 3 R; Ring A is a 6- to 12-membered aryl; Each R Ａ are independently selected from H, halogen, and CN; Each R Ｄ are independently H, CN, halogen, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ cycloalkyl and 3- to 6-membered heterocycloalkyl, １～６ Alkyl, C １－６ Alkoxy, C ３－６ the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; Each R is independently H, F, Cl, Br, I, OH, NH ２ and C １～６ alkyl, wherein C １～６ alkyl is optionally substituted with 1, 2 or 3 R'; L1 and L ３ are each independently 【Chemistry 2】 is selected from L 2 is CH 2 and 【Transformation 3】 Selected from Each R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Chemistry 4】 , C.H. ２ F, CHF ２ and CF ３ is selected from n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; q is 1, 2, 3, or 4; The 6-membered heteroaryl contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from NH and N. A compound represented by the formula:

2. Formula (IA) 【Transformation 5】 (In the formula, R １ is H, G is H, Ring B is selected from phenyl and 6-membered heteroaryl, wherein said phenyl or 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R; Ring C is C ４～６ cycloalkyl; Each R ２ are independently H and C １～６ alkyl, wherein C １～６ alkyl is optionally substituted with 1, 2 or 3 R; Each R ３ and R ４ are independently selected from H, halogen, and CN; Each R Ｄ１ , R Ｄ２ and R Ｄ３ are independently H, CN, halogen, C １～６ Alkyl and C １～６ alkoxy, wherein C １～６ Alkyl or C １～６ alkoxy is optionally substituted with 1, 2 or 3 R; R Ｄ４ are independently H, CN, halogen, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ cycloalkyl and 3- to 6-membered heterocycloalkyl, １～６ Alkyl, C ３－６ the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; Each R is independently H, F, Cl, Br, I, OH, NH ２ and C １～６ alkyl, wherein C １～６ alkyl is optionally substituted with 1, 2 or 3 R'; Each L1 and L ３ is, independently, 【Transformation 6】 is selected from L ２ is CH ２ and 【Transformation 7】 Selected from Each R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Transformation 8】 , C.H. ２ F, CHF ２ and CF ３ is selected from m is 0, 1, 2, 3, or 4; The 6-membered heteroaryl contains 1, 2, or 3 heteroatoms or heteroatom groups independently selected from NH and N. The compound according to claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, wherein

3. Formula (IB) 【Chemistry 9】 (In the formula, R １ is H, G is H, Each R ３ and R ４ are independently selected from H, halogen, and CN; each X １ , X ２ , X ３ and X ４ is independently selected from C(R) and N; Each R Ｄ１ , R Ｄ２ and R Ｄ３ are independently H, CN, halogen, C １～６ Alkyl and C １～６ alkoxy, wherein C １～６ Alkyl or C １～６ alkoxy is optionally substituted with 1, 2 or 3 R; R Ｄ４ are independently H, CN, halogen, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ cycloalkyl and 3- to 6-membered heterocycloalkyl, １～６ Alkyl, C ３－６ the cycloalkyl or 3- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R; Each R is independently H, F, Cl, Br, I, OH, NH ２ and C １～６ alkyl, wherein C １～６ alkyl is optionally substituted with 1, 2 or 3 R'; Each L1 and L ３ is, independently, 【Chemistry 10】 is selected from L ２ is CH ２ and 【Chemistry 11】 Selected from Each R' is independently H, halogen, C １～６ Alkyl, OH, NH ２ , 【Chemistry 12】 , C.H. ２ F, CHF ２ and CF ３ (selected from The compound according to claim 2, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, wherein

4. Formula (IB-1) or Formula (IB-2) 【Chemistry 13】 The compound according to claim 3, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, wherein

5. 2. The compound according to claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, wherein ring A is phenyl.

6. Each R ３ and R ４ is independently selected from H, F, Cl, Br, I, and CN, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, according to claim 2.

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

8. 2. The compound of claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, wherein Ring C is selected from cyclobutyl and cyclohexanyl. 【Request Item 9】 【Chemistry 14】 but, 【Chemistry 15】 2. The compound of claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, selected from:

10. 2. The compound of claim 1, its optical isomer, or a pharmacodynamically acceptable salt thereof, wherein Ring B is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and said phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl is optionally substituted with one, two, or three R. 【Request Item 11】 【Chemistry 16】 but, 【Chemistry 17】 【change】 2. The compound of claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, selected from:

12. Component: [Chemistry 18] but, 【Chemistry 19】 2. The compound of claim 1, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof, selected from:

13. R Ｄ４ are independently H, CN, F, Cl, Br, I, CF ３ , C.H. ３ , C.H. ２ CH ３ 3. The compound of claim 2, an optical isomer, or a pharmacodynamically acceptable salt thereof, wherein the compound is selected from cyclopropyl and cyclopropyl.

14. The following formula: 【Chemistry 20】 【change】 【change】 【change】 【change】 2. The compound of claim 1, having the formula: or a pharmacodynamically acceptable salt thereof.

15. The following formula: 【Chemistry 21】 15. The compound of claim 14, having the formula: or a pharmacodynamically acceptable salt thereof.

16. The following formula: 【Chemistry 22】 15. The compound of claim 14, having the formula: or a pharmacodynamically acceptable salt thereof.

17. The following formula: 【Chemistry 23】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1, having the formula: or a pharmacodynamically acceptable salt thereof.

18. The following formula: 【Chemistry 24】 18. The compound of claim 17, having the formula: or a pharmacodynamically acceptable salt thereof.

19. The following formula: 【Chemistry 25】 18. The compound of claim 17, having the formula: or a pharmacodynamically acceptable salt thereof.

20. The following formula: 【Chemistry 26】 18. The compound of claim 17, having the formula: or a pharmacodynamically acceptable salt thereof.

21. The following formula: 【Chemistry 27】 18. The compound of claim 17, having the formula: or a pharmacodynamically acceptable salt thereof.

22. A pharmaceutical composition for treating cancer, comprising the compound according to any one of claims 1 to 21, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof.

23. 23. The pharmaceutical composition of claim 22, wherein the cancer is prostate cancer.

24. 23. The pharmaceutical composition of claim 22, wherein the cancer is breast cancer.

25. A pharmaceutical composition for treating Kennedy's disease, comprising the compound according to any one of claims 1 to 21, an optical isomer thereof, or a pharmacodynamically acceptable salt thereof.

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